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COVID-19 vaccine hesitancy still weighs heavy for some rheumatic disease patients
With 49% of the U.S. population fully vaccinated against SARS-CoV-2, a new study highlights the degree of vaccine hesitancy among patients with rheumatic disease to get the vaccine.
The international study, published in May 2021 in Rheumatology, suggests that, of 1,258 patients surveyed worldwide, approximately 40% of patients said they would decline the vaccine.
“Sometimes it’s helpful to talk through their concerns,” said Jeffrey Curtis, MD, MPH, a University of Alabama at Birmingham rheumatologist who leads the American College of Rheumatology COVID-19 vaccine task force. Dr. Curtis recently reviewed the current literature on COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases (RMDs) at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
COVID-19 vaccinations for patients with autoimmune inflammatory rheumatic disease (AIIRD) is not straightforward. The immune response can be blunted by existing treatments and disease flares can occur.
The latest version of COVID-19 vaccination guidance for patients with RMDs from the ACR addresses vaccine use and implementation strategies. The guidance was issued as conditional or provisional because of the lack of evidence. Its principals are largely based on accepted practice for other vaccines. The guidance is routinely updated as new evidence becomes available. In his presentation at GRAPPA, Dr. Curtis reviewed the latest version of the guidance, which he emphasized is a guidance only and not meant to replace clinical judgment or shared decision-making with patients.
“This is a platform for you to start from as you are thinking about and discussing with your patient what might be best for him or her,” he said.
Concerns about impact of disease activity, treatments on effectiveness
Dr. Curtis highlighted some controversial aspects of COVID-19 vaccines, including heterogeneity of rheumatic diseases and treatment. Patients with AIIRD, including psoriatic arthritis, spondyloarthritis, RA, and lupus, are at higher risk for hospitalized COVID-19 and worse outcomes, and as such, they are prioritized for vaccination by the Centers for Disease Control and Prevention.
However, for AIIRD patients, the immune response to COVID-19 vaccination can be “blunted,” according to one study. This may be because of glucocorticoid use or high disease activity. Immunomodulatory therapies, such as methotrexate, rituximab, and abatacept, are known to diminish vaccine response in general. The evidence is less clear for tumor necrosis factor and Janus kinase inhibitors, but they are thought to have the same impact on vaccine effectiveness, Dr. Curtis said. But in these cases, if the effect of a COVID-19 vaccine drops from 90% to 70%, the benefits of vaccination still far outweighs the risk of contracting COVID-19.
“Although we don’t have strong data with clinical outcomes for autoimmune disease or inflammatory disease patients, I’ll run a hypothetical and say: ‘Look, if this vaccine starts 90%-95% effective, even if it’s only 70% effective in somebody with lupus or vasculitis or someone who is taking a higher dose of steroids, I’ll take 70% over nothing if you chose to be vaccinated,’ ” he said.
The benefit of vaccination also outweighs the potential risk of disease flare, he said. The risk is real, but to date, no studies have pointed to a significant risk of disease flare or worsening. However, there have been reported cases of myocardial infarction.
Autoimmune manifestations after vaccination vs. after infection
Researchers writing in the June 29, 2021, issue of JAMA Cardiology described case reports of acute myocarditis in 23 people who received the BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna) messenger RNA (mRNA) COVID-19 vaccines. Plus, there been subsequent reports of myocarditis in other patients, wrote David K. Shay, MD, MPH, in an accompanying editorial. Dr. Shay is a member of the CDC COVID-19 Response Team.
“What do we know about this possible association between myocarditis and immunization with mRNA-based COVID-19 vaccines, and what remains unclear? Acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism,” he said.
The cases of myocarditis are concerning, Dr. Curtis said, but the risk is very low with relatively few cases reported among 161 million fully vaccinated people in the United States.
“Certainly, we’re not seeking to minimize that, but the risk of getting COVID and some of the downstream sequelae (autoimmune manifestations) almost certainly outweigh the risks for some of the autoimmune manifestations or worsening [condition],” he said.
A nationwide cohort study from Denmark of 58,052 patients with inflammatory rheumatic disease published in December 2020 in Rheumatology, found that patients with COVID-19 who had an inflammatory rheumatic disease were more likely to be admitted to the hospital, compared with COVID-19 patients without rheumatic disease. Patients with rheumatic disease had a higher risk of a severe COVID-19 outcome, but it was not a statistically significant difference, said Dr. Curtis, adding that the individual factors such as age and treatment currently received largely determines the risk. The strongest associations between hospitalization for COVID-19 and rheumatic disease were found among patients with RA, vasculitis, and connective tissue disease. Dr. Curtis noted that his own new study results show that risk of death from a COVID-19 infection is higher for patients who have RA or psoriatic arthritis.
There have been published case reports of patients who have developed new-onset lupus, vasculitis, Kawasaki disease, multiple sclerosis, autoimmune cytopenias, and other manifestations after a COVID-19 infection. “These authors suggest that perhaps there is a transient influence on the immune system that leads to a loss of self-tolerance to antigens,” Dr. Curtis said. “Some patients may have an underlying predisposition to autoimmunity in which infections just unmask as we sometimes see with other infections – chronic hepatitis for example.”
Antibody tests not recommended
In its COVID-19 guidance, the ACR, like the Food and Drug Administration, recommends health care providers not to routinely order antibody tests for IgM or IgG to assess immunity after a person has been vaccinated or to assess the need for vaccination in an unvaccinated person. More research is needed to determine if antibodies provide protection, and if so, for how long and how much. Plus, the antibody testing process is not clear cut, so ordering the wrong test is possible, Dr. Curtis said. The tests should clearly differentiate between spike proteins or nucleocapsid proteins.
“The bottom line is that you might be ordering the wrong lab test. Even if you’re ordering the right lab test, I would assert that you probably don’t know what to do with the result. I would then ask you, ‘Does it mean they are protected? Does it mean they are not protected? What are you going to do with the results?’ ” he asked.
Kevin Winthrop, MD, MPH, a specialist in infectious diseases at Oregon Health & Science University, Portland, said that, at this point, it’s too early to know what antibody tests mean. “I think it is tempting to test some people, especially patients on B-cell depletion therapy and those on mycophenolate mofetil (MMF). Outside of those two types of [disease-modifying antirheumatic drug] users, I wouldn’t be tempted to test. We don’t know how well protected they are, but we assume they are protected to some extent,” he said. “They’re probably partially protected and as such, they should take the same precautions they were taking a year ago: masking and avoidance. I think that’s just how it’s going to be for those folks for another year until we get this thing sorted out.”
Modifications to existing rheumatic disease therapies
In its COVID-19 vaccine guidance, the ACR issued recommendations for some common rheumatic disease therapeutics before and/or after the COVID-19 vaccine is administered. The modifications are limited to MMF, methotrexate, JAK inhibitors, subcutaneous abatacept, acetaminophen, and NSAIDs. The recommendations include: hold mycophenolate for 1 week after vaccination if disease is stable; for patients with well-controlled disease, hold methotrexate for 1 week after each of the two mRNA vaccine doses; for patients with well-controlled disease receiving the Johnson & Johnson vaccine, hold methotrexate for 2 weeks after receiving the vaccine; hold JAK inhibitors for 1 week after each dose; for abatacept subcutaneous, hold treatment for 1 week before and after the first dose; and in patients with stable disease, hold acetaminophen and NSAIDs for 24 hours before vaccination, because taking either before vaccination could blunt the vaccine response, Dr. Curtis said.
Holding medication, such as methotrexate, could risk having a flare-up of disease. One study showed the rate of disease flare-up because of withholding standard treatment may be up to 11%, compared with 5.1% in patients who did not hold treatment, he said.
“The point is, if you hold some of these therapies, whether methotrexate or tofacitinib, arthritis will get a little bit worse,” Dr. Curtis said.
A study published on the preprint server medRxiv found that immunosuppressive therapies blunted the response of SARS-CoV-2 vaccines in patients with chronic inflammatory diseases, most significantly with glucocorticoids and B-cell therapies.
“That’s what’s led to a lot of the guidance statements about holding treatments for a week or 2 for rituximab. If you’re giving it at 6-month intervals, you want to schedule the vaccine dose or series at about month 5, or a month before the next cycle,” he said.
Talking with patients about COVID-19 vaccination
In talking with patients about vaccine safety, Dr. Curtis recommends addressing a few common misperceptions. First, COVID-19 viruses were not created with a live-attenuated virus (which would be contraindicated for immunosuppressed patients). “You can put patients’ mind at ease that none of the vaccine candidates or platforms – even those that say viral vector – put patients at risk for contracting the infection. These are nonreplicating. So, it’s like you extracted the engine that would allow this virus to replicate,” he said.
Of three COVID-19 vaccinations available in the United States, is one better than the other? The ACR COVID-19 vaccine task force did not reach a consensus on safety profiles of the vaccines because, without head-to-head comparisons, it’s impossible to know, he said.
In talking with patients, review the protocol for continuing with prescribed treatment modalities before the patient receives a COVID-19 vaccine. Safety concerns and concerns about the possibility of having a disease flare-up should be addressed, he said.
With 49% of the U.S. population fully vaccinated against SARS-CoV-2, a new study highlights the degree of vaccine hesitancy among patients with rheumatic disease to get the vaccine.
The international study, published in May 2021 in Rheumatology, suggests that, of 1,258 patients surveyed worldwide, approximately 40% of patients said they would decline the vaccine.
“Sometimes it’s helpful to talk through their concerns,” said Jeffrey Curtis, MD, MPH, a University of Alabama at Birmingham rheumatologist who leads the American College of Rheumatology COVID-19 vaccine task force. Dr. Curtis recently reviewed the current literature on COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases (RMDs) at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
COVID-19 vaccinations for patients with autoimmune inflammatory rheumatic disease (AIIRD) is not straightforward. The immune response can be blunted by existing treatments and disease flares can occur.
The latest version of COVID-19 vaccination guidance for patients with RMDs from the ACR addresses vaccine use and implementation strategies. The guidance was issued as conditional or provisional because of the lack of evidence. Its principals are largely based on accepted practice for other vaccines. The guidance is routinely updated as new evidence becomes available. In his presentation at GRAPPA, Dr. Curtis reviewed the latest version of the guidance, which he emphasized is a guidance only and not meant to replace clinical judgment or shared decision-making with patients.
“This is a platform for you to start from as you are thinking about and discussing with your patient what might be best for him or her,” he said.
Concerns about impact of disease activity, treatments on effectiveness
Dr. Curtis highlighted some controversial aspects of COVID-19 vaccines, including heterogeneity of rheumatic diseases and treatment. Patients with AIIRD, including psoriatic arthritis, spondyloarthritis, RA, and lupus, are at higher risk for hospitalized COVID-19 and worse outcomes, and as such, they are prioritized for vaccination by the Centers for Disease Control and Prevention.
However, for AIIRD patients, the immune response to COVID-19 vaccination can be “blunted,” according to one study. This may be because of glucocorticoid use or high disease activity. Immunomodulatory therapies, such as methotrexate, rituximab, and abatacept, are known to diminish vaccine response in general. The evidence is less clear for tumor necrosis factor and Janus kinase inhibitors, but they are thought to have the same impact on vaccine effectiveness, Dr. Curtis said. But in these cases, if the effect of a COVID-19 vaccine drops from 90% to 70%, the benefits of vaccination still far outweighs the risk of contracting COVID-19.
“Although we don’t have strong data with clinical outcomes for autoimmune disease or inflammatory disease patients, I’ll run a hypothetical and say: ‘Look, if this vaccine starts 90%-95% effective, even if it’s only 70% effective in somebody with lupus or vasculitis or someone who is taking a higher dose of steroids, I’ll take 70% over nothing if you chose to be vaccinated,’ ” he said.
The benefit of vaccination also outweighs the potential risk of disease flare, he said. The risk is real, but to date, no studies have pointed to a significant risk of disease flare or worsening. However, there have been reported cases of myocardial infarction.
Autoimmune manifestations after vaccination vs. after infection
Researchers writing in the June 29, 2021, issue of JAMA Cardiology described case reports of acute myocarditis in 23 people who received the BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna) messenger RNA (mRNA) COVID-19 vaccines. Plus, there been subsequent reports of myocarditis in other patients, wrote David K. Shay, MD, MPH, in an accompanying editorial. Dr. Shay is a member of the CDC COVID-19 Response Team.
“What do we know about this possible association between myocarditis and immunization with mRNA-based COVID-19 vaccines, and what remains unclear? Acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism,” he said.
The cases of myocarditis are concerning, Dr. Curtis said, but the risk is very low with relatively few cases reported among 161 million fully vaccinated people in the United States.
“Certainly, we’re not seeking to minimize that, but the risk of getting COVID and some of the downstream sequelae (autoimmune manifestations) almost certainly outweigh the risks for some of the autoimmune manifestations or worsening [condition],” he said.
A nationwide cohort study from Denmark of 58,052 patients with inflammatory rheumatic disease published in December 2020 in Rheumatology, found that patients with COVID-19 who had an inflammatory rheumatic disease were more likely to be admitted to the hospital, compared with COVID-19 patients without rheumatic disease. Patients with rheumatic disease had a higher risk of a severe COVID-19 outcome, but it was not a statistically significant difference, said Dr. Curtis, adding that the individual factors such as age and treatment currently received largely determines the risk. The strongest associations between hospitalization for COVID-19 and rheumatic disease were found among patients with RA, vasculitis, and connective tissue disease. Dr. Curtis noted that his own new study results show that risk of death from a COVID-19 infection is higher for patients who have RA or psoriatic arthritis.
There have been published case reports of patients who have developed new-onset lupus, vasculitis, Kawasaki disease, multiple sclerosis, autoimmune cytopenias, and other manifestations after a COVID-19 infection. “These authors suggest that perhaps there is a transient influence on the immune system that leads to a loss of self-tolerance to antigens,” Dr. Curtis said. “Some patients may have an underlying predisposition to autoimmunity in which infections just unmask as we sometimes see with other infections – chronic hepatitis for example.”
Antibody tests not recommended
In its COVID-19 guidance, the ACR, like the Food and Drug Administration, recommends health care providers not to routinely order antibody tests for IgM or IgG to assess immunity after a person has been vaccinated or to assess the need for vaccination in an unvaccinated person. More research is needed to determine if antibodies provide protection, and if so, for how long and how much. Plus, the antibody testing process is not clear cut, so ordering the wrong test is possible, Dr. Curtis said. The tests should clearly differentiate between spike proteins or nucleocapsid proteins.
“The bottom line is that you might be ordering the wrong lab test. Even if you’re ordering the right lab test, I would assert that you probably don’t know what to do with the result. I would then ask you, ‘Does it mean they are protected? Does it mean they are not protected? What are you going to do with the results?’ ” he asked.
Kevin Winthrop, MD, MPH, a specialist in infectious diseases at Oregon Health & Science University, Portland, said that, at this point, it’s too early to know what antibody tests mean. “I think it is tempting to test some people, especially patients on B-cell depletion therapy and those on mycophenolate mofetil (MMF). Outside of those two types of [disease-modifying antirheumatic drug] users, I wouldn’t be tempted to test. We don’t know how well protected they are, but we assume they are protected to some extent,” he said. “They’re probably partially protected and as such, they should take the same precautions they were taking a year ago: masking and avoidance. I think that’s just how it’s going to be for those folks for another year until we get this thing sorted out.”
Modifications to existing rheumatic disease therapies
In its COVID-19 vaccine guidance, the ACR issued recommendations for some common rheumatic disease therapeutics before and/or after the COVID-19 vaccine is administered. The modifications are limited to MMF, methotrexate, JAK inhibitors, subcutaneous abatacept, acetaminophen, and NSAIDs. The recommendations include: hold mycophenolate for 1 week after vaccination if disease is stable; for patients with well-controlled disease, hold methotrexate for 1 week after each of the two mRNA vaccine doses; for patients with well-controlled disease receiving the Johnson & Johnson vaccine, hold methotrexate for 2 weeks after receiving the vaccine; hold JAK inhibitors for 1 week after each dose; for abatacept subcutaneous, hold treatment for 1 week before and after the first dose; and in patients with stable disease, hold acetaminophen and NSAIDs for 24 hours before vaccination, because taking either before vaccination could blunt the vaccine response, Dr. Curtis said.
Holding medication, such as methotrexate, could risk having a flare-up of disease. One study showed the rate of disease flare-up because of withholding standard treatment may be up to 11%, compared with 5.1% in patients who did not hold treatment, he said.
“The point is, if you hold some of these therapies, whether methotrexate or tofacitinib, arthritis will get a little bit worse,” Dr. Curtis said.
A study published on the preprint server medRxiv found that immunosuppressive therapies blunted the response of SARS-CoV-2 vaccines in patients with chronic inflammatory diseases, most significantly with glucocorticoids and B-cell therapies.
“That’s what’s led to a lot of the guidance statements about holding treatments for a week or 2 for rituximab. If you’re giving it at 6-month intervals, you want to schedule the vaccine dose or series at about month 5, or a month before the next cycle,” he said.
Talking with patients about COVID-19 vaccination
In talking with patients about vaccine safety, Dr. Curtis recommends addressing a few common misperceptions. First, COVID-19 viruses were not created with a live-attenuated virus (which would be contraindicated for immunosuppressed patients). “You can put patients’ mind at ease that none of the vaccine candidates or platforms – even those that say viral vector – put patients at risk for contracting the infection. These are nonreplicating. So, it’s like you extracted the engine that would allow this virus to replicate,” he said.
Of three COVID-19 vaccinations available in the United States, is one better than the other? The ACR COVID-19 vaccine task force did not reach a consensus on safety profiles of the vaccines because, without head-to-head comparisons, it’s impossible to know, he said.
In talking with patients, review the protocol for continuing with prescribed treatment modalities before the patient receives a COVID-19 vaccine. Safety concerns and concerns about the possibility of having a disease flare-up should be addressed, he said.
With 49% of the U.S. population fully vaccinated against SARS-CoV-2, a new study highlights the degree of vaccine hesitancy among patients with rheumatic disease to get the vaccine.
The international study, published in May 2021 in Rheumatology, suggests that, of 1,258 patients surveyed worldwide, approximately 40% of patients said they would decline the vaccine.
“Sometimes it’s helpful to talk through their concerns,” said Jeffrey Curtis, MD, MPH, a University of Alabama at Birmingham rheumatologist who leads the American College of Rheumatology COVID-19 vaccine task force. Dr. Curtis recently reviewed the current literature on COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases (RMDs) at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
COVID-19 vaccinations for patients with autoimmune inflammatory rheumatic disease (AIIRD) is not straightforward. The immune response can be blunted by existing treatments and disease flares can occur.
The latest version of COVID-19 vaccination guidance for patients with RMDs from the ACR addresses vaccine use and implementation strategies. The guidance was issued as conditional or provisional because of the lack of evidence. Its principals are largely based on accepted practice for other vaccines. The guidance is routinely updated as new evidence becomes available. In his presentation at GRAPPA, Dr. Curtis reviewed the latest version of the guidance, which he emphasized is a guidance only and not meant to replace clinical judgment or shared decision-making with patients.
“This is a platform for you to start from as you are thinking about and discussing with your patient what might be best for him or her,” he said.
Concerns about impact of disease activity, treatments on effectiveness
Dr. Curtis highlighted some controversial aspects of COVID-19 vaccines, including heterogeneity of rheumatic diseases and treatment. Patients with AIIRD, including psoriatic arthritis, spondyloarthritis, RA, and lupus, are at higher risk for hospitalized COVID-19 and worse outcomes, and as such, they are prioritized for vaccination by the Centers for Disease Control and Prevention.
However, for AIIRD patients, the immune response to COVID-19 vaccination can be “blunted,” according to one study. This may be because of glucocorticoid use or high disease activity. Immunomodulatory therapies, such as methotrexate, rituximab, and abatacept, are known to diminish vaccine response in general. The evidence is less clear for tumor necrosis factor and Janus kinase inhibitors, but they are thought to have the same impact on vaccine effectiveness, Dr. Curtis said. But in these cases, if the effect of a COVID-19 vaccine drops from 90% to 70%, the benefits of vaccination still far outweighs the risk of contracting COVID-19.
“Although we don’t have strong data with clinical outcomes for autoimmune disease or inflammatory disease patients, I’ll run a hypothetical and say: ‘Look, if this vaccine starts 90%-95% effective, even if it’s only 70% effective in somebody with lupus or vasculitis or someone who is taking a higher dose of steroids, I’ll take 70% over nothing if you chose to be vaccinated,’ ” he said.
The benefit of vaccination also outweighs the potential risk of disease flare, he said. The risk is real, but to date, no studies have pointed to a significant risk of disease flare or worsening. However, there have been reported cases of myocardial infarction.
Autoimmune manifestations after vaccination vs. after infection
Researchers writing in the June 29, 2021, issue of JAMA Cardiology described case reports of acute myocarditis in 23 people who received the BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna) messenger RNA (mRNA) COVID-19 vaccines. Plus, there been subsequent reports of myocarditis in other patients, wrote David K. Shay, MD, MPH, in an accompanying editorial. Dr. Shay is a member of the CDC COVID-19 Response Team.
“What do we know about this possible association between myocarditis and immunization with mRNA-based COVID-19 vaccines, and what remains unclear? Acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism,” he said.
The cases of myocarditis are concerning, Dr. Curtis said, but the risk is very low with relatively few cases reported among 161 million fully vaccinated people in the United States.
“Certainly, we’re not seeking to minimize that, but the risk of getting COVID and some of the downstream sequelae (autoimmune manifestations) almost certainly outweigh the risks for some of the autoimmune manifestations or worsening [condition],” he said.
A nationwide cohort study from Denmark of 58,052 patients with inflammatory rheumatic disease published in December 2020 in Rheumatology, found that patients with COVID-19 who had an inflammatory rheumatic disease were more likely to be admitted to the hospital, compared with COVID-19 patients without rheumatic disease. Patients with rheumatic disease had a higher risk of a severe COVID-19 outcome, but it was not a statistically significant difference, said Dr. Curtis, adding that the individual factors such as age and treatment currently received largely determines the risk. The strongest associations between hospitalization for COVID-19 and rheumatic disease were found among patients with RA, vasculitis, and connective tissue disease. Dr. Curtis noted that his own new study results show that risk of death from a COVID-19 infection is higher for patients who have RA or psoriatic arthritis.
There have been published case reports of patients who have developed new-onset lupus, vasculitis, Kawasaki disease, multiple sclerosis, autoimmune cytopenias, and other manifestations after a COVID-19 infection. “These authors suggest that perhaps there is a transient influence on the immune system that leads to a loss of self-tolerance to antigens,” Dr. Curtis said. “Some patients may have an underlying predisposition to autoimmunity in which infections just unmask as we sometimes see with other infections – chronic hepatitis for example.”
Antibody tests not recommended
In its COVID-19 guidance, the ACR, like the Food and Drug Administration, recommends health care providers not to routinely order antibody tests for IgM or IgG to assess immunity after a person has been vaccinated or to assess the need for vaccination in an unvaccinated person. More research is needed to determine if antibodies provide protection, and if so, for how long and how much. Plus, the antibody testing process is not clear cut, so ordering the wrong test is possible, Dr. Curtis said. The tests should clearly differentiate between spike proteins or nucleocapsid proteins.
“The bottom line is that you might be ordering the wrong lab test. Even if you’re ordering the right lab test, I would assert that you probably don’t know what to do with the result. I would then ask you, ‘Does it mean they are protected? Does it mean they are not protected? What are you going to do with the results?’ ” he asked.
Kevin Winthrop, MD, MPH, a specialist in infectious diseases at Oregon Health & Science University, Portland, said that, at this point, it’s too early to know what antibody tests mean. “I think it is tempting to test some people, especially patients on B-cell depletion therapy and those on mycophenolate mofetil (MMF). Outside of those two types of [disease-modifying antirheumatic drug] users, I wouldn’t be tempted to test. We don’t know how well protected they are, but we assume they are protected to some extent,” he said. “They’re probably partially protected and as such, they should take the same precautions they were taking a year ago: masking and avoidance. I think that’s just how it’s going to be for those folks for another year until we get this thing sorted out.”
Modifications to existing rheumatic disease therapies
In its COVID-19 vaccine guidance, the ACR issued recommendations for some common rheumatic disease therapeutics before and/or after the COVID-19 vaccine is administered. The modifications are limited to MMF, methotrexate, JAK inhibitors, subcutaneous abatacept, acetaminophen, and NSAIDs. The recommendations include: hold mycophenolate for 1 week after vaccination if disease is stable; for patients with well-controlled disease, hold methotrexate for 1 week after each of the two mRNA vaccine doses; for patients with well-controlled disease receiving the Johnson & Johnson vaccine, hold methotrexate for 2 weeks after receiving the vaccine; hold JAK inhibitors for 1 week after each dose; for abatacept subcutaneous, hold treatment for 1 week before and after the first dose; and in patients with stable disease, hold acetaminophen and NSAIDs for 24 hours before vaccination, because taking either before vaccination could blunt the vaccine response, Dr. Curtis said.
Holding medication, such as methotrexate, could risk having a flare-up of disease. One study showed the rate of disease flare-up because of withholding standard treatment may be up to 11%, compared with 5.1% in patients who did not hold treatment, he said.
“The point is, if you hold some of these therapies, whether methotrexate or tofacitinib, arthritis will get a little bit worse,” Dr. Curtis said.
A study published on the preprint server medRxiv found that immunosuppressive therapies blunted the response of SARS-CoV-2 vaccines in patients with chronic inflammatory diseases, most significantly with glucocorticoids and B-cell therapies.
“That’s what’s led to a lot of the guidance statements about holding treatments for a week or 2 for rituximab. If you’re giving it at 6-month intervals, you want to schedule the vaccine dose or series at about month 5, or a month before the next cycle,” he said.
Talking with patients about COVID-19 vaccination
In talking with patients about vaccine safety, Dr. Curtis recommends addressing a few common misperceptions. First, COVID-19 viruses were not created with a live-attenuated virus (which would be contraindicated for immunosuppressed patients). “You can put patients’ mind at ease that none of the vaccine candidates or platforms – even those that say viral vector – put patients at risk for contracting the infection. These are nonreplicating. So, it’s like you extracted the engine that would allow this virus to replicate,” he said.
Of three COVID-19 vaccinations available in the United States, is one better than the other? The ACR COVID-19 vaccine task force did not reach a consensus on safety profiles of the vaccines because, without head-to-head comparisons, it’s impossible to know, he said.
In talking with patients, review the protocol for continuing with prescribed treatment modalities before the patient receives a COVID-19 vaccine. Safety concerns and concerns about the possibility of having a disease flare-up should be addressed, he said.
FROM THE GRAPPA 2021 ANNUAL MEETING
Vaccine mandates, passports, and Kant
Houston Methodist Hospital in June 2021 enforced an April mandate that all its employees, about 26,000 of them, must be vaccinated against COVID-19. In the following weeks, many other large health care systems adopted a similar employer mandate.
Compliance with Houston Methodist’s mandate has been very high at nearly 99%. There were some deferrals, mostly because of pregnancy. There were some “medical and personal” exemptions for less than 1% of employees. The reasons for those personal exemptions have not been made public. A lawsuit by 117 employees objecting to the vaccine mandate was dismissed by a federal district judge on June 12.
Objections to the vaccine mandate have rarely involved religious-based conscientious objections, which need to be accommodated differently, legally and ethically. The objections have been disagreements on the science. As a politician said decades ago: “People are entitled to their own opinions, but not their own facts.” A medical institution is an excellent organization for determining the risks and benefits of vaccination. The judge dismissing the case was very critical of the characterizations used by the plaintiffs.
The vaccine mandate has strong ethical support from both the universalizability principle of Kant and a consequentialist analysis. The U.S. Equal Employment Opportunity Commission on May 28, 2021, released technical assistance that has generally been interpreted to support an employer’s right to set vaccine requirements. HIPAA does not forbid an employer from asking about vaccination, but the EEOC guidance reminds employers that if they do ask, employers have legal obligations to protect the health information and keep it separate from other personnel files.
In the past few years, many hospitals and clinics have adopted mandates for influenza vaccines. In many children’s hospitals staff have been required to have chicken pox vaccines (or, as in my case, titers showing immunity from the real thing – I’m old) since the early 2000s. Measles titers (again, mine were acquired naturally – I still remember the illness and recommend against that) and TB status are occasionally required for locum tenens positions. I keep copies of these labs alongside copies of my diplomas. To me, the COVID-19 mandate is not capricious.
Some people have pointed out that the COVID-19 vaccines are not fully Food and Drug Administration approved. They are used under an emergency use authorization. Any traction that distinction might have had ethically and scientifically in November 2020 has disappeared with the experience of 9 months and 300 million doses in the United States. Dr. Fauci on July 11, 2021, said: “These vaccines are as good as officially approved with all the I’s dotted and the T’s crossed.”
On July 12, 2021, French President Macron, facing a resurgence of the pandemic because of the delta variant, announced a national vaccine mandate for all health care workers. He also announced plans to require proof of vaccination (or prior disease) in order to enter amusement parks, restaurants, and other public facilities. The ethics of his plans have been debated by ethicists and politicians for months under the rubric of a “vaccine passport.” England has required proof of vaccination or a recent negative COVID-19 test before entering soccer stadiums. In the United States, some localities, particularly those where the local politicians are against the vaccine, have passed laws proscribing the creation of these passport-like restrictions. Elsewhere, many businesses have already started to exclude customers who are not vaccinated. Airlines, hotels, and cruise ships are at the forefront of this. Society has started to create consequences for not getting the vaccine. President Macron indicated that the goal was now to put restrictions on the unvaccinated rather than on everyone.
Pediatricians are experts on the importance of consequences for misbehavior and refusals. It is a frequent topic of conversation with parents of toddlers and teenagers. Consequences are ethical, just, and effective ways of promoting safe and fair behavior. At this point, the public has been educated about the disease and the vaccines. In the United States, there has been ample access to the vaccine. It is time to enforce consequences.
Daily vaccination rates in the United States have slowed to 25% of the peak rates. The reasons for hesitancy have been analyzed in many publications. Further public education hasn’t been productive, so empathic listening has been urged to overcome hesitancy. (A similar program has long been advocated to deal with hesitancy for teenage HPV vaccines.) President Biden on July 6, 2021, proposed a program of going door to door to overcome resistance.
The world is in a race between vaccines and the delta variant. The Delta variant is moving the finish line, with some French epidemiologists advising President Macron that this more contagious variant may require a 90% vaccination level to achieve herd immunity. Israel has started giving a third booster shot in select situations and Pfizer is considering the idea. I agree with providing education, using empathic listening, and improving access. Those are all reasonable, even necessary, strategies. But at this point, I anchor my suggestions with the same advice pediatricians have long given to parents. Set rules and create consequences for misbehavior.
Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. He has no financial disclosures. Email him at [email protected].
Houston Methodist Hospital in June 2021 enforced an April mandate that all its employees, about 26,000 of them, must be vaccinated against COVID-19. In the following weeks, many other large health care systems adopted a similar employer mandate.
Compliance with Houston Methodist’s mandate has been very high at nearly 99%. There were some deferrals, mostly because of pregnancy. There were some “medical and personal” exemptions for less than 1% of employees. The reasons for those personal exemptions have not been made public. A lawsuit by 117 employees objecting to the vaccine mandate was dismissed by a federal district judge on June 12.
Objections to the vaccine mandate have rarely involved religious-based conscientious objections, which need to be accommodated differently, legally and ethically. The objections have been disagreements on the science. As a politician said decades ago: “People are entitled to their own opinions, but not their own facts.” A medical institution is an excellent organization for determining the risks and benefits of vaccination. The judge dismissing the case was very critical of the characterizations used by the plaintiffs.
The vaccine mandate has strong ethical support from both the universalizability principle of Kant and a consequentialist analysis. The U.S. Equal Employment Opportunity Commission on May 28, 2021, released technical assistance that has generally been interpreted to support an employer’s right to set vaccine requirements. HIPAA does not forbid an employer from asking about vaccination, but the EEOC guidance reminds employers that if they do ask, employers have legal obligations to protect the health information and keep it separate from other personnel files.
In the past few years, many hospitals and clinics have adopted mandates for influenza vaccines. In many children’s hospitals staff have been required to have chicken pox vaccines (or, as in my case, titers showing immunity from the real thing – I’m old) since the early 2000s. Measles titers (again, mine were acquired naturally – I still remember the illness and recommend against that) and TB status are occasionally required for locum tenens positions. I keep copies of these labs alongside copies of my diplomas. To me, the COVID-19 mandate is not capricious.
Some people have pointed out that the COVID-19 vaccines are not fully Food and Drug Administration approved. They are used under an emergency use authorization. Any traction that distinction might have had ethically and scientifically in November 2020 has disappeared with the experience of 9 months and 300 million doses in the United States. Dr. Fauci on July 11, 2021, said: “These vaccines are as good as officially approved with all the I’s dotted and the T’s crossed.”
On July 12, 2021, French President Macron, facing a resurgence of the pandemic because of the delta variant, announced a national vaccine mandate for all health care workers. He also announced plans to require proof of vaccination (or prior disease) in order to enter amusement parks, restaurants, and other public facilities. The ethics of his plans have been debated by ethicists and politicians for months under the rubric of a “vaccine passport.” England has required proof of vaccination or a recent negative COVID-19 test before entering soccer stadiums. In the United States, some localities, particularly those where the local politicians are against the vaccine, have passed laws proscribing the creation of these passport-like restrictions. Elsewhere, many businesses have already started to exclude customers who are not vaccinated. Airlines, hotels, and cruise ships are at the forefront of this. Society has started to create consequences for not getting the vaccine. President Macron indicated that the goal was now to put restrictions on the unvaccinated rather than on everyone.
Pediatricians are experts on the importance of consequences for misbehavior and refusals. It is a frequent topic of conversation with parents of toddlers and teenagers. Consequences are ethical, just, and effective ways of promoting safe and fair behavior. At this point, the public has been educated about the disease and the vaccines. In the United States, there has been ample access to the vaccine. It is time to enforce consequences.
Daily vaccination rates in the United States have slowed to 25% of the peak rates. The reasons for hesitancy have been analyzed in many publications. Further public education hasn’t been productive, so empathic listening has been urged to overcome hesitancy. (A similar program has long been advocated to deal with hesitancy for teenage HPV vaccines.) President Biden on July 6, 2021, proposed a program of going door to door to overcome resistance.
The world is in a race between vaccines and the delta variant. The Delta variant is moving the finish line, with some French epidemiologists advising President Macron that this more contagious variant may require a 90% vaccination level to achieve herd immunity. Israel has started giving a third booster shot in select situations and Pfizer is considering the idea. I agree with providing education, using empathic listening, and improving access. Those are all reasonable, even necessary, strategies. But at this point, I anchor my suggestions with the same advice pediatricians have long given to parents. Set rules and create consequences for misbehavior.
Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. He has no financial disclosures. Email him at [email protected].
Houston Methodist Hospital in June 2021 enforced an April mandate that all its employees, about 26,000 of them, must be vaccinated against COVID-19. In the following weeks, many other large health care systems adopted a similar employer mandate.
Compliance with Houston Methodist’s mandate has been very high at nearly 99%. There were some deferrals, mostly because of pregnancy. There were some “medical and personal” exemptions for less than 1% of employees. The reasons for those personal exemptions have not been made public. A lawsuit by 117 employees objecting to the vaccine mandate was dismissed by a federal district judge on June 12.
Objections to the vaccine mandate have rarely involved religious-based conscientious objections, which need to be accommodated differently, legally and ethically. The objections have been disagreements on the science. As a politician said decades ago: “People are entitled to their own opinions, but not their own facts.” A medical institution is an excellent organization for determining the risks and benefits of vaccination. The judge dismissing the case was very critical of the characterizations used by the plaintiffs.
The vaccine mandate has strong ethical support from both the universalizability principle of Kant and a consequentialist analysis. The U.S. Equal Employment Opportunity Commission on May 28, 2021, released technical assistance that has generally been interpreted to support an employer’s right to set vaccine requirements. HIPAA does not forbid an employer from asking about vaccination, but the EEOC guidance reminds employers that if they do ask, employers have legal obligations to protect the health information and keep it separate from other personnel files.
In the past few years, many hospitals and clinics have adopted mandates for influenza vaccines. In many children’s hospitals staff have been required to have chicken pox vaccines (or, as in my case, titers showing immunity from the real thing – I’m old) since the early 2000s. Measles titers (again, mine were acquired naturally – I still remember the illness and recommend against that) and TB status are occasionally required for locum tenens positions. I keep copies of these labs alongside copies of my diplomas. To me, the COVID-19 mandate is not capricious.
Some people have pointed out that the COVID-19 vaccines are not fully Food and Drug Administration approved. They are used under an emergency use authorization. Any traction that distinction might have had ethically and scientifically in November 2020 has disappeared with the experience of 9 months and 300 million doses in the United States. Dr. Fauci on July 11, 2021, said: “These vaccines are as good as officially approved with all the I’s dotted and the T’s crossed.”
On July 12, 2021, French President Macron, facing a resurgence of the pandemic because of the delta variant, announced a national vaccine mandate for all health care workers. He also announced plans to require proof of vaccination (or prior disease) in order to enter amusement parks, restaurants, and other public facilities. The ethics of his plans have been debated by ethicists and politicians for months under the rubric of a “vaccine passport.” England has required proof of vaccination or a recent negative COVID-19 test before entering soccer stadiums. In the United States, some localities, particularly those where the local politicians are against the vaccine, have passed laws proscribing the creation of these passport-like restrictions. Elsewhere, many businesses have already started to exclude customers who are not vaccinated. Airlines, hotels, and cruise ships are at the forefront of this. Society has started to create consequences for not getting the vaccine. President Macron indicated that the goal was now to put restrictions on the unvaccinated rather than on everyone.
Pediatricians are experts on the importance of consequences for misbehavior and refusals. It is a frequent topic of conversation with parents of toddlers and teenagers. Consequences are ethical, just, and effective ways of promoting safe and fair behavior. At this point, the public has been educated about the disease and the vaccines. In the United States, there has been ample access to the vaccine. It is time to enforce consequences.
Daily vaccination rates in the United States have slowed to 25% of the peak rates. The reasons for hesitancy have been analyzed in many publications. Further public education hasn’t been productive, so empathic listening has been urged to overcome hesitancy. (A similar program has long been advocated to deal with hesitancy for teenage HPV vaccines.) President Biden on July 6, 2021, proposed a program of going door to door to overcome resistance.
The world is in a race between vaccines and the delta variant. The Delta variant is moving the finish line, with some French epidemiologists advising President Macron that this more contagious variant may require a 90% vaccination level to achieve herd immunity. Israel has started giving a third booster shot in select situations and Pfizer is considering the idea. I agree with providing education, using empathic listening, and improving access. Those are all reasonable, even necessary, strategies. But at this point, I anchor my suggestions with the same advice pediatricians have long given to parents. Set rules and create consequences for misbehavior.
Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. He has no financial disclosures. Email him at [email protected].
Patients on methotrexate show T-cell response to Pfizer vaccine
People taking methotrexate had low antibody responses after the first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine, but did show evidence of T-cell–mediated immune responses, findings from a small study show.
The common immunosuppressant has previously been linked to poor antibody responses to mRNA COVID-19 vaccines, but this appears to be the first study to look at T-cell responses in people taking methotrexate.
The study findings were presented online July 11 at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published in The Lancet Rheumatology.
“These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice,” Satveer K. Mahil, MBBChir, PhD, from St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, and colleagues wrote.
“When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population,” they wrote. “Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved.”
Dr. Mahil and colleagues assessed 84 consecutive patients from a psoriasis specialist clinic that serves London and southeast England. Median age of the cohort was 43 years, and 85% were White. All had a confirmed psoriasis diagnosis, received the first dose of the Pfizer-BioNTech COVID-19 vaccine, and were taking either methotrexate (17 patients) or a targeted biologic (27 were taking a tumor necrosis factor inhibitor, 15 an interleukin-17 inhibitor, and 25 an IL-23 inhibitor). In addition, 17 healthy patients not receiving immunosuppression therapy who received the Pfizer-BioNTech vaccine served as the control group.
Four weeks after the study participants received their first dose of the vaccine, 78% of the immunosuppressed patients underwent seroconversion – producing measurable antibodies – as did 100% of the control group. Patients taking methotrexate had the lowest seroconversion rate at 47%, compared with 79% with TNF inhibitors, 83% with IL-23 inhibitors, and 100% with IL-17 inhibitors.
Participants taking methotrexate also had lower neutralizing activity against SARS-CoV-2 than control subjects and those taking a targeted biologic, who had similar levels of neutralizing activity.
All participants had low neutralizing titers against the alpha (B.1.1.7) variant.
The researchers also assessed cellular immunity, “defined as the presence of T cells secreting interferon-gamma, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein.”
A T-cell response was seen in 84% of participants taking immunosuppressants, including 93% of those in the methotrexate group and 69% of control subjects.
‘Some protection is better than none’
These findings regarding antibodies match what has been seen in other research, said Ignacio Sanz, MD, director of the Lowance Center for Human Immunology at Emory University, Atlanta.
It would be helpful to see antibody responses after the second doses, he added. Those data will be reported later, according to Dr. Mahil and colleagues.
“The authors make the valid point that T-cell immunity should also be measured. The information is meaningful and supports the idea that there could be protection still provided,” Dr. Sanz said in an interview, adding that it would have been helpful to see CD8 T-cell response as well.
“My message to patients, still, is that some protection is better than none, and that, indeed, protection may be afforded in different ways, including T-cell immunity, which, to the extent tested, seems to be induced,” he said. But discussion of B cells independent of their role in producing antibodies is missing.
“When it comes to B-cell responses, antibodies are the easier and more direct measurement. However, it is perfectly possible that the vaccine may fail to induce high antibody titers and still generate good B-cell immunity,” in the same way virus-specific memory B cells do, he explained. “They would not directly produce antibodies, yet they would be available for a good and quick response in the case of subsequent encounter with the virus and, incidentally, in the case of a booster dose. It is possible that the generation of antibody-producing plasma cells might be uncoupled from the generation of memory B cells.”
Temporarily stopping methotrexate
It is well known that methotrexate impairs humoral responses to influenza and pneumococcal vaccines, write Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, both from the Johns Hopkins University, Baltimore, in an accompanying comment.
Research has also shown that temporarily stopping methotrexate therapy for 2 weeks enhances response to the flu vaccine in patients with rheumatoid arthritis, which prompted the American College of Rheumatology to recommended temporary interruption of methotrexate for 1 week after each dose of the COVID-19 vaccine, the pair notes.
“Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups,” Dr. Connolly and Dr. Paik explained. “During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies.”
Mild adverse events after vaccination were reported by 75% of the immunosuppressed patients – most commonly injection-site pain, headache, and fatigue – and by 94% of control subjects. No participants reported moderate or severe adverse effects.
However, 11% of immunosuppressed patients reported a worsening of psoriasis symptoms after vaccination.
This research was funded by the U.K. National Institute for Health Research. Dr. Mahil has received departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sano, and UCB unrelated to this study. Seven other authors have relationships with a wide range of pharmaceutical and other companies. Dr. Sanz, Dr. Connolly, and Dr. Paik disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People taking methotrexate had low antibody responses after the first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine, but did show evidence of T-cell–mediated immune responses, findings from a small study show.
The common immunosuppressant has previously been linked to poor antibody responses to mRNA COVID-19 vaccines, but this appears to be the first study to look at T-cell responses in people taking methotrexate.
The study findings were presented online July 11 at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published in The Lancet Rheumatology.
“These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice,” Satveer K. Mahil, MBBChir, PhD, from St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, and colleagues wrote.
“When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population,” they wrote. “Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved.”
Dr. Mahil and colleagues assessed 84 consecutive patients from a psoriasis specialist clinic that serves London and southeast England. Median age of the cohort was 43 years, and 85% were White. All had a confirmed psoriasis diagnosis, received the first dose of the Pfizer-BioNTech COVID-19 vaccine, and were taking either methotrexate (17 patients) or a targeted biologic (27 were taking a tumor necrosis factor inhibitor, 15 an interleukin-17 inhibitor, and 25 an IL-23 inhibitor). In addition, 17 healthy patients not receiving immunosuppression therapy who received the Pfizer-BioNTech vaccine served as the control group.
Four weeks after the study participants received their first dose of the vaccine, 78% of the immunosuppressed patients underwent seroconversion – producing measurable antibodies – as did 100% of the control group. Patients taking methotrexate had the lowest seroconversion rate at 47%, compared with 79% with TNF inhibitors, 83% with IL-23 inhibitors, and 100% with IL-17 inhibitors.
Participants taking methotrexate also had lower neutralizing activity against SARS-CoV-2 than control subjects and those taking a targeted biologic, who had similar levels of neutralizing activity.
All participants had low neutralizing titers against the alpha (B.1.1.7) variant.
The researchers also assessed cellular immunity, “defined as the presence of T cells secreting interferon-gamma, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein.”
A T-cell response was seen in 84% of participants taking immunosuppressants, including 93% of those in the methotrexate group and 69% of control subjects.
‘Some protection is better than none’
These findings regarding antibodies match what has been seen in other research, said Ignacio Sanz, MD, director of the Lowance Center for Human Immunology at Emory University, Atlanta.
It would be helpful to see antibody responses after the second doses, he added. Those data will be reported later, according to Dr. Mahil and colleagues.
“The authors make the valid point that T-cell immunity should also be measured. The information is meaningful and supports the idea that there could be protection still provided,” Dr. Sanz said in an interview, adding that it would have been helpful to see CD8 T-cell response as well.
“My message to patients, still, is that some protection is better than none, and that, indeed, protection may be afforded in different ways, including T-cell immunity, which, to the extent tested, seems to be induced,” he said. But discussion of B cells independent of their role in producing antibodies is missing.
“When it comes to B-cell responses, antibodies are the easier and more direct measurement. However, it is perfectly possible that the vaccine may fail to induce high antibody titers and still generate good B-cell immunity,” in the same way virus-specific memory B cells do, he explained. “They would not directly produce antibodies, yet they would be available for a good and quick response in the case of subsequent encounter with the virus and, incidentally, in the case of a booster dose. It is possible that the generation of antibody-producing plasma cells might be uncoupled from the generation of memory B cells.”
Temporarily stopping methotrexate
It is well known that methotrexate impairs humoral responses to influenza and pneumococcal vaccines, write Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, both from the Johns Hopkins University, Baltimore, in an accompanying comment.
Research has also shown that temporarily stopping methotrexate therapy for 2 weeks enhances response to the flu vaccine in patients with rheumatoid arthritis, which prompted the American College of Rheumatology to recommended temporary interruption of methotrexate for 1 week after each dose of the COVID-19 vaccine, the pair notes.
“Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups,” Dr. Connolly and Dr. Paik explained. “During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies.”
Mild adverse events after vaccination were reported by 75% of the immunosuppressed patients – most commonly injection-site pain, headache, and fatigue – and by 94% of control subjects. No participants reported moderate or severe adverse effects.
However, 11% of immunosuppressed patients reported a worsening of psoriasis symptoms after vaccination.
This research was funded by the U.K. National Institute for Health Research. Dr. Mahil has received departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sano, and UCB unrelated to this study. Seven other authors have relationships with a wide range of pharmaceutical and other companies. Dr. Sanz, Dr. Connolly, and Dr. Paik disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People taking methotrexate had low antibody responses after the first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine, but did show evidence of T-cell–mediated immune responses, findings from a small study show.
The common immunosuppressant has previously been linked to poor antibody responses to mRNA COVID-19 vaccines, but this appears to be the first study to look at T-cell responses in people taking methotrexate.
The study findings were presented online July 11 at the 31st European Congress of Clinical Microbiology & Infectious Diseases and published in The Lancet Rheumatology.
“These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice,” Satveer K. Mahil, MBBChir, PhD, from St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, and colleagues wrote.
“When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population,” they wrote. “Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved.”
Dr. Mahil and colleagues assessed 84 consecutive patients from a psoriasis specialist clinic that serves London and southeast England. Median age of the cohort was 43 years, and 85% were White. All had a confirmed psoriasis diagnosis, received the first dose of the Pfizer-BioNTech COVID-19 vaccine, and were taking either methotrexate (17 patients) or a targeted biologic (27 were taking a tumor necrosis factor inhibitor, 15 an interleukin-17 inhibitor, and 25 an IL-23 inhibitor). In addition, 17 healthy patients not receiving immunosuppression therapy who received the Pfizer-BioNTech vaccine served as the control group.
Four weeks after the study participants received their first dose of the vaccine, 78% of the immunosuppressed patients underwent seroconversion – producing measurable antibodies – as did 100% of the control group. Patients taking methotrexate had the lowest seroconversion rate at 47%, compared with 79% with TNF inhibitors, 83% with IL-23 inhibitors, and 100% with IL-17 inhibitors.
Participants taking methotrexate also had lower neutralizing activity against SARS-CoV-2 than control subjects and those taking a targeted biologic, who had similar levels of neutralizing activity.
All participants had low neutralizing titers against the alpha (B.1.1.7) variant.
The researchers also assessed cellular immunity, “defined as the presence of T cells secreting interferon-gamma, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein.”
A T-cell response was seen in 84% of participants taking immunosuppressants, including 93% of those in the methotrexate group and 69% of control subjects.
‘Some protection is better than none’
These findings regarding antibodies match what has been seen in other research, said Ignacio Sanz, MD, director of the Lowance Center for Human Immunology at Emory University, Atlanta.
It would be helpful to see antibody responses after the second doses, he added. Those data will be reported later, according to Dr. Mahil and colleagues.
“The authors make the valid point that T-cell immunity should also be measured. The information is meaningful and supports the idea that there could be protection still provided,” Dr. Sanz said in an interview, adding that it would have been helpful to see CD8 T-cell response as well.
“My message to patients, still, is that some protection is better than none, and that, indeed, protection may be afforded in different ways, including T-cell immunity, which, to the extent tested, seems to be induced,” he said. But discussion of B cells independent of their role in producing antibodies is missing.
“When it comes to B-cell responses, antibodies are the easier and more direct measurement. However, it is perfectly possible that the vaccine may fail to induce high antibody titers and still generate good B-cell immunity,” in the same way virus-specific memory B cells do, he explained. “They would not directly produce antibodies, yet they would be available for a good and quick response in the case of subsequent encounter with the virus and, incidentally, in the case of a booster dose. It is possible that the generation of antibody-producing plasma cells might be uncoupled from the generation of memory B cells.”
Temporarily stopping methotrexate
It is well known that methotrexate impairs humoral responses to influenza and pneumococcal vaccines, write Caoilfhionn M. Connolly, MD, and Julie J. Paik, MD, both from the Johns Hopkins University, Baltimore, in an accompanying comment.
Research has also shown that temporarily stopping methotrexate therapy for 2 weeks enhances response to the flu vaccine in patients with rheumatoid arthritis, which prompted the American College of Rheumatology to recommended temporary interruption of methotrexate for 1 week after each dose of the COVID-19 vaccine, the pair notes.
“Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups,” Dr. Connolly and Dr. Paik explained. “During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies.”
Mild adverse events after vaccination were reported by 75% of the immunosuppressed patients – most commonly injection-site pain, headache, and fatigue – and by 94% of control subjects. No participants reported moderate or severe adverse effects.
However, 11% of immunosuppressed patients reported a worsening of psoriasis symptoms after vaccination.
This research was funded by the U.K. National Institute for Health Research. Dr. Mahil has received departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sano, and UCB unrelated to this study. Seven other authors have relationships with a wide range of pharmaceutical and other companies. Dr. Sanz, Dr. Connolly, and Dr. Paik disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New details of myocarditis linked to COVID vaccines
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
Few clinical guidelines exist for treating post-COVID symptoms
As doctors struggled through several surges of COVID-19 infections, most of what we learned was acquired through real-life experience. While many treatment options were promoted, most flat-out failed to be real therapeutics at all. Now that we have a safe and effective vaccine, we can prevent many infections from this virus. However, we are still left to manage the many post-COVID symptoms our patients continue to suffer with.
Symptoms following infection can last for months and range widely from “brain fog,” fatigue, dyspnea, chest pain, generalized weakness, depression, and a host of others. Patients may experience one or all of these symptoms, and there is currently no good way to predict who will go on to become a COVID “long hauler”.
Following the example of being educated by COVID as it happened, the same is true for managing post-COVID symptoms. The medical community still has a poor understanding of why some people develop it and there are few evidence-based studies to support any treatment modalities.
which they define as “new, recurring, or ongoing symptoms more than 4 weeks after infection, sometimes after initial symptom recovery.” It is important to note that these symptoms can occur in any degree of sickness during the acute infection, including in those who were asymptomatic. Even the actual name of this post-COVID syndrome is still being developed, with several other names being used for it as well.
While the guidelines are quite extensive, the actual clinical recommendations are still vague. For example, it is advised to let the patient know that post-COVID symptoms are still not well understood. While it is important to be transparent with patients, this does little to reassure them. Patients look to doctors, especially their primary care physicians, to guide them on the best treatment paths. Yet, we currently have none for post-COVID syndrome.
It is also advised to treat the patients’ symptoms and help improve functioning. For many diseases, doctors like to get to the root cause of the problem. Treating a symptom often masks an underlying condition. It may make the patient feel better and improve what they are capable of doing, which is important, but it also fails to unmask the real problem. It is also important to note that symptoms can be out of proportion to clinical findings and should not be dismissed: we just don’t have the answers yet.
One helpful recommendation is having a patient keep a diary of their symptoms. This will help both the patient and doctor learn what may be triggering factors. If it is, for example, exertion that induces breathlessness, perhaps the patient can gradually increase their level of activity to minimize symptoms. Additionally, a “comprehensive rehabilitation program” is also advised and this can greatly assist addressing all the issues a patient is experiencing, physically and medically.
It is also advised that management of underlying medical conditions be optimized. While this is very important, it is not something specific to post-COVID syndrome: All patients should have their underlying medical conditions well controlled. It might be that the patient is paying more attention to their overall health, which is a good thing. However, this does not necessarily reduce the current symptoms a patient is experiencing.
The CDC makes a good attempt to offer guidance in the frustrating management of post-COVID syndrome. However, their clinical guidelines fail to offer specific management tools specific to treating post-COVID patients. The recommendations offered are more helpful to health in general. The fact that more specific recommendations are lacking is simply caused by the lack of knowledge of this condition at present. As more research is conducted and more knowledge obtained, new guidelines should become more detailed.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].
As doctors struggled through several surges of COVID-19 infections, most of what we learned was acquired through real-life experience. While many treatment options were promoted, most flat-out failed to be real therapeutics at all. Now that we have a safe and effective vaccine, we can prevent many infections from this virus. However, we are still left to manage the many post-COVID symptoms our patients continue to suffer with.
Symptoms following infection can last for months and range widely from “brain fog,” fatigue, dyspnea, chest pain, generalized weakness, depression, and a host of others. Patients may experience one or all of these symptoms, and there is currently no good way to predict who will go on to become a COVID “long hauler”.
Following the example of being educated by COVID as it happened, the same is true for managing post-COVID symptoms. The medical community still has a poor understanding of why some people develop it and there are few evidence-based studies to support any treatment modalities.
which they define as “new, recurring, or ongoing symptoms more than 4 weeks after infection, sometimes after initial symptom recovery.” It is important to note that these symptoms can occur in any degree of sickness during the acute infection, including in those who were asymptomatic. Even the actual name of this post-COVID syndrome is still being developed, with several other names being used for it as well.
While the guidelines are quite extensive, the actual clinical recommendations are still vague. For example, it is advised to let the patient know that post-COVID symptoms are still not well understood. While it is important to be transparent with patients, this does little to reassure them. Patients look to doctors, especially their primary care physicians, to guide them on the best treatment paths. Yet, we currently have none for post-COVID syndrome.
It is also advised to treat the patients’ symptoms and help improve functioning. For many diseases, doctors like to get to the root cause of the problem. Treating a symptom often masks an underlying condition. It may make the patient feel better and improve what they are capable of doing, which is important, but it also fails to unmask the real problem. It is also important to note that symptoms can be out of proportion to clinical findings and should not be dismissed: we just don’t have the answers yet.
One helpful recommendation is having a patient keep a diary of their symptoms. This will help both the patient and doctor learn what may be triggering factors. If it is, for example, exertion that induces breathlessness, perhaps the patient can gradually increase their level of activity to minimize symptoms. Additionally, a “comprehensive rehabilitation program” is also advised and this can greatly assist addressing all the issues a patient is experiencing, physically and medically.
It is also advised that management of underlying medical conditions be optimized. While this is very important, it is not something specific to post-COVID syndrome: All patients should have their underlying medical conditions well controlled. It might be that the patient is paying more attention to their overall health, which is a good thing. However, this does not necessarily reduce the current symptoms a patient is experiencing.
The CDC makes a good attempt to offer guidance in the frustrating management of post-COVID syndrome. However, their clinical guidelines fail to offer specific management tools specific to treating post-COVID patients. The recommendations offered are more helpful to health in general. The fact that more specific recommendations are lacking is simply caused by the lack of knowledge of this condition at present. As more research is conducted and more knowledge obtained, new guidelines should become more detailed.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].
As doctors struggled through several surges of COVID-19 infections, most of what we learned was acquired through real-life experience. While many treatment options were promoted, most flat-out failed to be real therapeutics at all. Now that we have a safe and effective vaccine, we can prevent many infections from this virus. However, we are still left to manage the many post-COVID symptoms our patients continue to suffer with.
Symptoms following infection can last for months and range widely from “brain fog,” fatigue, dyspnea, chest pain, generalized weakness, depression, and a host of others. Patients may experience one or all of these symptoms, and there is currently no good way to predict who will go on to become a COVID “long hauler”.
Following the example of being educated by COVID as it happened, the same is true for managing post-COVID symptoms. The medical community still has a poor understanding of why some people develop it and there are few evidence-based studies to support any treatment modalities.
which they define as “new, recurring, or ongoing symptoms more than 4 weeks after infection, sometimes after initial symptom recovery.” It is important to note that these symptoms can occur in any degree of sickness during the acute infection, including in those who were asymptomatic. Even the actual name of this post-COVID syndrome is still being developed, with several other names being used for it as well.
While the guidelines are quite extensive, the actual clinical recommendations are still vague. For example, it is advised to let the patient know that post-COVID symptoms are still not well understood. While it is important to be transparent with patients, this does little to reassure them. Patients look to doctors, especially their primary care physicians, to guide them on the best treatment paths. Yet, we currently have none for post-COVID syndrome.
It is also advised to treat the patients’ symptoms and help improve functioning. For many diseases, doctors like to get to the root cause of the problem. Treating a symptom often masks an underlying condition. It may make the patient feel better and improve what they are capable of doing, which is important, but it also fails to unmask the real problem. It is also important to note that symptoms can be out of proportion to clinical findings and should not be dismissed: we just don’t have the answers yet.
One helpful recommendation is having a patient keep a diary of their symptoms. This will help both the patient and doctor learn what may be triggering factors. If it is, for example, exertion that induces breathlessness, perhaps the patient can gradually increase their level of activity to minimize symptoms. Additionally, a “comprehensive rehabilitation program” is also advised and this can greatly assist addressing all the issues a patient is experiencing, physically and medically.
It is also advised that management of underlying medical conditions be optimized. While this is very important, it is not something specific to post-COVID syndrome: All patients should have their underlying medical conditions well controlled. It might be that the patient is paying more attention to their overall health, which is a good thing. However, this does not necessarily reduce the current symptoms a patient is experiencing.
The CDC makes a good attempt to offer guidance in the frustrating management of post-COVID syndrome. However, their clinical guidelines fail to offer specific management tools specific to treating post-COVID patients. The recommendations offered are more helpful to health in general. The fact that more specific recommendations are lacking is simply caused by the lack of knowledge of this condition at present. As more research is conducted and more knowledge obtained, new guidelines should become more detailed.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].
Giving flu and COVID-19 shots at same time appears safe, effective: Study
Overall, the NVX-CoV2373 vaccine (Novavax) is showing 89.8% efficacy in an ongoing, placebo-controlled phase 3 study. When the researchers gave a smaller group of 431 volunteers from the same study an influenza shot at the same time, efficacy dropped slightly to 87.5%.
“These results demonstrate the promising opportunity for concomitant vaccination, which may lead to higher vaccination rates and further protection against both viruses,” said study coauthor Raja Rajaram, MD, medical affairs lead, Europe, Middle East, and Africa at Seqirus, the company that supplied the influenza vaccines for the research.
The research was published online June 13 as a medRxiv preprint.
“With these COVID-19 vaccines, there are essentially no concurrent use studies,” Paul A. Offit, MD, told this news organization when asked to comment.
Traditionally, how a new vaccine might interact with existing vaccines is studied before the product is cleared for use. That was not the case, however, with the COVID-19 vaccines made available through expedited emergency use authorization.
The researchers found no major safety concerns associated with concomitant vaccination, Dr. Rajaram said. In addition to safety, the aim of the current study was to determine whether either vaccine changes the immunogenicity or effectiveness of the other.
“It’s a small study, but it’s certainly encouraging to know that there didn’t seem to be a big decrease in immunogenicity either way and the safety profile was similar. Not identical, but similar,” added Dr. Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia.
Some adverse events were more common in the co-administration group. For example, injection-site tenderness was reported by 70%, versus 58% for those who got the COVID-19 shot alone. The same was true for pain at the injection site, 40% versus 29%; fatigue, 28% versus 19%; and muscle pain, 28% versus 21%.
Rates of unsolicited adverse events, adverse events that required medical attention, and serious adverse events were low and well balanced between groups.
Fewer antibodies important?
Although co-administering the two vaccines did not change the immune response for the influenza vaccine, the spike protein antibody response to the COVID-19 vaccine was less robust.
Antibody titer levels at day 35 were 46,678 among people in the Novavax vaccine alone group, compared with 31,236 titers in the participants who received both vaccines.
“This impact did not seem to be clinically meaningful as vaccine efficacy appeared to be preserved,” the researchers noted.
Gregory A. Poland, MD, an internist and part of the Vaccine Research Group at Mayo Clinic in Rochester, Minn., agreed. “I highly doubt that is significant,” he said in an interview.
Dr. Rajaram said the antibody findings are “slightly surprising but not completely unexpected” because the same observation has been made in other combination vaccine studies. He added that the antibody levels “remain very high, although we do not yet know what antibody levels are required to achieve protection against COVID-19.”
The decrease could become more concerning if people start with fewer antibodies and they drop over time with normal waning of protection, Dr. Poland said. This group could include people over age 65 or people who are immunocompromised. More data would be needed to confirm this, he added.
A boost for booster vaccines?
The research could carry implications for future COVID-19 booster shots, Dr. Poland said.
“Overall, the study results are reassuring and of potential practical importance if we have to give booster doses. It will make it easier to give them both in one visit,” said Dr. Poland, who was not affiliated with the research.
Although Novavax could be positioning itself as a logical choice for a COVID-19 booster based on the findings, Dr. Offit believes it is more important to focus on having more COVID-19 vaccine options available.
“There may be, as we say at the track, ‘courses for horses,’ ” he said, meaning that different vaccines may be better suited for different situations.
“It’s likely we’re going to find these vaccines have different safety profiles, they may have different populations for whom they work best, and they may have differences in terms of their long-term durability,” he added. Also, some may prove more effective against certain variants of concern.
The Novavax vaccine would add a new class of COVID-19 vaccine to the mRNA and adenovirus vaccines. NVX-CoV2373 is a recombinant spike protein vaccine.
“I think the more vaccines that are available here, the better,” Dr. Offit said.
Study limitations
Dr. Poland shared some caveats. The study was primarily conducted in adults aged 18-64 years, so there is less certainty on what could happen in people over 65. Furthermore, co-administration was evaluated after the first dose of the Novavax vaccine. “The reason I bring that up is most of the COVID-19 vaccine reactogenicity occurs with dose two, not dose one.
“All in all, it’s an important first step – but it’s only a first step,” Dr. Poland said. “We need more data, including in elderly people who are primarily at risk for morbidity and mortality from the flu.”
He suggested expanding the research to study co-administration of COVID-19 vaccines with different formulations of influenza vaccines.
The study was supported by Novavax. Dr. Offit had no relevant financial disclosures. Dr. Poland serves as a consultant to all of the COVID-19 vaccine companies.
A version of this article first appeared on Medscape.com.
Overall, the NVX-CoV2373 vaccine (Novavax) is showing 89.8% efficacy in an ongoing, placebo-controlled phase 3 study. When the researchers gave a smaller group of 431 volunteers from the same study an influenza shot at the same time, efficacy dropped slightly to 87.5%.
“These results demonstrate the promising opportunity for concomitant vaccination, which may lead to higher vaccination rates and further protection against both viruses,” said study coauthor Raja Rajaram, MD, medical affairs lead, Europe, Middle East, and Africa at Seqirus, the company that supplied the influenza vaccines for the research.
The research was published online June 13 as a medRxiv preprint.
“With these COVID-19 vaccines, there are essentially no concurrent use studies,” Paul A. Offit, MD, told this news organization when asked to comment.
Traditionally, how a new vaccine might interact with existing vaccines is studied before the product is cleared for use. That was not the case, however, with the COVID-19 vaccines made available through expedited emergency use authorization.
The researchers found no major safety concerns associated with concomitant vaccination, Dr. Rajaram said. In addition to safety, the aim of the current study was to determine whether either vaccine changes the immunogenicity or effectiveness of the other.
“It’s a small study, but it’s certainly encouraging to know that there didn’t seem to be a big decrease in immunogenicity either way and the safety profile was similar. Not identical, but similar,” added Dr. Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia.
Some adverse events were more common in the co-administration group. For example, injection-site tenderness was reported by 70%, versus 58% for those who got the COVID-19 shot alone. The same was true for pain at the injection site, 40% versus 29%; fatigue, 28% versus 19%; and muscle pain, 28% versus 21%.
Rates of unsolicited adverse events, adverse events that required medical attention, and serious adverse events were low and well balanced between groups.
Fewer antibodies important?
Although co-administering the two vaccines did not change the immune response for the influenza vaccine, the spike protein antibody response to the COVID-19 vaccine was less robust.
Antibody titer levels at day 35 were 46,678 among people in the Novavax vaccine alone group, compared with 31,236 titers in the participants who received both vaccines.
“This impact did not seem to be clinically meaningful as vaccine efficacy appeared to be preserved,” the researchers noted.
Gregory A. Poland, MD, an internist and part of the Vaccine Research Group at Mayo Clinic in Rochester, Minn., agreed. “I highly doubt that is significant,” he said in an interview.
Dr. Rajaram said the antibody findings are “slightly surprising but not completely unexpected” because the same observation has been made in other combination vaccine studies. He added that the antibody levels “remain very high, although we do not yet know what antibody levels are required to achieve protection against COVID-19.”
The decrease could become more concerning if people start with fewer antibodies and they drop over time with normal waning of protection, Dr. Poland said. This group could include people over age 65 or people who are immunocompromised. More data would be needed to confirm this, he added.
A boost for booster vaccines?
The research could carry implications for future COVID-19 booster shots, Dr. Poland said.
“Overall, the study results are reassuring and of potential practical importance if we have to give booster doses. It will make it easier to give them both in one visit,” said Dr. Poland, who was not affiliated with the research.
Although Novavax could be positioning itself as a logical choice for a COVID-19 booster based on the findings, Dr. Offit believes it is more important to focus on having more COVID-19 vaccine options available.
“There may be, as we say at the track, ‘courses for horses,’ ” he said, meaning that different vaccines may be better suited for different situations.
“It’s likely we’re going to find these vaccines have different safety profiles, they may have different populations for whom they work best, and they may have differences in terms of their long-term durability,” he added. Also, some may prove more effective against certain variants of concern.
The Novavax vaccine would add a new class of COVID-19 vaccine to the mRNA and adenovirus vaccines. NVX-CoV2373 is a recombinant spike protein vaccine.
“I think the more vaccines that are available here, the better,” Dr. Offit said.
Study limitations
Dr. Poland shared some caveats. The study was primarily conducted in adults aged 18-64 years, so there is less certainty on what could happen in people over 65. Furthermore, co-administration was evaluated after the first dose of the Novavax vaccine. “The reason I bring that up is most of the COVID-19 vaccine reactogenicity occurs with dose two, not dose one.
“All in all, it’s an important first step – but it’s only a first step,” Dr. Poland said. “We need more data, including in elderly people who are primarily at risk for morbidity and mortality from the flu.”
He suggested expanding the research to study co-administration of COVID-19 vaccines with different formulations of influenza vaccines.
The study was supported by Novavax. Dr. Offit had no relevant financial disclosures. Dr. Poland serves as a consultant to all of the COVID-19 vaccine companies.
A version of this article first appeared on Medscape.com.
Overall, the NVX-CoV2373 vaccine (Novavax) is showing 89.8% efficacy in an ongoing, placebo-controlled phase 3 study. When the researchers gave a smaller group of 431 volunteers from the same study an influenza shot at the same time, efficacy dropped slightly to 87.5%.
“These results demonstrate the promising opportunity for concomitant vaccination, which may lead to higher vaccination rates and further protection against both viruses,” said study coauthor Raja Rajaram, MD, medical affairs lead, Europe, Middle East, and Africa at Seqirus, the company that supplied the influenza vaccines for the research.
The research was published online June 13 as a medRxiv preprint.
“With these COVID-19 vaccines, there are essentially no concurrent use studies,” Paul A. Offit, MD, told this news organization when asked to comment.
Traditionally, how a new vaccine might interact with existing vaccines is studied before the product is cleared for use. That was not the case, however, with the COVID-19 vaccines made available through expedited emergency use authorization.
The researchers found no major safety concerns associated with concomitant vaccination, Dr. Rajaram said. In addition to safety, the aim of the current study was to determine whether either vaccine changes the immunogenicity or effectiveness of the other.
“It’s a small study, but it’s certainly encouraging to know that there didn’t seem to be a big decrease in immunogenicity either way and the safety profile was similar. Not identical, but similar,” added Dr. Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia.
Some adverse events were more common in the co-administration group. For example, injection-site tenderness was reported by 70%, versus 58% for those who got the COVID-19 shot alone. The same was true for pain at the injection site, 40% versus 29%; fatigue, 28% versus 19%; and muscle pain, 28% versus 21%.
Rates of unsolicited adverse events, adverse events that required medical attention, and serious adverse events were low and well balanced between groups.
Fewer antibodies important?
Although co-administering the two vaccines did not change the immune response for the influenza vaccine, the spike protein antibody response to the COVID-19 vaccine was less robust.
Antibody titer levels at day 35 were 46,678 among people in the Novavax vaccine alone group, compared with 31,236 titers in the participants who received both vaccines.
“This impact did not seem to be clinically meaningful as vaccine efficacy appeared to be preserved,” the researchers noted.
Gregory A. Poland, MD, an internist and part of the Vaccine Research Group at Mayo Clinic in Rochester, Minn., agreed. “I highly doubt that is significant,” he said in an interview.
Dr. Rajaram said the antibody findings are “slightly surprising but not completely unexpected” because the same observation has been made in other combination vaccine studies. He added that the antibody levels “remain very high, although we do not yet know what antibody levels are required to achieve protection against COVID-19.”
The decrease could become more concerning if people start with fewer antibodies and they drop over time with normal waning of protection, Dr. Poland said. This group could include people over age 65 or people who are immunocompromised. More data would be needed to confirm this, he added.
A boost for booster vaccines?
The research could carry implications for future COVID-19 booster shots, Dr. Poland said.
“Overall, the study results are reassuring and of potential practical importance if we have to give booster doses. It will make it easier to give them both in one visit,” said Dr. Poland, who was not affiliated with the research.
Although Novavax could be positioning itself as a logical choice for a COVID-19 booster based on the findings, Dr. Offit believes it is more important to focus on having more COVID-19 vaccine options available.
“There may be, as we say at the track, ‘courses for horses,’ ” he said, meaning that different vaccines may be better suited for different situations.
“It’s likely we’re going to find these vaccines have different safety profiles, they may have different populations for whom they work best, and they may have differences in terms of their long-term durability,” he added. Also, some may prove more effective against certain variants of concern.
The Novavax vaccine would add a new class of COVID-19 vaccine to the mRNA and adenovirus vaccines. NVX-CoV2373 is a recombinant spike protein vaccine.
“I think the more vaccines that are available here, the better,” Dr. Offit said.
Study limitations
Dr. Poland shared some caveats. The study was primarily conducted in adults aged 18-64 years, so there is less certainty on what could happen in people over 65. Furthermore, co-administration was evaluated after the first dose of the Novavax vaccine. “The reason I bring that up is most of the COVID-19 vaccine reactogenicity occurs with dose two, not dose one.
“All in all, it’s an important first step – but it’s only a first step,” Dr. Poland said. “We need more data, including in elderly people who are primarily at risk for morbidity and mortality from the flu.”
He suggested expanding the research to study co-administration of COVID-19 vaccines with different formulations of influenza vaccines.
The study was supported by Novavax. Dr. Offit had no relevant financial disclosures. Dr. Poland serves as a consultant to all of the COVID-19 vaccine companies.
A version of this article first appeared on Medscape.com.
Extensive limb swelling after vaccines – including SARS-CoV-2 vaccine
A 19-month-old boy comes to the office with a large firm erythematous swelling of his anterior left thigh that reaches from just below the inguinal crease to the patella. He got his routine immunizations 2 days prior to this visit including the fourth DTaP dose in his left thigh. Clinicians who care for children and who give routine immunizations occasionally see such an adverse effect following immunization (AEFI). These large local reactions have been described for many decades and occur after many vaccines.
What is extensive limb swelling (ELS)? ELS is defined as erythema/swelling crossing a joint or extending mostly joint to joint. It is a subset of large local AEFIs. ELS is generally firm and often erythematous with varying degrees of pain. ELS is now most frequent after pneumococcal conjugate vaccines (PCV) and DTaP, with a 1%-4% rate after DTaP boosters.1-3 ELS and other large local swelling reactions occur at nearly any age.1 And yet there is still much that is not known about their true pathogenesis. Likewise, there are no accurate predictors of which vaccinees will develop large inflammatory processes at or near the site of immunization.
ELS after standard vaccines
The largest report to date on AEFI of all ages, including ELS, covered 1990-2003.1 Two upfront caveats are: This study evaluated ELS before PCVs were available, and in adults, repeat 23-valent pneumococcal polysaccharide vaccine was the most common cause of ELS in this study, comprising 45% of all adult ELS.
Considering all ages, ELS onset was nearly always greater than 1 hour and was less than 24 hours post vaccine in almost 75% of patients. However, for those aged under 2 years, onset in less than 24 hours was even more frequent (84%). Interestingly, concomitant fever occurred in less than 25% regardless of age. In adults, ELS after tetanus- and diphtheria-containing vaccines occurred mostly in women (75%); whereas for ELS under 8 years of age, males predominated (about 60%). Of note, tetanus- and diphtheria-containing vaccines were the most frequent ELS-inducing vaccines in children, that is, 75% aged under 8 years and 55% for those aged 8-17 years. Focusing on pediatric ELS after DTaP by dose, 33% were after the fourth, 31% after the fifth, 12% after the second, 10% after the first, and 3% after the third dose. In the case above, ELS was after the fourth dose.
Clinicians caring for children know how to manage ELS after DTaP or PCVs. They understand that ELS looks scary and is uncomfortable but is not dangerous and requires no specific treatment. Supportive management, that is, pain reliever, cool compresses, and TLC, are warranted. ELS is not a contraindication to subsequent immunization with the same vaccine. That said, large local reactions or ELS do occur with subsequent doses of that same vaccine at varying rates up to 66% of the time. Management is the same with repeat episodes, and no sequelae are expected. Supportive management only is standard unless one suspects a very rare Arthus reaction. If central necrosis occurs or swelling evolution/resolution is not per expectations, referral to a vaccine expert can sort out if it is an Arthus reaction, in which case, subsequent use of the same vaccine in not recommended.
ELS and SARS-CoV-2 vaccines
With SARS-CoV-2 vaccines now authorized for adolescents and expected in a few months for younger children, large local AEFI reactions related to pediatric SARS-CoV-2 vaccines are expected, given that “COVID arm” is now well described in adults.4 Overall, ELS/large local reactions have been reported more frequently with the Moderna than Pfizer mRNA vaccine.4 In the almost 42% of adults having ELS post first dose, repeat ELS post second dose often appears sooner but also resolves more quickly, with no known sequelae.5
Some biopsies have shown delayed-type hypersensitivity reactions (DTH) (superficial perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells),6,7 while others show no DTH but these patients have findings of immediate hypersensitivity findings and negative skin testing to the vaccine.8 With regard to sex, Dutch ELS data in White adults reveal 90% occur in females – higher than the 75% female rate after standard vaccines.7 Onset of ELS data show that Pfizer mRNA vaccinees had onset on average at 38 hours (range, <1 hr to 12 days). Boston data mostly in White adults reveal later onset (median, 6 days; range, 2-12 days).4 In contrast, adults of color appear to have later onset (mean, 8 days; range, 4-14 days).9
In addition to the local swelling, patients had concurrent injection-site AEFIs of pain (65%), warmth (63%), and pruritus (26%), plus myalgia (51%), headache (48%), malaise (45%), fatigue (43%), chills (33%), arthralgia (30%), and fever (28%).7
What should we tell families about pediatric ELS before we give SARS-CoV-2 vaccines to children? Clinical pediatric SARS-CoV-2 vaccine trials are smaller “immunologic bridging” studies, not requiring proof of efficacy. So, the precise incidence of pediatric ELS (adult rate is estimated under 1/100,000) may not be known until months after general use. Nevertheless, part of our counseling of families will need to include ELS/large local reactions. Unless new data show otherwise, the spiel that clinicians have developed to counsel about the rare chance of ELS after routine vaccines should also be useful to inform families of the rare chance of ELS post SARS-CoV-2 vaccine.
The bottom line is that the management of pediatric ELS after SARS-CoV-2 vaccines should be the same as after standard vaccines. And remember, whether the reactions are DTH or not, neither immediate local injection-site reactions nor DTH reactions are contraindications to subsequent vaccination unless anaphylaxis or Arthus reaction is suspected.10,11
Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].
References
1. Woo EJ and the Vaccine Adverse Event Reporting System Working Group. Clin Infect Dis 2003;37:351-8.
2. Rennels MB et al. Pediatrics 2000;105:e12.
3. Huber BM, Goetschel P. J Pediatr. 2011;158:1033.
4. Blumenthal KG et al. N Engl J Med. 2021;384:1273-7.
5. McMahon DE et al. J Amer Acad Dermatol. 2021;85(1):46-55. 6. Johnston MS et al. JAMA Dermatol. 2021;157(6):716-20 .
7. ELS associated with the administration of Comirnaty®. WHO database Vigilyze (cited 2021 Feb 22). Available from https://vigilyze.who-umc.org/.
8. Baeck M et al. N Engl J Med. 2021 Jun. doi: 10.1056/NEJMc2104751.
9. Samarakoon U et al. N Eng J Med. 2021 Jun 9. doi: 10.1056/NEJMc2108620.
10. Kelso JM et al. J Allergy Clin Immunol. 2012;130:25-43.
11. Zafack JG et al. Pediatrics. 2017;140(3):e20163707.
A 19-month-old boy comes to the office with a large firm erythematous swelling of his anterior left thigh that reaches from just below the inguinal crease to the patella. He got his routine immunizations 2 days prior to this visit including the fourth DTaP dose in his left thigh. Clinicians who care for children and who give routine immunizations occasionally see such an adverse effect following immunization (AEFI). These large local reactions have been described for many decades and occur after many vaccines.
What is extensive limb swelling (ELS)? ELS is defined as erythema/swelling crossing a joint or extending mostly joint to joint. It is a subset of large local AEFIs. ELS is generally firm and often erythematous with varying degrees of pain. ELS is now most frequent after pneumococcal conjugate vaccines (PCV) and DTaP, with a 1%-4% rate after DTaP boosters.1-3 ELS and other large local swelling reactions occur at nearly any age.1 And yet there is still much that is not known about their true pathogenesis. Likewise, there are no accurate predictors of which vaccinees will develop large inflammatory processes at or near the site of immunization.
ELS after standard vaccines
The largest report to date on AEFI of all ages, including ELS, covered 1990-2003.1 Two upfront caveats are: This study evaluated ELS before PCVs were available, and in adults, repeat 23-valent pneumococcal polysaccharide vaccine was the most common cause of ELS in this study, comprising 45% of all adult ELS.
Considering all ages, ELS onset was nearly always greater than 1 hour and was less than 24 hours post vaccine in almost 75% of patients. However, for those aged under 2 years, onset in less than 24 hours was even more frequent (84%). Interestingly, concomitant fever occurred in less than 25% regardless of age. In adults, ELS after tetanus- and diphtheria-containing vaccines occurred mostly in women (75%); whereas for ELS under 8 years of age, males predominated (about 60%). Of note, tetanus- and diphtheria-containing vaccines were the most frequent ELS-inducing vaccines in children, that is, 75% aged under 8 years and 55% for those aged 8-17 years. Focusing on pediatric ELS after DTaP by dose, 33% were after the fourth, 31% after the fifth, 12% after the second, 10% after the first, and 3% after the third dose. In the case above, ELS was after the fourth dose.
Clinicians caring for children know how to manage ELS after DTaP or PCVs. They understand that ELS looks scary and is uncomfortable but is not dangerous and requires no specific treatment. Supportive management, that is, pain reliever, cool compresses, and TLC, are warranted. ELS is not a contraindication to subsequent immunization with the same vaccine. That said, large local reactions or ELS do occur with subsequent doses of that same vaccine at varying rates up to 66% of the time. Management is the same with repeat episodes, and no sequelae are expected. Supportive management only is standard unless one suspects a very rare Arthus reaction. If central necrosis occurs or swelling evolution/resolution is not per expectations, referral to a vaccine expert can sort out if it is an Arthus reaction, in which case, subsequent use of the same vaccine in not recommended.
ELS and SARS-CoV-2 vaccines
With SARS-CoV-2 vaccines now authorized for adolescents and expected in a few months for younger children, large local AEFI reactions related to pediatric SARS-CoV-2 vaccines are expected, given that “COVID arm” is now well described in adults.4 Overall, ELS/large local reactions have been reported more frequently with the Moderna than Pfizer mRNA vaccine.4 In the almost 42% of adults having ELS post first dose, repeat ELS post second dose often appears sooner but also resolves more quickly, with no known sequelae.5
Some biopsies have shown delayed-type hypersensitivity reactions (DTH) (superficial perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells),6,7 while others show no DTH but these patients have findings of immediate hypersensitivity findings and negative skin testing to the vaccine.8 With regard to sex, Dutch ELS data in White adults reveal 90% occur in females – higher than the 75% female rate after standard vaccines.7 Onset of ELS data show that Pfizer mRNA vaccinees had onset on average at 38 hours (range, <1 hr to 12 days). Boston data mostly in White adults reveal later onset (median, 6 days; range, 2-12 days).4 In contrast, adults of color appear to have later onset (mean, 8 days; range, 4-14 days).9
In addition to the local swelling, patients had concurrent injection-site AEFIs of pain (65%), warmth (63%), and pruritus (26%), plus myalgia (51%), headache (48%), malaise (45%), fatigue (43%), chills (33%), arthralgia (30%), and fever (28%).7
What should we tell families about pediatric ELS before we give SARS-CoV-2 vaccines to children? Clinical pediatric SARS-CoV-2 vaccine trials are smaller “immunologic bridging” studies, not requiring proof of efficacy. So, the precise incidence of pediatric ELS (adult rate is estimated under 1/100,000) may not be known until months after general use. Nevertheless, part of our counseling of families will need to include ELS/large local reactions. Unless new data show otherwise, the spiel that clinicians have developed to counsel about the rare chance of ELS after routine vaccines should also be useful to inform families of the rare chance of ELS post SARS-CoV-2 vaccine.
The bottom line is that the management of pediatric ELS after SARS-CoV-2 vaccines should be the same as after standard vaccines. And remember, whether the reactions are DTH or not, neither immediate local injection-site reactions nor DTH reactions are contraindications to subsequent vaccination unless anaphylaxis or Arthus reaction is suspected.10,11
Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].
References
1. Woo EJ and the Vaccine Adverse Event Reporting System Working Group. Clin Infect Dis 2003;37:351-8.
2. Rennels MB et al. Pediatrics 2000;105:e12.
3. Huber BM, Goetschel P. J Pediatr. 2011;158:1033.
4. Blumenthal KG et al. N Engl J Med. 2021;384:1273-7.
5. McMahon DE et al. J Amer Acad Dermatol. 2021;85(1):46-55. 6. Johnston MS et al. JAMA Dermatol. 2021;157(6):716-20 .
7. ELS associated with the administration of Comirnaty®. WHO database Vigilyze (cited 2021 Feb 22). Available from https://vigilyze.who-umc.org/.
8. Baeck M et al. N Engl J Med. 2021 Jun. doi: 10.1056/NEJMc2104751.
9. Samarakoon U et al. N Eng J Med. 2021 Jun 9. doi: 10.1056/NEJMc2108620.
10. Kelso JM et al. J Allergy Clin Immunol. 2012;130:25-43.
11. Zafack JG et al. Pediatrics. 2017;140(3):e20163707.
A 19-month-old boy comes to the office with a large firm erythematous swelling of his anterior left thigh that reaches from just below the inguinal crease to the patella. He got his routine immunizations 2 days prior to this visit including the fourth DTaP dose in his left thigh. Clinicians who care for children and who give routine immunizations occasionally see such an adverse effect following immunization (AEFI). These large local reactions have been described for many decades and occur after many vaccines.
What is extensive limb swelling (ELS)? ELS is defined as erythema/swelling crossing a joint or extending mostly joint to joint. It is a subset of large local AEFIs. ELS is generally firm and often erythematous with varying degrees of pain. ELS is now most frequent after pneumococcal conjugate vaccines (PCV) and DTaP, with a 1%-4% rate after DTaP boosters.1-3 ELS and other large local swelling reactions occur at nearly any age.1 And yet there is still much that is not known about their true pathogenesis. Likewise, there are no accurate predictors of which vaccinees will develop large inflammatory processes at or near the site of immunization.
ELS after standard vaccines
The largest report to date on AEFI of all ages, including ELS, covered 1990-2003.1 Two upfront caveats are: This study evaluated ELS before PCVs were available, and in adults, repeat 23-valent pneumococcal polysaccharide vaccine was the most common cause of ELS in this study, comprising 45% of all adult ELS.
Considering all ages, ELS onset was nearly always greater than 1 hour and was less than 24 hours post vaccine in almost 75% of patients. However, for those aged under 2 years, onset in less than 24 hours was even more frequent (84%). Interestingly, concomitant fever occurred in less than 25% regardless of age. In adults, ELS after tetanus- and diphtheria-containing vaccines occurred mostly in women (75%); whereas for ELS under 8 years of age, males predominated (about 60%). Of note, tetanus- and diphtheria-containing vaccines were the most frequent ELS-inducing vaccines in children, that is, 75% aged under 8 years and 55% for those aged 8-17 years. Focusing on pediatric ELS after DTaP by dose, 33% were after the fourth, 31% after the fifth, 12% after the second, 10% after the first, and 3% after the third dose. In the case above, ELS was after the fourth dose.
Clinicians caring for children know how to manage ELS after DTaP or PCVs. They understand that ELS looks scary and is uncomfortable but is not dangerous and requires no specific treatment. Supportive management, that is, pain reliever, cool compresses, and TLC, are warranted. ELS is not a contraindication to subsequent immunization with the same vaccine. That said, large local reactions or ELS do occur with subsequent doses of that same vaccine at varying rates up to 66% of the time. Management is the same with repeat episodes, and no sequelae are expected. Supportive management only is standard unless one suspects a very rare Arthus reaction. If central necrosis occurs or swelling evolution/resolution is not per expectations, referral to a vaccine expert can sort out if it is an Arthus reaction, in which case, subsequent use of the same vaccine in not recommended.
ELS and SARS-CoV-2 vaccines
With SARS-CoV-2 vaccines now authorized for adolescents and expected in a few months for younger children, large local AEFI reactions related to pediatric SARS-CoV-2 vaccines are expected, given that “COVID arm” is now well described in adults.4 Overall, ELS/large local reactions have been reported more frequently with the Moderna than Pfizer mRNA vaccine.4 In the almost 42% of adults having ELS post first dose, repeat ELS post second dose often appears sooner but also resolves more quickly, with no known sequelae.5
Some biopsies have shown delayed-type hypersensitivity reactions (DTH) (superficial perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells),6,7 while others show no DTH but these patients have findings of immediate hypersensitivity findings and negative skin testing to the vaccine.8 With regard to sex, Dutch ELS data in White adults reveal 90% occur in females – higher than the 75% female rate after standard vaccines.7 Onset of ELS data show that Pfizer mRNA vaccinees had onset on average at 38 hours (range, <1 hr to 12 days). Boston data mostly in White adults reveal later onset (median, 6 days; range, 2-12 days).4 In contrast, adults of color appear to have later onset (mean, 8 days; range, 4-14 days).9
In addition to the local swelling, patients had concurrent injection-site AEFIs of pain (65%), warmth (63%), and pruritus (26%), plus myalgia (51%), headache (48%), malaise (45%), fatigue (43%), chills (33%), arthralgia (30%), and fever (28%).7
What should we tell families about pediatric ELS before we give SARS-CoV-2 vaccines to children? Clinical pediatric SARS-CoV-2 vaccine trials are smaller “immunologic bridging” studies, not requiring proof of efficacy. So, the precise incidence of pediatric ELS (adult rate is estimated under 1/100,000) may not be known until months after general use. Nevertheless, part of our counseling of families will need to include ELS/large local reactions. Unless new data show otherwise, the spiel that clinicians have developed to counsel about the rare chance of ELS after routine vaccines should also be useful to inform families of the rare chance of ELS post SARS-CoV-2 vaccine.
The bottom line is that the management of pediatric ELS after SARS-CoV-2 vaccines should be the same as after standard vaccines. And remember, whether the reactions are DTH or not, neither immediate local injection-site reactions nor DTH reactions are contraindications to subsequent vaccination unless anaphylaxis or Arthus reaction is suspected.10,11
Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].
References
1. Woo EJ and the Vaccine Adverse Event Reporting System Working Group. Clin Infect Dis 2003;37:351-8.
2. Rennels MB et al. Pediatrics 2000;105:e12.
3. Huber BM, Goetschel P. J Pediatr. 2011;158:1033.
4. Blumenthal KG et al. N Engl J Med. 2021;384:1273-7.
5. McMahon DE et al. J Amer Acad Dermatol. 2021;85(1):46-55. 6. Johnston MS et al. JAMA Dermatol. 2021;157(6):716-20 .
7. ELS associated with the administration of Comirnaty®. WHO database Vigilyze (cited 2021 Feb 22). Available from https://vigilyze.who-umc.org/.
8. Baeck M et al. N Engl J Med. 2021 Jun. doi: 10.1056/NEJMc2104751.
9. Samarakoon U et al. N Eng J Med. 2021 Jun 9. doi: 10.1056/NEJMc2108620.
10. Kelso JM et al. J Allergy Clin Immunol. 2012;130:25-43.
11. Zafack JG et al. Pediatrics. 2017;140(3):e20163707.
Back-to-school threat: Missed vaccinations in children, teens
U.S. children and adolescents may be at higher risk for vaccine-preventable diseases this fall as vaccination levels have not caught up with prepandemic coverage, according to a study published in Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention.
“Pediatric outbreaks of vaccine-preventable diseases have the potential to derail efforts to reopen schools for the 2021-22 academic year and further delay nationwide efforts to return students to the classroom,” wrote Bhavini Patel Murthy, MD, with the immunization services division, National Center for Immunization and Respiratory Diseases, and colleagues.
The number of children getting routine vaccinations plummeted between March and May 2020, compared with the same months in 2019. Although vaccination rates increased again from June 2020 to September 2020, the rebound was not enough to reach prepandemic levels, according to the study.
At the beginning of the June–September 2020 period, the news was good, the authors wrote. After most stay-at-home orders were lifted, the number of weekly routine pediatric vaccinations started to approach, and even surpass, baseline prepandemic levels in most of the 10 jurisdictions studied.
“However,” the authors wrote, “across all age groups and across all vaccine types, none of the jurisdictions demonstrated a sustained or prolonged increase in the number of weekly doses administered above prepandemic administration levels, which would have been necessary to catch up children and adolescents who missed routine vaccinations.”
To overcome the gap, the authors said that clinicians should take the initiative. “Health care providers should assess the vaccination status of all pediatric patients, including adolescents, and contact those who are behind schedule to ensure that all children are fully vaccinated.”
As COVID-19 vaccinations become more readily available to children, the CDC recommends that providers consider giving COVID-19 shots along with other routinely recommended vaccines.
Martha Perry, MD, associate professor and medical director at the University of North Carolina Children’s Primary Care Clinic, Chapel Hill, said in an interview that getting the message out about the need to get children and adolescents caught up may require a national messaging campaign similar to that for COVID-19 vaccinations, as well as opening mass vaccination sites rather than families seeking vaccinations from individual providers.
She noted that, although schools may offer a checks and balances system for required vaccinations, children who are not yet school age depend on families getting individual appointments.
Size of the gaps
The MMWR article shows that the shortfall in vaccinations in June–September 2020, compared with those months the year before are striking.
For children younger than 2 years old and aged 2-6 years, diphtheria, tetanus, and acellular pertussis (DtaP) vaccinations declined an average of 9.1% and 6.7%, respectively.
Among children aged 12-23 months and 2-8 years, MMR vaccinations decreased 8.8% and 11.3%, respectively.
Among children aged 9-12 years and adolescents 13-17 years, human papillomavirus vaccinations decreased an average 12.2% and 28.1%, respectively. Among the same age groups, Tdap vaccinations dropped 21.3% and 30.0%, respectively.
Dr. Perry said that, although all the shortfalls are important, lags in vaccinations for measles and pertussis are particularly alarming in light of outbreaks in recent years.
Additionally, she said, as COVID-19 restrictions are lifting, some of the mitigation strategies, such as mask wearing, that kept other diseases at bay will not be in place, heightening the risk for infection.
The authors chose to measure weekly doses in March–May 2020, and June–September 2020 because many jurisdictions imposed and then lifted stay-at-home orders during these times. They analyzed data from 10 jurisdictions with high-performing information systems (Idaho, Iowa, Louisiana, Michigan, Minnesota, New York City, North Dakota, Oregon, Washington, and Wisconsin).
Adults missing vaccinations as well
Another analysis, commissioned by GlaxoSmithKline and conducted by Avalere Health, calculated 8.8 million missed adolescent vaccine doses and 17.2 million missed adult vaccine doses as a result of the pandemic and ongoing government restrictions and public health measures.
That study examined claims for CDC-recommended vaccines across commercial, managed Medicaid, Medicare Advantage, and Medicare fee-for-service Part B for January–November 2020, compared with the same period in 2019.
It also found that vaccine claims remain well below 2019 levels. Total noninfluenza vaccine claims submissions were down by between 13% and 35% among adolescents and 17% and 40% among adults, compared with the same period in 2019.
Dr. Perry said it will be critical for schools across the nation to enforce their policies on requiring up-to-date vaccinations even if online attendance is offered.
The workforce needed for this will be challenging, she noted.
“We’ve lost a lot of workforce in the health care field in the pandemic for a variety of reasons and it may be challenging to fill those positions,” she said.
She also said the study underlines the importance of each state having a vaccine registry so each provider can determine what vaccinations a child needs.
The study authors and Dr. Perry reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
U.S. children and adolescents may be at higher risk for vaccine-preventable diseases this fall as vaccination levels have not caught up with prepandemic coverage, according to a study published in Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention.
“Pediatric outbreaks of vaccine-preventable diseases have the potential to derail efforts to reopen schools for the 2021-22 academic year and further delay nationwide efforts to return students to the classroom,” wrote Bhavini Patel Murthy, MD, with the immunization services division, National Center for Immunization and Respiratory Diseases, and colleagues.
The number of children getting routine vaccinations plummeted between March and May 2020, compared with the same months in 2019. Although vaccination rates increased again from June 2020 to September 2020, the rebound was not enough to reach prepandemic levels, according to the study.
At the beginning of the June–September 2020 period, the news was good, the authors wrote. After most stay-at-home orders were lifted, the number of weekly routine pediatric vaccinations started to approach, and even surpass, baseline prepandemic levels in most of the 10 jurisdictions studied.
“However,” the authors wrote, “across all age groups and across all vaccine types, none of the jurisdictions demonstrated a sustained or prolonged increase in the number of weekly doses administered above prepandemic administration levels, which would have been necessary to catch up children and adolescents who missed routine vaccinations.”
To overcome the gap, the authors said that clinicians should take the initiative. “Health care providers should assess the vaccination status of all pediatric patients, including adolescents, and contact those who are behind schedule to ensure that all children are fully vaccinated.”
As COVID-19 vaccinations become more readily available to children, the CDC recommends that providers consider giving COVID-19 shots along with other routinely recommended vaccines.
Martha Perry, MD, associate professor and medical director at the University of North Carolina Children’s Primary Care Clinic, Chapel Hill, said in an interview that getting the message out about the need to get children and adolescents caught up may require a national messaging campaign similar to that for COVID-19 vaccinations, as well as opening mass vaccination sites rather than families seeking vaccinations from individual providers.
She noted that, although schools may offer a checks and balances system for required vaccinations, children who are not yet school age depend on families getting individual appointments.
Size of the gaps
The MMWR article shows that the shortfall in vaccinations in June–September 2020, compared with those months the year before are striking.
For children younger than 2 years old and aged 2-6 years, diphtheria, tetanus, and acellular pertussis (DtaP) vaccinations declined an average of 9.1% and 6.7%, respectively.
Among children aged 12-23 months and 2-8 years, MMR vaccinations decreased 8.8% and 11.3%, respectively.
Among children aged 9-12 years and adolescents 13-17 years, human papillomavirus vaccinations decreased an average 12.2% and 28.1%, respectively. Among the same age groups, Tdap vaccinations dropped 21.3% and 30.0%, respectively.
Dr. Perry said that, although all the shortfalls are important, lags in vaccinations for measles and pertussis are particularly alarming in light of outbreaks in recent years.
Additionally, she said, as COVID-19 restrictions are lifting, some of the mitigation strategies, such as mask wearing, that kept other diseases at bay will not be in place, heightening the risk for infection.
The authors chose to measure weekly doses in March–May 2020, and June–September 2020 because many jurisdictions imposed and then lifted stay-at-home orders during these times. They analyzed data from 10 jurisdictions with high-performing information systems (Idaho, Iowa, Louisiana, Michigan, Minnesota, New York City, North Dakota, Oregon, Washington, and Wisconsin).
Adults missing vaccinations as well
Another analysis, commissioned by GlaxoSmithKline and conducted by Avalere Health, calculated 8.8 million missed adolescent vaccine doses and 17.2 million missed adult vaccine doses as a result of the pandemic and ongoing government restrictions and public health measures.
That study examined claims for CDC-recommended vaccines across commercial, managed Medicaid, Medicare Advantage, and Medicare fee-for-service Part B for January–November 2020, compared with the same period in 2019.
It also found that vaccine claims remain well below 2019 levels. Total noninfluenza vaccine claims submissions were down by between 13% and 35% among adolescents and 17% and 40% among adults, compared with the same period in 2019.
Dr. Perry said it will be critical for schools across the nation to enforce their policies on requiring up-to-date vaccinations even if online attendance is offered.
The workforce needed for this will be challenging, she noted.
“We’ve lost a lot of workforce in the health care field in the pandemic for a variety of reasons and it may be challenging to fill those positions,” she said.
She also said the study underlines the importance of each state having a vaccine registry so each provider can determine what vaccinations a child needs.
The study authors and Dr. Perry reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
U.S. children and adolescents may be at higher risk for vaccine-preventable diseases this fall as vaccination levels have not caught up with prepandemic coverage, according to a study published in Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention.
“Pediatric outbreaks of vaccine-preventable diseases have the potential to derail efforts to reopen schools for the 2021-22 academic year and further delay nationwide efforts to return students to the classroom,” wrote Bhavini Patel Murthy, MD, with the immunization services division, National Center for Immunization and Respiratory Diseases, and colleagues.
The number of children getting routine vaccinations plummeted between March and May 2020, compared with the same months in 2019. Although vaccination rates increased again from June 2020 to September 2020, the rebound was not enough to reach prepandemic levels, according to the study.
At the beginning of the June–September 2020 period, the news was good, the authors wrote. After most stay-at-home orders were lifted, the number of weekly routine pediatric vaccinations started to approach, and even surpass, baseline prepandemic levels in most of the 10 jurisdictions studied.
“However,” the authors wrote, “across all age groups and across all vaccine types, none of the jurisdictions demonstrated a sustained or prolonged increase in the number of weekly doses administered above prepandemic administration levels, which would have been necessary to catch up children and adolescents who missed routine vaccinations.”
To overcome the gap, the authors said that clinicians should take the initiative. “Health care providers should assess the vaccination status of all pediatric patients, including adolescents, and contact those who are behind schedule to ensure that all children are fully vaccinated.”
As COVID-19 vaccinations become more readily available to children, the CDC recommends that providers consider giving COVID-19 shots along with other routinely recommended vaccines.
Martha Perry, MD, associate professor and medical director at the University of North Carolina Children’s Primary Care Clinic, Chapel Hill, said in an interview that getting the message out about the need to get children and adolescents caught up may require a national messaging campaign similar to that for COVID-19 vaccinations, as well as opening mass vaccination sites rather than families seeking vaccinations from individual providers.
She noted that, although schools may offer a checks and balances system for required vaccinations, children who are not yet school age depend on families getting individual appointments.
Size of the gaps
The MMWR article shows that the shortfall in vaccinations in June–September 2020, compared with those months the year before are striking.
For children younger than 2 years old and aged 2-6 years, diphtheria, tetanus, and acellular pertussis (DtaP) vaccinations declined an average of 9.1% and 6.7%, respectively.
Among children aged 12-23 months and 2-8 years, MMR vaccinations decreased 8.8% and 11.3%, respectively.
Among children aged 9-12 years and adolescents 13-17 years, human papillomavirus vaccinations decreased an average 12.2% and 28.1%, respectively. Among the same age groups, Tdap vaccinations dropped 21.3% and 30.0%, respectively.
Dr. Perry said that, although all the shortfalls are important, lags in vaccinations for measles and pertussis are particularly alarming in light of outbreaks in recent years.
Additionally, she said, as COVID-19 restrictions are lifting, some of the mitigation strategies, such as mask wearing, that kept other diseases at bay will not be in place, heightening the risk for infection.
The authors chose to measure weekly doses in March–May 2020, and June–September 2020 because many jurisdictions imposed and then lifted stay-at-home orders during these times. They analyzed data from 10 jurisdictions with high-performing information systems (Idaho, Iowa, Louisiana, Michigan, Minnesota, New York City, North Dakota, Oregon, Washington, and Wisconsin).
Adults missing vaccinations as well
Another analysis, commissioned by GlaxoSmithKline and conducted by Avalere Health, calculated 8.8 million missed adolescent vaccine doses and 17.2 million missed adult vaccine doses as a result of the pandemic and ongoing government restrictions and public health measures.
That study examined claims for CDC-recommended vaccines across commercial, managed Medicaid, Medicare Advantage, and Medicare fee-for-service Part B for January–November 2020, compared with the same period in 2019.
It also found that vaccine claims remain well below 2019 levels. Total noninfluenza vaccine claims submissions were down by between 13% and 35% among adolescents and 17% and 40% among adults, compared with the same period in 2019.
Dr. Perry said it will be critical for schools across the nation to enforce their policies on requiring up-to-date vaccinations even if online attendance is offered.
The workforce needed for this will be challenging, she noted.
“We’ve lost a lot of workforce in the health care field in the pandemic for a variety of reasons and it may be challenging to fill those positions,” she said.
She also said the study underlines the importance of each state having a vaccine registry so each provider can determine what vaccinations a child needs.
The study authors and Dr. Perry reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Third COVID-19 vaccine dose helped some transplant recipients
All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.
Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.
The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
Third dose results
In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.
Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.
Two of the participants had low-positive titers, and 16 were negative.
“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.
“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.
Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.
“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”
Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
Welcome news, but larger studies needed
“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”
He added, “We just want studies to confirm that – larger studies.”
Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.
Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.
“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving. For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”
He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.
“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.
“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses. This will allow primary care clinicians to tackle their many complex jobs.”
Possible solutions for those with low antibody responses
Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.
“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”
Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.
“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
Participant details
None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.
Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.
Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.
All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.
Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.
The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
Third dose results
In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.
Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.
Two of the participants had low-positive titers, and 16 were negative.
“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.
“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.
Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.
“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”
Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
Welcome news, but larger studies needed
“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”
He added, “We just want studies to confirm that – larger studies.”
Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.
Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.
“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving. For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”
He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.
“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.
“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses. This will allow primary care clinicians to tackle their many complex jobs.”
Possible solutions for those with low antibody responses
Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.
“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”
Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.
“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
Participant details
None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.
Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.
Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.
All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.
Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.
The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
Third dose results
In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.
Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.
Two of the participants had low-positive titers, and 16 were negative.
“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.
“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.
Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.
“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”
Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
Welcome news, but larger studies needed
“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”
He added, “We just want studies to confirm that – larger studies.”
Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.
Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.
“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving. For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”
He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.
“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.
“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses. This will allow primary care clinicians to tackle their many complex jobs.”
Possible solutions for those with low antibody responses
Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.
“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”
Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.
“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
Participant details
None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.
Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.
Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.
More evidence links COVID vaccines to rare cases of myocarditis in youth
a Centers for Disease Control and Prevention expert reported on June 10, detailing data on cases of myocarditis and pericarditis detected through a government safety system.
The side effect seems to be more common in teen boys and young men than in older adults and women and may occur in 16 cases for every 1 million people who got a second dose, said Tom Shimabukuro, MD, MPH, deputy director of the CDC’s Immunization Safety Office, who presented information on the cases at a meeting of an expert panel that advises the U.S. Food and Drug Administration on vaccines.
Telltale symptoms include chest pain, shortness of breath, and fever.
William Schaffner, MD, an infectious diseases specialist from Vanderbilt University, Nashville, Tenn., thinks certain characteristics are pointing toward a “rare, but real” signal. First, the events are clustering, occurring within days of vaccination. Second, they tend to be more common in males and younger people. Third, he says, the number of events is above the so-called “background rate” – the cases that could be expected in this age group even without vaccination.
“I don’t think we’re quite there yet. We haven’t tied a ribbon around it, but I think the data are trending in that direction,” he said.
The issue of myocarditis weighed heavily on the Vaccines and Related Biological Products Advisory Committee’s considerations of what kind and how much data might be needed to green light use of a vaccine for COVID in children.
Because the rates of hospitalization for COVID are low in kids, some felt that the FDA should require at least a year of study of the vaccines in clinical trials, the amount of data typically required for full approval, instead of the 2 months currently required for emergency use authorization. Others wondered whether the risks of vaccination – as low as they are – might outweigh the benefits in this age group.
“I don’t really see this as an emergency in children,” said committee member Michael Kurilla, MD, PhD, the director of clinical innovation at the National Institutes of Health. Dr. Kurilla, however, did say he thought having an expanded access program for children at high risk might make sense.
Most of the young adults who experienced myocarditis recovered quickly, though three needed intensive care and rehabilitation after their episodes. Among cases with known outcomes, 81% got better and 19% still have ongoing symptoms.
Adverse events reports
The data on myocarditis come from the Vaccine Adverse Events Reporting System, or VAERS, a database of health problems reported after vaccination. This reporting system, open to anyone, has benefits and limits. It gives the CDC and FDA the ability to rapidly detect potential safety issues, and it is large enough that it can detect rare events, something that’s beyond the power of even large clinical trials.
But it is observational, so that there’s no way to know if problems reported were caused by the vaccines or a coincidence.
But because VAERS works on an honor system, it can also be spammed, and it carries the bias of the person who’s doing the reporting, from clinicians to average patients. For that reason, Dr. Shimabukuro said they are actively investigating and confirming each report they get.
Out of more than 12 million doses administered to youth ages 16-24, the CDC says it has 275 reports of heart inflammation following vaccination in this age group. The CDC has analyzed a total 475 cases of myocarditis after vaccination in people under age 30 that were reported to VAERS.
The vaccines linked to the events are the mRNA vaccines made by Pfizer and Moderna. The only vaccines currently authorized for use in adolescents are made by Pfizer. Because the Pfizer vaccine was authorized for use in kids as young as 12 last month, there’s not yet enough data to draw conclusions about the risk of myocarditis in kids ages 12-15.
Younger age groups have only received about 9% of the total doses of the vaccine so far, but they represent about 50% of the myocarditis cases reported after vaccination. “We clearly have an imbalance there,” Dr. Shimabukuro said.
The number of events in this age group appears to be above the rate that would be expected for these age groups without vaccines in the picture, he said, explaining that the number of events are in line with similar adverse events seen in young people in Israel and reported by the Department of Defense. Israel found the incidence of myocarditis after vaccination was 50 cases per million for men ages 18-30.
More study needed
Another system tracking adverse events through hospitals, the Vaccine Safety Datalink, didn’t show reports of heart inflammation above numbers that are normally seen in the population, but it did show that inflammation was more likely after a second dose of the vaccine.
“Should this be included in informed consent?” asked Cody Meissner, MD, a pediatric infectious disease specialist at Tufts University, Boston, and a member of the FDA committee.
“I think it’s hard to deny there seem to be some [events that seem] to be occurring in terms of myocarditis,” he said.
Dr. Meissner said later in the committee’s discussion that his own hospital had recently admitted a 12-year-old boy who developed heart swelling 2 days after the second dose of vaccine with a high level of troponin, an enzyme that indicates damage to the heart. His level was over 9. “A very high level,” Dr. Meissner said.
“Will there be scarring to the myocardium? Will there be a predisposition to arrhythmias later on? Will there be an early onset of heart failure? We think that’s unlikely, but [we] don’t know that,” he said.
The CDC has scheduled an emergency meeting next week to convene an expert panel on immunization practices to further review the events.
In addition to the information presented at the FDA’s meeting, doctors at Oregon Health & Science University, Portland, recently described seven cases in teens – all boys – who developed heart inflammation within 4 days of getting the second dose of the Pfizer vaccine.
The study was published June 10 in Pediatrics. All the boys were hospitalized and treated with anti-inflammatory medications including NSAIDs and steroids. Most were discharged within a few days and all recovered from their symptoms.
A version of this article first appeared on Medscape.com.
a Centers for Disease Control and Prevention expert reported on June 10, detailing data on cases of myocarditis and pericarditis detected through a government safety system.
The side effect seems to be more common in teen boys and young men than in older adults and women and may occur in 16 cases for every 1 million people who got a second dose, said Tom Shimabukuro, MD, MPH, deputy director of the CDC’s Immunization Safety Office, who presented information on the cases at a meeting of an expert panel that advises the U.S. Food and Drug Administration on vaccines.
Telltale symptoms include chest pain, shortness of breath, and fever.
William Schaffner, MD, an infectious diseases specialist from Vanderbilt University, Nashville, Tenn., thinks certain characteristics are pointing toward a “rare, but real” signal. First, the events are clustering, occurring within days of vaccination. Second, they tend to be more common in males and younger people. Third, he says, the number of events is above the so-called “background rate” – the cases that could be expected in this age group even without vaccination.
“I don’t think we’re quite there yet. We haven’t tied a ribbon around it, but I think the data are trending in that direction,” he said.
The issue of myocarditis weighed heavily on the Vaccines and Related Biological Products Advisory Committee’s considerations of what kind and how much data might be needed to green light use of a vaccine for COVID in children.
Because the rates of hospitalization for COVID are low in kids, some felt that the FDA should require at least a year of study of the vaccines in clinical trials, the amount of data typically required for full approval, instead of the 2 months currently required for emergency use authorization. Others wondered whether the risks of vaccination – as low as they are – might outweigh the benefits in this age group.
“I don’t really see this as an emergency in children,” said committee member Michael Kurilla, MD, PhD, the director of clinical innovation at the National Institutes of Health. Dr. Kurilla, however, did say he thought having an expanded access program for children at high risk might make sense.
Most of the young adults who experienced myocarditis recovered quickly, though three needed intensive care and rehabilitation after their episodes. Among cases with known outcomes, 81% got better and 19% still have ongoing symptoms.
Adverse events reports
The data on myocarditis come from the Vaccine Adverse Events Reporting System, or VAERS, a database of health problems reported after vaccination. This reporting system, open to anyone, has benefits and limits. It gives the CDC and FDA the ability to rapidly detect potential safety issues, and it is large enough that it can detect rare events, something that’s beyond the power of even large clinical trials.
But it is observational, so that there’s no way to know if problems reported were caused by the vaccines or a coincidence.
But because VAERS works on an honor system, it can also be spammed, and it carries the bias of the person who’s doing the reporting, from clinicians to average patients. For that reason, Dr. Shimabukuro said they are actively investigating and confirming each report they get.
Out of more than 12 million doses administered to youth ages 16-24, the CDC says it has 275 reports of heart inflammation following vaccination in this age group. The CDC has analyzed a total 475 cases of myocarditis after vaccination in people under age 30 that were reported to VAERS.
The vaccines linked to the events are the mRNA vaccines made by Pfizer and Moderna. The only vaccines currently authorized for use in adolescents are made by Pfizer. Because the Pfizer vaccine was authorized for use in kids as young as 12 last month, there’s not yet enough data to draw conclusions about the risk of myocarditis in kids ages 12-15.
Younger age groups have only received about 9% of the total doses of the vaccine so far, but they represent about 50% of the myocarditis cases reported after vaccination. “We clearly have an imbalance there,” Dr. Shimabukuro said.
The number of events in this age group appears to be above the rate that would be expected for these age groups without vaccines in the picture, he said, explaining that the number of events are in line with similar adverse events seen in young people in Israel and reported by the Department of Defense. Israel found the incidence of myocarditis after vaccination was 50 cases per million for men ages 18-30.
More study needed
Another system tracking adverse events through hospitals, the Vaccine Safety Datalink, didn’t show reports of heart inflammation above numbers that are normally seen in the population, but it did show that inflammation was more likely after a second dose of the vaccine.
“Should this be included in informed consent?” asked Cody Meissner, MD, a pediatric infectious disease specialist at Tufts University, Boston, and a member of the FDA committee.
“I think it’s hard to deny there seem to be some [events that seem] to be occurring in terms of myocarditis,” he said.
Dr. Meissner said later in the committee’s discussion that his own hospital had recently admitted a 12-year-old boy who developed heart swelling 2 days after the second dose of vaccine with a high level of troponin, an enzyme that indicates damage to the heart. His level was over 9. “A very high level,” Dr. Meissner said.
“Will there be scarring to the myocardium? Will there be a predisposition to arrhythmias later on? Will there be an early onset of heart failure? We think that’s unlikely, but [we] don’t know that,” he said.
The CDC has scheduled an emergency meeting next week to convene an expert panel on immunization practices to further review the events.
In addition to the information presented at the FDA’s meeting, doctors at Oregon Health & Science University, Portland, recently described seven cases in teens – all boys – who developed heart inflammation within 4 days of getting the second dose of the Pfizer vaccine.
The study was published June 10 in Pediatrics. All the boys were hospitalized and treated with anti-inflammatory medications including NSAIDs and steroids. Most were discharged within a few days and all recovered from their symptoms.
A version of this article first appeared on Medscape.com.
a Centers for Disease Control and Prevention expert reported on June 10, detailing data on cases of myocarditis and pericarditis detected through a government safety system.
The side effect seems to be more common in teen boys and young men than in older adults and women and may occur in 16 cases for every 1 million people who got a second dose, said Tom Shimabukuro, MD, MPH, deputy director of the CDC’s Immunization Safety Office, who presented information on the cases at a meeting of an expert panel that advises the U.S. Food and Drug Administration on vaccines.
Telltale symptoms include chest pain, shortness of breath, and fever.
William Schaffner, MD, an infectious diseases specialist from Vanderbilt University, Nashville, Tenn., thinks certain characteristics are pointing toward a “rare, but real” signal. First, the events are clustering, occurring within days of vaccination. Second, they tend to be more common in males and younger people. Third, he says, the number of events is above the so-called “background rate” – the cases that could be expected in this age group even without vaccination.
“I don’t think we’re quite there yet. We haven’t tied a ribbon around it, but I think the data are trending in that direction,” he said.
The issue of myocarditis weighed heavily on the Vaccines and Related Biological Products Advisory Committee’s considerations of what kind and how much data might be needed to green light use of a vaccine for COVID in children.
Because the rates of hospitalization for COVID are low in kids, some felt that the FDA should require at least a year of study of the vaccines in clinical trials, the amount of data typically required for full approval, instead of the 2 months currently required for emergency use authorization. Others wondered whether the risks of vaccination – as low as they are – might outweigh the benefits in this age group.
“I don’t really see this as an emergency in children,” said committee member Michael Kurilla, MD, PhD, the director of clinical innovation at the National Institutes of Health. Dr. Kurilla, however, did say he thought having an expanded access program for children at high risk might make sense.
Most of the young adults who experienced myocarditis recovered quickly, though three needed intensive care and rehabilitation after their episodes. Among cases with known outcomes, 81% got better and 19% still have ongoing symptoms.
Adverse events reports
The data on myocarditis come from the Vaccine Adverse Events Reporting System, or VAERS, a database of health problems reported after vaccination. This reporting system, open to anyone, has benefits and limits. It gives the CDC and FDA the ability to rapidly detect potential safety issues, and it is large enough that it can detect rare events, something that’s beyond the power of even large clinical trials.
But it is observational, so that there’s no way to know if problems reported were caused by the vaccines or a coincidence.
But because VAERS works on an honor system, it can also be spammed, and it carries the bias of the person who’s doing the reporting, from clinicians to average patients. For that reason, Dr. Shimabukuro said they are actively investigating and confirming each report they get.
Out of more than 12 million doses administered to youth ages 16-24, the CDC says it has 275 reports of heart inflammation following vaccination in this age group. The CDC has analyzed a total 475 cases of myocarditis after vaccination in people under age 30 that were reported to VAERS.
The vaccines linked to the events are the mRNA vaccines made by Pfizer and Moderna. The only vaccines currently authorized for use in adolescents are made by Pfizer. Because the Pfizer vaccine was authorized for use in kids as young as 12 last month, there’s not yet enough data to draw conclusions about the risk of myocarditis in kids ages 12-15.
Younger age groups have only received about 9% of the total doses of the vaccine so far, but they represent about 50% of the myocarditis cases reported after vaccination. “We clearly have an imbalance there,” Dr. Shimabukuro said.
The number of events in this age group appears to be above the rate that would be expected for these age groups without vaccines in the picture, he said, explaining that the number of events are in line with similar adverse events seen in young people in Israel and reported by the Department of Defense. Israel found the incidence of myocarditis after vaccination was 50 cases per million for men ages 18-30.
More study needed
Another system tracking adverse events through hospitals, the Vaccine Safety Datalink, didn’t show reports of heart inflammation above numbers that are normally seen in the population, but it did show that inflammation was more likely after a second dose of the vaccine.
“Should this be included in informed consent?” asked Cody Meissner, MD, a pediatric infectious disease specialist at Tufts University, Boston, and a member of the FDA committee.
“I think it’s hard to deny there seem to be some [events that seem] to be occurring in terms of myocarditis,” he said.
Dr. Meissner said later in the committee’s discussion that his own hospital had recently admitted a 12-year-old boy who developed heart swelling 2 days after the second dose of vaccine with a high level of troponin, an enzyme that indicates damage to the heart. His level was over 9. “A very high level,” Dr. Meissner said.
“Will there be scarring to the myocardium? Will there be a predisposition to arrhythmias later on? Will there be an early onset of heart failure? We think that’s unlikely, but [we] don’t know that,” he said.
The CDC has scheduled an emergency meeting next week to convene an expert panel on immunization practices to further review the events.
In addition to the information presented at the FDA’s meeting, doctors at Oregon Health & Science University, Portland, recently described seven cases in teens – all boys – who developed heart inflammation within 4 days of getting the second dose of the Pfizer vaccine.
The study was published June 10 in Pediatrics. All the boys were hospitalized and treated with anti-inflammatory medications including NSAIDs and steroids. Most were discharged within a few days and all recovered from their symptoms.
A version of this article first appeared on Medscape.com.