Infectious Disease Practitioner

The COVID-19 pandemic has meant delays in cancer screening, diagnosis, and treatment — and a new study shows just how deadly delaying cancer treatment can be.

The study found evidence that longer time to starting treatment after diagnosis was generally associated with higher mortality across several common cancers, most notably for colon and early-stage lung cancer.

“There is a limit to how long we can safely defer treatment for cancer therapies, pandemic or not, which may be shorter than we think,” lead author Eugene Cone, MD, Combined Harvard Program in Urologic Oncology, Massachusetts General Hospital and Brigham & Women’s Hospital, Boston, told Medscape Medical News.

“When you consider that cancer screening may have been delayed during the pandemic, which would further increase the period between developing a disease and getting therapy, timely treatment for cancer has never been more important,” Cone added.

The study was published online December 14 in JAMA Network Open.
 

The sooner the better

Using the National Cancer Database, Cone and colleagues identified roughly 2.24 million patients diagnosed with nonmetastatic breast (52%), prostate (38%), colon (4%) and non-small cell lung cancer (NSCLC, 6%) between 2004 and 2015. Treatment and outcome data were analyzed from January to March 2020.

The time-to-treatment initiation (TTI) – the interval between cancer diagnosis and receipt of curative-intent therapy – was categorized as 8 to 60 days (reference), 61 to 120 days, 121 to 180 days, and 181 to 365 days. Median TTI was 32 days for breast, 79 days for prostate, 41 days for NSCLC, and 26 days for colon cancer.

All four cancers benefitted to some degree from a short interval between diagnosis and therapy, the researchers found.

Across all four cancers, increasing TTI was generally associated with higher predicted mortality at 5 and 10 years, although the degree varied by cancer type and stage. The most pronounced association between increasing TTI and mortality was observed for colon and lung cancer.

For example, for stage III colon cancer, 5- and 10-year predicted mortality was 38.9% and 54%, respectively, with TTI of 61 to 120 days, and increased to 47.8% and 63.8%, respectively, with TTI of 181 to 365 days.

Each additional 60-day delay was associated with a 3.2% to 6% increase in 5-year mortality for stage III colon cancer and a 0.9% to 4.6% increase for stage I colon cancer, with a longer 10-year time horizon showing larger effect sizes with increasing TTI.

For stage I NSCLC, 5- and 10-year predicted mortality was 47.4% and 72.6%, respectively, with TTI of 61 to 120 days compared with 47.6% and 72.8%, respectively, with TTI of 181 to 365 days.  

For stage I NSCLC, there was a 4% to 6.2% absolute increase in 5-year mortality for increased TTI groups compared with the 8- to 60-day reference group, with larger effect sizes on 10-year mortality. The data precluded conclusions about stage II NSCLC.

“For prostate cancer, deferral of treatment by even a few months was associated with a significant impact on mortality,” Cone told Medscape Medical News.

For high-risk prostate cancer, 5- and 10-year predicted mortality was 12.8% and 31.2%, respectively, with TTI of 61-120 days increasing to 14.1% and 33.8%, respectively with TTI at 181-365 days.

For intermediate-risk prostate cancer, 5- and 10-year predicted mortality was 7.4% and 20.4% with TTI of 61-120 days vs 8.3% and 22.6% with TTI at 181-365 days.

The data show all-cause mortality differences of 2.2% at 5 years and 4.6% at 10 years between high-risk prostate cancer patients who were treated expeditiously vs those waiting 4 to 6 months and differences of 0.9% at 5 years and 2.4% at 10 years for similar intermediate-risk patients.
 

No surprises

Turning to breast cancer, increased TTI was associated with the most negative survival effects for stage II and III breast cancer.

For stage II breast cancer, for example, 5- and 10-year predicted mortality was 17.7% and 30.5%, respectively, with TTI of 61-120 days vs 21.7% and 36.5% with TTI at 181-365 days. 

Even for stage I breast cancer patients, there were significant differences in all-cause mortality with delayed definitive therapy, although the effect size is clinically small, the researchers report.

Patients with stage IA or IB breast cancer who were not treated until 61 to 120 days after diagnosis had 1.3% and 2.3% increased mortality at 5 years and 10 years, respectively, and those waiting longer suffered even greater increases in mortality. “As such, our analysis underscores the importance of timely definitive treatment, even for stage I breast cancer,” the authors write.

Charles Shapiro, MD, director of translational breast cancer research for the Mount Sinai Health System, New York City, was not surprised by the data.

The observation that delays in initiating cancer treatment are associated with worse survival is “not new, as delays in primary surgical treatments and chemotherapy for early-stage disease is an adverse prognostic factor for clinical outcomes,” Shapiro told Medscape Medical News.

“The bottom line is primary surgery and the start of chemotherapy should probably occur as soon as clinically feasible,” said Shapiro, who was not involved in the study.

The authors of an accompanying editorial agree. 

This study supports avoiding unnecessary treatment delays and prioritizing timely cancer care, even during the COVID-19 pandemic, write Laura Van Metre Baum, MD, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee, and colleagues.

They note, however, that primary care, “the most important conduit for cancer screening and initial evaluation of new symptoms, has been the hardest hit economically and the most subject to profound disruption and restructuring during the current COVID-19 pandemic.

“In many centers, cancer care delivery has been disrupted and nonstandard therapies offered in an effort to minimize exposure of this high-risk group to the virus. The implications in appropriately balancing the urgency of cancer care and the threat of COVID-19 exposure in the pandemic are more complex,” the editorialists conclude.

Cone, Shapiro, and Van Metre Baum have disclosed no relevant financial relationships. This work won first prize in the Commission on Cancer 2020 Cancer Research Paper Competition and was virtually presented at the Commission on Cancer Plenary Session on October 30, 2020.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has meant delays in cancer screening, diagnosis, and treatment — and a new study shows just how deadly delaying cancer treatment can be.

The study found evidence that longer time to starting treatment after diagnosis was generally associated with higher mortality across several common cancers, most notably for colon and early-stage lung cancer.

“There is a limit to how long we can safely defer treatment for cancer therapies, pandemic or not, which may be shorter than we think,” lead author Eugene Cone, MD, Combined Harvard Program in Urologic Oncology, Massachusetts General Hospital and Brigham & Women’s Hospital, Boston, told Medscape Medical News.

“When you consider that cancer screening may have been delayed during the pandemic, which would further increase the period between developing a disease and getting therapy, timely treatment for cancer has never been more important,” Cone added.

The study was published online December 14 in JAMA Network Open.
 

The sooner the better

Using the National Cancer Database, Cone and colleagues identified roughly 2.24 million patients diagnosed with nonmetastatic breast (52%), prostate (38%), colon (4%) and non-small cell lung cancer (NSCLC, 6%) between 2004 and 2015. Treatment and outcome data were analyzed from January to March 2020.

The time-to-treatment initiation (TTI) – the interval between cancer diagnosis and receipt of curative-intent therapy – was categorized as 8 to 60 days (reference), 61 to 120 days, 121 to 180 days, and 181 to 365 days. Median TTI was 32 days for breast, 79 days for prostate, 41 days for NSCLC, and 26 days for colon cancer.

All four cancers benefitted to some degree from a short interval between diagnosis and therapy, the researchers found.

Across all four cancers, increasing TTI was generally associated with higher predicted mortality at 5 and 10 years, although the degree varied by cancer type and stage. The most pronounced association between increasing TTI and mortality was observed for colon and lung cancer.

For example, for stage III colon cancer, 5- and 10-year predicted mortality was 38.9% and 54%, respectively, with TTI of 61 to 120 days, and increased to 47.8% and 63.8%, respectively, with TTI of 181 to 365 days.

Each additional 60-day delay was associated with a 3.2% to 6% increase in 5-year mortality for stage III colon cancer and a 0.9% to 4.6% increase for stage I colon cancer, with a longer 10-year time horizon showing larger effect sizes with increasing TTI.

For stage I NSCLC, 5- and 10-year predicted mortality was 47.4% and 72.6%, respectively, with TTI of 61 to 120 days compared with 47.6% and 72.8%, respectively, with TTI of 181 to 365 days.  

For stage I NSCLC, there was a 4% to 6.2% absolute increase in 5-year mortality for increased TTI groups compared with the 8- to 60-day reference group, with larger effect sizes on 10-year mortality. The data precluded conclusions about stage II NSCLC.

“For prostate cancer, deferral of treatment by even a few months was associated with a significant impact on mortality,” Cone told Medscape Medical News.

For high-risk prostate cancer, 5- and 10-year predicted mortality was 12.8% and 31.2%, respectively, with TTI of 61-120 days increasing to 14.1% and 33.8%, respectively with TTI at 181-365 days.

For intermediate-risk prostate cancer, 5- and 10-year predicted mortality was 7.4% and 20.4% with TTI of 61-120 days vs 8.3% and 22.6% with TTI at 181-365 days.

The data show all-cause mortality differences of 2.2% at 5 years and 4.6% at 10 years between high-risk prostate cancer patients who were treated expeditiously vs those waiting 4 to 6 months and differences of 0.9% at 5 years and 2.4% at 10 years for similar intermediate-risk patients.
 

No surprises

Turning to breast cancer, increased TTI was associated with the most negative survival effects for stage II and III breast cancer.

For stage II breast cancer, for example, 5- and 10-year predicted mortality was 17.7% and 30.5%, respectively, with TTI of 61-120 days vs 21.7% and 36.5% with TTI at 181-365 days. 

Even for stage I breast cancer patients, there were significant differences in all-cause mortality with delayed definitive therapy, although the effect size is clinically small, the researchers report.

Patients with stage IA or IB breast cancer who were not treated until 61 to 120 days after diagnosis had 1.3% and 2.3% increased mortality at 5 years and 10 years, respectively, and those waiting longer suffered even greater increases in mortality. “As such, our analysis underscores the importance of timely definitive treatment, even for stage I breast cancer,” the authors write.

Charles Shapiro, MD, director of translational breast cancer research for the Mount Sinai Health System, New York City, was not surprised by the data.

The observation that delays in initiating cancer treatment are associated with worse survival is “not new, as delays in primary surgical treatments and chemotherapy for early-stage disease is an adverse prognostic factor for clinical outcomes,” Shapiro told Medscape Medical News.

“The bottom line is primary surgery and the start of chemotherapy should probably occur as soon as clinically feasible,” said Shapiro, who was not involved in the study.

The authors of an accompanying editorial agree. 

This study supports avoiding unnecessary treatment delays and prioritizing timely cancer care, even during the COVID-19 pandemic, write Laura Van Metre Baum, MD, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee, and colleagues.

They note, however, that primary care, “the most important conduit for cancer screening and initial evaluation of new symptoms, has been the hardest hit economically and the most subject to profound disruption and restructuring during the current COVID-19 pandemic.

“In many centers, cancer care delivery has been disrupted and nonstandard therapies offered in an effort to minimize exposure of this high-risk group to the virus. The implications in appropriately balancing the urgency of cancer care and the threat of COVID-19 exposure in the pandemic are more complex,” the editorialists conclude.

Cone, Shapiro, and Van Metre Baum have disclosed no relevant financial relationships. This work won first prize in the Commission on Cancer 2020 Cancer Research Paper Competition and was virtually presented at the Commission on Cancer Plenary Session on October 30, 2020.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has meant delays in cancer screening, diagnosis, and treatment — and a new study shows just how deadly delaying cancer treatment can be.

The study found evidence that longer time to starting treatment after diagnosis was generally associated with higher mortality across several common cancers, most notably for colon and early-stage lung cancer.

“There is a limit to how long we can safely defer treatment for cancer therapies, pandemic or not, which may be shorter than we think,” lead author Eugene Cone, MD, Combined Harvard Program in Urologic Oncology, Massachusetts General Hospital and Brigham & Women’s Hospital, Boston, told Medscape Medical News.

“When you consider that cancer screening may have been delayed during the pandemic, which would further increase the period between developing a disease and getting therapy, timely treatment for cancer has never been more important,” Cone added.

The study was published online December 14 in JAMA Network Open.
 

The sooner the better

Using the National Cancer Database, Cone and colleagues identified roughly 2.24 million patients diagnosed with nonmetastatic breast (52%), prostate (38%), colon (4%) and non-small cell lung cancer (NSCLC, 6%) between 2004 and 2015. Treatment and outcome data were analyzed from January to March 2020.

The time-to-treatment initiation (TTI) – the interval between cancer diagnosis and receipt of curative-intent therapy – was categorized as 8 to 60 days (reference), 61 to 120 days, 121 to 180 days, and 181 to 365 days. Median TTI was 32 days for breast, 79 days for prostate, 41 days for NSCLC, and 26 days for colon cancer.

All four cancers benefitted to some degree from a short interval between diagnosis and therapy, the researchers found.

Across all four cancers, increasing TTI was generally associated with higher predicted mortality at 5 and 10 years, although the degree varied by cancer type and stage. The most pronounced association between increasing TTI and mortality was observed for colon and lung cancer.

For example, for stage III colon cancer, 5- and 10-year predicted mortality was 38.9% and 54%, respectively, with TTI of 61 to 120 days, and increased to 47.8% and 63.8%, respectively, with TTI of 181 to 365 days.

Each additional 60-day delay was associated with a 3.2% to 6% increase in 5-year mortality for stage III colon cancer and a 0.9% to 4.6% increase for stage I colon cancer, with a longer 10-year time horizon showing larger effect sizes with increasing TTI.

For stage I NSCLC, 5- and 10-year predicted mortality was 47.4% and 72.6%, respectively, with TTI of 61 to 120 days compared with 47.6% and 72.8%, respectively, with TTI of 181 to 365 days.  

For stage I NSCLC, there was a 4% to 6.2% absolute increase in 5-year mortality for increased TTI groups compared with the 8- to 60-day reference group, with larger effect sizes on 10-year mortality. The data precluded conclusions about stage II NSCLC.

“For prostate cancer, deferral of treatment by even a few months was associated with a significant impact on mortality,” Cone told Medscape Medical News.

For high-risk prostate cancer, 5- and 10-year predicted mortality was 12.8% and 31.2%, respectively, with TTI of 61-120 days increasing to 14.1% and 33.8%, respectively with TTI at 181-365 days.

For intermediate-risk prostate cancer, 5- and 10-year predicted mortality was 7.4% and 20.4% with TTI of 61-120 days vs 8.3% and 22.6% with TTI at 181-365 days.

The data show all-cause mortality differences of 2.2% at 5 years and 4.6% at 10 years between high-risk prostate cancer patients who were treated expeditiously vs those waiting 4 to 6 months and differences of 0.9% at 5 years and 2.4% at 10 years for similar intermediate-risk patients.
 

No surprises

Turning to breast cancer, increased TTI was associated with the most negative survival effects for stage II and III breast cancer.

For stage II breast cancer, for example, 5- and 10-year predicted mortality was 17.7% and 30.5%, respectively, with TTI of 61-120 days vs 21.7% and 36.5% with TTI at 181-365 days. 

Even for stage I breast cancer patients, there were significant differences in all-cause mortality with delayed definitive therapy, although the effect size is clinically small, the researchers report.

Patients with stage IA or IB breast cancer who were not treated until 61 to 120 days after diagnosis had 1.3% and 2.3% increased mortality at 5 years and 10 years, respectively, and those waiting longer suffered even greater increases in mortality. “As such, our analysis underscores the importance of timely definitive treatment, even for stage I breast cancer,” the authors write.

Charles Shapiro, MD, director of translational breast cancer research for the Mount Sinai Health System, New York City, was not surprised by the data.

The observation that delays in initiating cancer treatment are associated with worse survival is “not new, as delays in primary surgical treatments and chemotherapy for early-stage disease is an adverse prognostic factor for clinical outcomes,” Shapiro told Medscape Medical News.

“The bottom line is primary surgery and the start of chemotherapy should probably occur as soon as clinically feasible,” said Shapiro, who was not involved in the study.

The authors of an accompanying editorial agree. 

This study supports avoiding unnecessary treatment delays and prioritizing timely cancer care, even during the COVID-19 pandemic, write Laura Van Metre Baum, MD, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee, and colleagues.

They note, however, that primary care, “the most important conduit for cancer screening and initial evaluation of new symptoms, has been the hardest hit economically and the most subject to profound disruption and restructuring during the current COVID-19 pandemic.

“In many centers, cancer care delivery has been disrupted and nonstandard therapies offered in an effort to minimize exposure of this high-risk group to the virus. The implications in appropriately balancing the urgency of cancer care and the threat of COVID-19 exposure in the pandemic are more complex,” the editorialists conclude.

Cone, Shapiro, and Van Metre Baum have disclosed no relevant financial relationships. This work won first prize in the Commission on Cancer 2020 Cancer Research Paper Competition and was virtually presented at the Commission on Cancer Plenary Session on October 30, 2020.

A version of this article first appeared on Medscape.com.

Everywhere they look within hospitals, researchers find RNA from SARS-CoV-2 in the air. But viable viruses typically are found only close to patients, according to a review of published studies.

The finding supports recommendations to use surgical masks in most parts of the hospital, reserving respirators (such as N95 or FFP2) for aerosol-generating procedures on patients’ respiratory tracts, said Gabriel Birgand, PhD, an infectious disease researcher at Imperial College London.

“When the virus is spreading a lot in the community, it’s probably more likely for you to be contaminated in your friends’ areas or in your building than in your work area, where you are well equipped and compliant with all the measures,” he said in an interview. “So it’s pretty good news.”

The systematic review by Dr. Birgand and colleagues was published in JAMA Network Open.

Recommended precautions to protect health care workers from SARS-CoV-2 infections remain controversial. Most authorities believe droplets are the primary route of transmission, which would mean surgical masks may be sufficient protection. But some research has suggested transmission by aerosols as well, making N95 respirators seem necessary. There is even disagreement about the definitions of the words “aerosol” and “droplet.”

To better understand where traces of the virus can be found in the air in hospitals, Dr. Birgand and colleagues analyzed all the studies they could find on the subject in English.

They identified 24 articles with original data. All of the studies used reverse transcription–polymerase chain reaction (PCR) tests to identify SARS-CoV-2 RNA. In five studies, attempts were also made to culture viable viruses. Three studies assessed the particle size relative to RNA concentration or viral titer.

Of 893 air samples across the 24 studies, 52.7% were taken from areas close to patients, 26.5% were taken in clinical areas, 13.7% in staff areas, 4.7% in public areas, and 2.4% in toilets or bathrooms.

Among those studies that quantified RNA, the median interquartile range of concentrations varied from 1.0 x 103 copies/m3 in clinical areas to 9.7 x 10³ copies/m³ in toilets or bathrooms.

One study found an RNA concentration of 2.0 x 10³ copies for particle sizes >4 mcm and 1.3 x 103 copies/m³ for particle sizes ≤4 mcm, both in patients’ rooms.

Three studies included viral cultures; of those, two resulted in positive cultures, both in a non-ICU setting. In one study, 3 of 39 samples were positive, and in the other, 4 of 4 were positive. Viral cultures in toilets, clinical areas, staff areas, and public areas were negative.

One of these studies assessed viral concentration and found that the median interquartile range was 4.8 tissue culture infectious dose (TCID50)/m³ for particles <1 mcm, 4.27 TCID50/m³ for particles 1-4 mcm, and 1.82 TCID50/m³ for particles >4 mcm.

Although viable viruses weren’t found in staff areas, the presence of viral RNA in places such as dining rooms and meeting rooms raises a concern, Dr. Birgand said.

“All of these staff areas are probably playing an important role in contamination,” he said. “It’s pretty easy to see when you are dining, you are not wearing a face mask, and it’s associated with a strong risk when there is a strong dissemination of the virus in the community.”

Studies on contact tracing among health care workers have also identified meeting rooms and dining rooms as the second most common source of infection after community contact, he said.

In general, the findings of the review correspond to epidemiologic studies, said Angela Rasmussen, PhD, a virologist with the Georgetown University Center for Global Health Science and Security, Washington, who was not involved in the review. “Absent aerosol-generating procedures, health care workers are largely not getting infected when they take droplet precautions.”

One reason may be that patients shed the most infectious viruses a couple of days before and after symptoms begin. By the time they’re hospitalized, they’re less likely to be contagious but may continue to shed viral RNA.

“We don’t really know the basis for the persistence of RNA being produced long after people have been infected and have recovered from the acute infection,” she said, “but it has been observed quite frequently.”

Although the virus cannot remain viable for very long in the air, remnants may still be detected in the form of RNA, Dr. Rasmussen said. In addition, hospitals often do a good job of ventilation.

She pointed out that it can be difficult to cultivate viruses in air samples because of contaminants such as bacteria and fungi. “That’s one of the limitations of a study like this. You’re not really sure if it’s because there’s no viable virus there or because you just aren’t able to collect samples that would allow you to determine that.”

Dr. Birgand and colleagues acknowledged other limitations. The studies they reviewed used different approaches to sampling. Different procedures may have been underway in the rooms being sampled, and factors such as temperature and humidity could have affected the results. In addition, the studies used different cycle thresholds for PCR positivity.

A version of this article first appeared on Medscape.com.

Everywhere they look within hospitals, researchers find RNA from SARS-CoV-2 in the air. But viable viruses typically are found only close to patients, according to a review of published studies.

The finding supports recommendations to use surgical masks in most parts of the hospital, reserving respirators (such as N95 or FFP2) for aerosol-generating procedures on patients’ respiratory tracts, said Gabriel Birgand, PhD, an infectious disease researcher at Imperial College London.

“When the virus is spreading a lot in the community, it’s probably more likely for you to be contaminated in your friends’ areas or in your building than in your work area, where you are well equipped and compliant with all the measures,” he said in an interview. “So it’s pretty good news.”

The systematic review by Dr. Birgand and colleagues was published in JAMA Network Open.

Recommended precautions to protect health care workers from SARS-CoV-2 infections remain controversial. Most authorities believe droplets are the primary route of transmission, which would mean surgical masks may be sufficient protection. But some research has suggested transmission by aerosols as well, making N95 respirators seem necessary. There is even disagreement about the definitions of the words “aerosol” and “droplet.”

To better understand where traces of the virus can be found in the air in hospitals, Dr. Birgand and colleagues analyzed all the studies they could find on the subject in English.

They identified 24 articles with original data. All of the studies used reverse transcription–polymerase chain reaction (PCR) tests to identify SARS-CoV-2 RNA. In five studies, attempts were also made to culture viable viruses. Three studies assessed the particle size relative to RNA concentration or viral titer.

Of 893 air samples across the 24 studies, 52.7% were taken from areas close to patients, 26.5% were taken in clinical areas, 13.7% in staff areas, 4.7% in public areas, and 2.4% in toilets or bathrooms.

Among those studies that quantified RNA, the median interquartile range of concentrations varied from 1.0 x 103 copies/m3 in clinical areas to 9.7 x 10³ copies/m³ in toilets or bathrooms.

One study found an RNA concentration of 2.0 x 10³ copies for particle sizes >4 mcm and 1.3 x 103 copies/m³ for particle sizes ≤4 mcm, both in patients’ rooms.

Three studies included viral cultures; of those, two resulted in positive cultures, both in a non-ICU setting. In one study, 3 of 39 samples were positive, and in the other, 4 of 4 were positive. Viral cultures in toilets, clinical areas, staff areas, and public areas were negative.

One of these studies assessed viral concentration and found that the median interquartile range was 4.8 tissue culture infectious dose (TCID50)/m³ for particles <1 mcm, 4.27 TCID50/m³ for particles 1-4 mcm, and 1.82 TCID50/m³ for particles >4 mcm.

Although viable viruses weren’t found in staff areas, the presence of viral RNA in places such as dining rooms and meeting rooms raises a concern, Dr. Birgand said.

“All of these staff areas are probably playing an important role in contamination,” he said. “It’s pretty easy to see when you are dining, you are not wearing a face mask, and it’s associated with a strong risk when there is a strong dissemination of the virus in the community.”

Studies on contact tracing among health care workers have also identified meeting rooms and dining rooms as the second most common source of infection after community contact, he said.

In general, the findings of the review correspond to epidemiologic studies, said Angela Rasmussen, PhD, a virologist with the Georgetown University Center for Global Health Science and Security, Washington, who was not involved in the review. “Absent aerosol-generating procedures, health care workers are largely not getting infected when they take droplet precautions.”

One reason may be that patients shed the most infectious viruses a couple of days before and after symptoms begin. By the time they’re hospitalized, they’re less likely to be contagious but may continue to shed viral RNA.

“We don’t really know the basis for the persistence of RNA being produced long after people have been infected and have recovered from the acute infection,” she said, “but it has been observed quite frequently.”

Although the virus cannot remain viable for very long in the air, remnants may still be detected in the form of RNA, Dr. Rasmussen said. In addition, hospitals often do a good job of ventilation.

She pointed out that it can be difficult to cultivate viruses in air samples because of contaminants such as bacteria and fungi. “That’s one of the limitations of a study like this. You’re not really sure if it’s because there’s no viable virus there or because you just aren’t able to collect samples that would allow you to determine that.”

Dr. Birgand and colleagues acknowledged other limitations. The studies they reviewed used different approaches to sampling. Different procedures may have been underway in the rooms being sampled, and factors such as temperature and humidity could have affected the results. In addition, the studies used different cycle thresholds for PCR positivity.

A version of this article first appeared on Medscape.com.

Everywhere they look within hospitals, researchers find RNA from SARS-CoV-2 in the air. But viable viruses typically are found only close to patients, according to a review of published studies.

The finding supports recommendations to use surgical masks in most parts of the hospital, reserving respirators (such as N95 or FFP2) for aerosol-generating procedures on patients’ respiratory tracts, said Gabriel Birgand, PhD, an infectious disease researcher at Imperial College London.

“When the virus is spreading a lot in the community, it’s probably more likely for you to be contaminated in your friends’ areas or in your building than in your work area, where you are well equipped and compliant with all the measures,” he said in an interview. “So it’s pretty good news.”

The systematic review by Dr. Birgand and colleagues was published in JAMA Network Open.

Recommended precautions to protect health care workers from SARS-CoV-2 infections remain controversial. Most authorities believe droplets are the primary route of transmission, which would mean surgical masks may be sufficient protection. But some research has suggested transmission by aerosols as well, making N95 respirators seem necessary. There is even disagreement about the definitions of the words “aerosol” and “droplet.”

To better understand where traces of the virus can be found in the air in hospitals, Dr. Birgand and colleagues analyzed all the studies they could find on the subject in English.

They identified 24 articles with original data. All of the studies used reverse transcription–polymerase chain reaction (PCR) tests to identify SARS-CoV-2 RNA. In five studies, attempts were also made to culture viable viruses. Three studies assessed the particle size relative to RNA concentration or viral titer.

Of 893 air samples across the 24 studies, 52.7% were taken from areas close to patients, 26.5% were taken in clinical areas, 13.7% in staff areas, 4.7% in public areas, and 2.4% in toilets or bathrooms.

Among those studies that quantified RNA, the median interquartile range of concentrations varied from 1.0 x 103 copies/m3 in clinical areas to 9.7 x 10³ copies/m³ in toilets or bathrooms.

One study found an RNA concentration of 2.0 x 10³ copies for particle sizes >4 mcm and 1.3 x 103 copies/m³ for particle sizes ≤4 mcm, both in patients’ rooms.

Three studies included viral cultures; of those, two resulted in positive cultures, both in a non-ICU setting. In one study, 3 of 39 samples were positive, and in the other, 4 of 4 were positive. Viral cultures in toilets, clinical areas, staff areas, and public areas were negative.

One of these studies assessed viral concentration and found that the median interquartile range was 4.8 tissue culture infectious dose (TCID50)/m³ for particles <1 mcm, 4.27 TCID50/m³ for particles 1-4 mcm, and 1.82 TCID50/m³ for particles >4 mcm.

Although viable viruses weren’t found in staff areas, the presence of viral RNA in places such as dining rooms and meeting rooms raises a concern, Dr. Birgand said.

“All of these staff areas are probably playing an important role in contamination,” he said. “It’s pretty easy to see when you are dining, you are not wearing a face mask, and it’s associated with a strong risk when there is a strong dissemination of the virus in the community.”

Studies on contact tracing among health care workers have also identified meeting rooms and dining rooms as the second most common source of infection after community contact, he said.

In general, the findings of the review correspond to epidemiologic studies, said Angela Rasmussen, PhD, a virologist with the Georgetown University Center for Global Health Science and Security, Washington, who was not involved in the review. “Absent aerosol-generating procedures, health care workers are largely not getting infected when they take droplet precautions.”

One reason may be that patients shed the most infectious viruses a couple of days before and after symptoms begin. By the time they’re hospitalized, they’re less likely to be contagious but may continue to shed viral RNA.

“We don’t really know the basis for the persistence of RNA being produced long after people have been infected and have recovered from the acute infection,” she said, “but it has been observed quite frequently.”

Although the virus cannot remain viable for very long in the air, remnants may still be detected in the form of RNA, Dr. Rasmussen said. In addition, hospitals often do a good job of ventilation.

She pointed out that it can be difficult to cultivate viruses in air samples because of contaminants such as bacteria and fungi. “That’s one of the limitations of a study like this. You’re not really sure if it’s because there’s no viable virus there or because you just aren’t able to collect samples that would allow you to determine that.”

Dr. Birgand and colleagues acknowledged other limitations. The studies they reviewed used different approaches to sampling. Different procedures may have been underway in the rooms being sampled, and factors such as temperature and humidity could have affected the results. In addition, the studies used different cycle thresholds for PCR positivity.

A version of this article first appeared on Medscape.com.

The human papillomavirus (HPV) vaccine, recommended by the Centers for Disease Control and Prevention for the prevention of HPV-associated genital warts and neoplasia, appears to be an effective and perhaps underappreciated treatment of existing cutaneous warts, according to expert speaking at the annual Coastal Dermatology symposium, held virtually.

The value of HPV vaccine for treating any cutaneous HPV-associated warts, not just genital lesions, has been suggested repeatedly in case reports and small studies, but a recently published review provides strong evidence that this is a practical clinical strategy, according to Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

“Clearly, if you have someone, particularly a youngster, and you’re having trouble getting rid of their warts and they are age 9 years or above – and they need the vaccine anyhow – that’s a win-win proposition,” Dr. Rosen said.

The current nonavalent HPV vaccine is approved for individuals from age 9 to age 45. Although the CDC recommends routine vaccination at age 11 or 12 years, it allows earlier vaccination within the label.

The recently published and updated evidence of a benefit from treatment comes from a systematic literature review. For the review, 63 articles were drawn from the PubMed and Cochrane databases. The studies yielded 4,439 patients with cutaneous warts at the time they received the HPV vaccine or who specifically received vaccine as a treatment strategy.

As has been suggested previously in the case series and in a limited number of prospective studies, the majority of warts, including cutaneous warts and anogenital warts, resolved following vaccine administration.

“Mostly these were common warts, plantar warts, and flat warts,” Dr. Rosen said, but the paper also reported successful treatment of recurrent respiratory papillomatosis, squamous cell carcinomas, and basal cell carcinomas.

Case reports and small studies associating HPV vaccine with successful resolution of warts are easy to find in the literature. For example, 60% of patients achieved a complete response and 30% a partial response to HPV vaccine in one small prospective study of 26 patients with genital warts. Following vaccination, no recurrences were observed after a median follow-up of more than 8 months.

In the review paper, most of the cases involved patients who received the quadrivalent HPV vaccine, Dr. Rosen noted. Only one received the updated nonavalent vaccine, which, in addition to protection against the 6, 11, 16, and 18 subtypes extends protection to subtypes 31, 33, 45, 52, and 58.

“You would expect the nonavalent vaccine to provide the same protection. It is the same vaccine. It just offers activity against more subtypes,” Dr. Rosen said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. He reported that he personally has used the nonavalent vaccine successfully to treat a cutaneous wart.

The nonavalent vaccine can be administered in just two doses for those who receive the first dose before age 15. In others, it is given in three doses at 1- to 2-month intervals, according to Dr. Rosen. He said the efficacy for preventing genital warts and most HPV-related neoplasia exceeds 90%, although it is lower for penile and anal cancer. The protection extends for at least 10 years, but he said that he believes that it is likely to be longer.

“The HPV vaccine is really, really safe,” Dr. Rosen said. Besides injection-site reactions, the most common adverse event is syncope. For this reason, patients are advised to stay seated for 30 minutes after administration.

There is some evidence for cross-immunity for HPV subtypes not covered by the vaccine, particularly among children, Dr. Rosen commented. Citing the review article, he said that, although almost all HPV-associated warts resolve in children when treated with the vaccine, response is somewhat lower in adolescents and further reduced in adults.

In an interview, the senior author of the recent literature review, Natasha A. Mesinkovska, MD, PhD, associate professor of dermatology, University of California, Irvine, agreed with Dr. Rosen about the value of HPV vaccine for patients not responding to conventional therapies for HPV-related cutaneous warts.

“I think HPV vaccine is an excellent option for those patients, even older ones at 45 years of age if cost is not an issue,” she said. She did offer a caveat. In a recent statement from the International Papillomavirus Society (IPVS) on a world shortage of HPV vaccine, it was estimated that supplies might be limited for the next 3-5 years.

Given this shortage, “obtaining them currently may prove to be difficult,” she cautioned.

This publication and Global Academy for Medical Education are owned by the same parent company.

The human papillomavirus (HPV) vaccine, recommended by the Centers for Disease Control and Prevention for the prevention of HPV-associated genital warts and neoplasia, appears to be an effective and perhaps underappreciated treatment of existing cutaneous warts, according to expert speaking at the annual Coastal Dermatology symposium, held virtually.

The value of HPV vaccine for treating any cutaneous HPV-associated warts, not just genital lesions, has been suggested repeatedly in case reports and small studies, but a recently published review provides strong evidence that this is a practical clinical strategy, according to Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

“Clearly, if you have someone, particularly a youngster, and you’re having trouble getting rid of their warts and they are age 9 years or above – and they need the vaccine anyhow – that’s a win-win proposition,” Dr. Rosen said.

The current nonavalent HPV vaccine is approved for individuals from age 9 to age 45. Although the CDC recommends routine vaccination at age 11 or 12 years, it allows earlier vaccination within the label.

The recently published and updated evidence of a benefit from treatment comes from a systematic literature review. For the review, 63 articles were drawn from the PubMed and Cochrane databases. The studies yielded 4,439 patients with cutaneous warts at the time they received the HPV vaccine or who specifically received vaccine as a treatment strategy.

As has been suggested previously in the case series and in a limited number of prospective studies, the majority of warts, including cutaneous warts and anogenital warts, resolved following vaccine administration.

“Mostly these were common warts, plantar warts, and flat warts,” Dr. Rosen said, but the paper also reported successful treatment of recurrent respiratory papillomatosis, squamous cell carcinomas, and basal cell carcinomas.

Case reports and small studies associating HPV vaccine with successful resolution of warts are easy to find in the literature. For example, 60% of patients achieved a complete response and 30% a partial response to HPV vaccine in one small prospective study of 26 patients with genital warts. Following vaccination, no recurrences were observed after a median follow-up of more than 8 months.

In the review paper, most of the cases involved patients who received the quadrivalent HPV vaccine, Dr. Rosen noted. Only one received the updated nonavalent vaccine, which, in addition to protection against the 6, 11, 16, and 18 subtypes extends protection to subtypes 31, 33, 45, 52, and 58.

“You would expect the nonavalent vaccine to provide the same protection. It is the same vaccine. It just offers activity against more subtypes,” Dr. Rosen said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. He reported that he personally has used the nonavalent vaccine successfully to treat a cutaneous wart.

The nonavalent vaccine can be administered in just two doses for those who receive the first dose before age 15. In others, it is given in three doses at 1- to 2-month intervals, according to Dr. Rosen. He said the efficacy for preventing genital warts and most HPV-related neoplasia exceeds 90%, although it is lower for penile and anal cancer. The protection extends for at least 10 years, but he said that he believes that it is likely to be longer.

“The HPV vaccine is really, really safe,” Dr. Rosen said. Besides injection-site reactions, the most common adverse event is syncope. For this reason, patients are advised to stay seated for 30 minutes after administration.

There is some evidence for cross-immunity for HPV subtypes not covered by the vaccine, particularly among children, Dr. Rosen commented. Citing the review article, he said that, although almost all HPV-associated warts resolve in children when treated with the vaccine, response is somewhat lower in adolescents and further reduced in adults.

In an interview, the senior author of the recent literature review, Natasha A. Mesinkovska, MD, PhD, associate professor of dermatology, University of California, Irvine, agreed with Dr. Rosen about the value of HPV vaccine for patients not responding to conventional therapies for HPV-related cutaneous warts.

“I think HPV vaccine is an excellent option for those patients, even older ones at 45 years of age if cost is not an issue,” she said. She did offer a caveat. In a recent statement from the International Papillomavirus Society (IPVS) on a world shortage of HPV vaccine, it was estimated that supplies might be limited for the next 3-5 years.

Given this shortage, “obtaining them currently may prove to be difficult,” she cautioned.

This publication and Global Academy for Medical Education are owned by the same parent company.

The human papillomavirus (HPV) vaccine, recommended by the Centers for Disease Control and Prevention for the prevention of HPV-associated genital warts and neoplasia, appears to be an effective and perhaps underappreciated treatment of existing cutaneous warts, according to expert speaking at the annual Coastal Dermatology symposium, held virtually.

The value of HPV vaccine for treating any cutaneous HPV-associated warts, not just genital lesions, has been suggested repeatedly in case reports and small studies, but a recently published review provides strong evidence that this is a practical clinical strategy, according to Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

“Clearly, if you have someone, particularly a youngster, and you’re having trouble getting rid of their warts and they are age 9 years or above – and they need the vaccine anyhow – that’s a win-win proposition,” Dr. Rosen said.

The current nonavalent HPV vaccine is approved for individuals from age 9 to age 45. Although the CDC recommends routine vaccination at age 11 or 12 years, it allows earlier vaccination within the label.

The recently published and updated evidence of a benefit from treatment comes from a systematic literature review. For the review, 63 articles were drawn from the PubMed and Cochrane databases. The studies yielded 4,439 patients with cutaneous warts at the time they received the HPV vaccine or who specifically received vaccine as a treatment strategy.

As has been suggested previously in the case series and in a limited number of prospective studies, the majority of warts, including cutaneous warts and anogenital warts, resolved following vaccine administration.

“Mostly these were common warts, plantar warts, and flat warts,” Dr. Rosen said, but the paper also reported successful treatment of recurrent respiratory papillomatosis, squamous cell carcinomas, and basal cell carcinomas.

Case reports and small studies associating HPV vaccine with successful resolution of warts are easy to find in the literature. For example, 60% of patients achieved a complete response and 30% a partial response to HPV vaccine in one small prospective study of 26 patients with genital warts. Following vaccination, no recurrences were observed after a median follow-up of more than 8 months.

In the review paper, most of the cases involved patients who received the quadrivalent HPV vaccine, Dr. Rosen noted. Only one received the updated nonavalent vaccine, which, in addition to protection against the 6, 11, 16, and 18 subtypes extends protection to subtypes 31, 33, 45, 52, and 58.

“You would expect the nonavalent vaccine to provide the same protection. It is the same vaccine. It just offers activity against more subtypes,” Dr. Rosen said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. He reported that he personally has used the nonavalent vaccine successfully to treat a cutaneous wart.

The nonavalent vaccine can be administered in just two doses for those who receive the first dose before age 15. In others, it is given in three doses at 1- to 2-month intervals, according to Dr. Rosen. He said the efficacy for preventing genital warts and most HPV-related neoplasia exceeds 90%, although it is lower for penile and anal cancer. The protection extends for at least 10 years, but he said that he believes that it is likely to be longer.

“The HPV vaccine is really, really safe,” Dr. Rosen said. Besides injection-site reactions, the most common adverse event is syncope. For this reason, patients are advised to stay seated for 30 minutes after administration.

There is some evidence for cross-immunity for HPV subtypes not covered by the vaccine, particularly among children, Dr. Rosen commented. Citing the review article, he said that, although almost all HPV-associated warts resolve in children when treated with the vaccine, response is somewhat lower in adolescents and further reduced in adults.

In an interview, the senior author of the recent literature review, Natasha A. Mesinkovska, MD, PhD, associate professor of dermatology, University of California, Irvine, agreed with Dr. Rosen about the value of HPV vaccine for patients not responding to conventional therapies for HPV-related cutaneous warts.

“I think HPV vaccine is an excellent option for those patients, even older ones at 45 years of age if cost is not an issue,” she said. She did offer a caveat. In a recent statement from the International Papillomavirus Society (IPVS) on a world shortage of HPV vaccine, it was estimated that supplies might be limited for the next 3-5 years.

Given this shortage, “obtaining them currently may prove to be difficult,” she cautioned.

This publication and Global Academy for Medical Education are owned by the same parent company.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Respiratory syncytial virus vaccine development has progressed rapidly in recent years, and there is hope that an efficacious vaccine soon may be approved.

Dr. Craig Lyerla/CDC

Louis Bont, MD, PhD, provided an overview of the most recent developments in the complex respiratory syncytial virus (RSV) vaccine landscape at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

RSV imposes significant burden worldwide, with 33 million patients, 3 million hospitalizations, and at least 120,000 deaths, reported Dr. Bont of the Wilhelmina Children’s Hospital, University Medical Centre, Utrecht, the Netherlands. Of those deaths, more than 50% are in infants younger than 5 months, and “about 99% of the children dying from RSV live in low- and middle-income countries.”

“There are high-risk populations, such as children with prematurity, congenital heart disease, lung disease, and Down syndrome, but about 73% of all children who are hospitalized for RSV infection were previously healthy children,” Dr. Bont explained. “So, we need to find a solution for all children to prevent RSV infection.”

As observed by Nienke Scheltema in a Lancet Global Health article, population distributions of RSV infection mortality show that, regardless of whether children have comorbidities or they are previously healthy, most children die at a very young age, Dr. Bont explained. These data suggest “that a maternal vaccine or an antibody prophylaxis approach from birth onwards or during the first RSV season is the solution for the problem.”

The path to developing an RSV vaccine has now narrowed its focus onto a structural element of RSV, the prefusion F protein. This shift started with the discovery by Jason McLellan (Science, 2013 [two papers]) that there are two variants of the RSV F-fusion protein: the very stable postfusion conformation and the prefusion active conformation, a metastable protein that exists for a “fraction of a second,” Dr. Bont said.

“The interesting thing is that epitopes that are visible at the prefusion, metastable state … induce highly neutralizing antibodies, whereas epitopes at the postfusion conformation do not,” Dr. Bont explained. “So, by stabilizing the prefusion state, we start inducing neutralizing antibodies that will protect against severe RSV infection, and this is the basic concept of all the vaccine developments currently ongoing.”

These RSV vaccine developments fall into five approach types: live-attenuated or chimeric vaccines, vector-based vaccines, monoclonal antibodies, particle-based vaccines, and subunit or protein-based vaccines.

One breakthrough, which was presented at last year’s ESPID meeting, is the monoclonal antibody nirsevimab. In addition to being nine times more potent than the broadly used antibody palivizumab, it is also more stable; whereas many antibodies have a half-life of 3 weeks, nirsevimab has a half-life of 100 days. “The idea is that a single injection at the start of the RSV season protects children in the first RSV season of their life, a dangerous episode for them.” Dr. Bont explained. The originators, AstraZeneca and Sanofi Pasteur, have “the vision that every child on this planet should receive a single injection with this antibody in the first season,” he explained.

Studies of nanoparticle-based maternal vaccines have also revealed interesting results: Although a phase 3 trial investigating such vaccines didn’t achieve its primary endpoint, “interestingly, 15% of all RSV infections were mild, and only 2% were very severe and leading to hypoxemia,” Dr. Bont noted. “But if we look at vaccine efficacy, we see the opposite – the vaccine was not very efficacious to prevent mild disease, but very efficacious to prevent severe hypoxemia; actually, this is exactly what you would like to see in a vaccine.”

Investigations into live-attenuated and vector-based vaccines have been promising as well, Dr. Bont shared. Studies of live-attenuated vaccines suggest they have a future and that we can move onto their next phase of clinical development, and a study investigating adenoviral vector-based vaccines has demonstrated safety, efficacy, and immunogenicity, though it has also shown that we should anticipate some side effects when using them.

Simple subunit vaccines for RSV are also being explored – a study of DS-Cav1, a stabilized prefusion F subunit protein candidate vaccine, has shown that it has a superior functional profile, compared with previous pre-F subunit vaccines. However, it seemed to be more efficacious against strains of RSV A than strains of RSV B, the dominant strain.

Dr. Bont also discussed exciting work by Sesterhenn et al., in which they used a computer-based program to develop their own vaccine. Using their in-depth knowledge of the RSV prefusion F protein and a computer program, Sesterhenn et al. developed a trivalent vaccine, produced it, and showed – both in vitro and in monkeys – that such vaccines can work up to the level of preclinical in vivo experiments.

“We can now make vaccines behind our computer,” Dr. Bont declared. “And the system doesn’t only work for RSV vaccines, but also for other pathogens – as long as you have an in-depth molecular knowledge of the target epitope,” he added.

Joanne Wildenbeest, MD, PhD, at the Utrecht University, the Netherlands commented: “Lower respiratory tract infections due to RSV are among the leading causes of death worldwide in children under the age of 5, especially young infants. The recent advances in the development of a vaccine and passive immunization are important steps towards the goal to reduce childhood mortality due to RSV worldwide. Since RSV-related mortality is mainly seen in developing countries it is important that, once a vaccine has been approved, it will also be made easily available to these countries.”

Dr. Bont reported the following disclosures: ReSViNET (a nonprofit foundation); investigator-initiated studies with the Bill & Melinda Gates Foundation, AbbVie, MedImmune, and MeMed; participation with Pfizer, Regeneron, and Janssen; and consultancy with GlaxoSmithKline, Ablynx, Novavax, and Janssen.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Mortality rates for inpatients with COVID-19 dropped significantly during the first 6 months of the pandemic, but outcomes depend on the hospital where patients receive care, new data show.

“[T]he characteristic that is most associated with poor or worsening hospital outcomes is high or increasing community case rates,” write David A. Asch, MD, MBA, executive director of the Center for Health Care Innovation at the University of Pennsylvania in Philadelphia, and colleagues.

The relationship between COVID-19 mortality rates and local disease prevalence suggests that “hospitals do worse when they are burdened with cases and is consistent with imperatives to flatten the curve,” the authors continue. “As case rates of COVID-19 increase across the nation, hospital mortality outcomes may worsen.”

The researchers published their study online December 22 in JAMA Internal Medicine.

The quick and substantial improvement in survival “is a tribute in part to new science — for example, the science that revealed the benefits of dexamethasone,” Asch told Medscape Medical News. “But it’s also a tribute to the doctors and nurses in the hospitals who developed experience. It’s a cliché to refer to them as heroes, but that is what they are. The science and the heroic experience continues on, and so I’m optimistic that we’ll see even more improvement over time.”

However, the data also indicate that “with lots of disease in the community, hospitals may have a harder time keeping patients alive,” Asch said.  “And of course the reason this is bad news is that community level case rates are rising all over, and in some cases at rapid rates. With that rise, we might be giving back some of our past gains in survival — just as the vaccine is beginning to be distributed.”
 

Examining mortality trends

The researchers analyzed administrative claims data from a large national health insurer. They included data from 38,517 adults who were admitted with COVID-19 to 955 US hospitals between January 1 and June 30 of this year. The investigators estimated hospitals’ risk-standardized rate of 30-day in-hospital mortality or referral to hospice, adjusted for patient-level characteristics.

Overall, 3179 patients (8.25%) died, and 1433 patients (3.7%) were referred to hospice. Risk-standardized mortality or hospice referral rates for individual hospitals ranged from 5.7% to 24.7%. The average rate was 9.1% in the best-performing quintile, compared with 15.7% in the worst-performing quintile.

In a subset of 398 hospitals that had at least 10 patients admitted for COVID-19 during early (January 1 through April 30) and later periods (between May 1 and June 30), rates in all but one hospital improved, and 94% improved by at least 25%. The average risk-standardized event rate declined from 16.6% to 9.3%.

“That rate of relative improvement is striking and encouraging, but perhaps not surprising,” Asch and coauthors write. “Early efforts at treating patients with COVID-19 were based on experience with previously known causes of severe respiratory illness. Later efforts could draw on experiences specific to SARS-CoV-2 infection.”

For instance, doctors tried different inpatient management approaches, such as early vs late assisted ventilation, differences in oxygen flow, prone or supine positioning, and anticoagulation. “Those efforts varied in how systematically they were evaluated, but our results suggest that valuable experience was gained,” the authors note.

In addition, variation between hospitals could reflect differences in quality or different admission thresholds, they continue.

The study provides “a reason for optimism that our healthcare system has improved in our ability to care for persons with COVID-19,” write Leon Boudourakis, MD, MHS, and Amit Uppal, MD, in a related commentary. Boudourakis and Uppal are both affiliated with NYC Health + Hospitals in New York City and with SUNY Downstate and New York University School of Medicine, respectively.

Similar improvements in mortality rates have been reported in the United Kingdom and in a New York City hospital system, the editorialists note. The lower mortality rates may represent clinical, healthcare system, and epidemiologic trends.

“Since the first wave of serious COVID-19 cases, physicians have learned a great deal about the best ways to treat this serious infection,” they say. “Steroids may decrease mortality in patients with respiratory failure. Remdesivir may shorten hospitalizations of patients with serious illness. Anticoagulation and prone positioning may help certain patients. Using noninvasive ventilation and high-flow oxygen therapy may spare subsets of patients from the harms of intubation, such as ventilator-induced lung injury.»
 

Overwhelmed hospitals

“Hospitals do not perform as well when they are overwhelmed,” which may be a reason for the correlation between community prevalence and mortality rates, Boudourakis and Uppal suggested. “In particular, patients with a precarious respiratory status require expert, meticulous therapy to avoid intubation; those who undergo intubation or have kidney failure require nuanced and timely expert care with ventilatory adjustments and kidney replacement therapy, which are difficult to perform optimally when hospital capacity is strained.”

Although the death rate has fallen to about 9% for hospitalized patients, “9% is still high,” Asch said.

“Our results show that hospitals can’t do it on their own,” Asch said. “They need all of us to keep the community spread of the disease down. The right answer now is the right answer since the beginning of the pandemic: Keep your distance, wash your hands, and wear a mask.”

Asch, Boudourakis, and Uppal have disclosed no relevant financial relationships. A study coauthor reported personal fees and grants from pharmaceutical companies outside the submitted work.

A version of this article first appeared on Medscape.com.

Mortality rates for inpatients with COVID-19 dropped significantly during the first 6 months of the pandemic, but outcomes depend on the hospital where patients receive care, new data show.

“[T]he characteristic that is most associated with poor or worsening hospital outcomes is high or increasing community case rates,” write David A. Asch, MD, MBA, executive director of the Center for Health Care Innovation at the University of Pennsylvania in Philadelphia, and colleagues.

The relationship between COVID-19 mortality rates and local disease prevalence suggests that “hospitals do worse when they are burdened with cases and is consistent with imperatives to flatten the curve,” the authors continue. “As case rates of COVID-19 increase across the nation, hospital mortality outcomes may worsen.”

The researchers published their study online December 22 in JAMA Internal Medicine.

The quick and substantial improvement in survival “is a tribute in part to new science — for example, the science that revealed the benefits of dexamethasone,” Asch told Medscape Medical News. “But it’s also a tribute to the doctors and nurses in the hospitals who developed experience. It’s a cliché to refer to them as heroes, but that is what they are. The science and the heroic experience continues on, and so I’m optimistic that we’ll see even more improvement over time.”

However, the data also indicate that “with lots of disease in the community, hospitals may have a harder time keeping patients alive,” Asch said.  “And of course the reason this is bad news is that community level case rates are rising all over, and in some cases at rapid rates. With that rise, we might be giving back some of our past gains in survival — just as the vaccine is beginning to be distributed.”
 

Examining mortality trends

The researchers analyzed administrative claims data from a large national health insurer. They included data from 38,517 adults who were admitted with COVID-19 to 955 US hospitals between January 1 and June 30 of this year. The investigators estimated hospitals’ risk-standardized rate of 30-day in-hospital mortality or referral to hospice, adjusted for patient-level characteristics.

Overall, 3179 patients (8.25%) died, and 1433 patients (3.7%) were referred to hospice. Risk-standardized mortality or hospice referral rates for individual hospitals ranged from 5.7% to 24.7%. The average rate was 9.1% in the best-performing quintile, compared with 15.7% in the worst-performing quintile.

In a subset of 398 hospitals that had at least 10 patients admitted for COVID-19 during early (January 1 through April 30) and later periods (between May 1 and June 30), rates in all but one hospital improved, and 94% improved by at least 25%. The average risk-standardized event rate declined from 16.6% to 9.3%.

“That rate of relative improvement is striking and encouraging, but perhaps not surprising,” Asch and coauthors write. “Early efforts at treating patients with COVID-19 were based on experience with previously known causes of severe respiratory illness. Later efforts could draw on experiences specific to SARS-CoV-2 infection.”

For instance, doctors tried different inpatient management approaches, such as early vs late assisted ventilation, differences in oxygen flow, prone or supine positioning, and anticoagulation. “Those efforts varied in how systematically they were evaluated, but our results suggest that valuable experience was gained,” the authors note.

In addition, variation between hospitals could reflect differences in quality or different admission thresholds, they continue.

The study provides “a reason for optimism that our healthcare system has improved in our ability to care for persons with COVID-19,” write Leon Boudourakis, MD, MHS, and Amit Uppal, MD, in a related commentary. Boudourakis and Uppal are both affiliated with NYC Health + Hospitals in New York City and with SUNY Downstate and New York University School of Medicine, respectively.

Similar improvements in mortality rates have been reported in the United Kingdom and in a New York City hospital system, the editorialists note. The lower mortality rates may represent clinical, healthcare system, and epidemiologic trends.

“Since the first wave of serious COVID-19 cases, physicians have learned a great deal about the best ways to treat this serious infection,” they say. “Steroids may decrease mortality in patients with respiratory failure. Remdesivir may shorten hospitalizations of patients with serious illness. Anticoagulation and prone positioning may help certain patients. Using noninvasive ventilation and high-flow oxygen therapy may spare subsets of patients from the harms of intubation, such as ventilator-induced lung injury.»
 

Overwhelmed hospitals

“Hospitals do not perform as well when they are overwhelmed,” which may be a reason for the correlation between community prevalence and mortality rates, Boudourakis and Uppal suggested. “In particular, patients with a precarious respiratory status require expert, meticulous therapy to avoid intubation; those who undergo intubation or have kidney failure require nuanced and timely expert care with ventilatory adjustments and kidney replacement therapy, which are difficult to perform optimally when hospital capacity is strained.”

Although the death rate has fallen to about 9% for hospitalized patients, “9% is still high,” Asch said.

“Our results show that hospitals can’t do it on their own,” Asch said. “They need all of us to keep the community spread of the disease down. The right answer now is the right answer since the beginning of the pandemic: Keep your distance, wash your hands, and wear a mask.”

Asch, Boudourakis, and Uppal have disclosed no relevant financial relationships. A study coauthor reported personal fees and grants from pharmaceutical companies outside the submitted work.

A version of this article first appeared on Medscape.com.

Mortality rates for inpatients with COVID-19 dropped significantly during the first 6 months of the pandemic, but outcomes depend on the hospital where patients receive care, new data show.

“[T]he characteristic that is most associated with poor or worsening hospital outcomes is high or increasing community case rates,” write David A. Asch, MD, MBA, executive director of the Center for Health Care Innovation at the University of Pennsylvania in Philadelphia, and colleagues.

The relationship between COVID-19 mortality rates and local disease prevalence suggests that “hospitals do worse when they are burdened with cases and is consistent with imperatives to flatten the curve,” the authors continue. “As case rates of COVID-19 increase across the nation, hospital mortality outcomes may worsen.”

The researchers published their study online December 22 in JAMA Internal Medicine.

The quick and substantial improvement in survival “is a tribute in part to new science — for example, the science that revealed the benefits of dexamethasone,” Asch told Medscape Medical News. “But it’s also a tribute to the doctors and nurses in the hospitals who developed experience. It’s a cliché to refer to them as heroes, but that is what they are. The science and the heroic experience continues on, and so I’m optimistic that we’ll see even more improvement over time.”

However, the data also indicate that “with lots of disease in the community, hospitals may have a harder time keeping patients alive,” Asch said.  “And of course the reason this is bad news is that community level case rates are rising all over, and in some cases at rapid rates. With that rise, we might be giving back some of our past gains in survival — just as the vaccine is beginning to be distributed.”
 

Examining mortality trends

The researchers analyzed administrative claims data from a large national health insurer. They included data from 38,517 adults who were admitted with COVID-19 to 955 US hospitals between January 1 and June 30 of this year. The investigators estimated hospitals’ risk-standardized rate of 30-day in-hospital mortality or referral to hospice, adjusted for patient-level characteristics.

Overall, 3179 patients (8.25%) died, and 1433 patients (3.7%) were referred to hospice. Risk-standardized mortality or hospice referral rates for individual hospitals ranged from 5.7% to 24.7%. The average rate was 9.1% in the best-performing quintile, compared with 15.7% in the worst-performing quintile.

In a subset of 398 hospitals that had at least 10 patients admitted for COVID-19 during early (January 1 through April 30) and later periods (between May 1 and June 30), rates in all but one hospital improved, and 94% improved by at least 25%. The average risk-standardized event rate declined from 16.6% to 9.3%.

“That rate of relative improvement is striking and encouraging, but perhaps not surprising,” Asch and coauthors write. “Early efforts at treating patients with COVID-19 were based on experience with previously known causes of severe respiratory illness. Later efforts could draw on experiences specific to SARS-CoV-2 infection.”

For instance, doctors tried different inpatient management approaches, such as early vs late assisted ventilation, differences in oxygen flow, prone or supine positioning, and anticoagulation. “Those efforts varied in how systematically they were evaluated, but our results suggest that valuable experience was gained,” the authors note.

In addition, variation between hospitals could reflect differences in quality or different admission thresholds, they continue.

The study provides “a reason for optimism that our healthcare system has improved in our ability to care for persons with COVID-19,” write Leon Boudourakis, MD, MHS, and Amit Uppal, MD, in a related commentary. Boudourakis and Uppal are both affiliated with NYC Health + Hospitals in New York City and with SUNY Downstate and New York University School of Medicine, respectively.

Similar improvements in mortality rates have been reported in the United Kingdom and in a New York City hospital system, the editorialists note. The lower mortality rates may represent clinical, healthcare system, and epidemiologic trends.

“Since the first wave of serious COVID-19 cases, physicians have learned a great deal about the best ways to treat this serious infection,” they say. “Steroids may decrease mortality in patients with respiratory failure. Remdesivir may shorten hospitalizations of patients with serious illness. Anticoagulation and prone positioning may help certain patients. Using noninvasive ventilation and high-flow oxygen therapy may spare subsets of patients from the harms of intubation, such as ventilator-induced lung injury.»
 

Overwhelmed hospitals

“Hospitals do not perform as well when they are overwhelmed,” which may be a reason for the correlation between community prevalence and mortality rates, Boudourakis and Uppal suggested. “In particular, patients with a precarious respiratory status require expert, meticulous therapy to avoid intubation; those who undergo intubation or have kidney failure require nuanced and timely expert care with ventilatory adjustments and kidney replacement therapy, which are difficult to perform optimally when hospital capacity is strained.”

Although the death rate has fallen to about 9% for hospitalized patients, “9% is still high,” Asch said.

“Our results show that hospitals can’t do it on their own,” Asch said. “They need all of us to keep the community spread of the disease down. The right answer now is the right answer since the beginning of the pandemic: Keep your distance, wash your hands, and wear a mask.”

Asch, Boudourakis, and Uppal have disclosed no relevant financial relationships. A study coauthor reported personal fees and grants from pharmaceutical companies outside the submitted work.

A version of this article first appeared on Medscape.com.

After infection with SARS-CoV-2, antibodies protect most health care workers from reinfection for up to 6 months, results of the first prospective study of the subject revealed.

Courtesy NIAID-RML

The main message for health care workers is, “if you’ve had COVID, at least in the short term, you are unlikely to get it again,” David Eyre, DPhil, senior author, associate professor at the Big Data Institute and infectious diseases clinician at the University of Oxford (England), said in an interview.

Dr. Eyre and colleagues assessed for the presence of two antibodies to SARS-CoV-2 among 12,541 health care workers in the United Kingdom, including about 10% who had a history of polymerase chain reaction (PCR)–confirmed infection. Of those, 223 who did not have antibodies tested positive on PCR for the virus during 31 weeks of follow-up; two participants who did not have antibodies at baseline tested positive.

The study was published online Dec. 23 in The New England Journal of Medicine.

“It’s great news because there have been so many questions regarding whether or not you can be protected against reinfection, and this health care worker study is really an elegant way to address that question,” Mark Slifka, PhD, said in an interview when asked to comment on the findings.

Although “there are millions of people in the U.S. who have been infected with COVID, we don’t know how common reinfection is,” said Dr. Slifka, a researcher at the Oregon National Primate Research Center and professor at Oregon Health & Science University, Portland.

The likelihood of a subsequent positive PCR test result was 1.09 per 10,000 days at risk among those without antibodies, compared with 0.13 per 10,000 days among those with anti-spike antibodies.

The investigators also assessed for the presence of anti–nucleocapsid IgG antibody titers. They found a significant trend for increasing PCR-positive test results with increasing antibody levels. As with the anti-spike antibody findings, 226 of 11,543 health care providers who did not have anti–nucleocapsid IgG antibodies subsequently tested positive on PCR; by contrast, two of 1,172 participants who did not have antibodies tested positive. Adjusted for age, sex, and calendar time, this finding translates to a 0.11 incidence rate ratio (0.13 per 10,000 days at risk; 95% confidence interval, 0.03-0.45; P = .002).

“This is a study a number of us have been trying to do,” said Christopher L. King, MD, PhD, professor of pathology and associate professor of medicine at Case Western Reserve University, Cleveland.

“To really follow a group like this longitudinally like they’ve done, with a large population, and to see such a big difference – it really confirms our suspicion that those who do become infected and develop an antibody response are significantly protected from reinfection.

“What’s great about this study is it’s nearly a 10-fold reduction in risk if you’ve recovered from COVID and have antibodies,” said Dr. King, who was not involved with the research. “That’s what a lot of us have been wanting to know.”
 

Unanswered questions remain

“How long this immunity lasts, we don’t know,” Dr. King said. He predicted that antibody protection could last a year to a year and a half. The duration of protection could vary. “We know some people lose their antibodies pretty quickly, and other people don’t,” he said.

Dr. Slifka said the suggestion of “a substantially reduced risk for at least 6 months ... is great news, and the timing couldn’t be better, because we’re rolling out the vaccines.”

Not all antibody responses are alike. For example, data indicate that antibody levels following immunization with the Pfizer/BioNTech or Moderna vaccines are higher on average than those of people who’ve had a natural infection, Dr. King said. He added that initial data on the AstraZeneca COVID-19 vaccine in development showed lower antibody levels compared with natural immunity.

The Centers for Disease Control and Prevention recommends immunization for those with a history of infection. “People who have gotten sick with COVID-19 may still benefit from getting vaccinated,” the CDC notes on its Facts About COVID-19 Vaccines website. “Due to the severe health risks associated with COVID-19 and the fact that re-infection with COVID-19 is possible, people may be advised to get a COVID-19 vaccine even if they have been sick with COVID-19 before,” the CDC stated.

The agency also notes that people appear to become susceptible to reinfection approximately 90 days after onset of infection. However, the new evidence from the UK study that persons have up to 6 months of immune protection might lead to a modification of recommendations, especially at a time when vaccine supplies are limited, Dr. Slifka said.

Another unanswered question is why the two study participants with antibodies subsequently tested positive for reinfection. “There are a lot of things that could have made these people more susceptible,” Dr. King said. For example, they could have been heavily exposed to SARS-CoV-2 or been immunocompromised for another reason.

Furthermore, the immune response involves more than antibody levels, Dr. King noted. Research in rhesus monkeys suggests that T cells play a role, but not as prominent a part as antibodies. “What I think is protecting us from infection is primarily the antibodies, although the T cells are probably important. Once you get infected, the T cells are probably playing a more important role in terms of whether you get very sick or not,” he said.
 

Multiplication + addition = more protected?

The 90% natural immunity protection in the study approaches the 95% efficacy associated with the Pfizer and Moderna vaccines, Dr. Slifka noted. Even without immunization, this could mean a portion of the U.S. population is already protected against future infection.

Furthermore, the CDC estimates that there are about 7.7 cases of COVID-19 for every case reported.

As of Sept. 30, the CDC reported that there were 6,891,764 confirmed cases. The agency estimated that overall, approximately 53 million people in the United States have been infected. More recent numbers from Johns Hopkins University’s Coronavirus Resource Center indicate that there were 18.2 million cases in the United States as of Dec. 22. If that tally is multiplied by 7.7, the total number protected could approach 140 million, Dr. Slifka said.

“That could really be a boost in terms of knocking this pandemic down in the next couple of months,” Dr. Slifka said.

“Now, if we were to modify the current recommendations and briefly defer vaccination of people with confirmed cases of COVID-19 until later on, we could start reaching herd immunity pretty quickly,” he added.
 

Real-life implications

“There is no such thing as 100% protection, even from the infection itself. So when you’re dealing with someone with possible exposure to COVID-19, you still need to follow the proper precautions,” Dr. Slifka said.

Nonetheless, he said, “This is great news for those on the front lines who are wondering whether or not they would have any protection if they had COVID-19 before. And the answer is yes – there is a very good chance they will have protection, based on this quite large study.”

One limitation of the study is that the population consisted predominantly of healthy adult health care workers aged 65 years or younger. “Further studies are needed to assess postinfection immunity in other populations, including children, older adults, and persons with coexisting conditions, including immunosuppression,” the researchers noted.

Dr. Eyre plans to continue following the health care workers in the study, some of whom have been vaccinated for COVID-19. This ongoing research will allow him and coinvestigators to “confirm the protection offered by vaccination and investigate how postvaccine antibody responses vary by whether you have had COVID-19 before or not. We also want to understand more about how long postinfection immunity lasts.”

Dr. Eyre has received grants as a Robinson Foundation Fellow and NIHR Oxford BRC senior fellow during the conduct of the study. Dr. Slifka and Dr. King report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

After infection with SARS-CoV-2, antibodies protect most health care workers from reinfection for up to 6 months, results of the first prospective study of the subject revealed.

Courtesy NIAID-RML

The main message for health care workers is, “if you’ve had COVID, at least in the short term, you are unlikely to get it again,” David Eyre, DPhil, senior author, associate professor at the Big Data Institute and infectious diseases clinician at the University of Oxford (England), said in an interview.

Dr. Eyre and colleagues assessed for the presence of two antibodies to SARS-CoV-2 among 12,541 health care workers in the United Kingdom, including about 10% who had a history of polymerase chain reaction (PCR)–confirmed infection. Of those, 223 who did not have antibodies tested positive on PCR for the virus during 31 weeks of follow-up; two participants who did not have antibodies at baseline tested positive.

The study was published online Dec. 23 in The New England Journal of Medicine.

“It’s great news because there have been so many questions regarding whether or not you can be protected against reinfection, and this health care worker study is really an elegant way to address that question,” Mark Slifka, PhD, said in an interview when asked to comment on the findings.

Although “there are millions of people in the U.S. who have been infected with COVID, we don’t know how common reinfection is,” said Dr. Slifka, a researcher at the Oregon National Primate Research Center and professor at Oregon Health & Science University, Portland.

The likelihood of a subsequent positive PCR test result was 1.09 per 10,000 days at risk among those without antibodies, compared with 0.13 per 10,000 days among those with anti-spike antibodies.

The investigators also assessed for the presence of anti–nucleocapsid IgG antibody titers. They found a significant trend for increasing PCR-positive test results with increasing antibody levels. As with the anti-spike antibody findings, 226 of 11,543 health care providers who did not have anti–nucleocapsid IgG antibodies subsequently tested positive on PCR; by contrast, two of 1,172 participants who did not have antibodies tested positive. Adjusted for age, sex, and calendar time, this finding translates to a 0.11 incidence rate ratio (0.13 per 10,000 days at risk; 95% confidence interval, 0.03-0.45; P = .002).

“This is a study a number of us have been trying to do,” said Christopher L. King, MD, PhD, professor of pathology and associate professor of medicine at Case Western Reserve University, Cleveland.

“To really follow a group like this longitudinally like they’ve done, with a large population, and to see such a big difference – it really confirms our suspicion that those who do become infected and develop an antibody response are significantly protected from reinfection.

“What’s great about this study is it’s nearly a 10-fold reduction in risk if you’ve recovered from COVID and have antibodies,” said Dr. King, who was not involved with the research. “That’s what a lot of us have been wanting to know.”
 

Unanswered questions remain

“How long this immunity lasts, we don’t know,” Dr. King said. He predicted that antibody protection could last a year to a year and a half. The duration of protection could vary. “We know some people lose their antibodies pretty quickly, and other people don’t,” he said.

Dr. Slifka said the suggestion of “a substantially reduced risk for at least 6 months ... is great news, and the timing couldn’t be better, because we’re rolling out the vaccines.”

Not all antibody responses are alike. For example, data indicate that antibody levels following immunization with the Pfizer/BioNTech or Moderna vaccines are higher on average than those of people who’ve had a natural infection, Dr. King said. He added that initial data on the AstraZeneca COVID-19 vaccine in development showed lower antibody levels compared with natural immunity.

The Centers for Disease Control and Prevention recommends immunization for those with a history of infection. “People who have gotten sick with COVID-19 may still benefit from getting vaccinated,” the CDC notes on its Facts About COVID-19 Vaccines website. “Due to the severe health risks associated with COVID-19 and the fact that re-infection with COVID-19 is possible, people may be advised to get a COVID-19 vaccine even if they have been sick with COVID-19 before,” the CDC stated.

The agency also notes that people appear to become susceptible to reinfection approximately 90 days after onset of infection. However, the new evidence from the UK study that persons have up to 6 months of immune protection might lead to a modification of recommendations, especially at a time when vaccine supplies are limited, Dr. Slifka said.

Another unanswered question is why the two study participants with antibodies subsequently tested positive for reinfection. “There are a lot of things that could have made these people more susceptible,” Dr. King said. For example, they could have been heavily exposed to SARS-CoV-2 or been immunocompromised for another reason.

Furthermore, the immune response involves more than antibody levels, Dr. King noted. Research in rhesus monkeys suggests that T cells play a role, but not as prominent a part as antibodies. “What I think is protecting us from infection is primarily the antibodies, although the T cells are probably important. Once you get infected, the T cells are probably playing a more important role in terms of whether you get very sick or not,” he said.
 

Multiplication + addition = more protected?

The 90% natural immunity protection in the study approaches the 95% efficacy associated with the Pfizer and Moderna vaccines, Dr. Slifka noted. Even without immunization, this could mean a portion of the U.S. population is already protected against future infection.

Furthermore, the CDC estimates that there are about 7.7 cases of COVID-19 for every case reported.

As of Sept. 30, the CDC reported that there were 6,891,764 confirmed cases. The agency estimated that overall, approximately 53 million people in the United States have been infected. More recent numbers from Johns Hopkins University’s Coronavirus Resource Center indicate that there were 18.2 million cases in the United States as of Dec. 22. If that tally is multiplied by 7.7, the total number protected could approach 140 million, Dr. Slifka said.

“That could really be a boost in terms of knocking this pandemic down in the next couple of months,” Dr. Slifka said.

“Now, if we were to modify the current recommendations and briefly defer vaccination of people with confirmed cases of COVID-19 until later on, we could start reaching herd immunity pretty quickly,” he added.
 

Real-life implications

“There is no such thing as 100% protection, even from the infection itself. So when you’re dealing with someone with possible exposure to COVID-19, you still need to follow the proper precautions,” Dr. Slifka said.

Nonetheless, he said, “This is great news for those on the front lines who are wondering whether or not they would have any protection if they had COVID-19 before. And the answer is yes – there is a very good chance they will have protection, based on this quite large study.”

One limitation of the study is that the population consisted predominantly of healthy adult health care workers aged 65 years or younger. “Further studies are needed to assess postinfection immunity in other populations, including children, older adults, and persons with coexisting conditions, including immunosuppression,” the researchers noted.

Dr. Eyre plans to continue following the health care workers in the study, some of whom have been vaccinated for COVID-19. This ongoing research will allow him and coinvestigators to “confirm the protection offered by vaccination and investigate how postvaccine antibody responses vary by whether you have had COVID-19 before or not. We also want to understand more about how long postinfection immunity lasts.”

Dr. Eyre has received grants as a Robinson Foundation Fellow and NIHR Oxford BRC senior fellow during the conduct of the study. Dr. Slifka and Dr. King report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

After infection with SARS-CoV-2, antibodies protect most health care workers from reinfection for up to 6 months, results of the first prospective study of the subject revealed.

Courtesy NIAID-RML

The main message for health care workers is, “if you’ve had COVID, at least in the short term, you are unlikely to get it again,” David Eyre, DPhil, senior author, associate professor at the Big Data Institute and infectious diseases clinician at the University of Oxford (England), said in an interview.

Dr. Eyre and colleagues assessed for the presence of two antibodies to SARS-CoV-2 among 12,541 health care workers in the United Kingdom, including about 10% who had a history of polymerase chain reaction (PCR)–confirmed infection. Of those, 223 who did not have antibodies tested positive on PCR for the virus during 31 weeks of follow-up; two participants who did not have antibodies at baseline tested positive.

The study was published online Dec. 23 in The New England Journal of Medicine.

“It’s great news because there have been so many questions regarding whether or not you can be protected against reinfection, and this health care worker study is really an elegant way to address that question,” Mark Slifka, PhD, said in an interview when asked to comment on the findings.

Although “there are millions of people in the U.S. who have been infected with COVID, we don’t know how common reinfection is,” said Dr. Slifka, a researcher at the Oregon National Primate Research Center and professor at Oregon Health & Science University, Portland.

The likelihood of a subsequent positive PCR test result was 1.09 per 10,000 days at risk among those without antibodies, compared with 0.13 per 10,000 days among those with anti-spike antibodies.

The investigators also assessed for the presence of anti–nucleocapsid IgG antibody titers. They found a significant trend for increasing PCR-positive test results with increasing antibody levels. As with the anti-spike antibody findings, 226 of 11,543 health care providers who did not have anti–nucleocapsid IgG antibodies subsequently tested positive on PCR; by contrast, two of 1,172 participants who did not have antibodies tested positive. Adjusted for age, sex, and calendar time, this finding translates to a 0.11 incidence rate ratio (0.13 per 10,000 days at risk; 95% confidence interval, 0.03-0.45; P = .002).

“This is a study a number of us have been trying to do,” said Christopher L. King, MD, PhD, professor of pathology and associate professor of medicine at Case Western Reserve University, Cleveland.

“To really follow a group like this longitudinally like they’ve done, with a large population, and to see such a big difference – it really confirms our suspicion that those who do become infected and develop an antibody response are significantly protected from reinfection.

“What’s great about this study is it’s nearly a 10-fold reduction in risk if you’ve recovered from COVID and have antibodies,” said Dr. King, who was not involved with the research. “That’s what a lot of us have been wanting to know.”
 

Unanswered questions remain

“How long this immunity lasts, we don’t know,” Dr. King said. He predicted that antibody protection could last a year to a year and a half. The duration of protection could vary. “We know some people lose their antibodies pretty quickly, and other people don’t,” he said.

Dr. Slifka said the suggestion of “a substantially reduced risk for at least 6 months ... is great news, and the timing couldn’t be better, because we’re rolling out the vaccines.”

Not all antibody responses are alike. For example, data indicate that antibody levels following immunization with the Pfizer/BioNTech or Moderna vaccines are higher on average than those of people who’ve had a natural infection, Dr. King said. He added that initial data on the AstraZeneca COVID-19 vaccine in development showed lower antibody levels compared with natural immunity.

The Centers for Disease Control and Prevention recommends immunization for those with a history of infection. “People who have gotten sick with COVID-19 may still benefit from getting vaccinated,” the CDC notes on its Facts About COVID-19 Vaccines website. “Due to the severe health risks associated with COVID-19 and the fact that re-infection with COVID-19 is possible, people may be advised to get a COVID-19 vaccine even if they have been sick with COVID-19 before,” the CDC stated.

The agency also notes that people appear to become susceptible to reinfection approximately 90 days after onset of infection. However, the new evidence from the UK study that persons have up to 6 months of immune protection might lead to a modification of recommendations, especially at a time when vaccine supplies are limited, Dr. Slifka said.

Another unanswered question is why the two study participants with antibodies subsequently tested positive for reinfection. “There are a lot of things that could have made these people more susceptible,” Dr. King said. For example, they could have been heavily exposed to SARS-CoV-2 or been immunocompromised for another reason.

Furthermore, the immune response involves more than antibody levels, Dr. King noted. Research in rhesus monkeys suggests that T cells play a role, but not as prominent a part as antibodies. “What I think is protecting us from infection is primarily the antibodies, although the T cells are probably important. Once you get infected, the T cells are probably playing a more important role in terms of whether you get very sick or not,” he said.
 

Multiplication + addition = more protected?

The 90% natural immunity protection in the study approaches the 95% efficacy associated with the Pfizer and Moderna vaccines, Dr. Slifka noted. Even without immunization, this could mean a portion of the U.S. population is already protected against future infection.

Furthermore, the CDC estimates that there are about 7.7 cases of COVID-19 for every case reported.

As of Sept. 30, the CDC reported that there were 6,891,764 confirmed cases. The agency estimated that overall, approximately 53 million people in the United States have been infected. More recent numbers from Johns Hopkins University’s Coronavirus Resource Center indicate that there were 18.2 million cases in the United States as of Dec. 22. If that tally is multiplied by 7.7, the total number protected could approach 140 million, Dr. Slifka said.

“That could really be a boost in terms of knocking this pandemic down in the next couple of months,” Dr. Slifka said.

“Now, if we were to modify the current recommendations and briefly defer vaccination of people with confirmed cases of COVID-19 until later on, we could start reaching herd immunity pretty quickly,” he added.
 

Real-life implications

“There is no such thing as 100% protection, even from the infection itself. So when you’re dealing with someone with possible exposure to COVID-19, you still need to follow the proper precautions,” Dr. Slifka said.

Nonetheless, he said, “This is great news for those on the front lines who are wondering whether or not they would have any protection if they had COVID-19 before. And the answer is yes – there is a very good chance they will have protection, based on this quite large study.”

One limitation of the study is that the population consisted predominantly of healthy adult health care workers aged 65 years or younger. “Further studies are needed to assess postinfection immunity in other populations, including children, older adults, and persons with coexisting conditions, including immunosuppression,” the researchers noted.

Dr. Eyre plans to continue following the health care workers in the study, some of whom have been vaccinated for COVID-19. This ongoing research will allow him and coinvestigators to “confirm the protection offered by vaccination and investigate how postvaccine antibody responses vary by whether you have had COVID-19 before or not. We also want to understand more about how long postinfection immunity lasts.”

Dr. Eyre has received grants as a Robinson Foundation Fellow and NIHR Oxford BRC senior fellow during the conduct of the study. Dr. Slifka and Dr. King report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

Although there is an effective vaccine against Bordetella pertussis, whooping cough remains a leading cause of death. Cases are increasing, and scientists face challenges in developing new vaccines.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Dimitri Diavatopoulos, PhD, associate professor at the Radboud University Medical Centre Nijmegen, the Netherlands, summarized the pertussis vaccination problem and what the Pertussis Correlates of Protection Europe (PERISCOPE) project seeks to achieve. Dr. Diavatopoulos has a longstanding interest in pertussis and immunity and will soon take over as the scientific coordinator of PERISCOPE.

Pertussis is a highly contagious infectious disease that causes uncontrollable coughing. The disease begins with an atypical cough and rhinorrhea before entering a paroxysmal stage characterized by cyanosis, lymphocytosis, vomiting, and whoops. Generally, fever is absent and coughing increases at night. Finally, after weeks to months, the patient enters a convalescent stage. The World Health Organization estimates that there are 16 million pertussis cases annually and approximately 195,000 deaths in children. Most cases are caused by Bordetella pertussis and are preventable by vaccination.

In the United States, following the introduction of a national immunization program using a whole-cell vaccine in the 1950s, cases fell significantly. After a lag phase, the adoption of an acellular vaccine in the United States in 1997 and the Netherlands in 2005 – usually in combination with diphtheria and tetanus via DTaP – saw an increase in case numbers. Dr. Diavatopoulos stated that control is no longer as good, compared with other infectious diseases prevented by the MMR vaccine, such as mumps, measles, and rubella.

In the face of increasing numbers, how do we move to the next generation of vaccines to improve control? There are several barriers to licensure, including the following:

• Universal recommendation for pertussis prevention means that more than 90% of the population will have received DTaP (usually in combination with polio and Haemophilus influenzae B) and be protected for several years after vaccination.

• Because DTaP vaccines are only efficacious for a limited time, the problem is not immediately apparent.

• Pertussis epidemics are cyclical, occurring every 3-5 years. These peaks and troughs complicate the development of epidemiological studies.

What this means is that large-scale Phase III efficacy studies, in which disease is used as the endpoint, are not feasible. Also, formal correlates of protection have not been identified.

The PERISCOPE Project started in March 2016 and is designed to respond to some of these issues. Funding is made available by a public private consortium involving the Bill & Melinda Gates foundation, the European Union, and European Federation of Pharmaceutical Industries and Associations (EFPIA) partners, and in this case, GlaxoSmithKline and Sanofi Pasteur. In total, there are 22 partners in this project.

The strategic objectives of this partnership include the following:

• Foster expertise and increase capacity in Europe to evaluate new pertussis vaccines both in clinical and preclinical models.

• Identify early biomarkers of long-lasting protective immunity to pertussis in humans. (This step will accelerate and de-risk clinical development of next generation pertussis vaccines.)

• Investigate the impact of maternal vaccination on infant response to pertussis vaccination.

The problem is that there is no one single study design that addresses all questions about the pertussis vaccine. For example, in PERISCOPE, the results of preclinical studies using the baboon or mouse models and addressing disease and colonization endpoints or immunogenicity do not perfectly model human infection and disease.

By comparison, controlled human infection studies provide information on colonization but not disease endpoints. Such studies, however, do provide information on immunogenicity endpoints. Also available are booster vaccination studies and infant vaccination studies providing data on immunogenicity, as well as safety information.

Finally, there are patient studies, such as household contact studies where immunogenicity can be correlated to disease endpoints. From these studies, it will be seen that what is needed is integration of evidence from clinical and preclinical studies to support a new vaccine registration.

PERISCOPE addresses these issues by developing novel, functional antibody and cellular assays and employing cutting-edge methods to characterize innate immune responses and cell-mediated systemic and mucosal immunity. PERISCOPE combines two major industrial partners with public researchers from academic and public health institutes and small and medium-sized enterprises with expertise in clinical trials, vaccinology, immunology, molecular microbiology, challenge models, and bioinformatics.

Andrew Gorringe, PhD, from Public Health England and the Research and Development Institute at Porton Down, Wiltshire, England, said, “Vaccines have greatly reduced the incidence of pertussis, but it remains the most prevalent ‘vaccine preventable’ disease. This is an exciting period for pertussis vaccine research as we find new ways to understand the immunity that protects from both infection and disease. The PERISCOPE project provides a collaborative environment that combines expertise across Europe to provide a route to the development of new, more effective vaccines.”

GSK and Sanofi Pasteur have cofunded the PERISCOPE Project. Dr. Diavatopoulos made no other financial disclosures.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

As the first American health care workers rolled up their sleeves for a COVID-19 vaccine, the images were instantly frozen in history, marking the triumph of scientific know-how and ingenuity. Cameras captured the first trucks pulling out of a warehouse in Portage, Mich., to the applause of workers and area residents. A day later, Boston Medical Center employees – some dressed in scrubs and wearing masks, face shields, and protective gowns – literally danced on the sidewalk when doses arrived. Some have photographed themselves getting the vaccine and posted it on social media, tagging it #MyCOVIDVax.

But the real story of the debut of COVID-19 vaccination is more methodical than monumental, a celebration of teamwork rather than of conquest. As hospitals waited for their first allotment, they reviewed their carefully drafted plans. They relied on each other, reaching across the usual divisions of competition and working collaboratively to share the limited supply. Their priority lists for the first vaccinations included environmental services workers who clean patient rooms and the critical care physicians who work to save lives.

“Health care workers have pulled together throughout this pandemic,” said Melanie Swift, MD, cochair of the COVID-19 Vaccine Allocation and Distribution Work Group at Mayo Clinic in Rochester, Minn. “We’ve gone through the darkest of years relying so heavily on each other,” she said. “Now we’re pulling together to get out of it.”

Still, a rollout of this magnitude has hitches. Stanford issued an apology Dec. 18 after its medical residents protested a vaccine distribution plan that left out nearly all of its residents and fellows, many of whom regularly treat patients with COVID-19.

There have already been more than 287,000 COVID-19 cases and 953 deaths among health care workers, according to the Centers for Disease Control and Prevention. In its guidance, the agency pointed out that the “continued protection of them at work, at home, and in the community remains a national priority.” That means vaccinating a workforce of about 21 million people, often the largest group of employees in a community.

“It collectively takes all of us to vaccinate our teams to maintain that stability in our health care infrastructure across the metro Atlanta area,” Christy Norman, PharmD, vice president of pharmacy services at Emory Healthcare, told reporters in a briefing as the health system awaited its first delivery.
 

Don’t waste a dose

One overriding imperative prevails: Hospitals don’t want to waste any doses. The storage requirements of the Pfizer vaccine make that tricky.

Once vials are removed from the pizza-box-shaped containers in ultracold storage and placed in a refrigerator, they must be used within 5 days. Thawed five-dose vials must be brought to room temperature before they are diluted, and they can remain at room temperature for no more than 2 hours. Once they are diluted with 1.8 mL of a 0.9% sodium chloride injection, the vials must be used within 6 hours.

COVID-19 precautions require employees to stay physically distant while they wait their turn for vaccination, which means the process can’t mirror typical large-scale flu immunization programs.

To prioritize groups, the vaccination planners at Mayo conducted a thorough risk stratification, considering each employee’s duties. Do they work in a dedicated COVID-19 unit? Do they handle lab tests or collect swabs? Do they work in the ICU or emergency department?

“We have applied some principles to make sure that as we roll it out, we prioritize people who are at greatest risk of ongoing exposure and who are really critical to maintaining the COVID response and other essential health services,” said Dr. Swift, associate medical director of Mayo’s occupational health service.

Mayo employees who are eligible for the first doses can sign up for appointments through the medical record system. If it seems likely that some doses will be left over at the end of the vaccination period – perhaps because of missed appointments – supervisors in high-risk areas can refer other health care workers. Mayo gave its first vaccines on Dec. 18, but the vaccination program began in earnest the following week. With the pleasant surprise that each five-dose vial actually provides six doses, 474 vials will allow for the vaccination of 2,844 employees in the top-priority group. “It’s going to expand each week or few days as we get more and more vaccine,” Dr. Swift said.
 

Sharing vials with small rural hospitals

Minnesota is using a hub-and-spoke system to give small rural hospitals access to the Pfizer vaccine, even though they lack ultracold storage and can’t use a minimum order of 975 doses. Large hospitals, acting as hubs, are sharing their orders. (The minimum order for Moderna is 100 doses.)

In south-central Minnesota, for example, two hub hospitals each have six spoke hospitals. Five of the 14 hospitals are independent, and the rest are part of large hospital systems, but affiliation doesn’t matter, said Eric Weller, regional health care preparedness coordinator for the South Central Healthcare Coalition. “We are all working together. It doesn’t matter what system you’re from,” he said. “We’re working for the good of the community.”

Each hospital designed a process to provide vaccine education, prioritize groups, allocate appointments, register people for vaccination, obtain signed consent forms, administer vaccines in a COVID-safe way, and provide follow-up appointments for the second dose. “We’re using some of the lessons we learned during H1N1,” said Mr. Weller, referring to immunization during the 2009 influenza pandemic. “The difference is that during H1N1, you could have lines of people.”

Coordinating the appointments will be more important than ever. “One of the vaccination strategies is to get people in groups of five, so you use one vial on those five people and don’t waste it,” he said.

Logistics are somewhat different for the Moderna vaccine, which will come in 10-dose vials that can be refrigerated for up to 30 days.

Both vaccines may produce mild flulike symptoms, such as fatigue, headache, or muscle pain, particularly after the second dose. That’s a sign that the immune system is reacting to the vaccine, but it’s also another consideration in the vaccination plans, because health care workers might take a day or two off work. “We’re not going to vaccinate a whole department at one time. It will be staggered,” said Kevin Smith, MD, medical director of the occupational medicine program at ProMedica, a health care system based in Toledo, Ohio.

Dr. Smith said he plans to encourage employees to use V-Safe, an app created by the CDC to track adverse effects in people who receive the vaccine. He pointed out that a day or two of achiness will be better than coping with the symptoms of COVID-19. Some employees who recovered from the infection still feel fatigued or haven’t regained their sense of taste and smell. “We are still monitoring quite a few employees to make sure they get back to 100%,” he said.
 

Hope for ending the pandemic

Public health officials have worried about vaccine hesitancy, even among health care workers, but so far, that concern seems overshadowed by enthusiasm. Dr. Smith said his department has been fielding calls from employees who want to know when they will be able to get the vaccine. “I think everyone feels relief,” he said. “We’re at the beginning of the end.”

At Mayo, Dr. Swift is surveying staff to gauge the willingness to get the vaccine, but she already senses excitement among employees. “No doubt there are still people who are hesitant, but I’m feeling a shift,” she said. “I’m feeling this momentum building of health care workers coming on board and wanting to take this vaccine, which is good, because they will set an example for their patients.”

For Colleen Kelley, MD, an infectious disease physician at Emory University in Atlanta who was principal investigator for an Emory-affiliated Moderna clinical trial site, it has been an emotional time. “Things were looking very bleak and dark for a time, and then we started to get these efficacy results that were greater than anyone imagined,” she said.

Dr. Kelley spends time talking to journalists and educating physician colleagues and hospital employees about how the vaccine was developed so quickly and how it works. “Everyone asks me, ‘Should I get it? Are you going to get it?’ My answer is ‘yes’ and ‘yes,’ “ she said. “I am 1,000% confident that the benefits of widespread vaccination outweigh the risks of continued COVID and a continued pandemic.”

A version of this article first appeared on Medscape.com.

As the first American health care workers rolled up their sleeves for a COVID-19 vaccine, the images were instantly frozen in history, marking the triumph of scientific know-how and ingenuity. Cameras captured the first trucks pulling out of a warehouse in Portage, Mich., to the applause of workers and area residents. A day later, Boston Medical Center employees – some dressed in scrubs and wearing masks, face shields, and protective gowns – literally danced on the sidewalk when doses arrived. Some have photographed themselves getting the vaccine and posted it on social media, tagging it #MyCOVIDVax.

But the real story of the debut of COVID-19 vaccination is more methodical than monumental, a celebration of teamwork rather than of conquest. As hospitals waited for their first allotment, they reviewed their carefully drafted plans. They relied on each other, reaching across the usual divisions of competition and working collaboratively to share the limited supply. Their priority lists for the first vaccinations included environmental services workers who clean patient rooms and the critical care physicians who work to save lives.

“Health care workers have pulled together throughout this pandemic,” said Melanie Swift, MD, cochair of the COVID-19 Vaccine Allocation and Distribution Work Group at Mayo Clinic in Rochester, Minn. “We’ve gone through the darkest of years relying so heavily on each other,” she said. “Now we’re pulling together to get out of it.”

Still, a rollout of this magnitude has hitches. Stanford issued an apology Dec. 18 after its medical residents protested a vaccine distribution plan that left out nearly all of its residents and fellows, many of whom regularly treat patients with COVID-19.

There have already been more than 287,000 COVID-19 cases and 953 deaths among health care workers, according to the Centers for Disease Control and Prevention. In its guidance, the agency pointed out that the “continued protection of them at work, at home, and in the community remains a national priority.” That means vaccinating a workforce of about 21 million people, often the largest group of employees in a community.

“It collectively takes all of us to vaccinate our teams to maintain that stability in our health care infrastructure across the metro Atlanta area,” Christy Norman, PharmD, vice president of pharmacy services at Emory Healthcare, told reporters in a briefing as the health system awaited its first delivery.
 

Don’t waste a dose

One overriding imperative prevails: Hospitals don’t want to waste any doses. The storage requirements of the Pfizer vaccine make that tricky.

Once vials are removed from the pizza-box-shaped containers in ultracold storage and placed in a refrigerator, they must be used within 5 days. Thawed five-dose vials must be brought to room temperature before they are diluted, and they can remain at room temperature for no more than 2 hours. Once they are diluted with 1.8 mL of a 0.9% sodium chloride injection, the vials must be used within 6 hours.

COVID-19 precautions require employees to stay physically distant while they wait their turn for vaccination, which means the process can’t mirror typical large-scale flu immunization programs.

To prioritize groups, the vaccination planners at Mayo conducted a thorough risk stratification, considering each employee’s duties. Do they work in a dedicated COVID-19 unit? Do they handle lab tests or collect swabs? Do they work in the ICU or emergency department?

“We have applied some principles to make sure that as we roll it out, we prioritize people who are at greatest risk of ongoing exposure and who are really critical to maintaining the COVID response and other essential health services,” said Dr. Swift, associate medical director of Mayo’s occupational health service.

Mayo employees who are eligible for the first doses can sign up for appointments through the medical record system. If it seems likely that some doses will be left over at the end of the vaccination period – perhaps because of missed appointments – supervisors in high-risk areas can refer other health care workers. Mayo gave its first vaccines on Dec. 18, but the vaccination program began in earnest the following week. With the pleasant surprise that each five-dose vial actually provides six doses, 474 vials will allow for the vaccination of 2,844 employees in the top-priority group. “It’s going to expand each week or few days as we get more and more vaccine,” Dr. Swift said.
 

Sharing vials with small rural hospitals

Minnesota is using a hub-and-spoke system to give small rural hospitals access to the Pfizer vaccine, even though they lack ultracold storage and can’t use a minimum order of 975 doses. Large hospitals, acting as hubs, are sharing their orders. (The minimum order for Moderna is 100 doses.)

In south-central Minnesota, for example, two hub hospitals each have six spoke hospitals. Five of the 14 hospitals are independent, and the rest are part of large hospital systems, but affiliation doesn’t matter, said Eric Weller, regional health care preparedness coordinator for the South Central Healthcare Coalition. “We are all working together. It doesn’t matter what system you’re from,” he said. “We’re working for the good of the community.”

Each hospital designed a process to provide vaccine education, prioritize groups, allocate appointments, register people for vaccination, obtain signed consent forms, administer vaccines in a COVID-safe way, and provide follow-up appointments for the second dose. “We’re using some of the lessons we learned during H1N1,” said Mr. Weller, referring to immunization during the 2009 influenza pandemic. “The difference is that during H1N1, you could have lines of people.”

Coordinating the appointments will be more important than ever. “One of the vaccination strategies is to get people in groups of five, so you use one vial on those five people and don’t waste it,” he said.

Logistics are somewhat different for the Moderna vaccine, which will come in 10-dose vials that can be refrigerated for up to 30 days.

Both vaccines may produce mild flulike symptoms, such as fatigue, headache, or muscle pain, particularly after the second dose. That’s a sign that the immune system is reacting to the vaccine, but it’s also another consideration in the vaccination plans, because health care workers might take a day or two off work. “We’re not going to vaccinate a whole department at one time. It will be staggered,” said Kevin Smith, MD, medical director of the occupational medicine program at ProMedica, a health care system based in Toledo, Ohio.

Dr. Smith said he plans to encourage employees to use V-Safe, an app created by the CDC to track adverse effects in people who receive the vaccine. He pointed out that a day or two of achiness will be better than coping with the symptoms of COVID-19. Some employees who recovered from the infection still feel fatigued or haven’t regained their sense of taste and smell. “We are still monitoring quite a few employees to make sure they get back to 100%,” he said.
 

Hope for ending the pandemic

Public health officials have worried about vaccine hesitancy, even among health care workers, but so far, that concern seems overshadowed by enthusiasm. Dr. Smith said his department has been fielding calls from employees who want to know when they will be able to get the vaccine. “I think everyone feels relief,” he said. “We’re at the beginning of the end.”

At Mayo, Dr. Swift is surveying staff to gauge the willingness to get the vaccine, but she already senses excitement among employees. “No doubt there are still people who are hesitant, but I’m feeling a shift,” she said. “I’m feeling this momentum building of health care workers coming on board and wanting to take this vaccine, which is good, because they will set an example for their patients.”

For Colleen Kelley, MD, an infectious disease physician at Emory University in Atlanta who was principal investigator for an Emory-affiliated Moderna clinical trial site, it has been an emotional time. “Things were looking very bleak and dark for a time, and then we started to get these efficacy results that were greater than anyone imagined,” she said.

Dr. Kelley spends time talking to journalists and educating physician colleagues and hospital employees about how the vaccine was developed so quickly and how it works. “Everyone asks me, ‘Should I get it? Are you going to get it?’ My answer is ‘yes’ and ‘yes,’ “ she said. “I am 1,000% confident that the benefits of widespread vaccination outweigh the risks of continued COVID and a continued pandemic.”

A version of this article first appeared on Medscape.com.

As the first American health care workers rolled up their sleeves for a COVID-19 vaccine, the images were instantly frozen in history, marking the triumph of scientific know-how and ingenuity. Cameras captured the first trucks pulling out of a warehouse in Portage, Mich., to the applause of workers and area residents. A day later, Boston Medical Center employees – some dressed in scrubs and wearing masks, face shields, and protective gowns – literally danced on the sidewalk when doses arrived. Some have photographed themselves getting the vaccine and posted it on social media, tagging it #MyCOVIDVax.

But the real story of the debut of COVID-19 vaccination is more methodical than monumental, a celebration of teamwork rather than of conquest. As hospitals waited for their first allotment, they reviewed their carefully drafted plans. They relied on each other, reaching across the usual divisions of competition and working collaboratively to share the limited supply. Their priority lists for the first vaccinations included environmental services workers who clean patient rooms and the critical care physicians who work to save lives.

“Health care workers have pulled together throughout this pandemic,” said Melanie Swift, MD, cochair of the COVID-19 Vaccine Allocation and Distribution Work Group at Mayo Clinic in Rochester, Minn. “We’ve gone through the darkest of years relying so heavily on each other,” she said. “Now we’re pulling together to get out of it.”

Still, a rollout of this magnitude has hitches. Stanford issued an apology Dec. 18 after its medical residents protested a vaccine distribution plan that left out nearly all of its residents and fellows, many of whom regularly treat patients with COVID-19.

There have already been more than 287,000 COVID-19 cases and 953 deaths among health care workers, according to the Centers for Disease Control and Prevention. In its guidance, the agency pointed out that the “continued protection of them at work, at home, and in the community remains a national priority.” That means vaccinating a workforce of about 21 million people, often the largest group of employees in a community.

“It collectively takes all of us to vaccinate our teams to maintain that stability in our health care infrastructure across the metro Atlanta area,” Christy Norman, PharmD, vice president of pharmacy services at Emory Healthcare, told reporters in a briefing as the health system awaited its first delivery.
 

Don’t waste a dose

One overriding imperative prevails: Hospitals don’t want to waste any doses. The storage requirements of the Pfizer vaccine make that tricky.

Once vials are removed from the pizza-box-shaped containers in ultracold storage and placed in a refrigerator, they must be used within 5 days. Thawed five-dose vials must be brought to room temperature before they are diluted, and they can remain at room temperature for no more than 2 hours. Once they are diluted with 1.8 mL of a 0.9% sodium chloride injection, the vials must be used within 6 hours.

COVID-19 precautions require employees to stay physically distant while they wait their turn for vaccination, which means the process can’t mirror typical large-scale flu immunization programs.

To prioritize groups, the vaccination planners at Mayo conducted a thorough risk stratification, considering each employee’s duties. Do they work in a dedicated COVID-19 unit? Do they handle lab tests or collect swabs? Do they work in the ICU or emergency department?

“We have applied some principles to make sure that as we roll it out, we prioritize people who are at greatest risk of ongoing exposure and who are really critical to maintaining the COVID response and other essential health services,” said Dr. Swift, associate medical director of Mayo’s occupational health service.

Mayo employees who are eligible for the first doses can sign up for appointments through the medical record system. If it seems likely that some doses will be left over at the end of the vaccination period – perhaps because of missed appointments – supervisors in high-risk areas can refer other health care workers. Mayo gave its first vaccines on Dec. 18, but the vaccination program began in earnest the following week. With the pleasant surprise that each five-dose vial actually provides six doses, 474 vials will allow for the vaccination of 2,844 employees in the top-priority group. “It’s going to expand each week or few days as we get more and more vaccine,” Dr. Swift said.
 

Sharing vials with small rural hospitals

Minnesota is using a hub-and-spoke system to give small rural hospitals access to the Pfizer vaccine, even though they lack ultracold storage and can’t use a minimum order of 975 doses. Large hospitals, acting as hubs, are sharing their orders. (The minimum order for Moderna is 100 doses.)

In south-central Minnesota, for example, two hub hospitals each have six spoke hospitals. Five of the 14 hospitals are independent, and the rest are part of large hospital systems, but affiliation doesn’t matter, said Eric Weller, regional health care preparedness coordinator for the South Central Healthcare Coalition. “We are all working together. It doesn’t matter what system you’re from,” he said. “We’re working for the good of the community.”

Each hospital designed a process to provide vaccine education, prioritize groups, allocate appointments, register people for vaccination, obtain signed consent forms, administer vaccines in a COVID-safe way, and provide follow-up appointments for the second dose. “We’re using some of the lessons we learned during H1N1,” said Mr. Weller, referring to immunization during the 2009 influenza pandemic. “The difference is that during H1N1, you could have lines of people.”

Coordinating the appointments will be more important than ever. “One of the vaccination strategies is to get people in groups of five, so you use one vial on those five people and don’t waste it,” he said.

Logistics are somewhat different for the Moderna vaccine, which will come in 10-dose vials that can be refrigerated for up to 30 days.

Both vaccines may produce mild flulike symptoms, such as fatigue, headache, or muscle pain, particularly after the second dose. That’s a sign that the immune system is reacting to the vaccine, but it’s also another consideration in the vaccination plans, because health care workers might take a day or two off work. “We’re not going to vaccinate a whole department at one time. It will be staggered,” said Kevin Smith, MD, medical director of the occupational medicine program at ProMedica, a health care system based in Toledo, Ohio.

Dr. Smith said he plans to encourage employees to use V-Safe, an app created by the CDC to track adverse effects in people who receive the vaccine. He pointed out that a day or two of achiness will be better than coping with the symptoms of COVID-19. Some employees who recovered from the infection still feel fatigued or haven’t regained their sense of taste and smell. “We are still monitoring quite a few employees to make sure they get back to 100%,” he said.
 

Hope for ending the pandemic

Public health officials have worried about vaccine hesitancy, even among health care workers, but so far, that concern seems overshadowed by enthusiasm. Dr. Smith said his department has been fielding calls from employees who want to know when they will be able to get the vaccine. “I think everyone feels relief,” he said. “We’re at the beginning of the end.”

At Mayo, Dr. Swift is surveying staff to gauge the willingness to get the vaccine, but she already senses excitement among employees. “No doubt there are still people who are hesitant, but I’m feeling a shift,” she said. “I’m feeling this momentum building of health care workers coming on board and wanting to take this vaccine, which is good, because they will set an example for their patients.”

For Colleen Kelley, MD, an infectious disease physician at Emory University in Atlanta who was principal investigator for an Emory-affiliated Moderna clinical trial site, it has been an emotional time. “Things were looking very bleak and dark for a time, and then we started to get these efficacy results that were greater than anyone imagined,” she said.

Dr. Kelley spends time talking to journalists and educating physician colleagues and hospital employees about how the vaccine was developed so quickly and how it works. “Everyone asks me, ‘Should I get it? Are you going to get it?’ My answer is ‘yes’ and ‘yes,’ “ she said. “I am 1,000% confident that the benefits of widespread vaccination outweigh the risks of continued COVID and a continued pandemic.”

A version of this article first appeared on Medscape.com.