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New RSV vaccine immunogenicity improved with protein engineering
Development of an effective respiratory syncytial virus (RSV) vaccine is feasible using a new technology that can contribute to development of other vaccines as well, according to results of a proof-of-concept study in Science.
The new method of protein engineering preserves the RSV antigen protein’s prefusion structure, including the epitope, thereby inducing antibodies that better “match,” and neutralize, the actual pathogen.
“Protein-based RSV vaccines have had a particularly complicated history, especially those in which the primary immunogen has been the fusion (F) glycoprotein, which exists in two major conformational states: prefusion (pre-F) and postfusion (post-F),” lead author Michelle Crank, MD, of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and her colleagues explained in the paper.
Since the failure of the whole-inactivated RSV vaccine in the 1960s, researchers have focused on F subunit vaccine candidates, but these contain only post-F or “structurally undefined” F protein.
“Although the products are immunogenic, a substantial proportion of antibodies elicited are non- or poorly neutralizing, and field trials have shown no or minimal efficacy,” the authors wrote.
But now researchers have an “atomic-level understanding of F conformational states, antigenic sites, and the specificity of the human B cell repertoire and serum antibody response to infection.” Having developed a way to engineer proteins to retain the F protein’s prefusion conformation, the researchers developed the DS-Cav1 vaccine with an F protein from RSV subtype A.
In their phase 1, randomized, open-label clinical trial, the researchers tested the safety, tolerability and immunogenicity of DS-Cav1. The trial involved 90 healthy adults, aged 18-50, who had no abnormal findings in clinical lab tests, their medical history, or a physical exam.
The participants received two intramuscular doses, 12 weeks apart, of either 50 mcg, 150 mcg or 500 mcg of the vaccine. In each of these dosage groups, half the participants received a vaccine with 0.5 mcg of alum as an adjuvant, and half received a vaccine without any adjuvants. Each of the six randomized dosage-adjuvant groups had 15 participants.
The investigators report on safety and immunogenicity through 28 days after the first vaccine dose among the first 40 participants enrolled, each randomly assigned into four groups of 10 for the 50 mcg and 150 mcg doses with and without the adjuvant. Their primary immunogenicity endpoint was neutralizing activity from the vaccine.
Neutralizing activity with RSV A was seven times higher with 50 mcg and 12-15 times higher with 150 mcg at week 4 than at baseline (P less than .001).
“These increases in neutralizing activity were higher than those previously reported for F protein subunit vaccines and exceeded the threefold increase in neutralization reported after experimental human challenge with RSV,” the authors noted. Neutralization levels remained 5-10 times higher than baseline at week 12 (P less than .001).
Even with RSV B, neutralizing activity from DS-Cav1 was 4-6 times greater with 50 mcg and 9 times greater with 150 mcg, both with and without alum (P less than .001).
“The boost in neutralizing activity to subtype B after a single immunization with a subtype A–based F vaccine reflected the high conservation of F between subtypes and suggested that multiple prior infections by both RSV A and B subtypes establishes a broad preexisting B-cell repertoire,” the authors wrote.
The adjuvant had no clinically significant effect on immunogenicity, and no serious adverse events occurred in the groups.
The findings reveal that DS-Cav1 induces antibodies far more functionally effective than seen in previous RSV vaccines while opening the door to using similar techniques with other vaccines, the authors wrote. “We are now entering an era of vaccinology in which new technologies provide avenues to define the structural basis of antigenicity and to rapidly isolate and characterize human monoclonal antibodies,” the researchers wrote, marking “a step toward a future of precision vaccines.”
The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several of the study authors are inventors on patents for stabilizing the RSV F protein.
Development of an effective respiratory syncytial virus (RSV) vaccine is feasible using a new technology that can contribute to development of other vaccines as well, according to results of a proof-of-concept study in Science.
The new method of protein engineering preserves the RSV antigen protein’s prefusion structure, including the epitope, thereby inducing antibodies that better “match,” and neutralize, the actual pathogen.
“Protein-based RSV vaccines have had a particularly complicated history, especially those in which the primary immunogen has been the fusion (F) glycoprotein, which exists in two major conformational states: prefusion (pre-F) and postfusion (post-F),” lead author Michelle Crank, MD, of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and her colleagues explained in the paper.
Since the failure of the whole-inactivated RSV vaccine in the 1960s, researchers have focused on F subunit vaccine candidates, but these contain only post-F or “structurally undefined” F protein.
“Although the products are immunogenic, a substantial proportion of antibodies elicited are non- or poorly neutralizing, and field trials have shown no or minimal efficacy,” the authors wrote.
But now researchers have an “atomic-level understanding of F conformational states, antigenic sites, and the specificity of the human B cell repertoire and serum antibody response to infection.” Having developed a way to engineer proteins to retain the F protein’s prefusion conformation, the researchers developed the DS-Cav1 vaccine with an F protein from RSV subtype A.
In their phase 1, randomized, open-label clinical trial, the researchers tested the safety, tolerability and immunogenicity of DS-Cav1. The trial involved 90 healthy adults, aged 18-50, who had no abnormal findings in clinical lab tests, their medical history, or a physical exam.
The participants received two intramuscular doses, 12 weeks apart, of either 50 mcg, 150 mcg or 500 mcg of the vaccine. In each of these dosage groups, half the participants received a vaccine with 0.5 mcg of alum as an adjuvant, and half received a vaccine without any adjuvants. Each of the six randomized dosage-adjuvant groups had 15 participants.
The investigators report on safety and immunogenicity through 28 days after the first vaccine dose among the first 40 participants enrolled, each randomly assigned into four groups of 10 for the 50 mcg and 150 mcg doses with and without the adjuvant. Their primary immunogenicity endpoint was neutralizing activity from the vaccine.
Neutralizing activity with RSV A was seven times higher with 50 mcg and 12-15 times higher with 150 mcg at week 4 than at baseline (P less than .001).
“These increases in neutralizing activity were higher than those previously reported for F protein subunit vaccines and exceeded the threefold increase in neutralization reported after experimental human challenge with RSV,” the authors noted. Neutralization levels remained 5-10 times higher than baseline at week 12 (P less than .001).
Even with RSV B, neutralizing activity from DS-Cav1 was 4-6 times greater with 50 mcg and 9 times greater with 150 mcg, both with and without alum (P less than .001).
“The boost in neutralizing activity to subtype B after a single immunization with a subtype A–based F vaccine reflected the high conservation of F between subtypes and suggested that multiple prior infections by both RSV A and B subtypes establishes a broad preexisting B-cell repertoire,” the authors wrote.
The adjuvant had no clinically significant effect on immunogenicity, and no serious adverse events occurred in the groups.
The findings reveal that DS-Cav1 induces antibodies far more functionally effective than seen in previous RSV vaccines while opening the door to using similar techniques with other vaccines, the authors wrote. “We are now entering an era of vaccinology in which new technologies provide avenues to define the structural basis of antigenicity and to rapidly isolate and characterize human monoclonal antibodies,” the researchers wrote, marking “a step toward a future of precision vaccines.”
The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several of the study authors are inventors on patents for stabilizing the RSV F protein.
Development of an effective respiratory syncytial virus (RSV) vaccine is feasible using a new technology that can contribute to development of other vaccines as well, according to results of a proof-of-concept study in Science.
The new method of protein engineering preserves the RSV antigen protein’s prefusion structure, including the epitope, thereby inducing antibodies that better “match,” and neutralize, the actual pathogen.
“Protein-based RSV vaccines have had a particularly complicated history, especially those in which the primary immunogen has been the fusion (F) glycoprotein, which exists in two major conformational states: prefusion (pre-F) and postfusion (post-F),” lead author Michelle Crank, MD, of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and her colleagues explained in the paper.
Since the failure of the whole-inactivated RSV vaccine in the 1960s, researchers have focused on F subunit vaccine candidates, but these contain only post-F or “structurally undefined” F protein.
“Although the products are immunogenic, a substantial proportion of antibodies elicited are non- or poorly neutralizing, and field trials have shown no or minimal efficacy,” the authors wrote.
But now researchers have an “atomic-level understanding of F conformational states, antigenic sites, and the specificity of the human B cell repertoire and serum antibody response to infection.” Having developed a way to engineer proteins to retain the F protein’s prefusion conformation, the researchers developed the DS-Cav1 vaccine with an F protein from RSV subtype A.
In their phase 1, randomized, open-label clinical trial, the researchers tested the safety, tolerability and immunogenicity of DS-Cav1. The trial involved 90 healthy adults, aged 18-50, who had no abnormal findings in clinical lab tests, their medical history, or a physical exam.
The participants received two intramuscular doses, 12 weeks apart, of either 50 mcg, 150 mcg or 500 mcg of the vaccine. In each of these dosage groups, half the participants received a vaccine with 0.5 mcg of alum as an adjuvant, and half received a vaccine without any adjuvants. Each of the six randomized dosage-adjuvant groups had 15 participants.
The investigators report on safety and immunogenicity through 28 days after the first vaccine dose among the first 40 participants enrolled, each randomly assigned into four groups of 10 for the 50 mcg and 150 mcg doses with and without the adjuvant. Their primary immunogenicity endpoint was neutralizing activity from the vaccine.
Neutralizing activity with RSV A was seven times higher with 50 mcg and 12-15 times higher with 150 mcg at week 4 than at baseline (P less than .001).
“These increases in neutralizing activity were higher than those previously reported for F protein subunit vaccines and exceeded the threefold increase in neutralization reported after experimental human challenge with RSV,” the authors noted. Neutralization levels remained 5-10 times higher than baseline at week 12 (P less than .001).
Even with RSV B, neutralizing activity from DS-Cav1 was 4-6 times greater with 50 mcg and 9 times greater with 150 mcg, both with and without alum (P less than .001).
“The boost in neutralizing activity to subtype B after a single immunization with a subtype A–based F vaccine reflected the high conservation of F between subtypes and suggested that multiple prior infections by both RSV A and B subtypes establishes a broad preexisting B-cell repertoire,” the authors wrote.
The adjuvant had no clinically significant effect on immunogenicity, and no serious adverse events occurred in the groups.
The findings reveal that DS-Cav1 induces antibodies far more functionally effective than seen in previous RSV vaccines while opening the door to using similar techniques with other vaccines, the authors wrote. “We are now entering an era of vaccinology in which new technologies provide avenues to define the structural basis of antigenicity and to rapidly isolate and characterize human monoclonal antibodies,” the researchers wrote, marking “a step toward a future of precision vaccines.”
The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several of the study authors are inventors on patents for stabilizing the RSV F protein.
FROM SCIENCE
Key clinical point:
Major finding: Epitope-neutralizing activity is 5-10 times greater 12 weeks after baseline with a 50 mcg or 150 mcg with and without alum adjuvant.
Study details: The findings are based on a prespecified interim analysis of 90 healthy adult participants in a phase 1, randomized, trial of DS-Cav1.
Disclosures: The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several authors are inventors on patents for stabilizing the RSV F protein.
Source: Crank MC et al. Science. 2019;365(6452):505-9.
mRNA technology for respiratory vaccines impresses
LJUBLJANA, SLOVENIA – Encouraging safety and immunogenicity results reported from phase 1 studies of the first mRNA vaccines against the potentially pandemic H10N8 avian influenza and H7N9 influenza viruses suggest a bright future for what appears to be a breakthrough technology in vaccine development.
“We have developed an mRNA platform that has the potential to be quite applicable to the vaccine space. It’s an agile platform with the potential for relatively rapid development of vaccine antigen without the use of dedicated facilities, or growth in eggs, or insects, or mammalian cells,” Lori Panther, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We now have a platform that is relatively plug and play. If one has the mRNA sequence that you’re after to produce the protein that you’re after, it is a relatively repetitive process somewhat irrespective of the goal of the protein that you’re going to manufacture. We’re introducing an mRNA into our cellular machinery – the destination is the cellular ribosome – where it hopefully is able to be translated with fidelity into the target protein. Essentially it’s like the biological equivalent of a software hack for our own cells,” explained Dr. Panther, who is director of clinical development for infectious diseases at Moderna, in Cambridge, Mass.
Indeed, Moderna has numerous ongoing or recently completed phase 1 clinical trials of mRNA vaccines developed to protect against a raft of viral infections: respiratory syncytial virus, cytomegalovirus (NCT03382405), zika, chikungunya (NCT03829384), human metapneumovirus, and parainfluenza virus 3, as well as the aforementioned H10N8 and H7N9 influenza viruses. And an mRNA varicella zoster virus vaccine is in preclinical studies.
The mRNA vaccines closely mimic native viral infections, eliciting both B- and T-cell responses.
Moreover, the company also has ongoing phase 1 studies of mRNA-based cancer vaccines – therapies targeting solid tumors and lymphomas – as well as mRNA-directed increased production of relaxin as a treatment for heart failure and of vascular endothelial growth factor to treat myocardial ischemia.
“For the purposes of my company, the desired protein at this juncture could be an antibody, it could be a tumor antigen, it could be an enzyme that will replace an enzyme that’s lacking in somebody with an inborn error of metabolism. Or it could be a vaccine antigen target,” Dr. Panther said.
In addition to highlighting the results of the two phase 1 proof-of-concept studies of mRNA vaccines targeting the feared H10N8 and H7N9 influenza viruses, she presented interim results of an ongoing 1-year study of an mRNA vaccine that contains two antigens simultaneously targeting human metapneumovirus (hMPV) and parainfluenza virus 3 (PIV3).
“The rationale behind this study is that, taken together, these are two viruses that are responsible for a fair bit of disease burden in terms of lower respiratory tract infections and hospitalizations in children [younger] than 12 months of age, which will be the target population,” the infectious disease specialist noted.
The early positive results of the mRNA influenza vaccine studies were of particular interest to her audience of pediatric infectious disease specialists. Since the first human H7N9 infections were reported in China in 2013, five outbreaks have occurred involving more than 1,500 documented infections, resulting in more than 600 deaths. And ever since the virulent H10N8 avian influenza virus popped up on the radar in 2013, infectious disease physicians the world over have been waiting for the other shoe to drop.
There is obvious appeal to a novel, precise, and rapidly scalable technology such as that promised by intracellular delivery of mRNA in order to ramp up high-volume production of effective vaccines in the face of a looming pandemic threat. Elsewhere at the meeting, it was noted that, during the H1N1 pandemic of 2009, it took 6 months for the first vaccine doses to become available using current antiquated egg-based production methods. Another 2 months elapsed before the necessary millions of doses were produced.
The details of the two phase 1 studies of the mRNA vaccines against H7N9 and H10N8 influenza have recently been published (Vaccine. 2019 May 31;37[25]:3326-34). The vaccines, delivered in the conventional manner via injection into the deltoid muscle, were well tolerated, with the most common adverse events being the familiar ones: injection site pain, erythema, headache, fatigue, and myalgia. The immune response was robust and durable.
In response to an audience question, Dr. Panther said the mRNA vaccines are amenable to development as intranasal formulations.
The ongoing 12-month, phase 1, dose-ranging study of the mRNA hMPV/PIV3 virus vaccine includes 124 healthy adults at three U.S. sites who received two vaccinations on days 1 and 28. One month after a single vaccination, hMPV neutralizing antibody titers were 6.2-6.4 times those in the placebo arm; PIV3 neutralization titers were increased 3.3-fold. The second injection didn’t further boost antibody titers, suggesting that, at least in this study population of preexposed adults, a single vaccination is sufficient.
The use of mRNA technology has been a long time in coming. Dr. Panther explained why: “It’s a big trick to take an mRNA that by its own nature is a pretty fragile molecule and to get it past the degrading enzymes, like RNAses, that are out to chew it up immediately, and then to sneak it across the cellular membrane and into the cytoplasm, all the while avoiding the innate immune responses that exist solely to recognize RNA that looks foreign and chew it up.”
Moderna has accomplished this using a proprietary lipid nanoparticle delivery system.
“Essentially it’s a lipid shield that surrounds the mRNAs and ushers them past those enzymes and past the innate immune response that would otherwise destroy them,” according to Dr. Panther.
She and her colleagues believe they may eventually be able to change the nucleotide sequence of their manufactured mRNAs in order to expand the immunogenicity epitope and achieve a stronger immune response than would result from natural infection.
LJUBLJANA, SLOVENIA – Encouraging safety and immunogenicity results reported from phase 1 studies of the first mRNA vaccines against the potentially pandemic H10N8 avian influenza and H7N9 influenza viruses suggest a bright future for what appears to be a breakthrough technology in vaccine development.
“We have developed an mRNA platform that has the potential to be quite applicable to the vaccine space. It’s an agile platform with the potential for relatively rapid development of vaccine antigen without the use of dedicated facilities, or growth in eggs, or insects, or mammalian cells,” Lori Panther, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We now have a platform that is relatively plug and play. If one has the mRNA sequence that you’re after to produce the protein that you’re after, it is a relatively repetitive process somewhat irrespective of the goal of the protein that you’re going to manufacture. We’re introducing an mRNA into our cellular machinery – the destination is the cellular ribosome – where it hopefully is able to be translated with fidelity into the target protein. Essentially it’s like the biological equivalent of a software hack for our own cells,” explained Dr. Panther, who is director of clinical development for infectious diseases at Moderna, in Cambridge, Mass.
Indeed, Moderna has numerous ongoing or recently completed phase 1 clinical trials of mRNA vaccines developed to protect against a raft of viral infections: respiratory syncytial virus, cytomegalovirus (NCT03382405), zika, chikungunya (NCT03829384), human metapneumovirus, and parainfluenza virus 3, as well as the aforementioned H10N8 and H7N9 influenza viruses. And an mRNA varicella zoster virus vaccine is in preclinical studies.
The mRNA vaccines closely mimic native viral infections, eliciting both B- and T-cell responses.
Moreover, the company also has ongoing phase 1 studies of mRNA-based cancer vaccines – therapies targeting solid tumors and lymphomas – as well as mRNA-directed increased production of relaxin as a treatment for heart failure and of vascular endothelial growth factor to treat myocardial ischemia.
“For the purposes of my company, the desired protein at this juncture could be an antibody, it could be a tumor antigen, it could be an enzyme that will replace an enzyme that’s lacking in somebody with an inborn error of metabolism. Or it could be a vaccine antigen target,” Dr. Panther said.
In addition to highlighting the results of the two phase 1 proof-of-concept studies of mRNA vaccines targeting the feared H10N8 and H7N9 influenza viruses, she presented interim results of an ongoing 1-year study of an mRNA vaccine that contains two antigens simultaneously targeting human metapneumovirus (hMPV) and parainfluenza virus 3 (PIV3).
“The rationale behind this study is that, taken together, these are two viruses that are responsible for a fair bit of disease burden in terms of lower respiratory tract infections and hospitalizations in children [younger] than 12 months of age, which will be the target population,” the infectious disease specialist noted.
The early positive results of the mRNA influenza vaccine studies were of particular interest to her audience of pediatric infectious disease specialists. Since the first human H7N9 infections were reported in China in 2013, five outbreaks have occurred involving more than 1,500 documented infections, resulting in more than 600 deaths. And ever since the virulent H10N8 avian influenza virus popped up on the radar in 2013, infectious disease physicians the world over have been waiting for the other shoe to drop.
There is obvious appeal to a novel, precise, and rapidly scalable technology such as that promised by intracellular delivery of mRNA in order to ramp up high-volume production of effective vaccines in the face of a looming pandemic threat. Elsewhere at the meeting, it was noted that, during the H1N1 pandemic of 2009, it took 6 months for the first vaccine doses to become available using current antiquated egg-based production methods. Another 2 months elapsed before the necessary millions of doses were produced.
The details of the two phase 1 studies of the mRNA vaccines against H7N9 and H10N8 influenza have recently been published (Vaccine. 2019 May 31;37[25]:3326-34). The vaccines, delivered in the conventional manner via injection into the deltoid muscle, were well tolerated, with the most common adverse events being the familiar ones: injection site pain, erythema, headache, fatigue, and myalgia. The immune response was robust and durable.
In response to an audience question, Dr. Panther said the mRNA vaccines are amenable to development as intranasal formulations.
The ongoing 12-month, phase 1, dose-ranging study of the mRNA hMPV/PIV3 virus vaccine includes 124 healthy adults at three U.S. sites who received two vaccinations on days 1 and 28. One month after a single vaccination, hMPV neutralizing antibody titers were 6.2-6.4 times those in the placebo arm; PIV3 neutralization titers were increased 3.3-fold. The second injection didn’t further boost antibody titers, suggesting that, at least in this study population of preexposed adults, a single vaccination is sufficient.
The use of mRNA technology has been a long time in coming. Dr. Panther explained why: “It’s a big trick to take an mRNA that by its own nature is a pretty fragile molecule and to get it past the degrading enzymes, like RNAses, that are out to chew it up immediately, and then to sneak it across the cellular membrane and into the cytoplasm, all the while avoiding the innate immune responses that exist solely to recognize RNA that looks foreign and chew it up.”
Moderna has accomplished this using a proprietary lipid nanoparticle delivery system.
“Essentially it’s a lipid shield that surrounds the mRNAs and ushers them past those enzymes and past the innate immune response that would otherwise destroy them,” according to Dr. Panther.
She and her colleagues believe they may eventually be able to change the nucleotide sequence of their manufactured mRNAs in order to expand the immunogenicity epitope and achieve a stronger immune response than would result from natural infection.
LJUBLJANA, SLOVENIA – Encouraging safety and immunogenicity results reported from phase 1 studies of the first mRNA vaccines against the potentially pandemic H10N8 avian influenza and H7N9 influenza viruses suggest a bright future for what appears to be a breakthrough technology in vaccine development.
“We have developed an mRNA platform that has the potential to be quite applicable to the vaccine space. It’s an agile platform with the potential for relatively rapid development of vaccine antigen without the use of dedicated facilities, or growth in eggs, or insects, or mammalian cells,” Lori Panther, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We now have a platform that is relatively plug and play. If one has the mRNA sequence that you’re after to produce the protein that you’re after, it is a relatively repetitive process somewhat irrespective of the goal of the protein that you’re going to manufacture. We’re introducing an mRNA into our cellular machinery – the destination is the cellular ribosome – where it hopefully is able to be translated with fidelity into the target protein. Essentially it’s like the biological equivalent of a software hack for our own cells,” explained Dr. Panther, who is director of clinical development for infectious diseases at Moderna, in Cambridge, Mass.
Indeed, Moderna has numerous ongoing or recently completed phase 1 clinical trials of mRNA vaccines developed to protect against a raft of viral infections: respiratory syncytial virus, cytomegalovirus (NCT03382405), zika, chikungunya (NCT03829384), human metapneumovirus, and parainfluenza virus 3, as well as the aforementioned H10N8 and H7N9 influenza viruses. And an mRNA varicella zoster virus vaccine is in preclinical studies.
The mRNA vaccines closely mimic native viral infections, eliciting both B- and T-cell responses.
Moreover, the company also has ongoing phase 1 studies of mRNA-based cancer vaccines – therapies targeting solid tumors and lymphomas – as well as mRNA-directed increased production of relaxin as a treatment for heart failure and of vascular endothelial growth factor to treat myocardial ischemia.
“For the purposes of my company, the desired protein at this juncture could be an antibody, it could be a tumor antigen, it could be an enzyme that will replace an enzyme that’s lacking in somebody with an inborn error of metabolism. Or it could be a vaccine antigen target,” Dr. Panther said.
In addition to highlighting the results of the two phase 1 proof-of-concept studies of mRNA vaccines targeting the feared H10N8 and H7N9 influenza viruses, she presented interim results of an ongoing 1-year study of an mRNA vaccine that contains two antigens simultaneously targeting human metapneumovirus (hMPV) and parainfluenza virus 3 (PIV3).
“The rationale behind this study is that, taken together, these are two viruses that are responsible for a fair bit of disease burden in terms of lower respiratory tract infections and hospitalizations in children [younger] than 12 months of age, which will be the target population,” the infectious disease specialist noted.
The early positive results of the mRNA influenza vaccine studies were of particular interest to her audience of pediatric infectious disease specialists. Since the first human H7N9 infections were reported in China in 2013, five outbreaks have occurred involving more than 1,500 documented infections, resulting in more than 600 deaths. And ever since the virulent H10N8 avian influenza virus popped up on the radar in 2013, infectious disease physicians the world over have been waiting for the other shoe to drop.
There is obvious appeal to a novel, precise, and rapidly scalable technology such as that promised by intracellular delivery of mRNA in order to ramp up high-volume production of effective vaccines in the face of a looming pandemic threat. Elsewhere at the meeting, it was noted that, during the H1N1 pandemic of 2009, it took 6 months for the first vaccine doses to become available using current antiquated egg-based production methods. Another 2 months elapsed before the necessary millions of doses were produced.
The details of the two phase 1 studies of the mRNA vaccines against H7N9 and H10N8 influenza have recently been published (Vaccine. 2019 May 31;37[25]:3326-34). The vaccines, delivered in the conventional manner via injection into the deltoid muscle, were well tolerated, with the most common adverse events being the familiar ones: injection site pain, erythema, headache, fatigue, and myalgia. The immune response was robust and durable.
In response to an audience question, Dr. Panther said the mRNA vaccines are amenable to development as intranasal formulations.
The ongoing 12-month, phase 1, dose-ranging study of the mRNA hMPV/PIV3 virus vaccine includes 124 healthy adults at three U.S. sites who received two vaccinations on days 1 and 28. One month after a single vaccination, hMPV neutralizing antibody titers were 6.2-6.4 times those in the placebo arm; PIV3 neutralization titers were increased 3.3-fold. The second injection didn’t further boost antibody titers, suggesting that, at least in this study population of preexposed adults, a single vaccination is sufficient.
The use of mRNA technology has been a long time in coming. Dr. Panther explained why: “It’s a big trick to take an mRNA that by its own nature is a pretty fragile molecule and to get it past the degrading enzymes, like RNAses, that are out to chew it up immediately, and then to sneak it across the cellular membrane and into the cytoplasm, all the while avoiding the innate immune responses that exist solely to recognize RNA that looks foreign and chew it up.”
Moderna has accomplished this using a proprietary lipid nanoparticle delivery system.
“Essentially it’s a lipid shield that surrounds the mRNAs and ushers them past those enzymes and past the innate immune response that would otherwise destroy them,” according to Dr. Panther.
She and her colleagues believe they may eventually be able to change the nucleotide sequence of their manufactured mRNAs in order to expand the immunogenicity epitope and achieve a stronger immune response than would result from natural infection.
REPORTING FROM ESPID 2019
Vaccination is not associated with increased risk of MS
(MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.
To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.
Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.
The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.
The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.
The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.
A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.
SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.
The analysis by Hapfelmeier et al. provides important evidence that vaccinations are not associated with multiple sclerosis (MS), said E. Ann Yeh, MD, a neurologist at the Hospital for Sick Children in Toronto, and Jennifer Graves, MD, PhD, a neurologist at the University of California, San Diego, in an accompanying editorial. On the contrary, the evidence supports a potential protective effect of vaccines on the risk of developing MS, they said.
“The reasons for this [finding] cannot be gleaned from this study and may range from biological to sociocultural/demographic reasons,” the authors added. “Infection, rather than vaccination, may be an MS trigger, or individuals obtaining vaccinations may be practicing other healthy behaviors protective for MS. These possibilities should be the subject of future studies.”
Until future studies are completed and their results published, the findings of Hapfelmeier et al. offer “strong evidence to share with worried patients and families when faced with the question of whether a vaccine in the recent or relatively distant past triggered the individual’s MS,” said Dr. Yeh and Dr. Graves.
The authors had various relationships with industry, including serving on advisory boards for and receiving funding from pharmaceutical companies.
The analysis by Hapfelmeier et al. provides important evidence that vaccinations are not associated with multiple sclerosis (MS), said E. Ann Yeh, MD, a neurologist at the Hospital for Sick Children in Toronto, and Jennifer Graves, MD, PhD, a neurologist at the University of California, San Diego, in an accompanying editorial. On the contrary, the evidence supports a potential protective effect of vaccines on the risk of developing MS, they said.
“The reasons for this [finding] cannot be gleaned from this study and may range from biological to sociocultural/demographic reasons,” the authors added. “Infection, rather than vaccination, may be an MS trigger, or individuals obtaining vaccinations may be practicing other healthy behaviors protective for MS. These possibilities should be the subject of future studies.”
Until future studies are completed and their results published, the findings of Hapfelmeier et al. offer “strong evidence to share with worried patients and families when faced with the question of whether a vaccine in the recent or relatively distant past triggered the individual’s MS,” said Dr. Yeh and Dr. Graves.
The authors had various relationships with industry, including serving on advisory boards for and receiving funding from pharmaceutical companies.
The analysis by Hapfelmeier et al. provides important evidence that vaccinations are not associated with multiple sclerosis (MS), said E. Ann Yeh, MD, a neurologist at the Hospital for Sick Children in Toronto, and Jennifer Graves, MD, PhD, a neurologist at the University of California, San Diego, in an accompanying editorial. On the contrary, the evidence supports a potential protective effect of vaccines on the risk of developing MS, they said.
“The reasons for this [finding] cannot be gleaned from this study and may range from biological to sociocultural/demographic reasons,” the authors added. “Infection, rather than vaccination, may be an MS trigger, or individuals obtaining vaccinations may be practicing other healthy behaviors protective for MS. These possibilities should be the subject of future studies.”
Until future studies are completed and their results published, the findings of Hapfelmeier et al. offer “strong evidence to share with worried patients and families when faced with the question of whether a vaccine in the recent or relatively distant past triggered the individual’s MS,” said Dr. Yeh and Dr. Graves.
The authors had various relationships with industry, including serving on advisory boards for and receiving funding from pharmaceutical companies.
(MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.
To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.
Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.
The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.
The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.
The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.
A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.
SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.
(MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.
To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.
Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.
The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.
The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.
The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.
A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.
SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.
FROM NEUROLOGY
Shoulder Injury Related to Vaccine Administration: A Rare Reaction
Localized reactions and transient pain at the site of vaccine administration are frequent and well-described occurrences that are typically short-lived and mild in nature. The most common findings at the injection site are soreness, erythema, and edema.1 Although less common, generalized shoulder dysfunction after vaccine administration also has been reported. Bodor and colleagues described a peri-articular inflammatory response that led to shoulder pain and weakness.2 A single case report by Kuether and colleagues described atraumatic osteonecrosis of the humeral head after H1N1 vaccine administration in the deltoid.3 In 2010, shoulder injury related to vaccine administration (SIRVA) was described by Atanasoff and colleagues as the rapid onset of shoulder pain and dysfunction persisting as a complication of deltoid muscle vaccination in a case series of 13 patients.4 In our report, we present a case of an active-duty male eventually diagnosed with SIRVA after influenza vaccination and discuss factors that may prevent vaccine-related shoulder injuries.
Case Presentation
A 31-year-old active-duty male presented to the Allergy clinic for evaluation of persistent left shoulder pain and decreased range of motion (ROM) following influenza vaccination 4 months prior. He reported a history of chronic low back and right shoulder pain. Although the patient had a traumatic injury to his right shoulder, which was corrected with surgery, he had no surgeries on the left shoulder. He reported no prior pain or known trauma to his left shoulder. He had no personal or family history of atopy or vaccine reactions.
The patient weighed 91 kg and received an intramuscular (IM) quadrivalent influenza vaccine with a 25-gauge, 1-inch needle during a mass influenza immunization. He recalled that the site of vaccination was slightly more than 3 cm below the top of the shoulder in a region correlating to the left deltoid. The vaccine was administered while he was standing with his arm extended, adducted, and internally rotated. The patient experienced intense pain immediately after the vaccination and noted decreased ROM. Initially, he dismissed the pain and decreased ROM as routine but sought medical attention when there was no improvement after 3 weeks.
Six weeks after the onset of symptoms, a magnetic resonance image (MRI) revealed tendinopathy of the left distal subscapularis, infraspinatus, supraspinatus, and teres minor tendon. These findings were suggestive of a small partial thickness tear of the supraspinatus (Figure 1), possible calcific tendinopathy of the distal teres minor (Figure 2), and underlying humeral head edema (Figure 3). The patient was evaluated by Orthopedics and experienced no relief from ibuprofen, celecoxib, and a steroid/lidocaine intra-articular injection. Laboratory studies included an unremarkable complete blood count and erythrocyte sedimentation rate. He was diagnosed with SIRVA and continued in physical therapy with incomplete resolution of symptoms 6 months postvaccination.
Discussion
According to a 2018 report issued by the Centers for Disease Control and Prevention, local reactions following immunizations are seen in up to 80% of administered vaccine doses.1 While most of these reactions are mild, transient, cutaneous reactions, rarely these also may persist and impact quality of life significantly. SIRVA is one such process that can lead to persistent musculoskeletal dysfunction. SIRVA presents as shoulder pain and limited ROM that occurs after the administration of an injectable vaccine. In 2011, the Institute of Medicine determined that evidence supported a causal relationship between vaccine administration and deltoid bursitis.5
In 2017, SIRVA was included in the Vaccine Injury Compensation Program (VICP), a federal program that can provide compensation to individuals injured by certain vaccines.6 A diagnosis of SIRVA can be considered in patients who experience pain within 48 hours of vaccination, have no prior history of pain or dysfunction of the affected shoulder prior to vaccine administration, and have symptoms limited to the shoulder in which the vaccine was administered where no other abnormality is present to explain these symptoms (eg, brachial neuritis, other neuropathy). Currently, patients with back pain or musculoskeletal complaints that do not include the shoulder following deltoid vaccination do not meet the reporting criteria for SIRVA in the VICP.6
The exact prevalence or incidence of SIRVA is unknown. In a 2017 systematic review of the literature and the Spanish Pharmacovigilance System database, Martín Arias and colleagues found 45 cases of new onset, unilateral shoulder dysfunction without associated neuropathy or autoimmune conditions following vaccine administration. They noted a female to male predominance (71.1% vs 28.9%) with a mean age of 53.6 years (range 22-89 y). Most of the cases occurred following influenza vaccine (62%); pneumococcal vaccine was the next most common (13%).7 Shoulder injury also has been reported after tetanus-diphtheria toxoids, human papilloma virus, and hepatitis A virus vaccines.4,7 The review noted that all patients had onset of pain within the first week following vaccination with the majority (81%) having pain in the first 24 hours. Two cases found in the Spanish database had pain onset 2 months postvaccination.7 Atanasoff and colleagues found that 93% of patients had pain onset within 24 hours of vaccination with 54% reporting immediate pain.4
The Vaccine Adverse Event Reporting System (VAERS) tracks reports of shoulder dysfunction following certain vaccinations, but the system is unable to establish causality. According to VAERS reporting, between 2010 and 2016, there were 1006 possible reports of shoulder dysfunction following inactivated influenza vaccination (IIV) compared with an estimated 130 million doses of IIV given each influenza season in the US.8
Bodor and Montalvo postulated that vaccine antigen was being over penetrated into the synovial space of the shoulder, as the subdeltoid/subacromial bursa is located a mere 0.8 to 1.6 cm below the skin surface in patients with healthy body mass index.2 Atanasoff and colleagues expounded that antibodies from previous vaccination or natural infection may then form antigen-antibody complexes, creating prolonged local immune and inflammatory responses leading to bursitis or tendonitis.4 Martín Arias and colleagues hypothesized that improper injection technique, including wrong insertion angle, incorrect needle type/size, and failure to account for the patient’s physical characteristics were the most likely causes of SIRVA.7
Proper vaccine administration ensures that vaccinations are delivered in a safe and efficacious manner. Safe vaccination practices include the use of trained personnel who receive comprehensive, competency-based training regarding vaccine administration.1 Aspiration prior to an injection is a practice that has not been evaluated fully. Given that the 2 routinely recommended locations for IM vaccines (deltoid muscle in adults or vastus lateralis muscle in infants) lack large blood vessels, the practice of aspiration prior to an IM vaccine is not currently deemed necessary.1 Additional safe vaccine practices include the selection of appropriate needle length for muscle penetration and that anatomic landmarks determine the location of vaccination.1 Despite this, in a survey of 100 medical professionals, half could not name any structure at risk from improper deltoid vaccination technique.9
Cook and colleagues used anthropomorphic data to evaluate the potential for injury to the subdeltoid/subacromial bursa and/or the axillary nerve.10 Based on these data, they recommended safe IM vaccine administration can be assured by using the midpoint of the deltoid muscle located midway between the acromion and deltoid tuberosity with the arm abducted to 60°.10,11 In 46% of SIRVA cases described by Atanasoff and colleagues, patients reported that the vaccine was administered “too high.”4 The study also recommended that the clinician and the patient be in the seated position to ensure proper needle angle and location of administration.4 For most adults, a 1-inch needle is appropriate for vaccine administration in the deltoid; however, in females weighing < 70 kg and males < 75 kg, a 5/8-inch needle is recommended to avoid injury.7
Our 91-kg patient was appropriately administered his vaccine with a 1-inch needle. As he experienced immediate pain, it is unlikely that his symptoms were due to an immune-mediated process, as this would not be expected to occur immediately. Improper location of vaccine administration is a proposed mechanism of injury for our patient, though this cannot be confirmed by history alone. His prior history of traumatic injury to the opposite shoulder could represent a confounding factor as no prior imaging was available for the vaccine-affected shoulder. A preexisting shoulder abnormality or injury cannot be completely excluded, and it is possible that an underlying prior shoulder injury was aggravated postvaccination.
Evaluation and Treatment
There is no standardized approach for the evaluation of SIRVA to date. Awareness of SIRVA and a high index of suspicion are necessary to evaluate patients with shoulder concerns postvaccination. Laboratory evaluation should be considered to evaluate for other potential diagnoses (eg, infection, rheumatologic concerns). Routine X-rays are not helpful in cases of SIRVA. Ultrasound may be considered as it can show bursa abnormalities consistent with bursitis.2 MRI of the affected shoulder may provide improved diagnostic capability if SIRVA is suspected. MRI findings vary but include intraosseous edema, bursitis, tendonitis, and rotator cuff tears.4,12 Complete rotator cuff tears were found in 15% of cases reviewed by Atanasoff and colleagues.4 While there is no recommended timing for MRI, 63% of MRIs were performed within 3 months of symptom onset.4 As SIRVA is not a neurologic injury, nerve conduction, electromyographic studies, and neurologic evaluation or testing are expected to be normal.
Treatment of SIRVA and other vaccine-related shoulder injuries typically have involved pain management (eg, nonsteroidal anti-inflammatory agents), intra-articular steroid injections, and physical therapy, though some patients never experience complete resolution of symptoms.2,4,7 Both patients with vaccination-related shoulder dysfunction described by Bodor and colleagues improved after intra-articular triamcinolone injections, with up to 3 injections before complete resolution of pain in one patient.2 Orthopedics evaluation may need to be considered for persistent symptoms. According to Atanasoff and colleagues, most patients were symptomatic for at least 6 months, and complete recovery was seen in less than one-third of patients.4 Although the development of SIRVA is not a contraindication to future doses of the presumed causative vaccine, subsequent vaccination should include careful consideration of other administration sites if possible (eg, vastus lateralis may be used for IM injections in adults) (Figure 4).
Reporting
A diagnosis or concern for SIRVA also should be reported to the VAERS, the national database established in order to detect possible safety problems with US-licensed vaccines. VAERS reports can be submitted by anyone with concerns for vaccine adverse reactions, including patients, caregivers, and health care professionals at vaers.hhs.gov/reportevent.html. Additional information regarding VICP can be obtained at www.hrsa.gov/vaccine-compensation/index.html.
Military-Specific Issues
The military values readiness, which includes ensuring that active-duty members remain up-to-date on life-saving vaccinations. Immunization is of critical importance to mobility and success of the overall mission. Mobility processing lines where immunizations can be provided to multiple active-duty members can be a successful strategy for mass immunizations. Although the quick administration of immunizations maintains readiness and provides a medically necessary service, it also may increase the chances of incorrect vaccine placement in the deltoid, causing long-term shoulder immobility that may impact a service member’s retainability. The benefits of mobility processing lines can continue to outweigh the risks of immunization administration by ensuring proper staff training, seating both the administrator and recipient of vaccination, and selecting a proper needle length and site of administration specific to each recipient.
Conclusion
Correct administration of vaccines is of utmost importance in preventing SIRVA and other vaccine-related shoulder dysfunctions. Proper staff training and refresher training can help prevent vaccine-related shoulder injuries. Additionally, clinicians should be aware of this potential complication and maintain a high index of suspicion when evaluating patients with postvaccination shoulder complaints.
1. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. https://www.cdc.gov/vaccines/pubs/pinkbook/vac-admin.html. Published 2015. Accessed June 3, 2019.
2. Bodor M, Montalvo E. Vaccination-related shoulder dysfunction. Vaccine. 2007;25(4):585-587.
3. Kuether G, Dietrich B, Smith T, Peter C, Gruessner S. Atraumatic osteonecrosis of the humeral head after influenza A-(H1N1) v-2009 vaccination. Vaccine. 2011;29(40):6830-6833.
4. Atanasoff S, Ryan T, Lightfoot R, Johann-Liang R. Shoulder injury related to vaccine administration (SIRVA). Vaccine. 2010;28(51):8049-8052.
5. Institute of Medicine. Adverse effects of vaccines: evidence and causality. http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality/Vaccine-report-brief-FINAL.pdf. Published August 2011. Accessed June 3, 2019.
6. Health Resources and Services Administration, Health and Human Services Administration. National vaccine injury compensation program: revisions to the vaccine injury table. https://www.federalregister.gov/documents/2017/01/19/2017-00701/national-vaccine-injury-compensation-program-revisions-to-the-vaccine-injury-table. Published January 19, 2017. Accessed June 3, 2019.
7. Martín Arias LH, Sanz Fadrique R, Sáinz Gil M, Salgueiro-Vazquez ME. Risk of bursitis and other injuries and dysfunctions of the shoulder following vaccinations. Vaccine. 2017;35(37):4870-4876.
8. Centers for Disease Control and Prevention. Reports of shoulder dysfunction following inactivated influenza vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2010-2016. https://stacks.cdc.gov/view/cdc/57624. Published January 4, 2018. Accessed June 3, 2019.
9. McGarvey MA, Hooper AC. The deltoid intramuscular injection site in the adult. Current practice among general practitioners and practice nurses. Ir Med J. 2005;98(4):105-107.
10. Cook IF. An evidence based protocol for the prevention of upper arm injury related to vaccine administration (UAIRVA). Hum Vaccin. 2011;7(8):845-848.
11. Cook IF. Best vaccination practice and medically attended injection site events following deltoid intramuscular injection. Hum Vaccin Immunother. 2015;11(5):1184-1191.
12. Okur G, Chaney KA, Lomasney LM. Magnetic resonance imaging of abnormal shoulder pain following influenza vaccination. Skeletal Radiol. 2014;43(9):1325-1331.
Localized reactions and transient pain at the site of vaccine administration are frequent and well-described occurrences that are typically short-lived and mild in nature. The most common findings at the injection site are soreness, erythema, and edema.1 Although less common, generalized shoulder dysfunction after vaccine administration also has been reported. Bodor and colleagues described a peri-articular inflammatory response that led to shoulder pain and weakness.2 A single case report by Kuether and colleagues described atraumatic osteonecrosis of the humeral head after H1N1 vaccine administration in the deltoid.3 In 2010, shoulder injury related to vaccine administration (SIRVA) was described by Atanasoff and colleagues as the rapid onset of shoulder pain and dysfunction persisting as a complication of deltoid muscle vaccination in a case series of 13 patients.4 In our report, we present a case of an active-duty male eventually diagnosed with SIRVA after influenza vaccination and discuss factors that may prevent vaccine-related shoulder injuries.
Case Presentation
A 31-year-old active-duty male presented to the Allergy clinic for evaluation of persistent left shoulder pain and decreased range of motion (ROM) following influenza vaccination 4 months prior. He reported a history of chronic low back and right shoulder pain. Although the patient had a traumatic injury to his right shoulder, which was corrected with surgery, he had no surgeries on the left shoulder. He reported no prior pain or known trauma to his left shoulder. He had no personal or family history of atopy or vaccine reactions.
The patient weighed 91 kg and received an intramuscular (IM) quadrivalent influenza vaccine with a 25-gauge, 1-inch needle during a mass influenza immunization. He recalled that the site of vaccination was slightly more than 3 cm below the top of the shoulder in a region correlating to the left deltoid. The vaccine was administered while he was standing with his arm extended, adducted, and internally rotated. The patient experienced intense pain immediately after the vaccination and noted decreased ROM. Initially, he dismissed the pain and decreased ROM as routine but sought medical attention when there was no improvement after 3 weeks.
Six weeks after the onset of symptoms, a magnetic resonance image (MRI) revealed tendinopathy of the left distal subscapularis, infraspinatus, supraspinatus, and teres minor tendon. These findings were suggestive of a small partial thickness tear of the supraspinatus (Figure 1), possible calcific tendinopathy of the distal teres minor (Figure 2), and underlying humeral head edema (Figure 3). The patient was evaluated by Orthopedics and experienced no relief from ibuprofen, celecoxib, and a steroid/lidocaine intra-articular injection. Laboratory studies included an unremarkable complete blood count and erythrocyte sedimentation rate. He was diagnosed with SIRVA and continued in physical therapy with incomplete resolution of symptoms 6 months postvaccination.
Discussion
According to a 2018 report issued by the Centers for Disease Control and Prevention, local reactions following immunizations are seen in up to 80% of administered vaccine doses.1 While most of these reactions are mild, transient, cutaneous reactions, rarely these also may persist and impact quality of life significantly. SIRVA is one such process that can lead to persistent musculoskeletal dysfunction. SIRVA presents as shoulder pain and limited ROM that occurs after the administration of an injectable vaccine. In 2011, the Institute of Medicine determined that evidence supported a causal relationship between vaccine administration and deltoid bursitis.5
In 2017, SIRVA was included in the Vaccine Injury Compensation Program (VICP), a federal program that can provide compensation to individuals injured by certain vaccines.6 A diagnosis of SIRVA can be considered in patients who experience pain within 48 hours of vaccination, have no prior history of pain or dysfunction of the affected shoulder prior to vaccine administration, and have symptoms limited to the shoulder in which the vaccine was administered where no other abnormality is present to explain these symptoms (eg, brachial neuritis, other neuropathy). Currently, patients with back pain or musculoskeletal complaints that do not include the shoulder following deltoid vaccination do not meet the reporting criteria for SIRVA in the VICP.6
The exact prevalence or incidence of SIRVA is unknown. In a 2017 systematic review of the literature and the Spanish Pharmacovigilance System database, Martín Arias and colleagues found 45 cases of new onset, unilateral shoulder dysfunction without associated neuropathy or autoimmune conditions following vaccine administration. They noted a female to male predominance (71.1% vs 28.9%) with a mean age of 53.6 years (range 22-89 y). Most of the cases occurred following influenza vaccine (62%); pneumococcal vaccine was the next most common (13%).7 Shoulder injury also has been reported after tetanus-diphtheria toxoids, human papilloma virus, and hepatitis A virus vaccines.4,7 The review noted that all patients had onset of pain within the first week following vaccination with the majority (81%) having pain in the first 24 hours. Two cases found in the Spanish database had pain onset 2 months postvaccination.7 Atanasoff and colleagues found that 93% of patients had pain onset within 24 hours of vaccination with 54% reporting immediate pain.4
The Vaccine Adverse Event Reporting System (VAERS) tracks reports of shoulder dysfunction following certain vaccinations, but the system is unable to establish causality. According to VAERS reporting, between 2010 and 2016, there were 1006 possible reports of shoulder dysfunction following inactivated influenza vaccination (IIV) compared with an estimated 130 million doses of IIV given each influenza season in the US.8
Bodor and Montalvo postulated that vaccine antigen was being over penetrated into the synovial space of the shoulder, as the subdeltoid/subacromial bursa is located a mere 0.8 to 1.6 cm below the skin surface in patients with healthy body mass index.2 Atanasoff and colleagues expounded that antibodies from previous vaccination or natural infection may then form antigen-antibody complexes, creating prolonged local immune and inflammatory responses leading to bursitis or tendonitis.4 Martín Arias and colleagues hypothesized that improper injection technique, including wrong insertion angle, incorrect needle type/size, and failure to account for the patient’s physical characteristics were the most likely causes of SIRVA.7
Proper vaccine administration ensures that vaccinations are delivered in a safe and efficacious manner. Safe vaccination practices include the use of trained personnel who receive comprehensive, competency-based training regarding vaccine administration.1 Aspiration prior to an injection is a practice that has not been evaluated fully. Given that the 2 routinely recommended locations for IM vaccines (deltoid muscle in adults or vastus lateralis muscle in infants) lack large blood vessels, the practice of aspiration prior to an IM vaccine is not currently deemed necessary.1 Additional safe vaccine practices include the selection of appropriate needle length for muscle penetration and that anatomic landmarks determine the location of vaccination.1 Despite this, in a survey of 100 medical professionals, half could not name any structure at risk from improper deltoid vaccination technique.9
Cook and colleagues used anthropomorphic data to evaluate the potential for injury to the subdeltoid/subacromial bursa and/or the axillary nerve.10 Based on these data, they recommended safe IM vaccine administration can be assured by using the midpoint of the deltoid muscle located midway between the acromion and deltoid tuberosity with the arm abducted to 60°.10,11 In 46% of SIRVA cases described by Atanasoff and colleagues, patients reported that the vaccine was administered “too high.”4 The study also recommended that the clinician and the patient be in the seated position to ensure proper needle angle and location of administration.4 For most adults, a 1-inch needle is appropriate for vaccine administration in the deltoid; however, in females weighing < 70 kg and males < 75 kg, a 5/8-inch needle is recommended to avoid injury.7
Our 91-kg patient was appropriately administered his vaccine with a 1-inch needle. As he experienced immediate pain, it is unlikely that his symptoms were due to an immune-mediated process, as this would not be expected to occur immediately. Improper location of vaccine administration is a proposed mechanism of injury for our patient, though this cannot be confirmed by history alone. His prior history of traumatic injury to the opposite shoulder could represent a confounding factor as no prior imaging was available for the vaccine-affected shoulder. A preexisting shoulder abnormality or injury cannot be completely excluded, and it is possible that an underlying prior shoulder injury was aggravated postvaccination.
Evaluation and Treatment
There is no standardized approach for the evaluation of SIRVA to date. Awareness of SIRVA and a high index of suspicion are necessary to evaluate patients with shoulder concerns postvaccination. Laboratory evaluation should be considered to evaluate for other potential diagnoses (eg, infection, rheumatologic concerns). Routine X-rays are not helpful in cases of SIRVA. Ultrasound may be considered as it can show bursa abnormalities consistent with bursitis.2 MRI of the affected shoulder may provide improved diagnostic capability if SIRVA is suspected. MRI findings vary but include intraosseous edema, bursitis, tendonitis, and rotator cuff tears.4,12 Complete rotator cuff tears were found in 15% of cases reviewed by Atanasoff and colleagues.4 While there is no recommended timing for MRI, 63% of MRIs were performed within 3 months of symptom onset.4 As SIRVA is not a neurologic injury, nerve conduction, electromyographic studies, and neurologic evaluation or testing are expected to be normal.
Treatment of SIRVA and other vaccine-related shoulder injuries typically have involved pain management (eg, nonsteroidal anti-inflammatory agents), intra-articular steroid injections, and physical therapy, though some patients never experience complete resolution of symptoms.2,4,7 Both patients with vaccination-related shoulder dysfunction described by Bodor and colleagues improved after intra-articular triamcinolone injections, with up to 3 injections before complete resolution of pain in one patient.2 Orthopedics evaluation may need to be considered for persistent symptoms. According to Atanasoff and colleagues, most patients were symptomatic for at least 6 months, and complete recovery was seen in less than one-third of patients.4 Although the development of SIRVA is not a contraindication to future doses of the presumed causative vaccine, subsequent vaccination should include careful consideration of other administration sites if possible (eg, vastus lateralis may be used for IM injections in adults) (Figure 4).
Reporting
A diagnosis or concern for SIRVA also should be reported to the VAERS, the national database established in order to detect possible safety problems with US-licensed vaccines. VAERS reports can be submitted by anyone with concerns for vaccine adverse reactions, including patients, caregivers, and health care professionals at vaers.hhs.gov/reportevent.html. Additional information regarding VICP can be obtained at www.hrsa.gov/vaccine-compensation/index.html.
Military-Specific Issues
The military values readiness, which includes ensuring that active-duty members remain up-to-date on life-saving vaccinations. Immunization is of critical importance to mobility and success of the overall mission. Mobility processing lines where immunizations can be provided to multiple active-duty members can be a successful strategy for mass immunizations. Although the quick administration of immunizations maintains readiness and provides a medically necessary service, it also may increase the chances of incorrect vaccine placement in the deltoid, causing long-term shoulder immobility that may impact a service member’s retainability. The benefits of mobility processing lines can continue to outweigh the risks of immunization administration by ensuring proper staff training, seating both the administrator and recipient of vaccination, and selecting a proper needle length and site of administration specific to each recipient.
Conclusion
Correct administration of vaccines is of utmost importance in preventing SIRVA and other vaccine-related shoulder dysfunctions. Proper staff training and refresher training can help prevent vaccine-related shoulder injuries. Additionally, clinicians should be aware of this potential complication and maintain a high index of suspicion when evaluating patients with postvaccination shoulder complaints.
Localized reactions and transient pain at the site of vaccine administration are frequent and well-described occurrences that are typically short-lived and mild in nature. The most common findings at the injection site are soreness, erythema, and edema.1 Although less common, generalized shoulder dysfunction after vaccine administration also has been reported. Bodor and colleagues described a peri-articular inflammatory response that led to shoulder pain and weakness.2 A single case report by Kuether and colleagues described atraumatic osteonecrosis of the humeral head after H1N1 vaccine administration in the deltoid.3 In 2010, shoulder injury related to vaccine administration (SIRVA) was described by Atanasoff and colleagues as the rapid onset of shoulder pain and dysfunction persisting as a complication of deltoid muscle vaccination in a case series of 13 patients.4 In our report, we present a case of an active-duty male eventually diagnosed with SIRVA after influenza vaccination and discuss factors that may prevent vaccine-related shoulder injuries.
Case Presentation
A 31-year-old active-duty male presented to the Allergy clinic for evaluation of persistent left shoulder pain and decreased range of motion (ROM) following influenza vaccination 4 months prior. He reported a history of chronic low back and right shoulder pain. Although the patient had a traumatic injury to his right shoulder, which was corrected with surgery, he had no surgeries on the left shoulder. He reported no prior pain or known trauma to his left shoulder. He had no personal or family history of atopy or vaccine reactions.
The patient weighed 91 kg and received an intramuscular (IM) quadrivalent influenza vaccine with a 25-gauge, 1-inch needle during a mass influenza immunization. He recalled that the site of vaccination was slightly more than 3 cm below the top of the shoulder in a region correlating to the left deltoid. The vaccine was administered while he was standing with his arm extended, adducted, and internally rotated. The patient experienced intense pain immediately after the vaccination and noted decreased ROM. Initially, he dismissed the pain and decreased ROM as routine but sought medical attention when there was no improvement after 3 weeks.
Six weeks after the onset of symptoms, a magnetic resonance image (MRI) revealed tendinopathy of the left distal subscapularis, infraspinatus, supraspinatus, and teres minor tendon. These findings were suggestive of a small partial thickness tear of the supraspinatus (Figure 1), possible calcific tendinopathy of the distal teres minor (Figure 2), and underlying humeral head edema (Figure 3). The patient was evaluated by Orthopedics and experienced no relief from ibuprofen, celecoxib, and a steroid/lidocaine intra-articular injection. Laboratory studies included an unremarkable complete blood count and erythrocyte sedimentation rate. He was diagnosed with SIRVA and continued in physical therapy with incomplete resolution of symptoms 6 months postvaccination.
Discussion
According to a 2018 report issued by the Centers for Disease Control and Prevention, local reactions following immunizations are seen in up to 80% of administered vaccine doses.1 While most of these reactions are mild, transient, cutaneous reactions, rarely these also may persist and impact quality of life significantly. SIRVA is one such process that can lead to persistent musculoskeletal dysfunction. SIRVA presents as shoulder pain and limited ROM that occurs after the administration of an injectable vaccine. In 2011, the Institute of Medicine determined that evidence supported a causal relationship between vaccine administration and deltoid bursitis.5
In 2017, SIRVA was included in the Vaccine Injury Compensation Program (VICP), a federal program that can provide compensation to individuals injured by certain vaccines.6 A diagnosis of SIRVA can be considered in patients who experience pain within 48 hours of vaccination, have no prior history of pain or dysfunction of the affected shoulder prior to vaccine administration, and have symptoms limited to the shoulder in which the vaccine was administered where no other abnormality is present to explain these symptoms (eg, brachial neuritis, other neuropathy). Currently, patients with back pain or musculoskeletal complaints that do not include the shoulder following deltoid vaccination do not meet the reporting criteria for SIRVA in the VICP.6
The exact prevalence or incidence of SIRVA is unknown. In a 2017 systematic review of the literature and the Spanish Pharmacovigilance System database, Martín Arias and colleagues found 45 cases of new onset, unilateral shoulder dysfunction without associated neuropathy or autoimmune conditions following vaccine administration. They noted a female to male predominance (71.1% vs 28.9%) with a mean age of 53.6 years (range 22-89 y). Most of the cases occurred following influenza vaccine (62%); pneumococcal vaccine was the next most common (13%).7 Shoulder injury also has been reported after tetanus-diphtheria toxoids, human papilloma virus, and hepatitis A virus vaccines.4,7 The review noted that all patients had onset of pain within the first week following vaccination with the majority (81%) having pain in the first 24 hours. Two cases found in the Spanish database had pain onset 2 months postvaccination.7 Atanasoff and colleagues found that 93% of patients had pain onset within 24 hours of vaccination with 54% reporting immediate pain.4
The Vaccine Adverse Event Reporting System (VAERS) tracks reports of shoulder dysfunction following certain vaccinations, but the system is unable to establish causality. According to VAERS reporting, between 2010 and 2016, there were 1006 possible reports of shoulder dysfunction following inactivated influenza vaccination (IIV) compared with an estimated 130 million doses of IIV given each influenza season in the US.8
Bodor and Montalvo postulated that vaccine antigen was being over penetrated into the synovial space of the shoulder, as the subdeltoid/subacromial bursa is located a mere 0.8 to 1.6 cm below the skin surface in patients with healthy body mass index.2 Atanasoff and colleagues expounded that antibodies from previous vaccination or natural infection may then form antigen-antibody complexes, creating prolonged local immune and inflammatory responses leading to bursitis or tendonitis.4 Martín Arias and colleagues hypothesized that improper injection technique, including wrong insertion angle, incorrect needle type/size, and failure to account for the patient’s physical characteristics were the most likely causes of SIRVA.7
Proper vaccine administration ensures that vaccinations are delivered in a safe and efficacious manner. Safe vaccination practices include the use of trained personnel who receive comprehensive, competency-based training regarding vaccine administration.1 Aspiration prior to an injection is a practice that has not been evaluated fully. Given that the 2 routinely recommended locations for IM vaccines (deltoid muscle in adults or vastus lateralis muscle in infants) lack large blood vessels, the practice of aspiration prior to an IM vaccine is not currently deemed necessary.1 Additional safe vaccine practices include the selection of appropriate needle length for muscle penetration and that anatomic landmarks determine the location of vaccination.1 Despite this, in a survey of 100 medical professionals, half could not name any structure at risk from improper deltoid vaccination technique.9
Cook and colleagues used anthropomorphic data to evaluate the potential for injury to the subdeltoid/subacromial bursa and/or the axillary nerve.10 Based on these data, they recommended safe IM vaccine administration can be assured by using the midpoint of the deltoid muscle located midway between the acromion and deltoid tuberosity with the arm abducted to 60°.10,11 In 46% of SIRVA cases described by Atanasoff and colleagues, patients reported that the vaccine was administered “too high.”4 The study also recommended that the clinician and the patient be in the seated position to ensure proper needle angle and location of administration.4 For most adults, a 1-inch needle is appropriate for vaccine administration in the deltoid; however, in females weighing < 70 kg and males < 75 kg, a 5/8-inch needle is recommended to avoid injury.7
Our 91-kg patient was appropriately administered his vaccine with a 1-inch needle. As he experienced immediate pain, it is unlikely that his symptoms were due to an immune-mediated process, as this would not be expected to occur immediately. Improper location of vaccine administration is a proposed mechanism of injury for our patient, though this cannot be confirmed by history alone. His prior history of traumatic injury to the opposite shoulder could represent a confounding factor as no prior imaging was available for the vaccine-affected shoulder. A preexisting shoulder abnormality or injury cannot be completely excluded, and it is possible that an underlying prior shoulder injury was aggravated postvaccination.
Evaluation and Treatment
There is no standardized approach for the evaluation of SIRVA to date. Awareness of SIRVA and a high index of suspicion are necessary to evaluate patients with shoulder concerns postvaccination. Laboratory evaluation should be considered to evaluate for other potential diagnoses (eg, infection, rheumatologic concerns). Routine X-rays are not helpful in cases of SIRVA. Ultrasound may be considered as it can show bursa abnormalities consistent with bursitis.2 MRI of the affected shoulder may provide improved diagnostic capability if SIRVA is suspected. MRI findings vary but include intraosseous edema, bursitis, tendonitis, and rotator cuff tears.4,12 Complete rotator cuff tears were found in 15% of cases reviewed by Atanasoff and colleagues.4 While there is no recommended timing for MRI, 63% of MRIs were performed within 3 months of symptom onset.4 As SIRVA is not a neurologic injury, nerve conduction, electromyographic studies, and neurologic evaluation or testing are expected to be normal.
Treatment of SIRVA and other vaccine-related shoulder injuries typically have involved pain management (eg, nonsteroidal anti-inflammatory agents), intra-articular steroid injections, and physical therapy, though some patients never experience complete resolution of symptoms.2,4,7 Both patients with vaccination-related shoulder dysfunction described by Bodor and colleagues improved after intra-articular triamcinolone injections, with up to 3 injections before complete resolution of pain in one patient.2 Orthopedics evaluation may need to be considered for persistent symptoms. According to Atanasoff and colleagues, most patients were symptomatic for at least 6 months, and complete recovery was seen in less than one-third of patients.4 Although the development of SIRVA is not a contraindication to future doses of the presumed causative vaccine, subsequent vaccination should include careful consideration of other administration sites if possible (eg, vastus lateralis may be used for IM injections in adults) (Figure 4).
Reporting
A diagnosis or concern for SIRVA also should be reported to the VAERS, the national database established in order to detect possible safety problems with US-licensed vaccines. VAERS reports can be submitted by anyone with concerns for vaccine adverse reactions, including patients, caregivers, and health care professionals at vaers.hhs.gov/reportevent.html. Additional information regarding VICP can be obtained at www.hrsa.gov/vaccine-compensation/index.html.
Military-Specific Issues
The military values readiness, which includes ensuring that active-duty members remain up-to-date on life-saving vaccinations. Immunization is of critical importance to mobility and success of the overall mission. Mobility processing lines where immunizations can be provided to multiple active-duty members can be a successful strategy for mass immunizations. Although the quick administration of immunizations maintains readiness and provides a medically necessary service, it also may increase the chances of incorrect vaccine placement in the deltoid, causing long-term shoulder immobility that may impact a service member’s retainability. The benefits of mobility processing lines can continue to outweigh the risks of immunization administration by ensuring proper staff training, seating both the administrator and recipient of vaccination, and selecting a proper needle length and site of administration specific to each recipient.
Conclusion
Correct administration of vaccines is of utmost importance in preventing SIRVA and other vaccine-related shoulder dysfunctions. Proper staff training and refresher training can help prevent vaccine-related shoulder injuries. Additionally, clinicians should be aware of this potential complication and maintain a high index of suspicion when evaluating patients with postvaccination shoulder complaints.
1. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. https://www.cdc.gov/vaccines/pubs/pinkbook/vac-admin.html. Published 2015. Accessed June 3, 2019.
2. Bodor M, Montalvo E. Vaccination-related shoulder dysfunction. Vaccine. 2007;25(4):585-587.
3. Kuether G, Dietrich B, Smith T, Peter C, Gruessner S. Atraumatic osteonecrosis of the humeral head after influenza A-(H1N1) v-2009 vaccination. Vaccine. 2011;29(40):6830-6833.
4. Atanasoff S, Ryan T, Lightfoot R, Johann-Liang R. Shoulder injury related to vaccine administration (SIRVA). Vaccine. 2010;28(51):8049-8052.
5. Institute of Medicine. Adverse effects of vaccines: evidence and causality. http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality/Vaccine-report-brief-FINAL.pdf. Published August 2011. Accessed June 3, 2019.
6. Health Resources and Services Administration, Health and Human Services Administration. National vaccine injury compensation program: revisions to the vaccine injury table. https://www.federalregister.gov/documents/2017/01/19/2017-00701/national-vaccine-injury-compensation-program-revisions-to-the-vaccine-injury-table. Published January 19, 2017. Accessed June 3, 2019.
7. Martín Arias LH, Sanz Fadrique R, Sáinz Gil M, Salgueiro-Vazquez ME. Risk of bursitis and other injuries and dysfunctions of the shoulder following vaccinations. Vaccine. 2017;35(37):4870-4876.
8. Centers for Disease Control and Prevention. Reports of shoulder dysfunction following inactivated influenza vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2010-2016. https://stacks.cdc.gov/view/cdc/57624. Published January 4, 2018. Accessed June 3, 2019.
9. McGarvey MA, Hooper AC. The deltoid intramuscular injection site in the adult. Current practice among general practitioners and practice nurses. Ir Med J. 2005;98(4):105-107.
10. Cook IF. An evidence based protocol for the prevention of upper arm injury related to vaccine administration (UAIRVA). Hum Vaccin. 2011;7(8):845-848.
11. Cook IF. Best vaccination practice and medically attended injection site events following deltoid intramuscular injection. Hum Vaccin Immunother. 2015;11(5):1184-1191.
12. Okur G, Chaney KA, Lomasney LM. Magnetic resonance imaging of abnormal shoulder pain following influenza vaccination. Skeletal Radiol. 2014;43(9):1325-1331.
1. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. https://www.cdc.gov/vaccines/pubs/pinkbook/vac-admin.html. Published 2015. Accessed June 3, 2019.
2. Bodor M, Montalvo E. Vaccination-related shoulder dysfunction. Vaccine. 2007;25(4):585-587.
3. Kuether G, Dietrich B, Smith T, Peter C, Gruessner S. Atraumatic osteonecrosis of the humeral head after influenza A-(H1N1) v-2009 vaccination. Vaccine. 2011;29(40):6830-6833.
4. Atanasoff S, Ryan T, Lightfoot R, Johann-Liang R. Shoulder injury related to vaccine administration (SIRVA). Vaccine. 2010;28(51):8049-8052.
5. Institute of Medicine. Adverse effects of vaccines: evidence and causality. http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality/Vaccine-report-brief-FINAL.pdf. Published August 2011. Accessed June 3, 2019.
6. Health Resources and Services Administration, Health and Human Services Administration. National vaccine injury compensation program: revisions to the vaccine injury table. https://www.federalregister.gov/documents/2017/01/19/2017-00701/national-vaccine-injury-compensation-program-revisions-to-the-vaccine-injury-table. Published January 19, 2017. Accessed June 3, 2019.
7. Martín Arias LH, Sanz Fadrique R, Sáinz Gil M, Salgueiro-Vazquez ME. Risk of bursitis and other injuries and dysfunctions of the shoulder following vaccinations. Vaccine. 2017;35(37):4870-4876.
8. Centers for Disease Control and Prevention. Reports of shoulder dysfunction following inactivated influenza vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2010-2016. https://stacks.cdc.gov/view/cdc/57624. Published January 4, 2018. Accessed June 3, 2019.
9. McGarvey MA, Hooper AC. The deltoid intramuscular injection site in the adult. Current practice among general practitioners and practice nurses. Ir Med J. 2005;98(4):105-107.
10. Cook IF. An evidence based protocol for the prevention of upper arm injury related to vaccine administration (UAIRVA). Hum Vaccin. 2011;7(8):845-848.
11. Cook IF. Best vaccination practice and medically attended injection site events following deltoid intramuscular injection. Hum Vaccin Immunother. 2015;11(5):1184-1191.
12. Okur G, Chaney KA, Lomasney LM. Magnetic resonance imaging of abnormal shoulder pain following influenza vaccination. Skeletal Radiol. 2014;43(9):1325-1331.
Facts to help you keep pace with the vaccine conversation
The current increase in measles cases in the United States has sharpened the focus on antivaccine activities. While the percentage of US children who are fully vaccinated remains high (≥ 94%), the number of un- or undervaccinated children has been growing1 because of nonmedical exemptions from school vaccine requirements due to concerns about vaccine safety and an underappreciation of the benefits of vaccines. Family physicians need to be conversant with several important aspects of this matter, including the magnitude of benefits provided by childhood vaccines, as well as the systems already in place for
- assessing vaccine effectiveness and safety,
- making recommendations on the use of vaccines,
- monitoring safety after vaccine approval, and
- compensating those affected by rare but serious vaccine-related adverse events (AEs).
Familiarity with these issues will allow for informed discussions with parents who are vaccine hesitant and with those who have read or heard inaccurate information.
The benefits of vaccines are indisputable
In 1999, the Centers for Disease Control and Prevention (CDC) published a list of 9 selected childhood infectious diseases and compared their incidences before and after immunization was available.2 Each of these infections causes morbidity, sequelae, and mortality at predictable rates depending on the infectious agent. The comparisons were dramatic: Measles, with a baseline annual morbidity of 503,282 cases, fell to just 89 cases; poliomyelitis decreased from 16,316 to 0; and Haemophilus influenzae type b declined from 20,000 to 54. In a 2014 analysis, the CDC stated that “among 78.6 million children born during 1994–2013, routine childhood immunization was estimated to prevent 322 million illnesses (averaging 4.1 illnesses per child) and 21 million hospitalizations (0.27 per child) over the course of their lifetimes and avert 732,000 premature deaths from vaccine-preventable illnesses” (TABLE).3
It is not unusual to hear a vaccine opponent say that childhood infectious diseases are not serious and that it is better for a child to contract the infection and let the immune system fight it naturally. Measles is often used as an example. This argument ignores some important aspects of vaccine benefits.
It is true in the United States that the average child who contracts measles will recover from it and not suffer immediate or long-term effects. However, it is also true that measles has a hospitalization rate of about 20% and a death rate of between 1/500 and 1/1000 cases.4 Mortality is much higher in developing countries. Prior to widespread use of measles vaccine, hundreds of thousands of cases of measles occurred each year. That translated into hundreds of preventable child deaths per year. An individual case does not tell the full story about the public health impact of infectious illnesses.
In addition, there are often unappreciated sequelae from child infections, such as shingles occurring years after resolution of a chickenpox infection. There are also societal consequences of child infections, such as deafness from congenital rubella and intergenerational transfer of infectious agents to family members at risk for serious consequences (influenza from a child to a grandparent). Finally, infected children pose a risk to those who cannot be vaccinated because of immune deficiencies and other medical conditions.
A multilayered US system monitors vaccine safety
Responsibility for assuring the safety of vaccines lies with the US Food and Drug Administration (FDA) Center for Biologics Evaluation and Research and with the CDC’s Immunization Safety Office (ISO). The FDA is responsible for the initial assessment of the effectiveness and safety of new vaccines and for ongoing monitoring of the manufacturing facilities where vaccines are produced. After FDA approval, safety is monitored using a multilayered system that includes the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD) system, the Clinical Immunization Safety Assessment (CISA) Project, and periodic reviews by the National Academy of Medicine (NAM), previously the Institute of Medicine. In addition, there is a large number of studies published each year by the nation’s—and world’s—medical research community on vaccine effectiveness and safety.
Continue to: VAERS
VAERS (https://vaers.hhs.gov/) is a passive reporting system that allows patients, physicians, and other health care providers to record suspected vaccine-related adverse events.5 It was created in 1990 and is run by the FDA and the CDC. It is not intended to be a comprehensive or definitive list of proven vaccine-related harms. As a passive reporting system, it is subject to both over- and underreporting, and the data from it are often misinterpreted and used incorrectly by vaccine opponents—eg, wrongly declaring that VAERS reports of possible AEs are proven cases. It provides a sentinel system that is monitored for indications of possible serious AEs linked to a particular vaccine. When a suspected interaction is detected, it is investigated by the VSD system.
VSD is a collaboration of the CDC’s ISO and 8 geographically distributed health care organizations with complete electronic patient medical information on their members. VSD conducts studies when a question about vaccine safety arises, when new vaccines are licensed, or when there are new vaccine recommendations. A description of VSD sites, the research methods used, and a list of publications describing study results can be found at https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html#organizations. If the VSD system finds a link between serious AEs and a particular vaccine, this association is reported to the Advisory Committee on Immunization Practices (ACIP) for consideration in changing recommendations regarding that vaccine. This happens only rarely.
CISA was established in 2001 as a network of vaccine safety experts at 7 academic medical centers who collaborate with the CDC’s ISO. CISA conducts studies on specific questions related to vaccine safety and provides a consultation service to clinicians and researchers who have questions about vaccine safety. A description of the CISA sites, past publications on vaccine safety, and ongoing research priorities can be found at https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html.
NAM (https://nam.edu/) conducts periodic reviews of vaccine safety and vaccine-caused AEs. The most recent was published in 2012 and looked at possible AEs of 8 vaccines containing 12 different antigens.6 The literature search for this review found more than 12,000 articles, which speaks to the volume of scientific work on vaccine safety. These NAM reports document the rarity of severe AEs to vaccines and are used with other information to construct the table for the Vaccine Injury Compensation Program (VICP), which is described below.
Are vaccines killing children?
Vaccine opponents frequently claim that vaccines cause much more harm than is documented, including the deaths of children. A vaccine opponent made this claim in my state (Arizona) at a legislative committee hearing even though our state child mortality review committee has been investigating all child deaths for decades and has never attributed a death to a vaccine.
Continue to: One study conducted...
One study conducted using the VSD system from January 1, 2005, to December 31, 2011, identified 1100 deaths occurring within 12 months of any vaccination among 2,189,504 VSD enrollees ages 9 to 26 years.7 They found that the risk of death in this age group was not increased during the 30 days after vaccination, and no deaths were found to be causally associated with vaccination. Deaths among children do occur and, due to the number of vaccines administered, some deaths will occur within a short time period after a vaccine. This temporal association does not prove the death was vaccine-caused, but vaccine opponents have claimed that it does.
The vaccine injury compensation system
In 1986, the federal government established a no-fault system—the National Vaccine Injury Compensation Program (VICP)—to compensate those who suffer a serious AE from a vaccine covered by the program. This system is administered by the Health Resources and Services Administration (HRSA) in the Department of Health and Human Services (DHHS). HRSA maintains a table of proven AEs of specific vaccines, based in part on the NAM report mentioned earlier. Petitions for compensation—with proof of an AE following the administration of a vaccine that is included on the HRSA table—are accepted and remunerated if the AE lasted > 6 months or resulted in hospitalization. Petitions that allege AEs following administration of a vaccine not included on the table are nevertheless reviewed by the staff of HRSA, who can still recommend compensation based on the medical evidence. If HRSA declines the petition, the petitioner can appeal the case in the US Court of Federal Claims, which makes the final decision on a petition’s validity and, if warranted, the type and amount of compensation.
From 2006 to 2017, > 3.4 billion doses of vaccines covered by VICP were distributed in the United States.8 During this period, 6293 petitions were adjudicated by the court; 4311 were compensated.8 For every 1 million doses of vaccine distributed, 1 individual was compensated. Seventy percent of these compensations were awarded to petitioners despite a lack of clear evidence that the patient’s condition was caused by a vaccine.8 The rate of compensation for conditions proven to be caused by a vaccine was 1/3.33 million.8
The VICP pays for attorney fees, in some cases even if the petition is denied, but does not allow contingency fees. Since the beginning of the program, more than $4 billion has been awarded.8 The program is funded by a 75-cent tax on each vaccine antigen. Because serious AEs are so rare, the trust fund established to administer the VICP finances has a surplus of about $6 billion.
The Advisory Committee on Immunization Practices
After a vaccine is approved for use by the FDA, ACIP makes recommendations for its use in the US civilian population.9,10 ACIP, created in 1964, was chartered as a federal advisory committee to provide expert external advice to the Director of the CDC and the Secretary of DHHS on the use of vaccines
Continue to: As an official...
As an official federal advisory committee governed by the Federal Advisory Committee Act, ACIP operates under strict requirements for public notification of meetings, allowing for written and oral public comment at its meetings, and timely publication of minutes. ACIP meeting minutes are posted soon after each meeting, along with draft recommendations. ACIP meeting agendas and slide presentations are available on the ACIP Web site (https://www.cdc.gov/vaccines/acip/index.html).
ACIP consists of 15 members serving overlapping 4-year terms, appointed by the Secretary of DHHS from a list of candidates proposed by the CDC. One member is a consumer representative; the other members have expertise in vaccinology, immunology, pediatrics, internal medicine, infectious diseases, preventive medicine, and public health. In the CDC, staff support for ACIP is provided by the National Center for Immunization and Respiratory Diseases, Office of Infectious Diseases.
ACIP holds 2-day meetings 3 times a year. Much of the work occurs between meetings, by work groups via phone conferences. Work groups are chaired by an ACIP member and staffed by one or more CDC programmatic, content-expert professionals. Membership of the work groups consists of at least 2 ACIP members, representatives from relevant professional clinical and public health organizations, and other individuals with specific expertise. Work groups propose recommendations to ACIP, which can adopt, revise, or reject them.
When formulating recommendations for a particular vaccine, ACIP considers the burden of disease prevented, the effectiveness and safety of the vaccine, cost effectiveness, and practical and logistical issues of implementing recommendations. ACIP also receives frequent reports from ISO regarding the safety of vaccines previously approved. Since 2011, ACIP has used a standardized, modified GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system to assess the evidence regarding effectiveness and safety of new vaccines and an evidence-to-recommendation framework to transparently explain how it arrives at recommendations.11,12
We can recommend vaccines with confidence
In the United States, we have a secure supply of safe vaccines, a transparent method of making vaccine recommendations, a robust system to monitor vaccine safety, and an efficient system to compensate those who experience a rare, serious adverse reaction to a vaccine. The US public health system has achieved a marked reduction in morbidity and mortality from childhood infectious diseases, mostly because of vaccines. Many people today have not experienced or seen children with these once-common childhood infections and may not appreciate the seriousness of childhood infectious diseases or the full value of vaccines. As family physicians, we can help address this problem and recommend vaccines to our patients with confidence.
1. Mellerson JL, Maxwell CB, Knighton CL, et al. Vaccine coverage for selected vaccines and exemption rates among children in kindergarten—United States, 2017-18 school year. MMWR Morb Mortal Wkly Rep. 2018;67:1115-1122.
2. CDC. Ten great public health achievements—United States, 1900-1999. MMWR Morb Mortal Wkly Rep. 1999;48:241-243.
3. Whitney CG, Zhou F, Singleton J, et al. Benefits from immunization during the Vaccines for Children Program era—United States, 1994-2013. MMWR Morb Mortal Wkly Rep. 2014;63:352-355.
4. CDC. Complications of measles. https://www.cdc.gov/measles/symptoms/complications.html. Accessed July 16, 2019.
5. Shimabukuro TT, Nguyen M, Martin D, et al. Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2015;33:4398-4405.
6. IOM (Institute of Medicine). Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press; 2012.
7. McCarthy NL, Gee J, Sukumaran L, et al. Vaccination and 30-day mortality risk in children, adolescents, and young adults. Pediatrics. 2016;137:1-8.
8. HRSA. Data and Statistics. https://www.hrsa.gov/sites/default/files/hrsa/vaccine-compensation/data/monthly-stats-may-2019.pdf. Accessed July 16, 2019.
9. Pickering LK, Orenstein WA, Sun W, et al. FDA licensure of and ACIP recommendations for vaccines. Vaccine. 2017;37:5027-5036.
10. Smith JC, Snider DE, Pickering LK. Immunization policy development in the United States: the role of the Advisory Committee on Immunization Practices. Ann Intern Med. 2009;150:45-49.
11. Ahmed F, Temte JL, Campos-Outcalt D, et al; for the ACIP Evidence Based Recommendations Work Group (EBRWG). Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine. 2011;29:9171-9176.
12. Lee G, Carr W. Updated framework for development of evidence-based recommendations by the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2018:76:1271-1272.
The current increase in measles cases in the United States has sharpened the focus on antivaccine activities. While the percentage of US children who are fully vaccinated remains high (≥ 94%), the number of un- or undervaccinated children has been growing1 because of nonmedical exemptions from school vaccine requirements due to concerns about vaccine safety and an underappreciation of the benefits of vaccines. Family physicians need to be conversant with several important aspects of this matter, including the magnitude of benefits provided by childhood vaccines, as well as the systems already in place for
- assessing vaccine effectiveness and safety,
- making recommendations on the use of vaccines,
- monitoring safety after vaccine approval, and
- compensating those affected by rare but serious vaccine-related adverse events (AEs).
Familiarity with these issues will allow for informed discussions with parents who are vaccine hesitant and with those who have read or heard inaccurate information.
The benefits of vaccines are indisputable
In 1999, the Centers for Disease Control and Prevention (CDC) published a list of 9 selected childhood infectious diseases and compared their incidences before and after immunization was available.2 Each of these infections causes morbidity, sequelae, and mortality at predictable rates depending on the infectious agent. The comparisons were dramatic: Measles, with a baseline annual morbidity of 503,282 cases, fell to just 89 cases; poliomyelitis decreased from 16,316 to 0; and Haemophilus influenzae type b declined from 20,000 to 54. In a 2014 analysis, the CDC stated that “among 78.6 million children born during 1994–2013, routine childhood immunization was estimated to prevent 322 million illnesses (averaging 4.1 illnesses per child) and 21 million hospitalizations (0.27 per child) over the course of their lifetimes and avert 732,000 premature deaths from vaccine-preventable illnesses” (TABLE).3
It is not unusual to hear a vaccine opponent say that childhood infectious diseases are not serious and that it is better for a child to contract the infection and let the immune system fight it naturally. Measles is often used as an example. This argument ignores some important aspects of vaccine benefits.
It is true in the United States that the average child who contracts measles will recover from it and not suffer immediate or long-term effects. However, it is also true that measles has a hospitalization rate of about 20% and a death rate of between 1/500 and 1/1000 cases.4 Mortality is much higher in developing countries. Prior to widespread use of measles vaccine, hundreds of thousands of cases of measles occurred each year. That translated into hundreds of preventable child deaths per year. An individual case does not tell the full story about the public health impact of infectious illnesses.
In addition, there are often unappreciated sequelae from child infections, such as shingles occurring years after resolution of a chickenpox infection. There are also societal consequences of child infections, such as deafness from congenital rubella and intergenerational transfer of infectious agents to family members at risk for serious consequences (influenza from a child to a grandparent). Finally, infected children pose a risk to those who cannot be vaccinated because of immune deficiencies and other medical conditions.
A multilayered US system monitors vaccine safety
Responsibility for assuring the safety of vaccines lies with the US Food and Drug Administration (FDA) Center for Biologics Evaluation and Research and with the CDC’s Immunization Safety Office (ISO). The FDA is responsible for the initial assessment of the effectiveness and safety of new vaccines and for ongoing monitoring of the manufacturing facilities where vaccines are produced. After FDA approval, safety is monitored using a multilayered system that includes the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD) system, the Clinical Immunization Safety Assessment (CISA) Project, and periodic reviews by the National Academy of Medicine (NAM), previously the Institute of Medicine. In addition, there is a large number of studies published each year by the nation’s—and world’s—medical research community on vaccine effectiveness and safety.
Continue to: VAERS
VAERS (https://vaers.hhs.gov/) is a passive reporting system that allows patients, physicians, and other health care providers to record suspected vaccine-related adverse events.5 It was created in 1990 and is run by the FDA and the CDC. It is not intended to be a comprehensive or definitive list of proven vaccine-related harms. As a passive reporting system, it is subject to both over- and underreporting, and the data from it are often misinterpreted and used incorrectly by vaccine opponents—eg, wrongly declaring that VAERS reports of possible AEs are proven cases. It provides a sentinel system that is monitored for indications of possible serious AEs linked to a particular vaccine. When a suspected interaction is detected, it is investigated by the VSD system.
VSD is a collaboration of the CDC’s ISO and 8 geographically distributed health care organizations with complete electronic patient medical information on their members. VSD conducts studies when a question about vaccine safety arises, when new vaccines are licensed, or when there are new vaccine recommendations. A description of VSD sites, the research methods used, and a list of publications describing study results can be found at https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html#organizations. If the VSD system finds a link between serious AEs and a particular vaccine, this association is reported to the Advisory Committee on Immunization Practices (ACIP) for consideration in changing recommendations regarding that vaccine. This happens only rarely.
CISA was established in 2001 as a network of vaccine safety experts at 7 academic medical centers who collaborate with the CDC’s ISO. CISA conducts studies on specific questions related to vaccine safety and provides a consultation service to clinicians and researchers who have questions about vaccine safety. A description of the CISA sites, past publications on vaccine safety, and ongoing research priorities can be found at https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html.
NAM (https://nam.edu/) conducts periodic reviews of vaccine safety and vaccine-caused AEs. The most recent was published in 2012 and looked at possible AEs of 8 vaccines containing 12 different antigens.6 The literature search for this review found more than 12,000 articles, which speaks to the volume of scientific work on vaccine safety. These NAM reports document the rarity of severe AEs to vaccines and are used with other information to construct the table for the Vaccine Injury Compensation Program (VICP), which is described below.
Are vaccines killing children?
Vaccine opponents frequently claim that vaccines cause much more harm than is documented, including the deaths of children. A vaccine opponent made this claim in my state (Arizona) at a legislative committee hearing even though our state child mortality review committee has been investigating all child deaths for decades and has never attributed a death to a vaccine.
Continue to: One study conducted...
One study conducted using the VSD system from January 1, 2005, to December 31, 2011, identified 1100 deaths occurring within 12 months of any vaccination among 2,189,504 VSD enrollees ages 9 to 26 years.7 They found that the risk of death in this age group was not increased during the 30 days after vaccination, and no deaths were found to be causally associated with vaccination. Deaths among children do occur and, due to the number of vaccines administered, some deaths will occur within a short time period after a vaccine. This temporal association does not prove the death was vaccine-caused, but vaccine opponents have claimed that it does.
The vaccine injury compensation system
In 1986, the federal government established a no-fault system—the National Vaccine Injury Compensation Program (VICP)—to compensate those who suffer a serious AE from a vaccine covered by the program. This system is administered by the Health Resources and Services Administration (HRSA) in the Department of Health and Human Services (DHHS). HRSA maintains a table of proven AEs of specific vaccines, based in part on the NAM report mentioned earlier. Petitions for compensation—with proof of an AE following the administration of a vaccine that is included on the HRSA table—are accepted and remunerated if the AE lasted > 6 months or resulted in hospitalization. Petitions that allege AEs following administration of a vaccine not included on the table are nevertheless reviewed by the staff of HRSA, who can still recommend compensation based on the medical evidence. If HRSA declines the petition, the petitioner can appeal the case in the US Court of Federal Claims, which makes the final decision on a petition’s validity and, if warranted, the type and amount of compensation.
From 2006 to 2017, > 3.4 billion doses of vaccines covered by VICP were distributed in the United States.8 During this period, 6293 petitions were adjudicated by the court; 4311 were compensated.8 For every 1 million doses of vaccine distributed, 1 individual was compensated. Seventy percent of these compensations were awarded to petitioners despite a lack of clear evidence that the patient’s condition was caused by a vaccine.8 The rate of compensation for conditions proven to be caused by a vaccine was 1/3.33 million.8
The VICP pays for attorney fees, in some cases even if the petition is denied, but does not allow contingency fees. Since the beginning of the program, more than $4 billion has been awarded.8 The program is funded by a 75-cent tax on each vaccine antigen. Because serious AEs are so rare, the trust fund established to administer the VICP finances has a surplus of about $6 billion.
The Advisory Committee on Immunization Practices
After a vaccine is approved for use by the FDA, ACIP makes recommendations for its use in the US civilian population.9,10 ACIP, created in 1964, was chartered as a federal advisory committee to provide expert external advice to the Director of the CDC and the Secretary of DHHS on the use of vaccines
Continue to: As an official...
As an official federal advisory committee governed by the Federal Advisory Committee Act, ACIP operates under strict requirements for public notification of meetings, allowing for written and oral public comment at its meetings, and timely publication of minutes. ACIP meeting minutes are posted soon after each meeting, along with draft recommendations. ACIP meeting agendas and slide presentations are available on the ACIP Web site (https://www.cdc.gov/vaccines/acip/index.html).
ACIP consists of 15 members serving overlapping 4-year terms, appointed by the Secretary of DHHS from a list of candidates proposed by the CDC. One member is a consumer representative; the other members have expertise in vaccinology, immunology, pediatrics, internal medicine, infectious diseases, preventive medicine, and public health. In the CDC, staff support for ACIP is provided by the National Center for Immunization and Respiratory Diseases, Office of Infectious Diseases.
ACIP holds 2-day meetings 3 times a year. Much of the work occurs between meetings, by work groups via phone conferences. Work groups are chaired by an ACIP member and staffed by one or more CDC programmatic, content-expert professionals. Membership of the work groups consists of at least 2 ACIP members, representatives from relevant professional clinical and public health organizations, and other individuals with specific expertise. Work groups propose recommendations to ACIP, which can adopt, revise, or reject them.
When formulating recommendations for a particular vaccine, ACIP considers the burden of disease prevented, the effectiveness and safety of the vaccine, cost effectiveness, and practical and logistical issues of implementing recommendations. ACIP also receives frequent reports from ISO regarding the safety of vaccines previously approved. Since 2011, ACIP has used a standardized, modified GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system to assess the evidence regarding effectiveness and safety of new vaccines and an evidence-to-recommendation framework to transparently explain how it arrives at recommendations.11,12
We can recommend vaccines with confidence
In the United States, we have a secure supply of safe vaccines, a transparent method of making vaccine recommendations, a robust system to monitor vaccine safety, and an efficient system to compensate those who experience a rare, serious adverse reaction to a vaccine. The US public health system has achieved a marked reduction in morbidity and mortality from childhood infectious diseases, mostly because of vaccines. Many people today have not experienced or seen children with these once-common childhood infections and may not appreciate the seriousness of childhood infectious diseases or the full value of vaccines. As family physicians, we can help address this problem and recommend vaccines to our patients with confidence.
The current increase in measles cases in the United States has sharpened the focus on antivaccine activities. While the percentage of US children who are fully vaccinated remains high (≥ 94%), the number of un- or undervaccinated children has been growing1 because of nonmedical exemptions from school vaccine requirements due to concerns about vaccine safety and an underappreciation of the benefits of vaccines. Family physicians need to be conversant with several important aspects of this matter, including the magnitude of benefits provided by childhood vaccines, as well as the systems already in place for
- assessing vaccine effectiveness and safety,
- making recommendations on the use of vaccines,
- monitoring safety after vaccine approval, and
- compensating those affected by rare but serious vaccine-related adverse events (AEs).
Familiarity with these issues will allow for informed discussions with parents who are vaccine hesitant and with those who have read or heard inaccurate information.
The benefits of vaccines are indisputable
In 1999, the Centers for Disease Control and Prevention (CDC) published a list of 9 selected childhood infectious diseases and compared their incidences before and after immunization was available.2 Each of these infections causes morbidity, sequelae, and mortality at predictable rates depending on the infectious agent. The comparisons were dramatic: Measles, with a baseline annual morbidity of 503,282 cases, fell to just 89 cases; poliomyelitis decreased from 16,316 to 0; and Haemophilus influenzae type b declined from 20,000 to 54. In a 2014 analysis, the CDC stated that “among 78.6 million children born during 1994–2013, routine childhood immunization was estimated to prevent 322 million illnesses (averaging 4.1 illnesses per child) and 21 million hospitalizations (0.27 per child) over the course of their lifetimes and avert 732,000 premature deaths from vaccine-preventable illnesses” (TABLE).3
It is not unusual to hear a vaccine opponent say that childhood infectious diseases are not serious and that it is better for a child to contract the infection and let the immune system fight it naturally. Measles is often used as an example. This argument ignores some important aspects of vaccine benefits.
It is true in the United States that the average child who contracts measles will recover from it and not suffer immediate or long-term effects. However, it is also true that measles has a hospitalization rate of about 20% and a death rate of between 1/500 and 1/1000 cases.4 Mortality is much higher in developing countries. Prior to widespread use of measles vaccine, hundreds of thousands of cases of measles occurred each year. That translated into hundreds of preventable child deaths per year. An individual case does not tell the full story about the public health impact of infectious illnesses.
In addition, there are often unappreciated sequelae from child infections, such as shingles occurring years after resolution of a chickenpox infection. There are also societal consequences of child infections, such as deafness from congenital rubella and intergenerational transfer of infectious agents to family members at risk for serious consequences (influenza from a child to a grandparent). Finally, infected children pose a risk to those who cannot be vaccinated because of immune deficiencies and other medical conditions.
A multilayered US system monitors vaccine safety
Responsibility for assuring the safety of vaccines lies with the US Food and Drug Administration (FDA) Center for Biologics Evaluation and Research and with the CDC’s Immunization Safety Office (ISO). The FDA is responsible for the initial assessment of the effectiveness and safety of new vaccines and for ongoing monitoring of the manufacturing facilities where vaccines are produced. After FDA approval, safety is monitored using a multilayered system that includes the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD) system, the Clinical Immunization Safety Assessment (CISA) Project, and periodic reviews by the National Academy of Medicine (NAM), previously the Institute of Medicine. In addition, there is a large number of studies published each year by the nation’s—and world’s—medical research community on vaccine effectiveness and safety.
Continue to: VAERS
VAERS (https://vaers.hhs.gov/) is a passive reporting system that allows patients, physicians, and other health care providers to record suspected vaccine-related adverse events.5 It was created in 1990 and is run by the FDA and the CDC. It is not intended to be a comprehensive or definitive list of proven vaccine-related harms. As a passive reporting system, it is subject to both over- and underreporting, and the data from it are often misinterpreted and used incorrectly by vaccine opponents—eg, wrongly declaring that VAERS reports of possible AEs are proven cases. It provides a sentinel system that is monitored for indications of possible serious AEs linked to a particular vaccine. When a suspected interaction is detected, it is investigated by the VSD system.
VSD is a collaboration of the CDC’s ISO and 8 geographically distributed health care organizations with complete electronic patient medical information on their members. VSD conducts studies when a question about vaccine safety arises, when new vaccines are licensed, or when there are new vaccine recommendations. A description of VSD sites, the research methods used, and a list of publications describing study results can be found at https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html#organizations. If the VSD system finds a link between serious AEs and a particular vaccine, this association is reported to the Advisory Committee on Immunization Practices (ACIP) for consideration in changing recommendations regarding that vaccine. This happens only rarely.
CISA was established in 2001 as a network of vaccine safety experts at 7 academic medical centers who collaborate with the CDC’s ISO. CISA conducts studies on specific questions related to vaccine safety and provides a consultation service to clinicians and researchers who have questions about vaccine safety. A description of the CISA sites, past publications on vaccine safety, and ongoing research priorities can be found at https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html.
NAM (https://nam.edu/) conducts periodic reviews of vaccine safety and vaccine-caused AEs. The most recent was published in 2012 and looked at possible AEs of 8 vaccines containing 12 different antigens.6 The literature search for this review found more than 12,000 articles, which speaks to the volume of scientific work on vaccine safety. These NAM reports document the rarity of severe AEs to vaccines and are used with other information to construct the table for the Vaccine Injury Compensation Program (VICP), which is described below.
Are vaccines killing children?
Vaccine opponents frequently claim that vaccines cause much more harm than is documented, including the deaths of children. A vaccine opponent made this claim in my state (Arizona) at a legislative committee hearing even though our state child mortality review committee has been investigating all child deaths for decades and has never attributed a death to a vaccine.
Continue to: One study conducted...
One study conducted using the VSD system from January 1, 2005, to December 31, 2011, identified 1100 deaths occurring within 12 months of any vaccination among 2,189,504 VSD enrollees ages 9 to 26 years.7 They found that the risk of death in this age group was not increased during the 30 days after vaccination, and no deaths were found to be causally associated with vaccination. Deaths among children do occur and, due to the number of vaccines administered, some deaths will occur within a short time period after a vaccine. This temporal association does not prove the death was vaccine-caused, but vaccine opponents have claimed that it does.
The vaccine injury compensation system
In 1986, the federal government established a no-fault system—the National Vaccine Injury Compensation Program (VICP)—to compensate those who suffer a serious AE from a vaccine covered by the program. This system is administered by the Health Resources and Services Administration (HRSA) in the Department of Health and Human Services (DHHS). HRSA maintains a table of proven AEs of specific vaccines, based in part on the NAM report mentioned earlier. Petitions for compensation—with proof of an AE following the administration of a vaccine that is included on the HRSA table—are accepted and remunerated if the AE lasted > 6 months or resulted in hospitalization. Petitions that allege AEs following administration of a vaccine not included on the table are nevertheless reviewed by the staff of HRSA, who can still recommend compensation based on the medical evidence. If HRSA declines the petition, the petitioner can appeal the case in the US Court of Federal Claims, which makes the final decision on a petition’s validity and, if warranted, the type and amount of compensation.
From 2006 to 2017, > 3.4 billion doses of vaccines covered by VICP were distributed in the United States.8 During this period, 6293 petitions were adjudicated by the court; 4311 were compensated.8 For every 1 million doses of vaccine distributed, 1 individual was compensated. Seventy percent of these compensations were awarded to petitioners despite a lack of clear evidence that the patient’s condition was caused by a vaccine.8 The rate of compensation for conditions proven to be caused by a vaccine was 1/3.33 million.8
The VICP pays for attorney fees, in some cases even if the petition is denied, but does not allow contingency fees. Since the beginning of the program, more than $4 billion has been awarded.8 The program is funded by a 75-cent tax on each vaccine antigen. Because serious AEs are so rare, the trust fund established to administer the VICP finances has a surplus of about $6 billion.
The Advisory Committee on Immunization Practices
After a vaccine is approved for use by the FDA, ACIP makes recommendations for its use in the US civilian population.9,10 ACIP, created in 1964, was chartered as a federal advisory committee to provide expert external advice to the Director of the CDC and the Secretary of DHHS on the use of vaccines
Continue to: As an official...
As an official federal advisory committee governed by the Federal Advisory Committee Act, ACIP operates under strict requirements for public notification of meetings, allowing for written and oral public comment at its meetings, and timely publication of minutes. ACIP meeting minutes are posted soon after each meeting, along with draft recommendations. ACIP meeting agendas and slide presentations are available on the ACIP Web site (https://www.cdc.gov/vaccines/acip/index.html).
ACIP consists of 15 members serving overlapping 4-year terms, appointed by the Secretary of DHHS from a list of candidates proposed by the CDC. One member is a consumer representative; the other members have expertise in vaccinology, immunology, pediatrics, internal medicine, infectious diseases, preventive medicine, and public health. In the CDC, staff support for ACIP is provided by the National Center for Immunization and Respiratory Diseases, Office of Infectious Diseases.
ACIP holds 2-day meetings 3 times a year. Much of the work occurs between meetings, by work groups via phone conferences. Work groups are chaired by an ACIP member and staffed by one or more CDC programmatic, content-expert professionals. Membership of the work groups consists of at least 2 ACIP members, representatives from relevant professional clinical and public health organizations, and other individuals with specific expertise. Work groups propose recommendations to ACIP, which can adopt, revise, or reject them.
When formulating recommendations for a particular vaccine, ACIP considers the burden of disease prevented, the effectiveness and safety of the vaccine, cost effectiveness, and practical and logistical issues of implementing recommendations. ACIP also receives frequent reports from ISO regarding the safety of vaccines previously approved. Since 2011, ACIP has used a standardized, modified GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system to assess the evidence regarding effectiveness and safety of new vaccines and an evidence-to-recommendation framework to transparently explain how it arrives at recommendations.11,12
We can recommend vaccines with confidence
In the United States, we have a secure supply of safe vaccines, a transparent method of making vaccine recommendations, a robust system to monitor vaccine safety, and an efficient system to compensate those who experience a rare, serious adverse reaction to a vaccine. The US public health system has achieved a marked reduction in morbidity and mortality from childhood infectious diseases, mostly because of vaccines. Many people today have not experienced or seen children with these once-common childhood infections and may not appreciate the seriousness of childhood infectious diseases or the full value of vaccines. As family physicians, we can help address this problem and recommend vaccines to our patients with confidence.
1. Mellerson JL, Maxwell CB, Knighton CL, et al. Vaccine coverage for selected vaccines and exemption rates among children in kindergarten—United States, 2017-18 school year. MMWR Morb Mortal Wkly Rep. 2018;67:1115-1122.
2. CDC. Ten great public health achievements—United States, 1900-1999. MMWR Morb Mortal Wkly Rep. 1999;48:241-243.
3. Whitney CG, Zhou F, Singleton J, et al. Benefits from immunization during the Vaccines for Children Program era—United States, 1994-2013. MMWR Morb Mortal Wkly Rep. 2014;63:352-355.
4. CDC. Complications of measles. https://www.cdc.gov/measles/symptoms/complications.html. Accessed July 16, 2019.
5. Shimabukuro TT, Nguyen M, Martin D, et al. Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2015;33:4398-4405.
6. IOM (Institute of Medicine). Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press; 2012.
7. McCarthy NL, Gee J, Sukumaran L, et al. Vaccination and 30-day mortality risk in children, adolescents, and young adults. Pediatrics. 2016;137:1-8.
8. HRSA. Data and Statistics. https://www.hrsa.gov/sites/default/files/hrsa/vaccine-compensation/data/monthly-stats-may-2019.pdf. Accessed July 16, 2019.
9. Pickering LK, Orenstein WA, Sun W, et al. FDA licensure of and ACIP recommendations for vaccines. Vaccine. 2017;37:5027-5036.
10. Smith JC, Snider DE, Pickering LK. Immunization policy development in the United States: the role of the Advisory Committee on Immunization Practices. Ann Intern Med. 2009;150:45-49.
11. Ahmed F, Temte JL, Campos-Outcalt D, et al; for the ACIP Evidence Based Recommendations Work Group (EBRWG). Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine. 2011;29:9171-9176.
12. Lee G, Carr W. Updated framework for development of evidence-based recommendations by the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2018:76:1271-1272.
1. Mellerson JL, Maxwell CB, Knighton CL, et al. Vaccine coverage for selected vaccines and exemption rates among children in kindergarten—United States, 2017-18 school year. MMWR Morb Mortal Wkly Rep. 2018;67:1115-1122.
2. CDC. Ten great public health achievements—United States, 1900-1999. MMWR Morb Mortal Wkly Rep. 1999;48:241-243.
3. Whitney CG, Zhou F, Singleton J, et al. Benefits from immunization during the Vaccines for Children Program era—United States, 1994-2013. MMWR Morb Mortal Wkly Rep. 2014;63:352-355.
4. CDC. Complications of measles. https://www.cdc.gov/measles/symptoms/complications.html. Accessed July 16, 2019.
5. Shimabukuro TT, Nguyen M, Martin D, et al. Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2015;33:4398-4405.
6. IOM (Institute of Medicine). Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press; 2012.
7. McCarthy NL, Gee J, Sukumaran L, et al. Vaccination and 30-day mortality risk in children, adolescents, and young adults. Pediatrics. 2016;137:1-8.
8. HRSA. Data and Statistics. https://www.hrsa.gov/sites/default/files/hrsa/vaccine-compensation/data/monthly-stats-may-2019.pdf. Accessed July 16, 2019.
9. Pickering LK, Orenstein WA, Sun W, et al. FDA licensure of and ACIP recommendations for vaccines. Vaccine. 2017;37:5027-5036.
10. Smith JC, Snider DE, Pickering LK. Immunization policy development in the United States: the role of the Advisory Committee on Immunization Practices. Ann Intern Med. 2009;150:45-49.
11. Ahmed F, Temte JL, Campos-Outcalt D, et al; for the ACIP Evidence Based Recommendations Work Group (EBRWG). Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine. 2011;29:9171-9176.
12. Lee G, Carr W. Updated framework for development of evidence-based recommendations by the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2018:76:1271-1272.
MMR vaccine maintains effectiveness after 10 years
according to Stephane Carryn, PhD, of GlaxoSmithKline and associates.
In a phase 3, observer-blind, randomized study published in Vaccine, 1,887 children aged 12-22 months received two doses of the MMR plus varicella (MMRV) vaccine Priorix-Tetra, one dose of the MMR vaccine Priorix with one dose of the varicella vaccine Varilrix delivered separately, or two doses of the MMR vaccine. Blood samples were collected at baseline and at days 42 and 84, then at year 1, 2, 4, 6, 8, and 10.
Antimeasles and antirubella antibodies declined moderately over the 10-year study period, but seropositivity remained high at 10 years, with about 94.0% of children remaining seropositive for antimeasles antibodies and about 96.6% remaining seropositive for antirubella antibodies. Children who received Priorix-Tetra had antimeasles antibody titers twice as high as those who received Priorix throughout the study. In addition, children who received a second dose of MMR vaccine later in life saw only a transient benefit in antimeasles and antirubella titers.
Antimumps antibody titer levels remained stable over the course of the study, and the seropositivity rate was about 90.0% at 10 years. Children who received a second MMR vaccine later in life saw a boosting effect in seropositivity and antimumps antibody titer levels.
“The responses obtained after receipt of one or two doses of MMR-containing vaccines remain well above the seropositivity thresholds up to 10 years post vaccination, regardless of the vaccine given and the schedule used,” the investigators concluded.
The study was funded and supported by GlaxoSmithKline. The study authors reported being employed by GlaxoSmithKline; two also reported owning shares in the company.
SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.
according to Stephane Carryn, PhD, of GlaxoSmithKline and associates.
In a phase 3, observer-blind, randomized study published in Vaccine, 1,887 children aged 12-22 months received two doses of the MMR plus varicella (MMRV) vaccine Priorix-Tetra, one dose of the MMR vaccine Priorix with one dose of the varicella vaccine Varilrix delivered separately, or two doses of the MMR vaccine. Blood samples were collected at baseline and at days 42 and 84, then at year 1, 2, 4, 6, 8, and 10.
Antimeasles and antirubella antibodies declined moderately over the 10-year study period, but seropositivity remained high at 10 years, with about 94.0% of children remaining seropositive for antimeasles antibodies and about 96.6% remaining seropositive for antirubella antibodies. Children who received Priorix-Tetra had antimeasles antibody titers twice as high as those who received Priorix throughout the study. In addition, children who received a second dose of MMR vaccine later in life saw only a transient benefit in antimeasles and antirubella titers.
Antimumps antibody titer levels remained stable over the course of the study, and the seropositivity rate was about 90.0% at 10 years. Children who received a second MMR vaccine later in life saw a boosting effect in seropositivity and antimumps antibody titer levels.
“The responses obtained after receipt of one or two doses of MMR-containing vaccines remain well above the seropositivity thresholds up to 10 years post vaccination, regardless of the vaccine given and the schedule used,” the investigators concluded.
The study was funded and supported by GlaxoSmithKline. The study authors reported being employed by GlaxoSmithKline; two also reported owning shares in the company.
SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.
according to Stephane Carryn, PhD, of GlaxoSmithKline and associates.
In a phase 3, observer-blind, randomized study published in Vaccine, 1,887 children aged 12-22 months received two doses of the MMR plus varicella (MMRV) vaccine Priorix-Tetra, one dose of the MMR vaccine Priorix with one dose of the varicella vaccine Varilrix delivered separately, or two doses of the MMR vaccine. Blood samples were collected at baseline and at days 42 and 84, then at year 1, 2, 4, 6, 8, and 10.
Antimeasles and antirubella antibodies declined moderately over the 10-year study period, but seropositivity remained high at 10 years, with about 94.0% of children remaining seropositive for antimeasles antibodies and about 96.6% remaining seropositive for antirubella antibodies. Children who received Priorix-Tetra had antimeasles antibody titers twice as high as those who received Priorix throughout the study. In addition, children who received a second dose of MMR vaccine later in life saw only a transient benefit in antimeasles and antirubella titers.
Antimumps antibody titer levels remained stable over the course of the study, and the seropositivity rate was about 90.0% at 10 years. Children who received a second MMR vaccine later in life saw a boosting effect in seropositivity and antimumps antibody titer levels.
“The responses obtained after receipt of one or two doses of MMR-containing vaccines remain well above the seropositivity thresholds up to 10 years post vaccination, regardless of the vaccine given and the schedule used,” the investigators concluded.
The study was funded and supported by GlaxoSmithKline. The study authors reported being employed by GlaxoSmithKline; two also reported owning shares in the company.
SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.
FROM VACCINE
Washington State removes exemption for MMR vaccine
Washington state parents may no longer cite personal or philosophical objections to refuse the MMR vaccine for their children, effective July 28, according to the state’s department of health.
“In Washington state we believe in our doctors. We believe in our nurses. We believe in our educators. We believe in science and we love our children,” Gov. Jay Inslee (D) said when he signed the bill into law on May 10. “And that is why in Washington State, we are against measles.”
The new law applies only to the MMR vaccine and “does not change religious and medical exemption laws. Children who have one of these types of exemptions on file are not affected by the new law,” the health department said.
Washington is one of 45 states that allows religious exemptions from school immunization requirements, according to the National Conference of State Legislatures, which also reported that 15 of those states allow personal-belief exemptions.
The five states that do not allow any form of nonmedical exemption are California, Maine, Mississippi, New York, and West Virginia.
Washington state parents may no longer cite personal or philosophical objections to refuse the MMR vaccine for their children, effective July 28, according to the state’s department of health.
“In Washington state we believe in our doctors. We believe in our nurses. We believe in our educators. We believe in science and we love our children,” Gov. Jay Inslee (D) said when he signed the bill into law on May 10. “And that is why in Washington State, we are against measles.”
The new law applies only to the MMR vaccine and “does not change religious and medical exemption laws. Children who have one of these types of exemptions on file are not affected by the new law,” the health department said.
Washington is one of 45 states that allows religious exemptions from school immunization requirements, according to the National Conference of State Legislatures, which also reported that 15 of those states allow personal-belief exemptions.
The five states that do not allow any form of nonmedical exemption are California, Maine, Mississippi, New York, and West Virginia.
Washington state parents may no longer cite personal or philosophical objections to refuse the MMR vaccine for their children, effective July 28, according to the state’s department of health.
“In Washington state we believe in our doctors. We believe in our nurses. We believe in our educators. We believe in science and we love our children,” Gov. Jay Inslee (D) said when he signed the bill into law on May 10. “And that is why in Washington State, we are against measles.”
The new law applies only to the MMR vaccine and “does not change religious and medical exemption laws. Children who have one of these types of exemptions on file are not affected by the new law,” the health department said.
Washington is one of 45 states that allows religious exemptions from school immunization requirements, according to the National Conference of State Legislatures, which also reported that 15 of those states allow personal-belief exemptions.
The five states that do not allow any form of nonmedical exemption are California, Maine, Mississippi, New York, and West Virginia.
Pertussis: Comparison studies show DTwP more durable
Children primed with DTaP vaccines have a weaker response to the pertussis component of the Tdap booster vaccine, compared with children primed with the whole-cell vaccine (DTwP), according to a study in Vaccine.
Michael D. Decker, MD, and colleagues conducted a study in children aged 11-12 years who had been primed with DTaP (NCT01629589) that essentially mirrored one from 6 years earlier in children primed with DTwP when it was still the more commonly used vaccine (NCT00319553). This later study randomized 211 patients to Tdap5 and 212 to Tdap3, both licensed Tdap vaccines that had been used and compared in the earlier study. The only 35% as high for Tdap5 (31.0 vs. 86.7 endotoxin units/mL, respectively; 95% confidence interval, 30%-40%) and 32% as high (44.1 vs. 136 endotoxin units/mL; 95% CI, 28%-38%) for Tdap3.
The authors noted that, because studies including children primed with DTwP are usually much older, comparisons like the one made in this study can be unreliable because of various possible confounding factors – such as changes in manufacturing process, different assays used, changing characteristics in study populations or pertussis transmission, and so on – cannot be entirely excluded. However, one of the strengths of this study, they suggested, is that “all were randomized experimental studies conducted by Sanofi Pasteur using similar procedures (including time of sera collection), and sera from all were assayed by a single laboratory (GCI) employing consistent, [Food and Drug Administration]–accepted assays.”
They did note that estimates of mean pertussis antibodies was limited by sample sizes; however, they believed the results were sufficient for the comparisons in the study.
All authors of the study were employees of Sanofi Pasteur, which funded the study and also manufactures the Tdap5 vaccine.
SOURCE: Decker MD et al. Vaccine. 2019 Jul 10. doi: 10.1016/j.vaccine.2019.07.015.
Children primed with DTaP vaccines have a weaker response to the pertussis component of the Tdap booster vaccine, compared with children primed with the whole-cell vaccine (DTwP), according to a study in Vaccine.
Michael D. Decker, MD, and colleagues conducted a study in children aged 11-12 years who had been primed with DTaP (NCT01629589) that essentially mirrored one from 6 years earlier in children primed with DTwP when it was still the more commonly used vaccine (NCT00319553). This later study randomized 211 patients to Tdap5 and 212 to Tdap3, both licensed Tdap vaccines that had been used and compared in the earlier study. The only 35% as high for Tdap5 (31.0 vs. 86.7 endotoxin units/mL, respectively; 95% confidence interval, 30%-40%) and 32% as high (44.1 vs. 136 endotoxin units/mL; 95% CI, 28%-38%) for Tdap3.
The authors noted that, because studies including children primed with DTwP are usually much older, comparisons like the one made in this study can be unreliable because of various possible confounding factors – such as changes in manufacturing process, different assays used, changing characteristics in study populations or pertussis transmission, and so on – cannot be entirely excluded. However, one of the strengths of this study, they suggested, is that “all were randomized experimental studies conducted by Sanofi Pasteur using similar procedures (including time of sera collection), and sera from all were assayed by a single laboratory (GCI) employing consistent, [Food and Drug Administration]–accepted assays.”
They did note that estimates of mean pertussis antibodies was limited by sample sizes; however, they believed the results were sufficient for the comparisons in the study.
All authors of the study were employees of Sanofi Pasteur, which funded the study and also manufactures the Tdap5 vaccine.
SOURCE: Decker MD et al. Vaccine. 2019 Jul 10. doi: 10.1016/j.vaccine.2019.07.015.
Children primed with DTaP vaccines have a weaker response to the pertussis component of the Tdap booster vaccine, compared with children primed with the whole-cell vaccine (DTwP), according to a study in Vaccine.
Michael D. Decker, MD, and colleagues conducted a study in children aged 11-12 years who had been primed with DTaP (NCT01629589) that essentially mirrored one from 6 years earlier in children primed with DTwP when it was still the more commonly used vaccine (NCT00319553). This later study randomized 211 patients to Tdap5 and 212 to Tdap3, both licensed Tdap vaccines that had been used and compared in the earlier study. The only 35% as high for Tdap5 (31.0 vs. 86.7 endotoxin units/mL, respectively; 95% confidence interval, 30%-40%) and 32% as high (44.1 vs. 136 endotoxin units/mL; 95% CI, 28%-38%) for Tdap3.
The authors noted that, because studies including children primed with DTwP are usually much older, comparisons like the one made in this study can be unreliable because of various possible confounding factors – such as changes in manufacturing process, different assays used, changing characteristics in study populations or pertussis transmission, and so on – cannot be entirely excluded. However, one of the strengths of this study, they suggested, is that “all were randomized experimental studies conducted by Sanofi Pasteur using similar procedures (including time of sera collection), and sera from all were assayed by a single laboratory (GCI) employing consistent, [Food and Drug Administration]–accepted assays.”
They did note that estimates of mean pertussis antibodies was limited by sample sizes; however, they believed the results were sufficient for the comparisons in the study.
All authors of the study were employees of Sanofi Pasteur, which funded the study and also manufactures the Tdap5 vaccine.
SOURCE: Decker MD et al. Vaccine. 2019 Jul 10. doi: 10.1016/j.vaccine.2019.07.015.
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Pentavalent DTaP-Hb-Hib vaccine is found noninferior to comparator
The to a similar, commercially available vaccine in infants, according to a study in Vaccine.
In this phase 3, randomized, single-blind, multicenter, noninferiority study, Sai Krishna Susarla of Human Biologicals Institute, which developed the test vaccine, and colleagues randomized 405 infants aged 6-8 weeks 2:1 to three doses of either the test vaccine or the comparator, Pentavac SD (Serum Institute of India). The percentages of seroconversion for diphtheria, pertussis, hepatitis B, and Hib were 98.44%, 92.61%, 99.22%, and 95.72% for the test vaccine, respectively, and 90.0%, 89.23%, 100%, and 90.77% for the comparator. In keeping with some previous studies, the percentages for tetanus were low at 50.97% with the test vaccine and 30.23% with the comparator. Despite the low seroconversion for tetanus, the test vaccine was determined to be noninferior to the comparator for it and the other four diseases it targets. The safety profile was also found to be comparable.
Although the study’s major limitation is that it was conducted in only one country, “the strength of the study is considered to be good” because “compliance to protocol was good, deviations were minimal, and ... very few subjects were withdrawn,” the researchers wrote.
Some of the researchers were employees of the sponsor, Human Biologicals Institute, which developed the test vaccine. Other researchers had no financial interest in the test vaccine and were unrelated to the sponsor, but did receive research grants for conducting the study at their respective sites.
SOURCE: Susarla SK et al. Vaccine. 2019 Jul 19. doi: 10.1016/j.vaccine.2019.06.067.
The to a similar, commercially available vaccine in infants, according to a study in Vaccine.
In this phase 3, randomized, single-blind, multicenter, noninferiority study, Sai Krishna Susarla of Human Biologicals Institute, which developed the test vaccine, and colleagues randomized 405 infants aged 6-8 weeks 2:1 to three doses of either the test vaccine or the comparator, Pentavac SD (Serum Institute of India). The percentages of seroconversion for diphtheria, pertussis, hepatitis B, and Hib were 98.44%, 92.61%, 99.22%, and 95.72% for the test vaccine, respectively, and 90.0%, 89.23%, 100%, and 90.77% for the comparator. In keeping with some previous studies, the percentages for tetanus were low at 50.97% with the test vaccine and 30.23% with the comparator. Despite the low seroconversion for tetanus, the test vaccine was determined to be noninferior to the comparator for it and the other four diseases it targets. The safety profile was also found to be comparable.
Although the study’s major limitation is that it was conducted in only one country, “the strength of the study is considered to be good” because “compliance to protocol was good, deviations were minimal, and ... very few subjects were withdrawn,” the researchers wrote.
Some of the researchers were employees of the sponsor, Human Biologicals Institute, which developed the test vaccine. Other researchers had no financial interest in the test vaccine and were unrelated to the sponsor, but did receive research grants for conducting the study at their respective sites.
SOURCE: Susarla SK et al. Vaccine. 2019 Jul 19. doi: 10.1016/j.vaccine.2019.06.067.
The to a similar, commercially available vaccine in infants, according to a study in Vaccine.
In this phase 3, randomized, single-blind, multicenter, noninferiority study, Sai Krishna Susarla of Human Biologicals Institute, which developed the test vaccine, and colleagues randomized 405 infants aged 6-8 weeks 2:1 to three doses of either the test vaccine or the comparator, Pentavac SD (Serum Institute of India). The percentages of seroconversion for diphtheria, pertussis, hepatitis B, and Hib were 98.44%, 92.61%, 99.22%, and 95.72% for the test vaccine, respectively, and 90.0%, 89.23%, 100%, and 90.77% for the comparator. In keeping with some previous studies, the percentages for tetanus were low at 50.97% with the test vaccine and 30.23% with the comparator. Despite the low seroconversion for tetanus, the test vaccine was determined to be noninferior to the comparator for it and the other four diseases it targets. The safety profile was also found to be comparable.
Although the study’s major limitation is that it was conducted in only one country, “the strength of the study is considered to be good” because “compliance to protocol was good, deviations were minimal, and ... very few subjects were withdrawn,” the researchers wrote.
Some of the researchers were employees of the sponsor, Human Biologicals Institute, which developed the test vaccine. Other researchers had no financial interest in the test vaccine and were unrelated to the sponsor, but did receive research grants for conducting the study at their respective sites.
SOURCE: Susarla SK et al. Vaccine. 2019 Jul 19. doi: 10.1016/j.vaccine.2019.06.067.
FROM VACCINE
PHiD-CV with 4CMenB safe, effective for infants
Concomitant administration of pneumococcal and meningococcal vaccines is not only safe but also offers the potential to improve vaccine uptake and reduce the number of doctors’ visits required for routine vaccination, advised Marco Aurelio P. Safadi, MD, PhD, of Santa Casa de São Paulo School of Medical Sciences, Brazil, and associates.
In a post hoc analysis of a phase 3b open-label study, Dr. Safadi and associates sought to evaluate immune response in pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered concomitantly with either meningococcal serogroup B (4CMenB) vaccine and CRM-conjugated meningococcal serogroup C vaccine (MenC-CRM) or with MenC-CRM alone using reduced schedules in 213 healthy infants aged 83-104 days. Study participants were enrolled and randomized to one of two groups between April 2011 and December 2014 at four sites in Brazil (Vaccine. 2019 Jul 18. doi: 10.1016/j.vaccine.2019.07.021).
Similar immune response was seen with vaccine serotypes and vaccine-related pneumococcal serotypes 6A and 19A in children who had received concomitant administration of PHiD-CV, 4CMenB, and MenC-CRM without 4CMenB.
Dr. Safadi and associates pointed out that PHiD-CV was given in accordance with a 3+1 dosing schedule, while 4CMenB used a reduced 2+1 schedule, which was observed to produce an immune response and provide an acceptable safety profile.
The findings yielded valuable information for the 2+1 PHiD-CV vaccination schedule, which was recently introduced in Brazil, the researchers said. The post-booster results further reflect the “immunogenicity following 3-dose priming.”
The post hoc nature of this study design effectively demonstrated that or with MenC-CRM alone, they explained.
The study was supported by GlaxoSmithKline (GSK) Biologicals. Three authors are employees of the GSK group of companies, and three others received a grant from the GSK companies, two of whom received compensation from other pharmaceutical companies. The institution of one of the authors received clinical trial fees from the GSK companies, and received personal fees/nonfinancial support/grants/other from the GSK companies and many other pharmaceutical companies.
Concomitant administration of pneumococcal and meningococcal vaccines is not only safe but also offers the potential to improve vaccine uptake and reduce the number of doctors’ visits required for routine vaccination, advised Marco Aurelio P. Safadi, MD, PhD, of Santa Casa de São Paulo School of Medical Sciences, Brazil, and associates.
In a post hoc analysis of a phase 3b open-label study, Dr. Safadi and associates sought to evaluate immune response in pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered concomitantly with either meningococcal serogroup B (4CMenB) vaccine and CRM-conjugated meningococcal serogroup C vaccine (MenC-CRM) or with MenC-CRM alone using reduced schedules in 213 healthy infants aged 83-104 days. Study participants were enrolled and randomized to one of two groups between April 2011 and December 2014 at four sites in Brazil (Vaccine. 2019 Jul 18. doi: 10.1016/j.vaccine.2019.07.021).
Similar immune response was seen with vaccine serotypes and vaccine-related pneumococcal serotypes 6A and 19A in children who had received concomitant administration of PHiD-CV, 4CMenB, and MenC-CRM without 4CMenB.
Dr. Safadi and associates pointed out that PHiD-CV was given in accordance with a 3+1 dosing schedule, while 4CMenB used a reduced 2+1 schedule, which was observed to produce an immune response and provide an acceptable safety profile.
The findings yielded valuable information for the 2+1 PHiD-CV vaccination schedule, which was recently introduced in Brazil, the researchers said. The post-booster results further reflect the “immunogenicity following 3-dose priming.”
The post hoc nature of this study design effectively demonstrated that or with MenC-CRM alone, they explained.
The study was supported by GlaxoSmithKline (GSK) Biologicals. Three authors are employees of the GSK group of companies, and three others received a grant from the GSK companies, two of whom received compensation from other pharmaceutical companies. The institution of one of the authors received clinical trial fees from the GSK companies, and received personal fees/nonfinancial support/grants/other from the GSK companies and many other pharmaceutical companies.
Concomitant administration of pneumococcal and meningococcal vaccines is not only safe but also offers the potential to improve vaccine uptake and reduce the number of doctors’ visits required for routine vaccination, advised Marco Aurelio P. Safadi, MD, PhD, of Santa Casa de São Paulo School of Medical Sciences, Brazil, and associates.
In a post hoc analysis of a phase 3b open-label study, Dr. Safadi and associates sought to evaluate immune response in pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered concomitantly with either meningococcal serogroup B (4CMenB) vaccine and CRM-conjugated meningococcal serogroup C vaccine (MenC-CRM) or with MenC-CRM alone using reduced schedules in 213 healthy infants aged 83-104 days. Study participants were enrolled and randomized to one of two groups between April 2011 and December 2014 at four sites in Brazil (Vaccine. 2019 Jul 18. doi: 10.1016/j.vaccine.2019.07.021).
Similar immune response was seen with vaccine serotypes and vaccine-related pneumococcal serotypes 6A and 19A in children who had received concomitant administration of PHiD-CV, 4CMenB, and MenC-CRM without 4CMenB.
Dr. Safadi and associates pointed out that PHiD-CV was given in accordance with a 3+1 dosing schedule, while 4CMenB used a reduced 2+1 schedule, which was observed to produce an immune response and provide an acceptable safety profile.
The findings yielded valuable information for the 2+1 PHiD-CV vaccination schedule, which was recently introduced in Brazil, the researchers said. The post-booster results further reflect the “immunogenicity following 3-dose priming.”
The post hoc nature of this study design effectively demonstrated that or with MenC-CRM alone, they explained.
The study was supported by GlaxoSmithKline (GSK) Biologicals. Three authors are employees of the GSK group of companies, and three others received a grant from the GSK companies, two of whom received compensation from other pharmaceutical companies. The institution of one of the authors received clinical trial fees from the GSK companies, and received personal fees/nonfinancial support/grants/other from the GSK companies and many other pharmaceutical companies.
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