Vaccines

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.

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.

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.

It is true that the average American child who contracts measles will recover from it and not suffer long-term effects. However, it is also true that measles has a death rate of between 1/500 and 1/1000 cases.

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. ACIP also provides guidance on the use of other biologicals, antibiotics, and antivirals for treatment and prevention of vaccine-preventable infections.

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.

Infected children pose a risk to those who cannot be vaccinated because of immune deficiencies and other medical conditions.

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.

It is true that the average American child who contracts measles will recover from it and not suffer long-term effects. However, it is also true that measles has a death rate of between 1/500 and 1/1000 cases.

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. ACIP also provides guidance on the use of other biologicals, antibiotics, and antivirals for treatment and prevention of vaccine-preventable infections.

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.

Infected children pose a risk to those who cannot be vaccinated because of immune deficiencies and other medical conditions.

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.

It is true that the average American child who contracts measles will recover from it and not suffer long-term effects. However, it is also true that measles has a death rate of between 1/500 and 1/1000 cases.

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. ACIP also provides guidance on the use of other biologicals, antibiotics, and antivirals for treatment and prevention of vaccine-preventable infections.

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.

Infected children pose a risk to those who cannot be vaccinated because of immune deficiencies and other medical conditions.

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.

Children who received one or two doses of an MMR-containing vaccine maintained an antibody count well above the seropositivity threshold 10 years after receiving the vaccine, 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.

lfranki@mdedge.com

SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.

Children who received one or two doses of an MMR-containing vaccine maintained an antibody count well above the seropositivity threshold 10 years after receiving the vaccine, 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.

lfranki@mdedge.com

SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.

Children who received one or two doses of an MMR-containing vaccine maintained an antibody count well above the seropositivity threshold 10 years after receiving the vaccine, 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.

lfranki@mdedge.com

SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.

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.

rfranki@mdedge.com

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.

rfranki@mdedge.com

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.

rfranki@mdedge.com

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.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

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 geometric mean concentrations of antipertussis antibodies in DTaP-primed children after receiving either Tdap vaccine were lower than in DTwP-primed children receiving the same respective vaccines: 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.

cpalmer@mdedge.com

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.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

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 geometric mean concentrations of antipertussis antibodies in DTaP-primed children after receiving either Tdap vaccine were lower than in DTwP-primed children receiving the same respective vaccines: 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.

cpalmer@mdedge.com

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.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

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 geometric mean concentrations of antipertussis antibodies in DTaP-primed children after receiving either Tdap vaccine were lower than in DTwP-primed children receiving the same respective vaccines: 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.

cpalmer@mdedge.com

SOURCE: Decker MD et al. Vaccine. 2019 Jul 10. doi: 10.1016/j.vaccine.2019.07.015.

The DTaP, hepatitis B virus, and Haemophilus influenzae type b (Hib) vaccine was found to be noninferior to a similar, commercially available vaccine in infants, according to a study in Vaccine.

MarianVejcik/Getty Images

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.

cpalmer@mdedge.com

SOURCE: Susarla SK et al. Vaccine. 2019 Jul 19. doi: 10.1016/j.vaccine.2019.06.067.

The DTaP, hepatitis B virus, and Haemophilus influenzae type b (Hib) vaccine was found to be noninferior to a similar, commercially available vaccine in infants, according to a study in Vaccine.

MarianVejcik/Getty Images

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.

cpalmer@mdedge.com

SOURCE: Susarla SK et al. Vaccine. 2019 Jul 19. doi: 10.1016/j.vaccine.2019.06.067.

The DTaP, hepatitis B virus, and Haemophilus influenzae type b (Hib) vaccine was found to be noninferior to a similar, commercially available vaccine in infants, according to a study in Vaccine.

MarianVejcik/Getty Images

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.

cpalmer@mdedge.com

SOURCE: Susarla SK et al. Vaccine. 2019 Jul 19. doi: 10.1016/j.vaccine.2019.06.067.

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.

MarianVejcik/Getty Images

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 “PHiD-CV was immunogenic for the 10 vaccine serotypes and vaccine-related serotypes 6A and 19A” when given at the same time with 4CMenB and MenC-CRM 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.

MarianVejcik/Getty Images

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 “PHiD-CV was immunogenic for the 10 vaccine serotypes and vaccine-related serotypes 6A and 19A” when given at the same time with 4CMenB and MenC-CRM 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.

MarianVejcik/Getty Images

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 “PHiD-CV was immunogenic for the 10 vaccine serotypes and vaccine-related serotypes 6A and 19A” when given at the same time with 4CMenB and MenC-CRM 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.

The week ending July 18 brought an increase in the number of cases, the number of outbreaks, and the number of states with cases in 2019, according to the Centers for Disease Control and Prevention.

The total number of confirmed cases of measles in the United States is now up to 1,148 for the year, which is 25 more than the previous week, the CDC said on July 22. The highest 1-week total for the year was the 90 cases reported during the week of April 11.

The number of outbreaks is back up to five as California returned to the list after a 1-week absence and El Paso, Tex., made its first appearance of the year. The current outbreak in California – the state’s fifth – is occurring in Los Angeles, which is now up to 16 total cases in 2019. El Paso just reported its fourth case on July 17, and the city’s health department noted that “it had been more than 25 years since El Paso saw its last case of measles before these four recent cases.” Outbreaks also are ongoing in Rockland County, N.Y.; New York City; and three counties in Washington State.

States that joined the ranks of the measles-infected during this most recent reporting week were Alaska and Ohio, which brings the total number to 30 for the year, the CDC said.

The Alaska Department of Health and Social Services said that it “has confirmed a single case of measles in an unvaccinated teenager from the Kenai Peninsula who recently traveled out of state to Arizona via Seattle.” The Ohio case is a “young adult from Stark County [who] recently traveled to a state with confirmed measles cases,” according to the state’s health department.

rfranki@mdedge.com

The week ending July 18 brought an increase in the number of cases, the number of outbreaks, and the number of states with cases in 2019, according to the Centers for Disease Control and Prevention.

The total number of confirmed cases of measles in the United States is now up to 1,148 for the year, which is 25 more than the previous week, the CDC said on July 22. The highest 1-week total for the year was the 90 cases reported during the week of April 11.

The number of outbreaks is back up to five as California returned to the list after a 1-week absence and El Paso, Tex., made its first appearance of the year. The current outbreak in California – the state’s fifth – is occurring in Los Angeles, which is now up to 16 total cases in 2019. El Paso just reported its fourth case on July 17, and the city’s health department noted that “it had been more than 25 years since El Paso saw its last case of measles before these four recent cases.” Outbreaks also are ongoing in Rockland County, N.Y.; New York City; and three counties in Washington State.

States that joined the ranks of the measles-infected during this most recent reporting week were Alaska and Ohio, which brings the total number to 30 for the year, the CDC said.

The Alaska Department of Health and Social Services said that it “has confirmed a single case of measles in an unvaccinated teenager from the Kenai Peninsula who recently traveled out of state to Arizona via Seattle.” The Ohio case is a “young adult from Stark County [who] recently traveled to a state with confirmed measles cases,” according to the state’s health department.

rfranki@mdedge.com

The week ending July 18 brought an increase in the number of cases, the number of outbreaks, and the number of states with cases in 2019, according to the Centers for Disease Control and Prevention.

The total number of confirmed cases of measles in the United States is now up to 1,148 for the year, which is 25 more than the previous week, the CDC said on July 22. The highest 1-week total for the year was the 90 cases reported during the week of April 11.

The number of outbreaks is back up to five as California returned to the list after a 1-week absence and El Paso, Tex., made its first appearance of the year. The current outbreak in California – the state’s fifth – is occurring in Los Angeles, which is now up to 16 total cases in 2019. El Paso just reported its fourth case on July 17, and the city’s health department noted that “it had been more than 25 years since El Paso saw its last case of measles before these four recent cases.” Outbreaks also are ongoing in Rockland County, N.Y.; New York City; and three counties in Washington State.

States that joined the ranks of the measles-infected during this most recent reporting week were Alaska and Ohio, which brings the total number to 30 for the year, the CDC said.

The Alaska Department of Health and Social Services said that it “has confirmed a single case of measles in an unvaccinated teenager from the Kenai Peninsula who recently traveled out of state to Arizona via Seattle.” The Ohio case is a “young adult from Stark County [who] recently traveled to a state with confirmed measles cases,” according to the state’s health department.

rfranki@mdedge.com

Fluad (aIIV3), an adjuvanted flu vaccine that’s recommended for people aged 65 and older, does a better job than do conventional flu vaccines in young children, according to an industry-funded synthesis of six studies.

KatarzynaBialasiewicz/Thinkstock

The vaccine “offers significant advances over conventional inactivated influenza vaccines and presents an acceptable safety profile in children 6 months through 5 years of age,” Sanjay S. Patel, PhD, of Novartis Vaccines and Diagnostics, Cambridge, Mass., and associates wrote in the analysis, published in the International Journal of Infectious Diseases. “The noteworthy increases in antibody responses and decreases in influenza cases following vaccination suggest an alternative for use in a population that is heavily impacted by influenza disease.”

Children are, of course, vulnerable to flu. The Centers for Disease Control and Prevention reported that 186 children died of flu during the landmark 2017-2018 flu season. That’s the highest number of pediatric flu deaths since they became a notifiable condition in 2004 (exclusive of the 2009 pandemic, when 358 pediatric deaths were reported from April 15, 2009, to October 2, 2010).The CDC said the vaccine during that flu season had an overall effectiveness level of 40%. According to research of others, however, flu vaccines are less effective in younger children than in adolescents and adults (Vaccine. 2014;32[31]:3886-94; Cochrane Database Syst Rev. 2008. doi: 10.1002/14651858.CD004879.pub3).

Fluad – a MF59-adjuvanted inactivated trivalent seasonal influenza vaccine – is used in adults over 65 in the United States and 29 other countries, and it is approved for children aged 6 months through 23 months in Canada.

Dr. Patel and associates examined the results of six studies – one phase 1b, three phase 2, and two phase 3 – that tested Fluad with or without other vaccines in 11,942 children aged 6 months to 5 years. The studies, mostly multicenter, were conducted in various countries, mainly in Europe and South and Central America, from 2006 to 2012.

In general, children in the intervention groups in the studies received two doses of the Fluad vaccine 4 weeks apart: two 0.25-mL doses for children aged 6-35 months and two 0.5-mL doses for those aged 3 years or older. In most of the studies, parallel control groups received nonadjuvanted trivalent or quadrivalent influenza vaccines.

Most participants (93%-94%) completed the studies. Solicited adverse effects were common in all groups (72% in the Fluad group vs. 67% who received IIV3 vaccines), and generally mild to moderate and resolved in 1-3 days. Unsolicited adverse effects were similar (55% and 62%, respectively) in the two flu vaccine groups. The authors wrote that “these data reflect a safety profile consistent with other licensed inactivated influenza vaccines administered to children.”

As for results, Dr. Patel and colleagues said, “HI [hemagglutination inhibition] antibody responses to both homologous and heterologous influenza strains are higher following vaccination with aIIV3, and this increase in immunogenicity is observed across all age subgroups in children aged 6 months through 5 years, and most profound in the children 6 to 36 months.”

For example, in one of the phase 3 studies when the influenza viruses were antigenically matched (homologous) for A/H1N1 among the children aged 6-35 months seroconversion was 100% for allV3 (Fluad) and 38% for IIV3-1/IIV3-4 (trivalent/quadrivalent flu vaccines); among children aged 3-5 years seroconversion was 100% for allV3 and 82% for IIV3-1/IIV3-4. For AH3N2 homologous among children aged 6-35 months, seroconversion was 98% for allV3 and 44% for IIV3-1/IIV3-4. For the B strain homologous among children aged 6-35 months, seroconversion was 88% for allV3 and 19% for IIV3-1/IIV3-4; among children aged 3-5 years seroconversion for B was 99% for allV3 and 59% for IIV3-1/IIV3-4.

In the same study when the influenza viruses were antigenically mismatched (heterologous) for A/H1N1 among children of all ages 6 months to greater than 72 months, seroconversion was 96% for allV3 (Fluad) and 44% for IIV3-1/IIV3-4; for A/H3N2 it was 98% for allV3 and 49% for IIV3-1/IIV3-4, and for the B strain it was 10% for allV3 and 3% for IIV3-1/IIV3-4.

They added that “in addition, aIIV3 had the fastest onset of immunogenicity and longest persistence of immune response, which has implications for the real-world clinical setting, where the influenza season might start earlier than expected or last longer, and second (follow-up) vaccinations may be missed.”

Dr. Patel and associates said the MF59 adjuvant in Fluad “recruits immune cells (primarily monocytes, macrophages, neutrophils, and dendritic cells) at the site of injection and differentiates them into antigen-presenting cells. With an MF59-adjuvanted vaccine, more antigen is transported from the injection site to the draining lymph node, wherein MF59 leads to T-cell activation and an increased B-cell expansion and a greater number and diversity of antibodies.”

According to goodrx.com, one syringe of Fluad 0.5 mL costs $45-$74 with coupon. The same dose of Fluzone Quadrivalent, a flu vaccine recently approved by the Food and Drug Administration for use in young children aged 6-35 months, costs $31 with coupon.

The study was funded by Novartis Vaccines and Diagnostics and Seqirus (formerly part of Novartis Vaccines and Diagnostics). The study authors disclosed employment by Novartis and Seqirus.

SOURCE: Patel SS et al. Int J Infect Dis. 2019. doi: 10.1016/j.ijid.2019.05.009.

Fluad (aIIV3), an adjuvanted flu vaccine that’s recommended for people aged 65 and older, does a better job than do conventional flu vaccines in young children, according to an industry-funded synthesis of six studies.

KatarzynaBialasiewicz/Thinkstock

The vaccine “offers significant advances over conventional inactivated influenza vaccines and presents an acceptable safety profile in children 6 months through 5 years of age,” Sanjay S. Patel, PhD, of Novartis Vaccines and Diagnostics, Cambridge, Mass., and associates wrote in the analysis, published in the International Journal of Infectious Diseases. “The noteworthy increases in antibody responses and decreases in influenza cases following vaccination suggest an alternative for use in a population that is heavily impacted by influenza disease.”

Children are, of course, vulnerable to flu. The Centers for Disease Control and Prevention reported that 186 children died of flu during the landmark 2017-2018 flu season. That’s the highest number of pediatric flu deaths since they became a notifiable condition in 2004 (exclusive of the 2009 pandemic, when 358 pediatric deaths were reported from April 15, 2009, to October 2, 2010).The CDC said the vaccine during that flu season had an overall effectiveness level of 40%. According to research of others, however, flu vaccines are less effective in younger children than in adolescents and adults (Vaccine. 2014;32[31]:3886-94; Cochrane Database Syst Rev. 2008. doi: 10.1002/14651858.CD004879.pub3).

Fluad – a MF59-adjuvanted inactivated trivalent seasonal influenza vaccine – is used in adults over 65 in the United States and 29 other countries, and it is approved for children aged 6 months through 23 months in Canada.

Dr. Patel and associates examined the results of six studies – one phase 1b, three phase 2, and two phase 3 – that tested Fluad with or without other vaccines in 11,942 children aged 6 months to 5 years. The studies, mostly multicenter, were conducted in various countries, mainly in Europe and South and Central America, from 2006 to 2012.

In general, children in the intervention groups in the studies received two doses of the Fluad vaccine 4 weeks apart: two 0.25-mL doses for children aged 6-35 months and two 0.5-mL doses for those aged 3 years or older. In most of the studies, parallel control groups received nonadjuvanted trivalent or quadrivalent influenza vaccines.

Most participants (93%-94%) completed the studies. Solicited adverse effects were common in all groups (72% in the Fluad group vs. 67% who received IIV3 vaccines), and generally mild to moderate and resolved in 1-3 days. Unsolicited adverse effects were similar (55% and 62%, respectively) in the two flu vaccine groups. The authors wrote that “these data reflect a safety profile consistent with other licensed inactivated influenza vaccines administered to children.”

As for results, Dr. Patel and colleagues said, “HI [hemagglutination inhibition] antibody responses to both homologous and heterologous influenza strains are higher following vaccination with aIIV3, and this increase in immunogenicity is observed across all age subgroups in children aged 6 months through 5 years, and most profound in the children 6 to 36 months.”

For example, in one of the phase 3 studies when the influenza viruses were antigenically matched (homologous) for A/H1N1 among the children aged 6-35 months seroconversion was 100% for allV3 (Fluad) and 38% for IIV3-1/IIV3-4 (trivalent/quadrivalent flu vaccines); among children aged 3-5 years seroconversion was 100% for allV3 and 82% for IIV3-1/IIV3-4. For AH3N2 homologous among children aged 6-35 months, seroconversion was 98% for allV3 and 44% for IIV3-1/IIV3-4. For the B strain homologous among children aged 6-35 months, seroconversion was 88% for allV3 and 19% for IIV3-1/IIV3-4; among children aged 3-5 years seroconversion for B was 99% for allV3 and 59% for IIV3-1/IIV3-4.

In the same study when the influenza viruses were antigenically mismatched (heterologous) for A/H1N1 among children of all ages 6 months to greater than 72 months, seroconversion was 96% for allV3 (Fluad) and 44% for IIV3-1/IIV3-4; for A/H3N2 it was 98% for allV3 and 49% for IIV3-1/IIV3-4, and for the B strain it was 10% for allV3 and 3% for IIV3-1/IIV3-4.

They added that “in addition, aIIV3 had the fastest onset of immunogenicity and longest persistence of immune response, which has implications for the real-world clinical setting, where the influenza season might start earlier than expected or last longer, and second (follow-up) vaccinations may be missed.”

Dr. Patel and associates said the MF59 adjuvant in Fluad “recruits immune cells (primarily monocytes, macrophages, neutrophils, and dendritic cells) at the site of injection and differentiates them into antigen-presenting cells. With an MF59-adjuvanted vaccine, more antigen is transported from the injection site to the draining lymph node, wherein MF59 leads to T-cell activation and an increased B-cell expansion and a greater number and diversity of antibodies.”

According to goodrx.com, one syringe of Fluad 0.5 mL costs $45-$74 with coupon. The same dose of Fluzone Quadrivalent, a flu vaccine recently approved by the Food and Drug Administration for use in young children aged 6-35 months, costs $31 with coupon.

The study was funded by Novartis Vaccines and Diagnostics and Seqirus (formerly part of Novartis Vaccines and Diagnostics). The study authors disclosed employment by Novartis and Seqirus.

SOURCE: Patel SS et al. Int J Infect Dis. 2019. doi: 10.1016/j.ijid.2019.05.009.

Fluad (aIIV3), an adjuvanted flu vaccine that’s recommended for people aged 65 and older, does a better job than do conventional flu vaccines in young children, according to an industry-funded synthesis of six studies.

KatarzynaBialasiewicz/Thinkstock

The vaccine “offers significant advances over conventional inactivated influenza vaccines and presents an acceptable safety profile in children 6 months through 5 years of age,” Sanjay S. Patel, PhD, of Novartis Vaccines and Diagnostics, Cambridge, Mass., and associates wrote in the analysis, published in the International Journal of Infectious Diseases. “The noteworthy increases in antibody responses and decreases in influenza cases following vaccination suggest an alternative for use in a population that is heavily impacted by influenza disease.”

Children are, of course, vulnerable to flu. The Centers for Disease Control and Prevention reported that 186 children died of flu during the landmark 2017-2018 flu season. That’s the highest number of pediatric flu deaths since they became a notifiable condition in 2004 (exclusive of the 2009 pandemic, when 358 pediatric deaths were reported from April 15, 2009, to October 2, 2010).The CDC said the vaccine during that flu season had an overall effectiveness level of 40%. According to research of others, however, flu vaccines are less effective in younger children than in adolescents and adults (Vaccine. 2014;32[31]:3886-94; Cochrane Database Syst Rev. 2008. doi: 10.1002/14651858.CD004879.pub3).

Fluad – a MF59-adjuvanted inactivated trivalent seasonal influenza vaccine – is used in adults over 65 in the United States and 29 other countries, and it is approved for children aged 6 months through 23 months in Canada.

Dr. Patel and associates examined the results of six studies – one phase 1b, three phase 2, and two phase 3 – that tested Fluad with or without other vaccines in 11,942 children aged 6 months to 5 years. The studies, mostly multicenter, were conducted in various countries, mainly in Europe and South and Central America, from 2006 to 2012.

In general, children in the intervention groups in the studies received two doses of the Fluad vaccine 4 weeks apart: two 0.25-mL doses for children aged 6-35 months and two 0.5-mL doses for those aged 3 years or older. In most of the studies, parallel control groups received nonadjuvanted trivalent or quadrivalent influenza vaccines.

Most participants (93%-94%) completed the studies. Solicited adverse effects were common in all groups (72% in the Fluad group vs. 67% who received IIV3 vaccines), and generally mild to moderate and resolved in 1-3 days. Unsolicited adverse effects were similar (55% and 62%, respectively) in the two flu vaccine groups. The authors wrote that “these data reflect a safety profile consistent with other licensed inactivated influenza vaccines administered to children.”

As for results, Dr. Patel and colleagues said, “HI [hemagglutination inhibition] antibody responses to both homologous and heterologous influenza strains are higher following vaccination with aIIV3, and this increase in immunogenicity is observed across all age subgroups in children aged 6 months through 5 years, and most profound in the children 6 to 36 months.”

For example, in one of the phase 3 studies when the influenza viruses were antigenically matched (homologous) for A/H1N1 among the children aged 6-35 months seroconversion was 100% for allV3 (Fluad) and 38% for IIV3-1/IIV3-4 (trivalent/quadrivalent flu vaccines); among children aged 3-5 years seroconversion was 100% for allV3 and 82% for IIV3-1/IIV3-4. For AH3N2 homologous among children aged 6-35 months, seroconversion was 98% for allV3 and 44% for IIV3-1/IIV3-4. For the B strain homologous among children aged 6-35 months, seroconversion was 88% for allV3 and 19% for IIV3-1/IIV3-4; among children aged 3-5 years seroconversion for B was 99% for allV3 and 59% for IIV3-1/IIV3-4.

In the same study when the influenza viruses were antigenically mismatched (heterologous) for A/H1N1 among children of all ages 6 months to greater than 72 months, seroconversion was 96% for allV3 (Fluad) and 44% for IIV3-1/IIV3-4; for A/H3N2 it was 98% for allV3 and 49% for IIV3-1/IIV3-4, and for the B strain it was 10% for allV3 and 3% for IIV3-1/IIV3-4.

They added that “in addition, aIIV3 had the fastest onset of immunogenicity and longest persistence of immune response, which has implications for the real-world clinical setting, where the influenza season might start earlier than expected or last longer, and second (follow-up) vaccinations may be missed.”

Dr. Patel and associates said the MF59 adjuvant in Fluad “recruits immune cells (primarily monocytes, macrophages, neutrophils, and dendritic cells) at the site of injection and differentiates them into antigen-presenting cells. With an MF59-adjuvanted vaccine, more antigen is transported from the injection site to the draining lymph node, wherein MF59 leads to T-cell activation and an increased B-cell expansion and a greater number and diversity of antibodies.”

According to goodrx.com, one syringe of Fluad 0.5 mL costs $45-$74 with coupon. The same dose of Fluzone Quadrivalent, a flu vaccine recently approved by the Food and Drug Administration for use in young children aged 6-35 months, costs $31 with coupon.

The study was funded by Novartis Vaccines and Diagnostics and Seqirus (formerly part of Novartis Vaccines and Diagnostics). The study authors disclosed employment by Novartis and Seqirus.

SOURCE: Patel SS et al. Int J Infect Dis. 2019. doi: 10.1016/j.ijid.2019.05.009.

Adjuvanted trivalent inactivated influenza vaccine (aIIV3) appears as safe as nonadjuvanted flu vaccines for children at risk for serious flu complications, according to a study in the International Journal of Infectious Diseases.

©Micah Young/istockphoto.com

Sanjay S. Patel, PhD, of Novartis Vaccines and Diagnostics, Cambridge, Mass., and colleagues performed a retrospective analysis on an integrated dataset that drew from six randomized clinical trials comparing aIIV3 with nonadjuvanted trivalent inactivated influenza vaccine (IIV3). The dataset comprised 10,794 patients aged 6 months through 5 years, of whom 373 (3%) were deemed at risk of influenza complications after review of their medical history for conditions such as heart disease, asthma, and endocrine disorders.

The rates of solicited adverse events (such as erythema, diarrhea, fever, and localized swelling) were 74% in the aIIV3 group and 73% in the IIV3 group. The rates for any unsolicited adverse events (such as upper respiratory tract infection) for aIIV3 and IIV3 were 54% and 59%, respectively (Int J Infect Dis. 2019. doi: 10.1016/j.ijid.2019.04.023).

One of the six studies included in the dataset randomized 2,655 children for immunogenicity analyses, of whom 103 (4%) were deemed at risk. Hemagglutination inhibition assay geometric mean titers against homologous A/H1N1, A/H3N2, and B strains 21 days after the second of two doses of vaccines were two to three times higher in the aIIV3 than in the IIV3 group, which suggests that aIIV3 is more immunogenic than IIV3. As the investigators noted, this is likely because the adjuvanted vaccine induces a greater magnitude of immune response to the vaccine, something already lower in children than in adults, as well as more breadth of response, meaning the response goes beyond strains included in the vaccines.

The small number of at-risk children in the study poses a limitation on its findings. Dr. Patel and associates said that, regardless, the results of immunogenicity analyses were strong. “Overall, this analysis indicates that aIIV3 has a similar safety profile in young children with underlying medical conditions, consistent with other licensed inactivated influenza vaccines.”

Novartis Vaccines and Diagnostics originally funded the study, but was later acquired by CSL Group and now operates as Seqirus, which continued funding for the study. The authors were employees of one or the other of these companies.

cpalmer@mdedge.com

Adjuvanted trivalent inactivated influenza vaccine (aIIV3) appears as safe as nonadjuvanted flu vaccines for children at risk for serious flu complications, according to a study in the International Journal of Infectious Diseases.

©Micah Young/istockphoto.com

Sanjay S. Patel, PhD, of Novartis Vaccines and Diagnostics, Cambridge, Mass., and colleagues performed a retrospective analysis on an integrated dataset that drew from six randomized clinical trials comparing aIIV3 with nonadjuvanted trivalent inactivated influenza vaccine (IIV3). The dataset comprised 10,794 patients aged 6 months through 5 years, of whom 373 (3%) were deemed at risk of influenza complications after review of their medical history for conditions such as heart disease, asthma, and endocrine disorders.

The rates of solicited adverse events (such as erythema, diarrhea, fever, and localized swelling) were 74% in the aIIV3 group and 73% in the IIV3 group. The rates for any unsolicited adverse events (such as upper respiratory tract infection) for aIIV3 and IIV3 were 54% and 59%, respectively (Int J Infect Dis. 2019. doi: 10.1016/j.ijid.2019.04.023).

One of the six studies included in the dataset randomized 2,655 children for immunogenicity analyses, of whom 103 (4%) were deemed at risk. Hemagglutination inhibition assay geometric mean titers against homologous A/H1N1, A/H3N2, and B strains 21 days after the second of two doses of vaccines were two to three times higher in the aIIV3 than in the IIV3 group, which suggests that aIIV3 is more immunogenic than IIV3. As the investigators noted, this is likely because the adjuvanted vaccine induces a greater magnitude of immune response to the vaccine, something already lower in children than in adults, as well as more breadth of response, meaning the response goes beyond strains included in the vaccines.

The small number of at-risk children in the study poses a limitation on its findings. Dr. Patel and associates said that, regardless, the results of immunogenicity analyses were strong. “Overall, this analysis indicates that aIIV3 has a similar safety profile in young children with underlying medical conditions, consistent with other licensed inactivated influenza vaccines.”

Novartis Vaccines and Diagnostics originally funded the study, but was later acquired by CSL Group and now operates as Seqirus, which continued funding for the study. The authors were employees of one or the other of these companies.

cpalmer@mdedge.com

Adjuvanted trivalent inactivated influenza vaccine (aIIV3) appears as safe as nonadjuvanted flu vaccines for children at risk for serious flu complications, according to a study in the International Journal of Infectious Diseases.

©Micah Young/istockphoto.com

Sanjay S. Patel, PhD, of Novartis Vaccines and Diagnostics, Cambridge, Mass., and colleagues performed a retrospective analysis on an integrated dataset that drew from six randomized clinical trials comparing aIIV3 with nonadjuvanted trivalent inactivated influenza vaccine (IIV3). The dataset comprised 10,794 patients aged 6 months through 5 years, of whom 373 (3%) were deemed at risk of influenza complications after review of their medical history for conditions such as heart disease, asthma, and endocrine disorders.

The rates of solicited adverse events (such as erythema, diarrhea, fever, and localized swelling) were 74% in the aIIV3 group and 73% in the IIV3 group. The rates for any unsolicited adverse events (such as upper respiratory tract infection) for aIIV3 and IIV3 were 54% and 59%, respectively (Int J Infect Dis. 2019. doi: 10.1016/j.ijid.2019.04.023).

One of the six studies included in the dataset randomized 2,655 children for immunogenicity analyses, of whom 103 (4%) were deemed at risk. Hemagglutination inhibition assay geometric mean titers against homologous A/H1N1, A/H3N2, and B strains 21 days after the second of two doses of vaccines were two to three times higher in the aIIV3 than in the IIV3 group, which suggests that aIIV3 is more immunogenic than IIV3. As the investigators noted, this is likely because the adjuvanted vaccine induces a greater magnitude of immune response to the vaccine, something already lower in children than in adults, as well as more breadth of response, meaning the response goes beyond strains included in the vaccines.

The small number of at-risk children in the study poses a limitation on its findings. Dr. Patel and associates said that, regardless, the results of immunogenicity analyses were strong. “Overall, this analysis indicates that aIIV3 has a similar safety profile in young children with underlying medical conditions, consistent with other licensed inactivated influenza vaccines.”

Novartis Vaccines and Diagnostics originally funded the study, but was later acquired by CSL Group and now operates as Seqirus, which continued funding for the study. The authors were employees of one or the other of these companies.

cpalmer@mdedge.com