Safety surveillance of meningococcal group B vaccine (Bexsero®), Vaccine Adverse Event Reporting System, 2015-2018.

BACKGROUND: Bexsero® (GlaxoSmithKline) is a four-component Neisseria meningitidis serogroup B vaccine (MenB-4C). It was licensed in the United States in 2015 for use among individuals ages 10-25 years. We aimed to assess the post-licensure safety profile of MenB-4C by examining reports received in the Vaccine Adverse Event Reporting System (VAERS). METHODS: VAERS is a national passive surveillance system for adverse events (AEs) following immunization that uses the Medical Dictionary for Regulatory Activities to code reported AEs and the Code of Federal Regulations to classify reports by seriousness. In this case series, we analyzed U.S. reports involving MenB-4C received between January 23, 2015 through December 31, 2018. We used Empirical Bayesian data mining to identify MenB-4C/AE combinations reported at least twice as often as expected. RESULTS: VAERS received 1,867 reports following MenB-4C administration, representing 332 reports per million doses distributed. Most reports were for females (59%), with a median age of 17 years (interquartile range: 16-18 years); 40% of reports described simultaneous administration of other vaccines. The majority of reports were classified as non-serious (96%). The most commonly reported AEs were injection site pain (22%), pyrexia (16%), and headache (16%). Data mining identified disproportionate reporting for "injected limb mobility decreased" secondary to injection site reactions, including extensive swelling of the vaccinated limb and injection site pain. CONCLUSIONS: Analysis of passive surveillance data from over 5.6 million doses of MenB-4C distributed in the United States did not reveal new safety concerns. The large majority of reports were classified as non-serious and the reported AEs were generally consistent with the safety experience described in clinical studies and the product's package insert. While our results are reassuring, continued post-marketing surveillance is warranted.

Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018.

BACKGROUND: Myopericarditis after vaccination has been sporadically reported in the medical literature. Here, we present a thorough descriptive analysis of reports to a national passive vaccine safety surveillance system (VAERS) of myopericarditis after vaccines licensed for use in the United States. METHODS: We identified U.S. reports of myopericarditis received by VAERS during 1990-2018 that met a published case definition for myopericarditis or were physician-diagnosed. We stratified analysis by age group (<19, 19-49, ≥50 years), describing reports by serious/non-serious status, sex, time to symptom onset after vaccination, vaccine(s) administered, and exposure to other known causes of myopericarditis. We used Empirical Bayesian data mining to detect disproportionate reporting of myopericarditis after vaccination. RESULTS: VAERS received 620,195 reports during 1990-2018: 708 (0.1%) met the case definition or were physician-diagnosed as myopericarditis. Most (79%) myopericarditis reports described males; 69% were serious; 72% had symptom onset ≤ 2 weeks postvaccination. Overall, smallpox (59%) and anthrax (23%) vaccines were most commonly reported. By age, among persons aged < 19 years, Haemophilus influenzae type b (22, 22%) and hepatitis B (18, 18%); among persons aged 19-49 years smallpox (387, 79%); among persons aged ≥ 50 years inactivated influenza (31, 36%) and live attenuated zoster (19, 22%) vaccines were most commonly reported. The vaccines most commonly reported remained unchanged when excluding 138 reports describing other known causes of myopericarditis. Data mining revealed disproportionate reporting of myopericarditis only after smallpox vaccine. CONCLUSIONS: Despite the introduction of new vaccines over the years, myopericarditis remains rarely reported after vaccines licensed for use in the United States. In this analysis, myopericarditis was most commonly reported after smallpox vaccine, and less commonly after other vaccines.

Adverse events following quadrivalent meningococcal diphtheria toxoid conjugate vaccine (Menactra®) reported to the Vaccine Adverse Event Reporting System (VAERS), 2005-2016.

BACKGROUND: Post marketing safety evaluations of quadrivalent meningococcal diphtheria-toxoid conjugate vaccine (MenACWY-D) have focused on post-vaccination risk of Guillain Barré syndrome (GBS), adverse events (AEs) after maternal vaccination, and comparative studies with the newer quadrivalent meningococcal CRM197 conjugate vaccine (MenACWY-CRM). To provide an updated general safety assessment, we reviewed reports of AEs following MenACWY-D submitted to the Vaccine Adverse Event Reporting System (VAERS). METHODS: VAERS is a national spontaneous reporting vaccine safety surveillance system co-administered by the Centers for Disease Control and Prevention and the U.S. Food and Drug Administration. We searched the VAERS database for U.S. reports of AEs after administration of MenACWY-D from January 2005 through June 2016. We conducted clinical reviews of serious reports after MenACWY-D administered alone, reports of MenACWY-D use during pregnancy, and reports of selected pre-specified outcomes. We screened for disproportionate reporting of AEs after MenACWY-D using empirical Bayesian data mining. RESULTS: VAERS received 13,075 U.S. reports after receipt of MenACWY-D; most (86%) described vaccination in adolescents, were classified as non-serious (94%), and described AEs consistent with pre-licensure studies. We did not find any evidence that reported deaths were related to vaccination. In serious reports, GBS and meningococcal infection were the most commonly reported medical conditions. Many reports of MenACWY-D use during pregnancy described inadvertent vaccination; most (61%) did not report any AE. CONCLUSIONS: Findings from our comprehensive review of reports to VAERS following MenACWY-D are consistent with data from pre-licensure studies and provide further reassurance on the safety of MenACWY-D.

Erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis reported after vaccination, 1999-2017.

BACKGROUND: Since the last review of vaccine safety surveillance data for erythema multiforme (EM), Stevens Johnson syndrome (SJS), SJS/TEN, and toxic epidermal necrolysis (TEN) (EM/SJS/TEN), over 37 new vaccines have been introduced in the United States. We sought to describe reported EM/SJS/TEN after vaccines during 1999-2017. METHODS: We identified U.S. reports of EM/SJS/TEN received by the Vaccine Adverse Event Reporting System (VAERS) during 1999-2017. We stratified analysis by condition (EM, SJS, or TEN), and analyzed reports by serious or non-serious status, sex, age group, time from vaccination to symptom onset, exposure to known causes of EM/SJS/TEN, and vaccines administered. We used Empirical Bayesian data mining to detect vaccine-AE pairs reported more frequently than expected. RESULTS: Of 466,027 reports to VAERS during 1999-2017, we identified 984 reports of EM, 89 reports of SJS, 6 reports of SJS/TEN, and 7 reports of TEN. Few reports of EM (9%), and most reports of SJS (52%), SJS/TEN (100%), and TEN (100%) were serious. Overall, 55% of reports described males, 48% described children aged < 4 years; 58% of EM/SJS/TEN occurred ≤ 7 days after vaccination. Few reports (≤5%) described exposure to known causes of EM/SJS/TEN. Overall, childhood vaccines (e.g., combined measles, mumps, and rubella vaccine) were most commonly reported. We identified 6 deaths; 4 were exposed to medications associated with EM/SJS/TEN. EM after smallpox vaccine was reported disproportionately among people aged 19-49 years. CONCLUSIONS: EM/SJS/TEN were rarely reported after vaccination; data mining identified a known association between EM and smallpox vaccine.

Reports of atypical shoulder pain and dysfunction following inactivated influenza vaccine, Vaccine Adverse Event Reporting System (VAERS), 2010-2017.

BACKGROUND: Vaccines administered into or too close to underlying joint structures have the potential to cause shoulder injuries. Limited data exist on the epidemiology of such events. OBJECTIVE: To describe case reports of atypical shoulder pain and dysfunction following injection of inactivated influenza vaccine (IIV). METHODS: We searched the Vaccine Adverse Event Reporting System (VAERS) database from July 2010 to June 2017 for reports of atypical shoulder pain and dysfunction following IIV. When identifying reports, we made no assumptions about true incident injury or causality with respect to vaccination. Pain had to begin <48 h after vaccination and signs and symptoms had to continue for >7 days to differentiate from self-limited local reactions. We conducted descriptive analysis. RESULTS: We identified 1220 reports that met our case definition (2.0% of all IIV reports, range 1.5%-2.5% across influenza seasons). Median age was 52 years (range 16-94) and most patients (82.6%) were female. Shoulder pain (44.1%), injected limb mobility decreased (40.8%), joint range of motion decreased (21.2%), rotator cuff syndrome (9.2%), and bursitis (9.0%) were frequently reported. In 86.6% of reports, signs and symptoms had not resolved by the time of report submission. In reports that included descriptions suggesting contributing factors (n = 266), vaccination given "too high" on the arm was cited in 81.2%. Nearly half (n = 605, 49.6%) of reports described a healthcare provider evaluation. Treatments included non-narcotic analgesics, physical therapy, and corticosteroid injection. Vaccinations were most commonly administered in a pharmacy or retail store (41.0%) or doctor's office or hospital (31.6%). CONCLUSIONS: Reports of atypical shoulder pain and dysfunction following IIV were uncommon, considering the amount of IIV use, and stable across influenza seasons. While specific etiology of cases is unknown, improperly administered vaccine, which is preventable, might be a factor. Prevention strategies include education, training, and adherence to best practices for vaccine administration.

Safety of the 9-Valent Human Papillomavirus Vaccine.

BACKGROUND: The 9-valent human papillomavirus vaccine (9vHPV) was approved for females and males aged 9 to 26 years in 2014. We analyzed postlicensure surveillance reports to the Vaccine Adverse Event Reporting System (VAERS). METHODS: We searched VAERS data for US reports of adverse events (AEs) after 9vHPV from December 2014 through December 2017. We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reporting. Physicians reviewed reports for selected prespecified conditions. RESULTS: VAERS received 7244 reports after 9vHPV: 31.2% among females, 21.6% among males, and for 47.2%, sex was not reported. Overall, 97.4% of reports were nonserious. Dizziness, syncope, headache, and injection site reactions were most commonly reported; the most commonly reported AEs were similar between females and males. Two reports of death after 9vHPV were verified; no information in autopsy reports or death certificates suggested a causal relationship with vaccination. Approximately 28 million 9vHPV doses were distributed during the study period; crude AE reporting rates were 259 reports per million 9vHPV doses distributed for all reports and 7 per million doses distributed for serious reports. Syncope (a known AE associated with human papillomavirus vaccination) and several types of vaccine administration errors (eg, administered at wrong age) exceeded the statistical threshold for empirical Bayesian data mining findings. CONCLUSIONS: No new or unexpected safety concerns or reporting patterns of 9vHPV with clinically important AEs were detected. The safety profile of 9vHPV is consistent with data from prelicensure trials and from postmarketing safety data of its predecessor, the quadrivalent human papillomavirus vaccine.

Adverse events following adenovirus type 4 and type 7 vaccine, live, oral in the Vaccine Adverse Event Reporting System (VAERS), United States, October 2011-July 2018.

BACKGROUND: In March 2011, the U.S. Food and Drug Administration licensed adenovirus type 4 and type 7 vaccine, live, oral (Barr Labs, Inc.) (adenovirus vaccine) for use in military personnel 17 through 50 years of age. The vaccine was first universally administered to U.S. military recruits in October 2011. We investigated adverse event (AE) reports following the adenovirus vaccine submitted to the Vaccine Adverse Event Reporting System (VAERS). METHODS: We searched the VAERS database for U.S. reports among persons who received adenovirus vaccine during October 2011 through July 2018 including participants in a military observational study. We reviewed all serious reports and accompanying medical records. We compared the proportion of serious reports in a proxy military recruit population and reviewed all reports of suspected allergic reactions following adenovirus vaccination. RESULTS: During the analytic period, VAERS received 100 reports following adenovirus vaccination; 39 (39%) were classified as serious and of these, 17 (44%) were from the observational study. One death was reported. Males accounted for 72% of reports. Median age of vaccinees was 19 years (range 17-32). The most frequently reported serious AEs were Guillain Barré syndrome (GBS) (n = 12) and anaphylaxis (n = 8); of these, two GBS and all the anaphylaxis reports were reported in the observational study. Reports documented concurrent receipt of multiple other vaccines (95%) and penicillin G (IM Pen G) or other antibiotics (50%). CONCLUSIONS: The reporting rate for serious AEs was higher than with other vaccines administered in the comparison military recruit population (39% vs 18%); however, we identified no unexpected or concerning pattern of adenovirus vaccine AEs. Co-administration of vaccines and IM Pen G was commonly reported in this military population. These exposures may have contributed to the GBS and anaphylaxis outcomes observed with the adenovirus vaccine. Future adenovirus vaccine safety studies in a population without these co-administrations would be helpful in clarifying the vaccine's safety profile.

Postlicensure Safety Surveillance of Recombinant Zoster Vaccine (Shingrix) - United States, October 2017-June 2018.

Recombinant zoster vaccine (RZV; Shingrix), an adjuvanted glycoprotein vaccine, was licensed by the Food and Drug Administration (FDA) and recommended by the Advisory Committee on Immunization Practices for adults aged ≥50 years in October 2017 (1). The previously licensed live-attenuated zoster vaccine (ZVL; Zostavax) is recommended for adults aged ≥60 years. RZV is administered intramuscularly as a 2-dose series, with an interval of 2-6 months between doses. In prelicensure clinical trials, 85% of 6,773 vaccinated study participants reported local or systemic reactions after receiving RZV, with approximately 17% experiencing a grade 3 reaction (erythema or induration >3.5 inches or systemic symptoms that interfere with normal activity). However, rates of serious adverse events (i.e., hospitalization, prolongation of existing hospitalization, life-threatening illness, permanent disability, congenital anomaly or birth defect, or death) were similar in the RZV and placebo groups (2). After licensure, CDC and FDA began safety monitoring of RZV in the Vaccine Adverse Event Reporting System (VAERS) (3). During the first 8 months of use, when approximately 3.2 million RZV doses were distributed (GlaxoSmithKline, personal communication, 2018), VAERS received a total of 4,381 reports of adverse events, 130 (3.0%) of which were classified as serious. Commonly reported signs and symptoms included pyrexia (fever) (1,034; 23.6%), injection site pain (985; 22.5%), and injection site erythema (880; 20.1%). No unexpected patterns were detected in reports of adverse events or serious adverse events. Findings from early monitoring of RZV are consistent with the safety profile observed in prelicensure clinical trials.

Anaphylaxis after vaccination reported to the Vaccine Adverse Event Reporting System, 1990-2016.

BACKGROUND: Anaphylaxis, a rare and potentially life-threatening hypersensitivity reaction, can occur after vaccination. OBJECTIVE: We sought to describe reports of anaphylaxis after vaccination made to the Vaccine Adverse Event Reporting System (VAERS) during 1990-2016. METHODS: We identified domestic reports of anaphylaxis within VAERS using a combination of Medical Dictionary for Regulatory Activity queries and Preferred Terms. We performed a descriptive analysis, including history of hypersensitivity (anaphylaxis, respiratory allergies, and drug allergies) and vaccines given. We reviewed all serious reports and all nonserious reports with available medical records to determine if they met the Brighton Collaboration case definition for anaphylaxis or received a physician's diagnosis. RESULTS: During the analytic period, VAERS received 467,960 total reports; 828 met the Brighton Collaboration case definition or received a physician's diagnosis of anaphylaxis: 654 (79%) were classified as serious, and 669 (81%) had medical records available. Of 478 reports in children aged less than 19 years, 65% were male; childhood vaccines were most commonly reported. Of 350 reports in persons aged 19 years or greater, 80% were female, and influenza vaccines were most frequently reported. Overall, 41% of reports described persons with no history of hypersensitivity. We identified 8 deaths, 4 among persons with no history of hypersensitivity. CONCLUSION: Anaphylaxis after vaccination is rare in the United States and can occur among persons with no history of hypersensitivity. Most persons recover fully with treatment, but serious complications, including death, can occur.

Adverse events after vaccination among HIV-positive persons, 1990-2016.

Human immunodeficiency virus (HIV) causes immune dysregulation, potentially affecting response to vaccines in infected persons. We investigated if unexpected adverse events (AEs) or unusual patterns of AEs after vaccination were reported among HIV-positive persons. We searched for domestic reports among HIV-positive persons to the Vaccine Adverse Event Reporting System (VAERS) during 1990-2016. We analyzed reports by age group (<19 and ≥19 years), sex, serious or non-serious status, live vaccine type (live versus inactivated), AEs reported, and CD4 counts. Of 532,235 reports received, 353 (0.07%) described HIV-positive persons, of whom 67% were aged ≥19 years, and 57% were male; most reports (75%) were non-serious. The most commonly reported inactivated vaccines were pneumococcal polysaccharide (27%) and inactivated influenza (27%); the mostly reported common live virus vaccines were combination measles, mumps, and rubella (8%) and varicella (6%). Injection site reactions were commonly reported (39%). Of 67 reports with CD4 counts available, 41 (61%) described persons immunocompromised at time of vaccination (CD4 count <500 cells/mm3), and differed from overall reports only in that varicella was the most common live virus vaccine (4 reports). Of 22 reports describing failure to protect against infection, 6 described persons immunocompromised at time of vaccination, among whom varicella vaccine was most common (3 reports). Of 66 reports describing live virus vaccines, 7 described persons with disseminated infection: 6 had disseminated varicella, 3 of whom had vaccine strain varicella-zoster virus. Of 18 reported deaths, 7 resulted from disseminated infection: 6 were among immunocompromised persons, 1 of whom had vaccine strain varicella-zoster virus. We identified no unexpected or unusual patterns of AEs among HIV-positive persons. These data reinforce current vaccine recommendations for this risk group. However, healthcare providers should know their HIV-positive patients' immune status because immunocompromising conditions can potentially increase the risk of rare, but severe, AEs following vaccination with live virus vaccines.

Safety of currently licensed hepatitis B surface antigen vaccines in the United States, Vaccine Adverse Event Reporting System (VAERS), 2005-2015.

INTRODUCTION: Currently four recombinant hepatitis B (HepB) vaccines are in use in the United States. HepB vaccines are recommended for infants, children and adults. We assessed adverse events (AEs) following HepB vaccines reported to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system. METHODS: We searched VAERS for reports of AEs following single antigen HepB vaccine and HepB-containing vaccines (either given alone or with other vaccines), from January 2005 - December 2015. We conducted descriptive analyses and performed empirical Bayesian data mining to assess disproportionate reporting. We reviewed serious reports including reports of special interest. RESULTS: VAERS received 20,231 reports following HepB or HepB-containing vaccines: 10,291 (51%) in persons <2 years of age; 2588 (13%) in persons 2-18 years and 5867 (29%) in persons >18 years; for 1485 (7.3%) age was missing. Dizziness and nausea (8.4% each) were the most frequently reported AEs following a single antigen HepB vaccine: fever (23%) and injection site erythema (11%) were most frequent following Hep-containing vaccines. Of the 4444 (22%) reports after single antigen HepB vaccine, 303 (6.8%) were serious, including 45 deaths. Most commonly reported cause of death was Sudden Infant Death Syndrome (197). Most common non-death serious reports following single antigen HepB vaccines among infants aged <1 month, were nervous system disorders (15) among children aged 1-23 months; infections and infestation (8) among persons age 2-18 years blood and lymphatic systemic disorders; and general disorders and administration site conditions among persons age >18 years. Most common vaccination error following single antigen HepB was incorrect product storage. CONCLUSIONS: Review current U.S.-licensed HepB vaccines administered alone or in combination with other vaccines did not reveal new or unexpected safety concerns. Vaccination errors were identified which indicate the need for training and education of providers on HepB vaccine indications and recommendations.

Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010-2015.

BACKGROUND: Limited data are available describing the post-licensure safety of meningococcal vaccines, including Menveo®. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in all age groups. METHODS: VAERS is a national spontaneous vaccine safety surveillance system co-administered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adverse events in persons who received Menveo from 1 January 2010 through 31 December 2015. We clinically reviewed reports and available medical records for serious AEs, selected pre-specified outcomes, and vaccination during pregnancy. We used empirical Bayesian data mining to identify AEs that were disproportionately reported after receipt of Menveo. RESULTS: During the study period, VAERS received 2614 US reports after receipt of Menveo. Of these, 67 were classified as serious, including 1 report of death. Adolescents (aged 11-18years) accounted for 74% of reports. Most of the reported AEs were non-serious and described AEs consistent with data from pre-licensure studies. Anaphylaxis and syncope were the two most common events in the serious reports. We did not identify any new safety concerns after review of AEs that exceeded the data mining threshold, although we did observe disproportionate reporting for terms that were not associated with an adverse event (e.g., "incorrect drug dosage form administered", "wrong technique in drug usage process"). Although reports were limited, we did not find any evidence for concern regarding the use of Menveo during pregnancy. CONCLUSIONS: In our review of VAERS reports, findings of AEs were consistent with the data from pre-licensure studies. Vaccine providers should continue to emphasize and adhere to proper administration of the vaccine.

Notes from the Field: Administration Error Involving a Meningococcal Conjugate Vaccine--United States, March 1, 2010-September 22, 2015.

Menveo (GlaxoSmithKline, previously Novartis AG) is a conjugate vaccine that was recommended in October 2010 for routine use in adolescents (preferably aged 11 or 12 years, with a booster at 16 years), and among persons aged 2 through 54 years with certain immunosuppressive conditions, to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135 (1). These recommendations have since been updated (2). Menveo is supplied in two vials that must be combined before administration. The MenA lyophilized (freeze-dried) component must be reconstituted with the MenCYW-135 liquid component (Figure). To administer the vaccine, the liquid component is drawn into a syringe, and used to reconstitute the lyophilized component. The resulting solution is administered by intramuscular injection. Failure to prepare Menveo as directed by the manufacturer's instructions can lead to lack of protection against the intended pathogens (N. meningitidis serogroups A, C, Y, and/or W-135) (3). Recently, an immunization provider administered only the lyophilized component of Menveo, subsequently administered a properly prepared dose of Menveo to the same patient, and asked CDC if this practice was safe. This question prompted CDC to search the Vaccine Adverse Event Reporting System (VAERS) database for reports during March 1, 2010-September 22, 2015, of only one component of Menveo being administered. Additionally, to more broadly identify disproportional reporting of adverse events in general following Menveo immunization compared with other vaccines in VAERS (including errors in vaccine preparation and administration), the Food and Drug Administration performed data mining with empiric Bayesian methods (4).

A large outbreak of histoplasmosis among American travelers associated with a hotel in Acapulco, Mexico, spring 2001.

During spring 2001, college students from Pennsylvania reported an acute febrile respiratory illness after returning from spring break vacation in Acapulco, Mexico. Acute pulmonary histoplasmosis was presumptively diagnosed and the cluster of illness was reported to the Centers of Disease Control and Prevention. A large investigation then ensued, which included finding student-travelers for interviews and requesting sera for histoplasmosis testing. We defined a clinical case by fever and at least one of the following: cough, shortness of breath, chest pain, or headache, in an Acapulco traveler during March-May 2001. A laboratory-confirmed case had positive serology. An initial study determined that the likely site of histoplasmosis exposure was Hotel H; we therefore performed a large cohort study among travelers who stayed at Hotel H. Of 757 contacted, 262 (36%) met the clinical case definition. Of 273 serum specimens tested, 148 (54%) were positive. Frequent use of Hotel H's stairwells, where construction was ongoing, was associated with increased risk of illness (relative risk = 10.5, 95% confidence interval = 3.7-30.5; P < 0.001). This is the first histoplasmosis outbreak associated with a hotel undergoing construction. Hotels in endemic areas should consider construction precaution measures to prevent histoplasmosis among their guests.