Post-licensure safety study of new-onset immune-mediated diseases, herpes zoster, and anaphylaxis in adult recipients of HepB-CpG vaccine versus HepB-alum vaccine.

BACKGROUND: HepB-CpG (Heplisav-B) is a licensed hepatitis B vaccine with a novel adjuvant that requires 2 doses (0, 1 month) compared to HepB-alum (Engerix-B) which requires 3 doses (0, 1, 6 months). Monitoring safety outcomes following receipt of vaccines with novel adjuvants outside trial settings is important. Hence, as part of a post-marketing commitment, we compared the incidence of new-onset immune-mediated diseases, herpes zoster (HZ), and anaphylaxis among recipients of HepB-CpG versus HepB-alum. METHODS: This cohort study included adults not on dialysis who received ≥1 dose of hepatitis B vaccine from 8/7/2018 to 10/31/2019, during which HepB-CpG was routinely administered in 7 of 15 Kaiser Permanente Southern California medical centers while HepB-alum was administered in the other 8 centers. Recipients of HepB-CpG or HepB-alum were followed through electronic health records for 13 months for occurrence of pre-specified new-onset immune-mediated diseases, HZ, and anaphylaxis identified using diagnosis codes. Incidence rates were compared using Poisson regression with inverse probability of treatment weighting when there was ≥80 % power to detect a relative risk (RR) of 5 for anaphylaxis and RR of 3 for other outcomes. Chart review to confirm new-onset diagnosis was conducted for outcomes with statistically significant elevated risk. RESULTS: There were 31,183 HepB-CpG and 38,442 HepB-alum recipients (overall 49.0 % female, 48.5 % age ≥50 years, and 49.6 % Hispanic). Among immune-mediated events that occurred frequently enough for formal comparison, rates among HepB-CpG versus Hep-B-alum recipients were similar except for rheumatoid arthritis (RA) (adjusted RR 1.53 [95 % CI: 1.07, 2.18]). After chart confirmation of new-onset RA, the adjusted RR was 0.93 (0.34, 2.49). The adjusted RR for HZ was 1.06 (0.89, 1.27). Anaphylaxis occurred in 0 HepB-CpG and 2 HepB-alum recipients. CONCLUSIONS: This large post-licensure study did not identify evidence of safety concerns for HepB-CpG compared to HepB-alum for immune-mediated diseases, HZ, or anaphylaxis.

Association Between 2-Dose vs 3-Dose Hepatitis B Vaccine and Acute Myocardial Infarction.

Importance: The 2-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) generated higher seroprotection in prelicensure trials than did a 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine; Engerix-B). However, in 1 trial, a higher number of acute myocardial infarction (MI) events were observed among those who received the HepB-CpG vaccine than among those who received the HepB-alum vaccine, an outcome requiring further study. Objective: To compare the rate of acute MI between recipients of HepB-CpG vaccine and HepB-alum vaccine. Design, Setting, and Participants: This prospective cohort noninferiority study was conducted at Kaiser Permanente Southern California (KPSC), an integrated health care system with 15 medical centers and approximately 4.7 million members. The study included 69 625 adults not undergoing dialysis who received at least 1 dose of a hepatitis B vaccine in either family medicine or internal medicine departments at KPSC from August 7, 2018, to October 31, 2019 (November 30, 2020, final follow-up). Exposures: Receipt of HepB-CpG vaccine vs HepB-alum vaccine. The first dose during the study period was the index dose. Main Outcomes and Measures: Individuals were followed up for 13 months after the index dose for occurrence of type 1 acute MI. Potential events were identified using diagnosis codes and adjudicated by cardiologists. The adjusted hazard ratio (HR) of acute MI was estimated comparing recipients of HepB-CpG vaccine with recipients of HepB-alum vaccine, with inverse probability of treatment weighting (IPTW) to adjust for demographic and clinical characteristics. The upper limit of the 1-sided 97.5% CI was compared with a noninferiority margin of 2. Results: Of the 31 183 recipients of HepB-CpG vaccine (median age, 49 years; IQR, 38-56 years), 51.2% (n = 15 965) were men, and 52.7% (n = 16 423) were Hispanic. Of the 38 442 recipients of HepB-alum (median age, 49 years; IQR, 39-56 years), 50.8% (19 533) were men, and 47.1% (n = 18 125) were Hispanic. Characteristics were well-balanced between vaccine groups after IPTW. Fifty-two type 1 acute MI events were confirmed among recipients of HepB-CpG vaccine for a rate of 1.67 per 1000-person-years, and 71 type 1 acute MI events were confirmed among recipients of HepB-alum vaccine for a rate of 1.86 per 1000 person-years (absolute rate difference, -0.19 [95% CI, -0.82 to 0.44]; adjusted HR, 0.92 [1-sided 97.5% CI, ∞ to 1.32], which was below the noninferiority margin; P < .001 for noninferiority). Conclusions and Relevance: In this cohort study, receipt of HepB-CpG vaccine compared with HepB-alum vaccine did not meet the statistical criterion for increased risk of acute myocardial infarction.

Recombinant Adjuvanted Zoster Vaccine and Reduced Risk of Coronavirus Disease 2019 Diagnosis and Hospitalization in Older Adults.

BACKGROUND: Some vaccines elicit nonspecific immune responses that may protect against heterologous infections. We evaluated the association between recombinant adjuvanted zoster vaccine (RZV) and coronavirus disease 2019 (COVID-19) outcomes at Kaiser Permanente Southern California. METHODS: In a cohort design, adults aged ≥50 years who received ≥1 RZV dose before 1 March 2020 were matched 1:2 to unvaccinated individuals and followed until 31 December 2020. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 outcomes were estimated using Cox proportional hazards regression. In a test-negative design, cases had a positive severe acute respiratory syndrome coronavirus 2 test and controls had only negative tests, during 1 March-31 December 2020. Adjusted odds ratios (aORs) and 95% CIs for RZV receipt were estimated using logistic regression. RESULTS: In the cohort design, 149 244 RZV recipients were matched to 298 488 unvaccinated individuals. The aHRs for COVID-19 diagnosis and hospitalization were 0.84 (95% CI, .81-.87) and 0.68 (95% CI, .64-.74), respectively. In the test-negative design, 8.4% of 75 726 test-positive cases and 13.1% of 340 898 test-negative controls had received ≥1 RZV dose (aOR, 0.84 [95% CI, .81-.86]). CONCLUSIONS: RZV vaccination was associated with a 16% lower risk of COVID-19 diagnosis and 32% lower risk of hospitalization. Further study of vaccine-induced nonspecific immunity for potential attenuation of future pandemics is warranted.

Challenges in Phase 4 post-licensure safety studies using real world data in the United States: Hepatitis B vaccine example.

Post-licensure vaccine safety studies are essential to identify adverse events that may not have been detected in pre-licensure clinical trials and to address questions that arose during the pre-licensure phase. These studies are increasingly conducted using real-world data collected as part of routine health care delivery. However, design of post-licensure vaccine safety studies involves many pragmatic and scientific decisions, which must be made while balancing diverse stakeholder opinions. Challenges include selecting exposure and comparison groups, deciding on the most appropriate outcome, determining sample size and length of follow-up time, and other analytic considerations. As an example of this process and to inform other post-licensure vaccine safety studies in real-world settings, we discuss our experience with design of an FDA-required Phase 4 post-licensure safety study of a hepatitis B vaccine in a large integrated health care organization in the United States.

Real-world evidence of quadrivalent meningococcal conjugate vaccine safety in the United States: a systematic review.

Two quadrivalent meningococcal conjugate vaccines (MenACWY) that prevent invasive meningococcal disease caused by N. meningitidis serogroups A, C, Y, and W have been licensed in the U.S. in the past 10-15 years. We systematically reviewed published studies conducted in the U.S. to evaluate the real-world safety evidence of meningococcal conjugate vaccines. We performed a literature search in PubMed of publications from 01/01/2005 to 02/29/2020 and identified 18 studies meeting inclusion criteria. Populations included high-risk persons aged 2 months to 10 years, adolescents/adults aged ≥11 years, pregnant populations, and hematopoietic cell transplant recipients. We extracted information about study setting, study design, exposure, outcomes, comparison group, follow-up/look back period, study population, sample size, available demographic/indication information, results, key conclusion, and reference. These published studies found no new significant safety concerns related to MenACWY. Consideration for future research includes a post-licensure safety evaluation of a new MenACWY product approved in April 2020.

Association of Number of Doses With Hepatitis B Vaccine Series Completion in US Adults.

Importance: Receipt of hepatitis B virus vaccine is important to prevent infection. However, adherence to the hepatitis B vaccine series among adults at risk of infection has been low. Objective: To assess whether recipients of a 2-dose hepatitis B vaccine with cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) are more likely to complete their series compared with recipients of a 3-dose vaccine with alum adjuvant (comparator vaccine; Engerix-B [HepB-alum]). Design, Setting, and Participants: This nested cohort study was conducted from August 7 to December 31, 2018, at Kaiser Permanente Southern California, an integrated health care system with a diverse population of approximately 4.6 million members. Adults not receiving dialysis who received a first dose of a hepatitis B vaccine series in family practice or internal medicine departments of 15 Kaiser Permanente Southern California medical centers were followed up through electronic health records for up to 1 year after receipt of the first dose. Data were analyzed from March 16 to September 23, 2020. Exposures: Receipt of a first dose of the HepB-CpG vaccine (2-dose vaccine) vs receipt of a first dose of the HepB-alum vaccine (3-dose vaccine). Main Outcomes and Measures: Series completion within the recommended vaccine schedule plus 3 months (primary outcome) and series completion within 1 year after receipt of the first dose (secondary outcome). Results: Of 4727 individuals who initiated the HepB-CpG vaccine series and 6161 individuals who initiated the HepB-alum vaccine series included in the study, 2876 (60.8%) and 3789 (61.5%), respectively, were ages 40 to 59 years, 2415 (51.1%) and 3113 (50.5%) were male, and 2364 (50.0%) and 2881 (46.8%) were Hispanic. The vaccine series was completed within the recommended schedule plus 3 months for 2111 (44.7%) individuals who initiated the HepB-CpG vaccine series and 1607 (26.1%) individuals who initiated the HepB-alum vaccine series, and within 1 year for 2858 (60.5%) and 1989 (32.3%) individuals, respectively. The individuals who initiated the HepB-CpG vaccine series were significantly more likely to complete the series (adjusted relative risk, 1.77; 95% CI, 1.68-1.87). Results were consistent across clinical and demographic strata. Conclusions and Relevance: In this study, use of the HepB-CpG vaccine was associated with hepatitis B vaccine series completion, but tailored strategies to increase completion of hepatitis B vaccine series are warranted.

Severe Morbidity and Short- and Mid- to Long-term Mortality in Older Adults Hospitalized with Respiratory Syncytial Virus Infection.

BACKGROUND: We describe the clinical epidemiology and outcomes among a large cohort of older adults hospitalized with respiratory syncytial virus (RSV) infection in the United States. METHODS: Hospitalized adults aged ≥60 years who tested positive for RSV between 1 January 2011 and 30 June 2015 were identified from Kaiser Permanente Southern California. Patient-level demographics, comorbidities, clinical presentation, utilization, complications, and mortality were evaluated. RESULTS: There were 664 patients hospitalized with RSV (61% female, 64% aged ≥75 years). Baseline chronic diseases were prevalent (all >30%); 66% developed pneumonia, 80% of which were radiographically confirmed. Very severe tachypnea (≥26 breaths/minute) was common (56%); 21% required ventilator support and 18% were admitted to intensive care unit. Mortality during hospitalization was 5.6% overall (4.6% in 60-74 year olds and 6.1% in ≥75 year olds). Cumulative mortality within 1, 3, 6, and 12 months of admission was 8.6%, 12.3%, 17.2%, and 25.8%, respectively. CONCLUSION: RSV infection in hospitalized older adults often manifested as severe, life-threatening lower respiratory tract illness with high rates of pneumonia, requirement for ventilatory support, and short- and long-term mortality. Increased recognition of the substantial RSV disease burden in adults will be important in evaluation and use of urgently needed interventions.

Cost of Hospitalization Associated With Respiratory Syncytial Virus Infection Versus Influenza Infection in Hospitalized Older Adults.

Despite the severity of respiratory syncytial virus (RSV) disease in older adults, data on its costs are limited. We compared hospitalization costs for 2090 adults aged ≥ 60 years hospitalized with RSV or influenza by assigning direct health care costs. Hospitalization with RSV was associated with longer hospitalization and increased frequency of diagnosis-related groups for pulmonary complications, resulting in costs at least as great as those for influenza ($16 034 vs $15 163; 95% confidence interval for the difference, -$811 to $2547). Awareness of RSV disease burden in adults is needed to facilitate vaccination and treatment when they become available.

Safety of MenACWY-CRM vaccine exposure during pregnancy.

BACKGROUND: Although the meningococcal conjugate MenACWY-CRM vaccine is not approved for use in pregnant women, unintentional exposure during pregnancy can occur, especially during early pregnancy among women of child-bearing age. This study provides safety information about inadvertent MenACWY-CRM vaccination during pregnancy. METHODS: The evaluated population consisted of pregnant female members of Kaiser Permanente Southern California who inadvertently received MenACWY-CRM at 11-21 years of age during 09/30/2011-06/30/2013 within 28 days prior to conception or during pregnancy. Chart abstraction was conducted to identify pregnancy and birth outcomes, including spontaneous and induced abortions, preterm births, low weight births, and major congenital malformations (MCMs). RESULTS: There were 92 women who received MenACWY-CRM during the pregnancy exposure period, mainly during the first trimester (76.1%). Hispanics represented the largest race/ethnicity category (68.5%). Among the known pregnancy outcomes (n = 66; excluding induced abortions and unknown pregnancy outcomes), the prevalence of spontaneous abortions was 18.2% (n = 12). Among live born infants (n = 55; from 54 pregnancies), 14.5% (n = 8) were born preterm (<37 weeks gestation) and 9.1% (n = 5) had a low birthweight (<2500 g). The prevalence rate of MCMs among live born infants (n = 55) was 1.8% (n = 1). CONCLUSIONS: This study provides baseline prevalence estimates of spontaneous abortions, preterm births, low weight births, and MCMs among women inadvertently exposed to MenACWY-CRM during the pregnancy period. These estimates appear to be comparable with U.S. background prevalence estimates.

Safety of quadrivalent meningococcal conjugate vaccine in infants and toddlers 2 to 23-months old.

INTRODUCTION: The quadrivalent meningococcal conjugate vaccine MenACWY-CRM is recommended for 2-23 month-old infants/toddlers at increased risk for meningococcal disease. This study adds to the current knowledge of MenACWY-CRM safety among this age group in a clinical care setting. METHODS: Kaiser Permanente Southern California members aged 2-23 months who received MenACWY-CRM between July 2014 and June 2017 were included. Electronic health records were searched for emergency department (ED) and hospitalization encounters, and diagnoses associated with these visits up to 6 months after each dose. RESULTS: There were 138 infants/toddlers who received MenACWY-CRM, with 59.4% being African American and 66.7% receiving only one dose. Most infants either had a high-risk condition (i.e., anatomic/functional asplenia or DiGeorge syndrome) (42.0%), or a travel indication (54.3%). The incidence rate of ED visits was 0.6/person-year (95% confidence interval [CI]: 0.5-0.8), 0.4/person-year (CI: 0.3-0.5) for hospitalizations, and 0.1/person-year (CI: 0.1-0.3) for ED to hospital transfers. Overall, 29.0% of recipients had an incident diagnosis in the ED or hospital setting. Fever and acute upper respiratory infections were the most common diagnoses, with 46 out of 47 diagnoses occurring among infants with high-risk conditions. CONCLUSIONS: Data from this descriptive observational study do not suggest safety concerns associated with MenACWY-CRM when used as part of clinical care of 2-23 month-old infants/toddlers indicated for vaccination.

Severe Morbidity and Mortality Associated With Respiratory Syncytial Virus Versus Influenza Infection in Hospitalized Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of serious respiratory illness in older adults. Comparison of RSV and influenza infection in hospitalized older adults may increase awareness of adult RSV disease burden. METHODS: Hospitalized adults aged ≥60 years who tested positive for RSV or influenza between 1 January 2011 and 30 June 2015 were identified from Kaiser Permanente Southern California electronic medical records. Baseline characteristics, comorbidities, utilization, and outcomes were compared. RESULTS: The study included 645 RSV- and 1878 influenza-infected hospitalized adults. Patients with RSV were older than those with influenza (mean, 78.5 vs 77.4 years; P = .035) and more likely to have congestive heart failure (35.3% vs 24.5%; P < .001) and chronic obstructive pulmonary disease (COPD) (29.8% vs 24.3%; P = .006) at baseline. In adjusted analyses, RSV infection was associated with greater odds of length of stay ≥7 days (odds ratio [OR] = 1.5; 95% confidence interval [CI], 1.2-1.8; P < .001); pneumonia (OR = 2.7; 95% CI, 2.2-3.2; P < .001); intensive care unit admission (OR = 1.3; 95% CI, 1.0-1.7; P = .023); exacerbation of COPD (OR = 1.7; 95% CI, 1.3-2.4; P = .001); and greater mortality within 1 year of admission (OR = 1.3; 95% CI, 1.0-1.6; P = .019). CONCLUSIONS: RSV infection may result in greater morbidity and mortality among older hospitalized adults than influenza. Increased recognition of adult RSV disease burden will be important in the evaluation and use of new RSV vaccines and antivirals.

Safety of Quadrivalent Meningococcal Conjugate Vaccine in Children 2-10 Years.

BACKGROUND: Quadrivalent meningococcal conjugate vaccine is recommended for children, adolescents and adults at increased risk of meningococcal disease. In 2011, MenACWY-CRM (Menveo, GSK, Siena, Italy) was approved for children 2-10 years of age in the United States. Although no safety concerns arose from clinical trials, it remains important to monitor its safety in routine clinical settings. METHODS: Kaiser Permanente Southern California members 2-10 years old who received MenACWY-CRM between September 2011 and September 2014 were included. Electronic health records were searched using a validated algorithm to identify 26 prespecified events of interests (EOIs) and serious medically attended events (SMAEs) from inpatient or emergency settings up to 1 year after MenACWY-CRM vaccination. SMAEs were categorized by International Classification of Diseases, 9th revision diagnostic categories. All events were reviewed to confirm the diagnosis and symptom onset date. The study was descriptive (NCT01452438); no statistical tests were performed. RESULTS: Among 387 vaccinated children, 327 with ≥6 months membership before vaccination were analyzed. Among EOIs, 9 asthma cases and 1 myasthenia gravis case underwent chart review which confirmed 1 incident asthma case occurring 237 days after concomitant vaccination with MenACWY-CRM and typhoid vaccine. Thirty-one children experienced SMAEs, most commonly because of unrelated injury and poisoning. The remaining events occurred sporadically after vaccination and most were unlikely related to vaccination based on medical record review. CONCLUSIONS: One incident EOI of asthma late in the 1-year observation period and sporadic distribution of SMAEs were observed. These data do not suggest safety concerns associated with MenACWY-CRM vaccination in children 2-10 years old.

Safety of Quadrivalent Meningococcal Conjugate Vaccine in 11- to 21-Year-Olds.

BACKGROUND: Meningococcal conjugate vaccination is recommended in the United States. This study evaluates the safety of quadrivalent meningococcal conjugate vaccine in a cohort aged 11 to 21 years. METHODS: This cohort study with self-controlled case-series analysis was conducted at Kaiser Permanente Southern California. Individuals receiving MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, during September 30, 2011 to June 30, 2013, were included. Twenty-six prespecified events of interest (EOIs), including neurologic, rheumatologic, hematologic, endocrine, renal, pediatric, and pediatric infectious disease EOIs, were identified through electronic health records 1 year after vaccination. Of these, 16 were reviewed by case review committees. Specific risk and comparison windows after vaccination were predefined for each EOI. The relative incidence (RI) and 95% confidence intervals (CIs) were estimated through conditional Poisson regression models, adjusted for seasonality. RESULTS: This study included 48 899 vaccinated individuals. No cases were observed in the risk window for 14 of 26 EOIs. The RI for Bell's palsy, a case review committee-reviewed EOI, was statistically significant (adjusted RI: 2.9, 95% CI: 1.1-7.5). Stratified analyses demonstrated an increased risk for Bell's palsy in subjects receiving concomitant vaccines (RI = 5.0, 95% CI = 1.4-17.8), and no increased risk for those without concomitant vaccine (RI = 1.1, 95% CI = 0.2-5.5). CONCLUSIONS: We observed a temporal association between occurrence of Bell's palsy and receipt of MenACWY-CRM concomitantly with other vaccines. The association needs further investigation as it could be due to chance, concomitant vaccination, or underlying medical history predisposing to Bell's palsy.

Accuracy of influenza vaccination status in a computer-based immunization tracking system of a managed care organization.

Influenza vaccine safety and effectiveness studies conducted using electronic medical records rely on accurate assessment of influenza vaccination status. However, influenza immunization in non-traditional settings (e.g., the workplace) may not be captured in patient immunization tracking systems. We compared influenza vaccination status from electronic records with self-reported vaccination status for five hundred and two 50-79 years olds enrolled in a large managed care organization. Influenza vaccination status in the medical record had a high positive predictive value and specificity (both >99%). The negative predictive value was 80% and sensitivity was 78%. These data suggest that an electronic record of influenza vaccination reliably indicates immunization, while the absence of such a record is only moderately accurate, partly due to vaccines received in non-traditional settings.