Post-licensure Safety Research Articles

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

BackgroundHepB-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. MethodsThis 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. ResultsThere 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. ConclusionsThis 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.

Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines.

The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

115. 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

Abstract Background HepB-CpG (Heplisav-B; Dynavax) is a licensed hepatitis B vaccine with a novel adjuvant that requires only 2 doses (0, 1 month) compared to a 3-dose (0, 1, 6 months) HepB-alum vaccine (Engerix-B; GlaxoSmithKline). Monitoring of safety outcomes following receipt of vaccines with novel adjuvants is important. Hence, as part of an FDA postmarketing commitment, we compared the incidence of new-onset immune-mediated diseases, herpes zoster (HZ), and anaphylaxis among recipients of HepB-CpG versus HepB-alum at Kaiser Permanente Southern California (KPSC). Methods This cohort study included adults not on dialysis who received ≥1 dose of a hepatitis B vaccine from 8/7/2018 to 10/31/2019, during which HepB-CpG was routinely administered in 7 of 15 KPSC medical centers while HepB-alum was administered at the other 8 medical centers. Recipients of HepB-CpG or HepB-alum were followed through electronic health records for 13 months after receipt of the first dose during the vaccine accrual period 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 a RR of 3 for all other outcomes Results There were 31,183 HepB-CpG and 38,442 HepB-alum recipients (overall 49.0% female, 48.5% ≥50 years of age, 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]). (Table 1) After adjudication of new-onset RA, the adjusted RR was 0.93 (0.34, 2.49). (Table 2) The adjusted RR for HZ was 1.06 (0.89, 1.27). Anaphylaxis occurred in 0 HepB-CpG and 2 HepB-alum recipients. Conclusion These data suggest no safety concerns for HepB-CpG compared to HepB-alum for select immune-mediated diseases, HZ, or anaphylaxis in this observational study of over 69,000 recipients of hepatitis B vaccines. Disclosures Bradley Ackerson, MD, Dynavax: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Seqirus: Grant/Research Support Lina S. Sy, MPH, Dynavax: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support|Seqirus: Grant/Research Support Jeff Slezak, MS, ALK, Inc.: Grant/Research Support|Dynavax: Grant/Research Support|Novavax, Inc.: Grant/Research Support|Pfizer, Inc.: Grant/Research Support Lei Qian, PhD, Dynavax: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support Kristi Reynolds, PhD, Amgen: Grant/Research Support|Dynavax: Grant/Research Support|Merck: Grant/Research Support|Novartis: Grant/Research Support Runxin Huang, MS, Dynavax: Grant/Research Support Zendi Solano, BS, Dynavax: Grant/Research Support|Gilead: Grant/Research Support|GlaxoSmithKline: Grant/Research Support William Towner, MD, Dynavax: Grant/Research Support|Gilead: Grant/Research Support|Merck: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|ViiV: Grant/Research Support Sijia Qiu, MS, Dynavax: Grant/Research Support|Moderna: Grant/Research Support Sarah Simmons, MPH, Dynavax: Grant/Research Support|Glaxo-Smith Kline: Grant/Research Support|Pfizer: Grant/Research Support Steven Jacobsen, MD, Dynavax: Grant/Research Support Katia J. Bruxvoort, PhD, MPH, Dynavax: Grant/Research Support|Gilead: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Seqirus: Grant/Research Support.

Economic impact of vaccine safety incident in Ukraine: The economic case for safety system investment

BackgroundVaccine confidence and coverage decreased following a death temporally but not causally related to measles vaccination in Ukraine in 2008. Large measles outbreaks including international exportations followed. Herein we characterize this experience including associated costs. MethodsMixed-methods were used to characterize this vaccine safety incident and quantify health and economic costs. Qualitative interviews illuminate the incident, social climate, and corruption that influenced vaccine confidence in Ukraine. A literature review explored attitudes toward vaccines in the USSR and post-independence Ukraine. Infectious disease incidence was examined before and after the vaccine safety incident. An economic analysis estimated associated healthcare costs, including prevention and outbreak control measures, additional vaccination activities due to failure of the 2008 campaign, treatment costs for new cases domestically and foreign exportation, and productivity loss from treatment time and mortality for new cases. FindingsVaccine hesitancy and distrust in government and public health programs due to corruption existed in Ukraine before the vaccine safety incident. The mishandling of the 2008 incident catalyzed the decline of vaccine confidence and prompted poor procurement decisions, leading to a drop in infant vaccination coverage, increased domestic measles cases, and exportation of measles. The estimated cost of this incident was approximately $140 million from 2008 to 2018. InterpretationAbsent a rapid and credible vaccine safety response, a coincidental death following immunization resulted in major outbreaks of measles with substantial economic costs. Adequate investments in a post-licensure safety system may help avoid similar future incidents.

Active Postlicensure Safety Surveillance for Recombinant Zoster Vaccine Using Electronic Health Record Data.

Recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, United Kingdom) is an adjuvanted glycoprotein vaccine that was licensed in 2017 to prevent herpes zoster (shingles) and its complications in older adults. In this prospective, postlicensure Vaccine Safety Datalink study using electronic health records, we sequentially monitored a real-world population of adults aged ≥50 years who received care in multiple US Vaccine Safety Datalink health systems to identify potentially increased risks of 10 prespecified health outcomes, including stroke, anaphylaxis, and Guillain-Barré syndrome (GBS). Among 647,833 RZV doses administered from January 2018 through December 2019, we did not detect a sustained increased risk of any monitored outcome for RZV recipients relative to either historical (2013-2017) recipients of zoster vaccine live, a live attenuated virus vaccine (Zostavax; Merck & Co., Inc., Kenilworth, New Jersey), or contemporary non-RZV vaccine recipients who had an annual well-person visit during the 2018-2019 study period. We confirmed prelicensure trial findings of increased risks of systemic and local reactions following RZV. Our study provides additional reassurance about the overall safety of RZV. Despite a large sample, uncertainty remains regarding potential associations with GBS due to the limited number of confirmed GBS cases that were observed.

Digital biomarkers for post-licensure safety monitoring

Post-licensure safety data form the cornerstone of safety surveillance. However, such data have some limitations related to the subjectiveness of reporting and recording, primary purpose of the collected data, or heterogeneity. Routine capture of richer data would in part help mitigate these limitations, enabling earlier, more reliable safety insights. Digital health tools that remotely acquire health-related information are increasingly available and used by patients and the wider population. However, they are rarely used for pharmacovigilance purposes. Here, we review different cases that reveal the opportunities and challenges of using these technologies for enhanced safety assessment in routine healthcare delivery. We believe such approaches will advance our understanding of the safety of drugs and vaccines in the future.

Myocarditis and pericarditis: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data

Myocarditis and/or pericarditis (also known as myopericarditis) are inflammatory diseases involving the myocardium (with non-ischemic myocyte necrosis) and/or the pericardial sac. Myocarditis/pericarditis (MPC) may present with variable clinical signs, symptoms, etiologies and outcomes, including acute heart failure, sudden death, and chronic dilated cardiomyopathy. Possible undiagnosed and/or subclinical acute myocarditis, with undefined potential for delayed manifestations, presents further challenges for diagnosing an acute disease and may go undetected in the setting of infection as well as adverse drug/vaccine reactions.The most common causes of MPC are viral, with non-infectious, drug/vaccine associated hypersensitivity and/or autoimmune causes being less well defined and with potentially different inflammatory mechanisms and treatment responses. Potential cardiac adverse events following immunization (AEFIs) encompass a larger scope of diagnoses such as triggering or exacerbating ischemic cardiac events, cardiomyopathy with potential heart failure, arrhythmias and sudden death. The current published experience does not support a potential causal association with vaccines based on epidemiologic evidence of relative risk increases compared with background unvaccinated incidence. The only evidence supporting a possible causal association of MPC with a vaccine comes from case reports.Hypersensitivity MPC as a drug/vaccine induced cardiac adverse event has long been a concern for post-licensure safety surveillance, as well as safety data submission for licensure. Other cardiac adverse events, such as dilated cardiomyopathy, were also defined in the CDC definitions for adverse events after smallpox vaccination in 2006. In addition, several groups have attempted to develop and improve the definition and adjudication of post-vaccination cardiovascular events. We developed the current case definitions for myocarditis and pericarditis as an AEFI building on experience and lessons learnt, as well as a comprehensive literature review. Considerations of other etiologies and causal relationships are outside the scope of this document.

Smartphone-based active vaccine safety surveillance (SmartVax) at a Swiss adult vaccination clinic - a pilot study.

Post-licensure surveillance of adverse events following immunisation (AEFI) is critical for detecting rare but severe AEFI. SmartVax software, using smartphone technology, actively solicits reports of AEFI via automated, opt-out SMS surveys to vaccine recipients in the days following immunisation. We report on a pilot study to test the feasibility and acceptance of SmartVax in Switzerland. Between February and September 2020, consecutive subjects immunised at an adult immunisation clinic and the employee health service at the University Hospital of Basel were screened. Participants included three subgroups: healthcare workers (HCW), subjects with immune-mediated inflammatory diseases (IMID) and clients of the regular adult immunisation clinic. Three days after vaccination, participants received an SMS inquiring if they had any AEFI. In the case of an AEFI, subjects received an automated SMS with a link to an online survey assessing the type and temporal evolution of the AEFI. Descriptive statistics of response rate, time-to-response, frequency and type of AEFI by vaccine and clinical subgroup were performed. Of 293 subjects screened, 276 were included (46.6% routine vaccination check-up visits, 33.3% HCW, 20.1% IMID patients) receiving 625 vaccinations during 360 immunisation visits. The SMS response rate was high (90.3%), with a median time-to-respond of 47 minutes (interquartile range11-205). After 29.8% of immunisation visits at least one AEFI was reported. There were no differences in frequency or type of AEFI between the three clinical subgroups. The recombinant, adjuvanted zoster vaccine Shingrix® was associated with the highest rate of local and systemic reactions. Monitoring post-licensure vaccine safety using the active SMS-based surveillance system SmartVax is feasible in Switzerland. We observed a high acceptance in the diverse study population, including healthcare workers and IMID patients. High response rates in the elderly and reliable monitoring almost in real-time make SmartVax a promising tool for COVID-19 vaccine safety monitoring.

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

BackgroundBexsero® (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). MethodsVAERS 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. ResultsVAERS 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. ConclusionsAnalysis 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.

Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine using the national adverse event following immunization surveillance system from Zhejiang province, 2018-2020

ABSTRACT Objectives To evaluate the reporting rate of adverse events following immunization (AEFI) of the quadrivalent human papillomavirus vaccine (4vHPV) and to compare the reporting rate of AEFI following 4vHPV with those following other vaccines. Methods Review and describe the AEFI reported to national adverse event following immunization surveillance system (NAEFISS) in Zhejiang province from 2018 to 2020. Reporting rates of AEFI were calculated by age, city, severity of AEFI, categories of AEFI, and reaction categories. The data mining algorithm used in this study was reporting odds ratio (ROR). A value of ROR‑1.96SE >1 (standard error [SE]) was considered as positive signal. Results NAEFISS received 238 reports after receipt of 4vHPV and 899,282 doses of 4vHPV were administered during the study period, with a crude reporting rate of 2.7/10000 doses. Fever/redness/induration (101 reports) was the most common event reported (1.12/10000 doses). Two cases of anaphylactic shock, three cases of Guillain Barre Syndrome and two cases of acute disseminated encephalomyelitis were reported. ROR showed positive signals for seizure (ROR‑1.96SE: 2.1), syncope (ROR‑1.96SE: 1.3), allergic rash (ROR‑1.96SE: 1.6) and headache (ROR‑1.96SE: 2.1). Conclusion The present analysis did not identify new/unexpected safety concerns. Further epidemiological studies are required to systematically validate the data provided by NAEFISS.

Myocarditis After SARS-CoV-2 Vaccination: True, True, and… Related?

Myocarditis After SARS-CoV-2 Vaccination: True, True, and… Related?

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.

Post-licensure observational safety study after meningococcal B vaccine 4CMenB (Bexsero) vaccination within the routine UK immunisation program

The study investigated the safety of 4-component meningococcal serogroup B vaccination (4CMenB) in routine care. 4CMenB exposure and seizures, febrile seizures and Kawasaki disease were identified from The Health Improvement Network (THIN) database of UK electronic primary healthcare records, 2015–2018. A self-controlled case series analysis was completed. Anaphylaxis, Guillain-Barré syndrome and acute disseminated encephalomyelitis were secondary outcomes.A total of 107,231 children aged 1–18 months received ≥1 doses of 4CMenB vaccination. Most 4CMenB exposure (93%) was on the same day as other vaccines within a complete national immunisation program stage. With day 0 as day of vaccination, 43 seizures occurred in days 0–6 after 239,505 doses, and 23 febrile seizures occurred in days 0–6, and 4 Kawasaki disease cases in days 1–28 after 194,929 4CMenB doses. Adjusted incidence rate ratios including all 4CMenB exposures were 1.43 (95%CI: 1.02–2.02) for seizures and 1.72 (95%CI: 1.08–2.75) for febrile seizures. There were insufficient cases to model Kawasaki disease, and no cases of the secondary outcomes in risk periods when they may be associated with the vaccination.This study shows few cases of the outcomes after vaccination including 4CMenB with an increased risk of seizures and febrile seizures. It is not possible to attribute the finding to one specific vaccination as the majority of 4CMenB was given with other vaccinations.Trial registration: NA.

Enhanced post-licensure safety surveillance of a new recombinant acellular pertussis vaccine licensed as a monovalent (aP, Pertagen®) and tetanus, reduced-dose diphtheria combination (TdaP, Boostagen®) vaccine for immunization of adolescents and adults in Thailand

A new generation of recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin (PTgen) was licensed as a monovalent pertussis vaccine (aPgen; Pertagen®) and in combination with tetanus and reduced-dose diphtheria (TdaPgen; Boostagen®) for active immunization in individuals aged 11 years and older in Thailand in 2016. We here report post-marketing safety data on the use of the vaccines in individuals in the community obtained through active pharmacovigilance surveillance including pregnant women participating in a prospective observational study.Between May 2017 and February 2020 for TdaPgen and between June 2018 and February 2020 for aPgen, participating health care providers vaccinated and collected safety data for 11,429 exposed adolescents and adults. This included 1778 pregnant women. The incidence rate of adverse events following immunization (AEFIs) was 11.5 per 1000 of vaccinated individuals (95% confidence interval (95% CI) 9.7–13.6). AEFIs mostly concerned local pain at the injection site and muscle pain, and symptoms were mild and mostly resolved within a few days with no complications. The incidence rate of AEFIs in women vaccinated during pregnancy was 1.1 per 1000 (95% CI 0.3–4.1). Of 833 pregnant women vaccinated with recombinant aPgen or TdaPgen, 91.4% (95% CI 89.3–93.3) had uncomplicated pregnancies and 98.7% (95% CI 97.7–99.4) of the 855 babies delivered by these women were born healthy, which exceeds rates generally reported in Thailand. There were no vaccine-related serious adverse events reported during the surveillance period. In conclusion, active pharmacovigilance confirms that the recombinant pertussis vaccines aPgen (Pertagen) and TdaPgen (Boostagen) are safe in adolescents and adults, including pregnant women vaccinated in the second or third trimester of pregnancy.

Postapproval Vaccine Safety Surveillance for COVID-19 Vaccines in the US

This Viewpoint reviews systems in place to monitor postlicensure vaccine safety, and recommends harmonizing end points and protocols across vaccine trials and surveillance systems to enable timely identification and reliable evaluation of potential adverse events.

Monitoring the safety of high-dose, trivalent inactivated influenza vaccine in the vaccine adverse event reporting system (VAERS), 2011 – 2019

BackgroundOn 12/23/2009 a new high-dose trivalent inactivated influenza vaccine (IIV3-HD) was licensed for adults aged ≥65 years. We assessed the post-licensure safety data for IIV3-HD in the Vaccine Adverse Event Reporting System (VAERS) during 2011–2019. MethodsWe searched VAERS for reports after IIV3-HD during 1/1/2011–06/30/2019 in persons aged ≥65 years. Medical records were reviewed for all death reports and for certain pre-specified conditions (e.g. Guillain Barré Syndrome [GBS], anaphylaxis). We also reviewed certain groups who received IIV3-HD erroneously (e.g. pregnant women, children). Empirical Bayesian data mining was used to identify disproportional reporting. ResultsVAERS received 12,320 reports after IIV3-HD;723 reports (5.9%) were serious. The most common adverse events (AEs) among serious reports were pyrexia (30.2%), asthenia (28.9%), and dyspnea (24.9%), and among non-serious reports were injection site erythema (16.8%), pain in extremity (15.8%), and injection site pain (14.2%). Among 55 death reports, the most common causes of death were diseases of the circulatory system (n = 23;41.8%). Based on medical record review, there were 61 reports of GBS and 13 of anaphylaxis. There were 13 reports of pregnant-women who inadvertently received IIV3-HD; three reports described arm pain or local reactions, and 10 did not report any AE. Among 59 reports of children who erroneously received IIV3-HD, 31 experienced an AE (most commonly injection site or constitutional reactions) and the remaining 28 reports did not describe any AE. ConclusionsPost-licensure safety data of IIV3-HD during 9 influenza seasons revealed no new or unexpected safety concerns among individuals ≥65 years. Inadvertent administration of IIV3-HD to children or pregnant women was observed, although with no serious AEs reported. Training and education of providers in vaccine recommendations and groups for whom the vaccine is indicated may help in preventing these vaccine administration errors. This review provides baseline information for future monitoring of the quadrivalent-high-dose influenza vaccine.

Adverse events following immunization with the live-attenuated recombinant Japanese encephalitis vaccine (IMOJEV®) in Taiwan, 2017–18

BackgroundJapanese encephalitis (JE) is a significant public health concern in the Asia-Pacific region, with a case-fatality rate of around 20% for those who develop encephalitis. Mouse-brain derived vaccines against JE have been used in the publicly funded national immunization program (NIP) in Taiwan since 1968. They were replaced with a live-attenuated recombinant vaccine (JE-CV, IMOJEV®) in May 2017. We assessed reports of adverse events (AE) following the introduction of JE-CV into the Taiwan NIP to characterize its post-licensure safety profile. MethodsAEs reported between 1 May 2017 and 31 December 2018 post vaccination with JE-CV were extracted from the National Adverse Drug Reactions (ADR) Reporting System, a passive surveillance system run by the Taiwan Food and Drug Administration. The report rates were calculated based on the number of doses distributed by the manufacturer during the assessment period. ResultsThere were 51 AEs reported among 30 subjects (12 girls and 18 boys; mean age 25 months), with a reporting rate of 4.7 AEs per 100,000 doses distributed. The AEs occurred after a median of.1-day post vaccination. Eight subjects had received concomitant vaccination with another vaccines. There were four serious AEs reported: febrile seizure, acute renal failure, viral respiratory tract infection, and injection site cellulitis. None of these serious AEs were classified as being causally related to JE-CV vaccination. ConclusionThese post-licensure AE surveillance data confirm the favorable safety profile of JE-CV.

Systematic Review and Meta-analysis of Postlicensure Observational Studies on Human Papillomavirus Vaccination and Autoimmune and Other Rare Adverse Events.

Because of the limited number of subjects in prelicensure studies, autoimmune diseases and other rare adverse effects of vaccines may go undetected. Since 2006, millions of human papillomavirus (HPV) vaccine doses have been distributed and a considerable amount of postlicensure safety data has been generated. The objective of this study was to review available HPV postlicensure safety studies and to summarize risk estimates of autoimmune and other rare diseases. For this systematic review and meta-analysis, we searched literature databases to identify any postlicensure safety studies related to HPV vaccination and autoimmune adverse events from inception to April 16, 2019. Pooled risk estimates were computed using fixed- or random-effects models if at least 2 estimates per disease and per HPV vaccine were available. Twenty-two studies met our inclusion criteria. The studies applied various methodologies and used different types of data sources and outcome definitions. Quadrivalent HPV vaccine (4vHPV) was most commonly assessed. Type 1 diabetes mellitus, immune thrombocytopenia purpura and thyroiditis diseases were most frequently reported. The meta-analysis was conducted on 35 diseases corresponding to 48 pooled risk estimates. Majority of the pooled estimates showed no significant effect (n = 43). Three negative (paralysis, immune thrombocytopenia purpura and chronic fatigue syndrome) and 2 positive (Hashimoto and Raynaud diseases) associations were detected. Our study demonstrated an absence of clear association between HPV vaccines and autoimmune and other rare diseases. The review also highlights the need for more systematic collaborations to monitor rare safety adverse events.

An Introduction of the Active Vaccine Safety Surveillance System in Foreign Countries

Vaccines require higher safety standards than most other medicinal products because they are given to healthy individuals, including infants, children, and elderly. Despite various activities by national agencies, public concern about vaccine safety often arises. Post-marketing activities for vaccine safety can be broadly classified into passive and active surveillances. Many countries as well as Korea operate passive vaccine safety surveillance systems that report adverse events related to vaccines. However, the active surveillance systems operate only in several countries, such as the United States of America (USA), Europe, Canada and Australia. In the US, Vaccine Safety Datalink (VSD) and Post-Licensure Rapid Immunization Safety Monitoring (PRISM) were developed in 1990 and 2009 respectively for monitoring vaccine actively. In the case of Europe, the Vaccine Adverse Event Surveillance and Communication (VAESCO) consortium was launched in 2008. After the end of VAESCO, the Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) was organized to establish a vaccine benefit-risk monitoring framework in 2013. Canada has been operating a vaccine active monitoring system known as the Canadian Immunization Monitoring Program, ACTive (IMPACT) since 1991. The objective of this review was to describe and compare background, databases, and analysis systems of various vaccine active surveillance systems in the US, Europe, and Canada. We described the examples of studies on the safety of influenza A (H1N1) vaccines carried out in each system. This review could help provide directions for the future development of the ideal active vaccine safety surveillance system in Korea. Key words: Vaccine, Safety, Active vaccine surveillance system, Database, H1N1 influenza virus vaccine

Kawasaki disease and 13-valent pneumococcal conjugate vaccination among young children: A self-controlled risk interval and cohort study with null results.

BackgroundKawasaki disease is an acute vasculitis that primarily affects children younger than 5 years of age. Its etiology is unknown. The United States Vaccine Safety Datalink conducted postlicensure safety surveillance for 13-valent pneumococcal conjugate vaccine (PCV13), comparing the risk of Kawasaki disease within 28 days of PCV13 vaccination with the historical risk after 7-valent PCV (PCV7) vaccination and using chart-validation. A relative risk (RR) of 2.38 (95% CI 0.92–6.38) was found. Concurrently, the Food and Drug Administration (FDA) conducted a postlicensure safety review that identified cases of Kawasaki disease through adverse event reporting. The FDA decided to initiate a larger study of Kawasaki disease risk following PCV13 vaccination in the claims-based Sentinel/Postlicensure Rapid Immunization Safety Monitoring (PRISM) surveillance system. The objective of this study was to determine the existence and magnitude of any increased risk of Kawasaki disease in the 28 days following PCV13 vaccination.Methods and findingsThe study population included mostly commercially insured children from birth to <24 months of age in 2010 to 2015 from across the US. Using claims data of participating Sentinel/PRISM data-providing organizations, PCV13 vaccinations were identified by means of current procedural terminology (CPT), Healthcare Common Procedure Coding System (HCPCS), and National Drug Code (NDC) codes. Potential cases of Kawasaki disease were identified by first-in-365-days International Classification of Diseases 9th revision (ICD-9) code 446.1 or International Classification of Diseases 10th revision (ICD-10) code M30.3 in the inpatient setting. Medical records were sought for potential cases and adjudicated by board-certified pediatricians. The primary analysis used chart-confirmed cases with adjudicated symptom onset in a self-controlled risk interval (SCRI) design, which controls for time-invariant potential confounders. The prespecified risk interval was Days 1–28 after vaccination; a 28-day-long control interval followed this risk interval. A secondary analytic approach used a cohort design, with alternative potential risk intervals of Days 1–28 and Days 1–42. The varying background risk of Kawasaki disease by age was adjusted for in both designs. In the primary analysis, there were 43 confirmed cases of Kawasaki disease in the risk interval and 44 in the control interval. The age-adjusted risk estimate was 1.07 (95% CI 0.70–1.63; p = 0.76). In the secondary, cohort analyses, which included roughly 700 potential cases and more than 3 million person-years, the risk estimates of potential Kawasaki disease in the risk interval versus in unexposed person-time were 0.84 (95% CI 0.65–1.08; p = 0.18) for the Days 1–28 risk interval and 0.97 (95% CI 0.79–1.19; p = 0.80) for the Days 1–42 risk interval. The main limitation of the study was that we lacked the resources to conduct medical record review for all the potential cases of Kawasaki disease. As a result, potential cases rather than chart-confirmed cases were used in the cohort analyses.ConclusionsWith more than 6 million doses of PCV13 administered, no evidence was found of an association between PCV13 vaccination and Kawasaki disease onset in the 4 weeks after vaccination nor of an elevated risk extending or concentrated somewhat beyond 4 weeks. These null results were consistent across alternative designs, age-adjustment methods, control intervals, and categories of Kawasaki disease case included.