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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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

Risk of spontaneous abortion and other pregnancy outcomes in 15–25 year old women exposed to human papillomavirus-16/18 AS04-adjuvanted vaccine in the United Kingdom

AbstractBackgroundWe assessed the risk of spontaneous abortion (SA) after inadvertent exposure to HPV-16/18-vaccine during pregnancy using an observational cohort design.MethodsThe study population included women aged 15–25 years registered with the Clinical Practice Research Datalink General Practice OnLine Database in the United Kingdom (UK), who received at least one HPV-16/18-vaccine dose between 1st September 2008 and 30th June 2011. Exposed women had the first day of gestation between 30 days before and 45 days (90 days for the extended exposure period) after any HPV-16/18-vaccine dose. Non-exposed women had the first day of gestation 120 days–18 months after the last dose. SA defined as foetal loss between weeks 1 and 23 of gestation (UK definition).ResultsThe frequency of SA was 11.6% (among 207 exposed) and 9.0% (632 non-exposed), women: hazard ratio (HR) adjusted for age at first day of gestation 1.30 (95% confidence interval: 0.79–2.12). Sensitivity analysis per number of doses administered (−30 to +45-day risk period) showed a HR for SA of 1.11 (0.64–1.91) for 18/178 women with one dose during the risk period versus 2.55 (1.09–5.93) in 6/29 women with two doses within a 4–5 weeks period. The proportion of pre-term/full-term/postterm deliveries, small/large for gestational age infants, and birth defects was not significantly different between exposed and non-exposed women. Results were consistent using a (United States) SA definition of foetal loss between weeks 1–19 and/or the extended risk period.ConclusionThere was no evidence of an increased risk of SA and other adverse pregnancy outcomes in young women inadvertently HPV-16/18-vaccinated around gestation. Nevertheless, women who are pregnant or trying to become pregnant are advised to postpone vaccination until completion of pregnancy

Incidence Rates of Autoimmune Diseases in European Healthcare Databases: A Contribution of the ADVANCE Project

Introduction: The public–private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data. Methods: Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell’s palsy, Guillain–Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. Results: Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell’s palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6–24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6–0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. Conclusion: A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data

Real-world evidence regulatory and public health applications using secondary healthcare data sources for post licensure vaccine safety: the use case of the Human papillomavirus vaccine

Vaccines help to protect individuals and populations against harmful diseases. However, vaccines, as any other medicines, can trigger side effects or adverse events that range from mild to severe symptoms or diseases. Because severe adverse events are rare, they may go undetected during the clinical development phases which are conducted on a limited number of participants. Therefore, assessing risks associated to vaccines after their approval for use is necessary to provide reassurance on benefit-risk profile of vaccines and to maintain public confidence in vaccine programmes. The monitoring of benefit-risk profiles of vaccines is a process that starts at early clinical development phases and includes passive, enhanced and active surveillance activities. Over the last years, the use of real-world data (RWD) and existing healthcare data sources has grown to assess vaccine safety post-licensure. RWD are, for instance, data electronically collected by physicians during routine clinical practice or disease diagnosis or procedures at hospital level or pharmacy claims. With collaboration initiatives at global level, the implementation of multi-data sources studies using RWD became a standard in vaccine safety assessment, which necessitates the development of methods such as common analytical approaches to overcome the observed heterogeneity across data sources. In the thesis, in first instance, we emphasize the increasing use of multi-data sources studies and the use of distributed data networks to generate data on vaccine safety. The main advantage of multi-data sources studies is that they allow to gain statistical power to study rare outcomes by increasing study population size, and therefore maximizing the likelihood to detect and assess rare adverse events that may occur following vaccination. However, the applicability of multi-data sources studies has limitations related to the observed heterogeneity across data sources. Because a variety of types of data source exists which includes inpatient and/or outpatient medical diagnoses from hospitalization data sources, medical records from general practitioners or family pediatricians’ data sources and record-linkage data sources that link hospitalization data and general practitioners’ data or link data from registries, it is of importance to consider the data provenance and the setting where diseases are typically diagnosed for a correct data interpretation. Second, we discuss and provide methodological considerations in vaccine safety signal evaluation studies, which are based on the experience from the bivalent HPV vaccine post-authorization safety studies. We highlight that harmonized clinical case definition can minimize bias linked to heterogeneity across studies, misclassification of exposure can be overcome by using active comparators and tailored statistical methods should preferably be used when assessing rare adverse events. Third, we discuss future perspective for the study of vaccines in the European context with the development of EU DARWIN and the conduct of fit-for-purpose data sources exercises. To conclude, this thesis underlines the methodological improvements in vaccine safety assessment which should be maintained globally to ensure reproducibility and comparability of study results

Letter to the editor concerning the article ‘Association between rotavirus vaccination and risk of intussusception among neonates and infants: a systematic review and meta-analysis’ (JAMA Netw Open. 2019;2(10):e1912458)

A recent meta-analysis investigating the association between intussusception (IS) and rotavirus (RV) vaccination demonstrated an absence of risk up to 2 years after vaccination. Meta-analyses including only randomized clinical trials are inadequate to identify a potential increased risk of rare adverse events such as IS. The study conducted failed to discuss relevant limitations. Additionally, the safety profiles of newer RV vaccines, evaluated in clinical studies with limited sample size, were considered comparable with that of the well-established and widely used RV vaccines, RotaTeq and Rotarix. We, therefore, re-emphasize that extensive and updated evidence from post-marketing surveillance indicates a slight increased risk of IS, mostly within 7 days of RV vaccination, with a benefit/risk profile assessment in favor of RV vaccination

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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

Association between rotavirus gastroenteritis and intussusception: suggested evidence from a retrospective study in claims databases in the United States

The etiology of intussusception (IS), a serious gastrointestinal obstruction, remains unclear. Limited evidence suggests a role for viral infection. We investigated the risk of IS after rotavirus gastroenteritis (RV GE) in the first year of life. In this retrospective, self-controlled case series (SCCS), we assessed the risk of IS after RV GE using data from United States administrative claims databases. Incidence rate ratios (IRR) of IS were calculated for the 7- and 21-day risk periods after RV GE (main analysis) or after fracture (sensitivity analysis). A total of 290,912,068 subjects were screened; 42 presented claims for RV GE and IS, and 66 for fracture and IS. The IRRs of IS after RV GE were 79.6 (95% confidence interval, CI: 38.6–164.4) and 25.5 (95% CI: 13.2–49.2) in the 7- and 21-day risk periods. The sensitivity analysis showed an association between IS and fracture for both periods, suggesting potential confounding. Post-hoc analyses did not confirm the association between fracture and IS but suggested a potential association between RV GE and IS. A temporal association between RV GE and IS was detected using claims databases. Due to some limitations of the data sources, this association should be further investigated

A recombinant 31.5 kDa keratinase and a crude exo-antigen from Microsporum canis fail to protect against a homologous experimental infection in guinea pigs

peer reviewedA Microsporum canis recombinant 31.5 kDa keratinase and a M. canis crude exo-antigen were tested as vaccines in an experimental infection model in guinea pigs. Animals were vaccinated subcutaneously three times at two-week intervals with either the keratinase, the exo-antigen or the adjuvant alone. Cutaneous challenge was performed blindly. Both humoral and cellular-specific immune responses to M. canis antigens were evaluated every 14 days, while a blind evaluation of clinical lesion development and fungal persistency in skin were monitored weekly. Vaccination induced very high and significant (P < 0.01) antibody responses towards both antigens. High cell-mediated immune responses to both immunogens were also induced by vaccination. After challenge, however, scores reflecting the severity of dermatophytic lesions did not differ significantly between vaccinated and control groups at any time after challenge. These results suggest that, in the guinea pig, the induction of specific immune responses against the M. canis-secreted antigens used in this study are not protective against challenge exposure

A recombinant 31.5 kDa keratinase and a crude exo-antigen from Microsporum canis fail to protect against a homologous experimental infection in guinea pigs.

peer reviewedA Microsporum canis recombinant 31.5 kDa keratinase and a M. canis crude exo-antigen were tested as vaccines in an experimental infection model in guinea pigs. Animals were vaccinated subcutaneously three times at two-week intervals with either the keratinase, the exo-antigen or the adjuvant alone. Cutaneous challenge was performed blindly. Both humoral and cellular-specific immune responses to M. canis antigens were evaluated every 14 days, while a blind evaluation of clinical lesion development and fungal persistency in skin were monitored weekly. Vaccination induced very high and significant (P < 0.01) antibody responses towards both antigens. High cell-mediated immune responses to both immunogens were also induced by vaccination. After challenge, however, scores reflecting the severity of dermatophytic lesions did not differ significantly between vaccinated and control groups at any time after challenge. These results suggest that, in the guinea pig, the induction of specific immune responses against the M. canis-secreted antigens used in this study are not protective against challenge exposure

Risk of new onset autoimmune disease in 9- to 25-year-old women exposed to human papillomavirus-16/18 AS04-adjuvanted vaccine in the United Kingdom

To assess the risk of autoimmune disease (AD) in 9-25 year-old women within 1 year after the first AS04-HPV-16/18vaccine dose, a retrospective, observational database cohort study was conducted using CPRD GOLD. From CPRD GOLD 4 cohorts (65,000 subjects each) were retrieved: 1 exposed female cohort (received ≥1 AS04-HPV-16/18 vaccine dose between Sep2008-Aug2010) and 3 unexposed cohorts: historical female (Sep2005-Aug2007), concurrent male, and historical male. Co-primary endpoints were confirmed neuroinflammatory/ophthalmic AD and other AD, secondary endpoints were confirmed individual AD. Risk of new onset of AD was compared between cohorts (reference: historical cohort) using Poisson regression. The main analysis using confirmed cases showed no neuroinflammatory/ophthalmic AD cases in the female exposed cohort. Incidence rate ratio (IRR) (95% CI) of other AD was 1.41 (0.86 to 2.31) in female and 1.77 (0.94 to 3.35) in male cohorts when compared to the female and male historical cohort, respectively. Secondary endpoints were evaluated for diseases with \u3e10 cases, which were Crohn\u27s disease (IRR: 1.21 [0.37 to 3.95] for female and 4.22 [0.47 to 38.02] for male cohorts), autoimmune thyroiditis (IRR: 3.75 [1.25 to 11.31] for female and no confirmed cases for male cohorts) and type 1 diabetes (IRR: 0.30 [0.11 to 0.83] for female and 2.46 [1.08 to 5.60] for male cohorts). Analysis using confirmed and non-confirmed cases showed similar results, except for autoimmune thyroiditis in females, IRR: 1.45 (0.79 to 2.64). There was no evidence of an increased risk of AD in women aged 9 to 25 years after AS04-HPV-16/18 vaccination