Vincent Bauchau

Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: A prospective cohort study

Infection with influenza virus during pregnancy poses a significant risk of complications for both mother and fetus. During the H1N1 2009 pandemic, pregnant women constituted one of the priority groups for vaccination in many countries, creating a need for close monitoring of the safety of the vaccine in pregnant women. We present findings from an analysis of a cohort of pregnant women (N=267) from a prospective, observational, post-authorization safety study of the AS03-adjuvanted split virion H1N1 (2009) pandemic vaccine. There were 265 known pregnancy outcomes with 261 live births, four spontaneous abortions with no congenital anomalies, and no stillbirths. There were six live births with congenital anomalies, of which one was diagnosed before vaccination. A total of 247 women (94.6%), of whom four had twin pregnancies, delivered at term, and 14 women (5.4%), of whom two had twin pregnancies, delivered preterm (between Weeks 24 and 36 of gestation), with three of them (1.1%) occurring before 32 weeks (very preterm). Twenty-one neonates (8.1%) had a low birth weight (<2.5 kg), of whom nine (3.5%) were term neonates. The prevalence of all outcomes was in line with the expected rates. The adverse events reported were consistent with the events anticipated to be reported by this study population. No adverse events of special interest were reported. The results of this analysis suggest that exposure to the AS03 adjuvanted H1N1 (2009) vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes including spontaneous abortion, congenital anomalies, preterm delivery, low birth weight neonates, or maternal complications. Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection.

Using time-to-onset for detecting safety signals in spontaneous reports of adverse events following immunization: a proof of concept study

Disproportionality analyses (DPA) are widely used in pharmacovigilance for detecting safety signals from spontaneous reports of adverse events. In these analyses, time‐to‐onset (TTO; the time between vaccination and the onset of the adverse event) is rarely considered. Our objective is to assess the potential use of TTO to improve signal detection (SD).

Signal detection on spontaneous reports of adverse events following immunisation: a comparison of the performance of a disproportionality-based algorithm and a time-to-onset-based algorithm.

Disproportionality methods measure how unexpected the observed number of adverse events is. Time‐to‐onset (TTO) methods measure how unexpected the TTO distribution of a vaccine‐event pair is compared with what is expected from other vaccines and events. Our purpose is to compare the performance associated with each method.

Anaphylaxis following H1N1 pandemic vaccines: Safety data in perspective

We present here a detailed analysis of anaphylaxis cases reported to GlaxoSmithKline safety database following vaccination with its H1N1 pandemic influenza vaccines, Pandemrix™ and Arepanrix™. Cases were assessed according to the Brighton Collaboration Case Definition (BCCD) as either confirmed diagnosis (97/395, 24.6%), insufficient information to fulfil the minimal criteria of the case definition (117/395, 29.6%) or anaphylaxis excluded (181/395, 45.8%). There was no evidence that the rate of anaphylaxis following vaccination with Pandemrix™ or Arepanrix™ is increased with respect to the rates of anaphylaxis for other vaccines. Our analysis also highlighted the challenges of reliably determining the rate of anaphylaxis as an adverse event in the postmarketing setting following mass vaccination, as anaphylaxis was excluded in 45.8% of reported cases.

Pandemrix™ and narcolepsy: A critical appraisal of the observational studies

A link between Pandemrix™ (AS03-adjuvanted H1N1 pandemic influenza vaccine, GSK Vaccines, Belgium) and narcolepsy was first suspected in 2010 in Sweden and Finland following a number of reports in children and adolescents. Initial scepticism about the reported association faded as additional countries reported similar findings, leading several regulatory authorities to restrict the use of Pandemrix™. The authors acknowledge that currently available data suggest an increased risk of narcolepsy following vaccination with Pandemrix™; however, from an epidemiologists perspective, significant methodological limitations of the studies have not been fully addressed and raise questions about the reported risk estimates. We review the most important biases and confounders that potentially occurred in 12 European studies of the observed association between Pandemrix™ and narcolepsy, and call for further analyses and debate.

Post-marketing monitoring of intussusception after rotavirus vaccination in Japan.

RotarixTM was launched in November 2011 in Japan to prevent rotavirus gastroenteritis. Some studies suggest that RotarixTM may have a temporal association with a risk of intussusception (IS). We assessed a possible association between IS and RotarixTM vaccination in Japan.

Safety of AS03-adjuvanted split-virion H1N1 (2009) pandemic influenza vaccine: a prospective cohort study

Objectives To assess the safety of an AS03-adjuvanted split virion H1N1 (2009) vaccine (Pandemrix) in persons vaccinated during the national pandemic influenza vaccination campaign in the UK. Design Prospective, cohort, observational, postauthorisation safety study. Setting 87 general practices forming part of the Medical Research Council General Practice Research Framework and widely distributed throughout England. Participants A cohort of 9143 individuals aged 7 months to 97 years who received at least one dose of the AS03-adjuvanted H1N1 pandemic vaccine during the national pandemic influenza vaccination campaign in the UK was enrolled. 94% completed the 6-month follow-up. Exclusion criteria were previous vaccination with other H1N1 pandemic vaccine and any child in care. Primary and secondary outcome measures Medically attended adverse events (MAEs) occurring within 31 days after any dose, serious adverse events (SAEs) and adverse events of special interest (AESIs) following vaccination were collected for all participants. Solicited adverse events (AEs) were assessed in a subset of participants. Results MAEs were reported in 1219 participants and SAEs in 113 participants during the 31-day postvaccination period. The most frequently reported MAEs and SAEs were consistent with events expected to be reported during the winter season in this population: lower respiratory tract infections, asthma and pneumonia. The most commonly reported solicited AEs were irritability in young children aged <5 years (61.8%), muscle aches in children aged 5–17 years (61.9%) and adults (46.9%). 18 AESIs, experienced by 14 patients, met the criteria to be considered for the observed-to-expected analyses. AESIs above the expected number were neuritis (1 case within 31 days) and convulsions (8 cases within 181 days). There were 41 deaths during the 181-day period after vaccination, fewer than expected. Conclusions Results indicate that the AS03-adjuvanted H1N1 pandemic vaccine showed a clinically acceptable reactogenicity and safety profile in all age and risk groups studied. Trial registration ClinicalTrials.gov, NCT00996853.

Optimization of a quantitative signal detection algorithm for spontaneous reports of adverse events post immunization

To optimize the efficiency of signal detection by maximizing the proportion of true positive (TP) signals among signals detected by a disproportionality algorithm.

Application of Probabilistic Multiple-Bias Analyses to a Cohort- and a Case-Control Study on the Association between Pandemrix™ and Narcolepsy.

Background An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine Pandemrix™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies. Methods We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible. Results Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72–28.11) reduced to a median value of 6.06 (2.5th- 97.5th percentile: 2.49–15.1) and the French odds ratio of 5.43 (95% CI: 2.6–10.08) to 1.85 (2.5th—97.5th percentile: 0.85–4.08). Conclusion We illustrate multiple-bias analyses using two studies on the Pandemrix™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed Pandemrix™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive.

The ADVANCE Code of Conduct for collaborative vaccine studies

Lessons learnt from the 2009 (H1N1) flu pandemic highlighted factors limiting the capacity to collect European data on vaccine exposure, safety and effectiveness, including lack of rapid access to available data sources or expertise, difficulties to establish efficient interactions between multiple parties, lack of confidence between private and public sectors, concerns about possible or actual conflicts of interest (or perceptions thereof) and inadequate funding mechanisms. The Innovative Medicines Initiatives Accelerated Development of VAccine benefit-risk Collaboration in Europe (ADVANCE) consortium was established to create an efficient and sustainable infrastructure for rapid and integrated monitoring of post-approval benefit-risk of vaccines, including a code of conduct and governance principles for collaborative studies. The development of the code of conduct was guided by three core and common values (best science, strengthening public health, transparency) and a review of existing guidance and relevant published articles. The ADVANCE Code of Conduct includes 45 recommendations in 10 topics (Scientific integrity, Scientific independence, Transparency, Conflicts of interest, Study protocol, Study report, Publication, Subject privacy, Sharing of study data, Research contract). Each topic includes a definition, a set of recommendations and a list of additional reading. The concept of the study team is introduced as a key component of the ADVANCE Code of Conduct with a core set of roles and responsibilities. It is hoped that adoption of the ADVANCE Code of Conduct by all partners involved in a study will facilitate and speed-up its initiation, design, conduct and reporting. Adoption of the ADVANCE Code of Conduct should be stated in the study protocol, study report and publications and journal editors are encouraged to use it as an indication that good principles of public health, science and transparency were followed throughout the study.