Discussion

Detection of adverse events: what are the current sensitivity limits during clinical development?

9-valent human papillomavirus vaccine (9vHPV) was approved by the Food and Drug Administration (FDA) in December 2014. 9vHPV is not recommended during pregnancy, but some women of childbearing age may be inadvertently exposed. This study aims to evaluate reports submitted to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women exposed to 9vHPV.

We searched the VAERS database, a national post-licensure vaccine safety surveillance system, for reports of pregnant women vaccinated with 9vHPV in the United States between December 10, 2014 and December 31, 2017. Disproportionate reporting of adverse events (AEs) was assessed using proportional reporting ratios (PRRs).

A total of 82 pregnancy reports were identified. Sixty reports (73.2%) did not describe an AE and were submitted only to report the vaccine exposure during pregnancy. The most frequently reported pregnancy-specific AE was spontaneous abortion (n = 3; 3.7%), followed by vaginal bleeding (n = 2; 2.4%). Among non-pregnancy-specific AEs, injection site reaction (n = 3; 3.7%) was most common. No disproportionate reporting of any AE was found.

No unexpected AEs were observed among these pregnancy reports.

The risk of immediate adverse events due to the inflammation created by a vaccine is a potential concern for pediatric vaccine programs.

We analyzed data on children born between March 2006 and March 2009 in the province of Ontario. Using the self-controlled case series design, we examined the risk of the combined endpoint of emergency room visit and hospital admission in the immediate 3 days post vaccination to a control period 9–18 days after vaccination. We examined the end points of emergency room visits, hospital admissions and death separately as secondary outcomes.

We examined 969,519 separate vaccination events. The relative incidence of our combined end point was 0.85 (0.80–0.90) for vaccination at age 2 months, 0.74 (0.69–0.79) at age 4 months and 0.68 (0.63–0.72) at age 6 months. The relative incidence was reduced for the individual endpoints of emergency room visits, admissions and death. There were 5 or fewer deaths in the risk interval of all 969,519 vaccination events. In a post hoc analysis we observed a large reduction in events in the immediate 3 days prior to vaccination suggesting a large healthy vaccinee effect.

There was no increased incidence of the combined end point of emergency room visits and hospitalizations in the 3-day period immediately following vaccination, nor for individual endpoints or death. The health vaccinee effect could create the perception of worsening health following vaccines in the absence of any vaccine adverse effect and could also mask an effect in the immediate post-vaccination period.

In the early 1980’s concerns about the safety of the whole cell pertussis vaccine in the United States resulted in declining vaccination rates and the withdrawal of multiple vaccine providers from the market. While the possibility of inflammation and febrile reactions to the vaccine were acknowledged by public health authorities, parents also claimed the vaccine was associated with sudden infant death syndrome and encephalopathy. Epidemiological studies examining this question, however, consistently failed to identify an association. We argue that these reactions may have occurred in metabolically vulnerable children, specifically those with defects in fatty acid oxidation. In these children the combination of anorexia and fever that could be caused by the vaccine may have resulted in hypoglycemic episodes and possibly death. We believe that this association was not detected because these conditions were not recognized at the time and because these conditions are uncommon. Nevertheless, at a population level, enough events could have occurred to cause concern amongst parents.

Measures to improve vaccine safety are essential for successful immunization programs. Therefore, an activity for vaccine adverse events prevention and surveillance, named the Green Channel, was established in the Veneto ion of Italy in 1992. This report summarizes the results of 10 years activity of a specialized pre-vaccination counseling service, offered to 543 selected at risk individuals referred for prior AEFIs or suspected contraindications (CI) to vaccine administration. Furthermore, data on 1762 AEFIs reported in this region are analyzed and discussed. This joint activity appeared effective and it is proposed as a model.