Review of long-term immunogenicity following HPV vaccination: Gaps in current knowledge.

The licensed HPV vaccines are highly efficacious and induce high levels of neutralizing antibody levels, the assumed mediators of protection. However, a correlate of protection against HPV is lacking, and the evidence is still limited as to long-term persistence of antibodies, especially following reduced dosing schedules. The World Health Organization (WHO) urges immunization of young girls as part of the strategy to eliminate cervical cancer, thus long-lasting protection is required. The current review describes long-term follow-up regarding vaccine-induced seropositivity and antibody level development following the different vaccines and dosing schedules. Implications and opportunities of long-term vaccine-induced immune responses are discussed, such as the gaps in monitoring of long-term immunogenicity, the possibilities of reduced dosing schedules, and the importance of evidence for durable immunity.

Ten years of HPV vaccination in the Netherlands: current evidence and future challenges in HPV-related disease prevention.

INTRODUCTION: Girls-only vaccination against human papillomavirus (HPV) type 16 and 18 was implemented in the Netherlands in 2009. Despite the evidence of the efficacy against precancerous lesions, cross-protection induced by the vaccine and a greater potential for cancer prevention than cervical cancer only, vaccine coverage in the girls-only program has remained below target levels. AREAS COVERED: In this paper, we review the literature from the Netherlands on the effectiveness and cost-effectiveness of HPV vaccination since vaccine introduction, give an account of the coverage, safety and effectiveness of HPV vaccination as has been reported in the Dutch surveillance program and discuss challenges of the current HPV vaccination program. EXPERT COMMENTARY: Girls-only HPV vaccination may confer a substantial health gain in HPV-related disease prevention. However, vaccine coverage declined remarkably recently possibly related to safety concerns, limiting the benefits from girls' vaccination and increasing the potential additional benefit of sex-neutral HPV vaccination. Considering the emergence of novel vaccination and screening options and the change from cytology- to HPV-based screening in 2017, further research is required to inform decisions on the optimization of an integrated vaccination and screening program.

No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls.

INTRODUCTION: In 2013, the Netherlands Pharmacovigilance Center Lareb published an overview of reports of long-lasting fatigue following bivalent HPV-vaccination (2vHPV). After an update of this overview in 2015, concerns regarding the safety of 2vHPV was picked up by the media, which led to further reports of long-lasting fatigue. Therefore, the Dutch National Institute for Public Health and the Environment (RIVM) investigated a possible association between HPV-vaccination and long-term fatigue. METHODS: In this retrospective cohort study conducted in the Integrated Primary Care Information database, we investigated the occurrence of chronic fatigue syndrome (CFS), fatigue ≥6 months and 3-6 months in all girls born in 1991-2000 during the follow-up period January 1st 2007-December 31st 2014 (2007-2008 pre-vaccination and 2009-2014 post-vaccination). Patients with certain fatigue ≥6 m were asked for consent to link their primary care information with vaccination data. Incidence rates per 10,000 person years (PY) for 12-16-year-old girls were compared between pre- and post-HPV-vaccine era. A self-controlled case series (SCCS) analysis was performed using consenting vaccinated cases. A primary high-risk period of 12 months after each dose was defined. RESULTS: The cohort consisted of 69,429 12-16-year-old girls accounting for 2758 PY pre-vaccination and 57,214 PY post-vaccination. Differences between pre- and post-vaccination incidences (CFS: 3.6 (95% CI 0.5-25.7)/10,000 PY and 0.9 (0.4-2.1); certain fatigue ≥6 m: 7.3 (1.8-29.0) and 19.4 (16.1-23.4); certain fatigue 3-6 m: 0.0 and 16.6 (13.6-20.3), respectively) were not statistically significant. SCCS analyses in 16 consenting vaccinated cases resulted in an age-adjusted RR of 0.62 (95%CI 0.07-5.49). CONCLUSIONS: Fatigue ≥6 m and 3-6 m was frequently found among adolescent girls, but CFS was rarely diagnosed. No statistically significant increased incidence rates were found post-vaccination compared to similar age groups of girls pre-vaccination. The SCCS analysis included a low number of cases but revealed no elevated risk of certain fatigue ≥6 m in the high-risk period.

Impact of infant pneumococcal conjugate vaccination on community acquired pneumonia hospitalization in all ages in the Netherlands.

BACKGROUND: The long-term impact of pneumococcal conjugate vaccines on pneumonia hospitalizations in all age-groups varies between countries. In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was implemented for newborns in 2006 and replaced by PCV10 in 2011. We assessed the impact of PCVs on community-acquired pneumonia (CAP) hospitalization rates in all age-groups. METHODS: A time series analysis using Poisson regression was performed on 155,994 CAP hospitalizations. Hospitalization rates were calculated using the total number of hospitalizations as denominator. The time trend in the pre-PCV period (1999-2006) was extrapolated to predict the hospitalization rate in the post-PCV period (2006-2014) if PCV had not been implemented. Rate ratios over time were calculated by comparing observed and predicted time trends. RESULTS: In children <5 years of age, the observed hospitalization rates during the post-PCV period were significantly lower than predicted if PCV had not been implemented (0-6 months: 0.62, 95% CI: 0.41-0.96; 6 months - 1 year: 0.67, 95% CI: 0.50-0.90; 2-4 years: 0.78, 95% CI: 0.61-0.97). In all other age-groups, rate ratios declined over time but did not reach statistical significance. CONCLUSIONS: After introduction of PCV, CAP hospitalizations declined in young children but no clear impact of PCV on CAP hospitalizations was seen in other age-groups.

Examining a possible association between human papilloma virus (HPV) vaccination and migraine: results of a cohort study in the Netherlands.

UNLABELLED: Since the introduction of the bivalent human papilloma virus (HPV) vaccine in the Netherlands, migraine has been reported as a notable event in the passive safety surveillance system. Research on the association between HPV vaccination and migraine is needed. Therefore, potential migraine cases in 2008-2010 were selected from a group of general practitioners and linked to the vaccination registry. Data were analysed in three ways: (i) incidences of migraine postvaccination (2009/2010) were compared to pre-vaccination incidences (2008); (ii) in a cohort, incidence rates of migraine in vaccinated and unvaccinated girls were compared and (iii) in a self-controlled case series analysis, the relative incidence of migraine in potentially high-risk periods was compared to non-high-risk periods. Incidence rates of migraine for 12- to 16-year-old girls and boys postvaccination were slightly higher than pre-vaccination incidence rates. Incidence rate ratios (IRRs) for vaccinated compared to unvaccinated girls were not statistically significantly higher. Furthermore, the RR for migraine in the high-risk period of 6 weeks following each dose versus non-high-risk period was 4.3 (95% confidence interval (CI) 0.69-26.6) for certain migraine. CONCLUSION: Using different methods, no statistically significant association between HPV vaccination and incident migraine was found. However, the number of cases was low; to definitively exclude the risk, an increased sample size is needed.