Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis

Author summary Why was this study done? In Denmark, there was a human papilloma virus (HPV) vaccination crisis in 2015, where reports of suspected adverse effects after HPV vaccination started increasing and the HPV vaccination uptake decreased dramatically.All available evidence has found the HPV vaccine to be safe and the specific cause of the reported adverse effects remains unknown.The reported symptoms were overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like.Infections are thought to be triggers of CFS, and we hypothesise that infections in temporal proximity to vaccination could also play a role for the development of suspected adverse effects following HPV vaccination. What did the researchers find? Females who had a treated infection in temporal proximity to HPV vaccination were more likely to be referred to a specialised hospital setting (HPV centre) because of suspected adverse effects after HPV vaccination compared to HPV-vaccinated females without an infection. The case-crossover and case time-control analyses made to control for potential unmeasured confounding supported this finding. What do these findings mean? Infections might be a trigger of the suspected adverse effects in a subset of females referred to an HPV centre.More research is needed in order to confirm these findings and to clarify whether infections alone or in combination with HPV vaccine could have caused the reported symptoms. BackgroundPublic trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. Methods and findingsThe study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period +/- 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test +/- 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. ConclusionsTreated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies.

Automated summary

Females with infections near the time of HPV vaccination were more likely to be referred to an HPV centre for suspected adverse effects. Further research is needed to confirm these findings and determine the role of infections in causing reported symptoms following HPV vaccination.