Human papillomavirus nonavalent (HPV9) vaccination and risk of immune mediated diseases, myocarditis, pericarditis, and thromboembolic outcomes in Denmark: self-controlled case series study.

Objective: To assess the associations between vaccination with the nonavalent human papillomavirus (HPV9) vaccine and immune mediated diseases, myocarditis, pericarditis, arterial thromboembolism, and venous thromboembolism with or without thrombocytopenia, in adolescent girls and boys in Denmark. Design: Self-controlled case series study. Setting: Population based study of linked nationwide health registers in Denmark for HPV vaccination and hospital diagnosis data, 1 October 2017 (or age 10 years) to 31 December 2022 or censored. Personal data were obtained from the Central Person Register. Information on dates of HPV vaccination and type of vaccine were obtained from the Danish Vaccination Register. Primary or secondary diagnoses of inpatient or outpatient hospital contact were sourced from the Danish National Patient Register. Participants: Source cohort 854 586. 350 687 individuals aged 10-17 years living in Denmark received at least one dose of HPV9 vaccine. Self-controlled case series analysis of 3354 individuals (1913 girls and 1441 boys) who received at least one dose of HPV9 vaccine and had at least one outcome. Main outcome measures: Rate ratios of the study outcomes in a 28 day or 180 day risk period (depending on the type of outcome) after HPV9 vaccination compared with the reference period were calculated. 47 immune mediated diseases, myocarditis, pericarditis, and seven thromboembolic outcomes were assessed. A safety signal for a specific outcome was identified if at least three outcomes were seen in the risk period after vaccination, the rate ratio was significantly increased (lower bound of the 95% confidence interval (CI) for the self-controlled case series rate ratio >1.0), and the false discovery rate adjusted P value was significant (<0.05). Results: 696 776 doses of any HPV vaccine were given during the study period, including 673 530 doses of HPV9 vaccine in 350 687 individuals who received at least one dose. In the self-controlled case series analysis, rate ratios of all immune mediated outcomes combined were 0.99 (95% CI 0.86 to 1.13) and 1.03 (0.89 to 1.20) in girls and boys, respectively, after HPV9 vaccination. Rate ratios for any of the 47 analysed immune mediated outcomes were not increased in the risk periods in girls after vaccination. The only increased rate ratio seen was for Raynaud's disease (rate ratio 2.62, 95% CI 1.07 to 6.40) after HPV9 vaccination in boys, which did not fulfil the criteria of a safety signal. These findings should be interpreted in the light of the study limitations. None of the other 55 outcomes examined showed an association with HPV9 vaccination. Conclusions: The results of this study did not suggest an association between HPV9 vaccination and the study outcomes in adolescent boys and girls aged 10-17 years. This study contributes to the evidence on the safety of the HPV9 vaccine.