Sex Difference in the Immunogenicity of the Quadrivalent Human Papilloma Virus Vaccine: Systematic Review and Meta-Analysis

Background: Immunological differences between males and females in response to viral vaccines were described but not yet directly compared for HPV vaccines. Methods: We conducted a systematic review and meta-analysis of the immunogenicity of the qHPVV. We searched Medline, Embase, and CENTRAL for trials published until September 17, 2019. Inclusion criteria were 3-doses and reporting GMTs. We performed random-effects meta-analyses and meta-regression separated by age group and sex. Findings: Our search yielded 1809 unique studies. 334 full texts were screened and data from 18 studies were extracted. Females had higher pooled geometric mean titers. Log transformed GMTs in male children (<16) years were: against HPV6: 6·62 (95% CI 6·29-6·94; I²=86·0%), against HPV11: 7·07 (95% CI 6·90-7·23; I²=63.1%), against HPV16: 8·53 (95% CI 8·28-8·78; I²=73·0%), and against HPV18 7·21 (95% CI 7·08-7·34; I²=26·4%). In females: against HPV6 7·10 (95% CI 6·79-7·41; I²=96·6%), HPV11: 7·32 (95% CI 7·15-7·50; I²=90·6%), HPV16: 8·71 (95% CI 8·52-8·91; I²=90·2%), and HPV18 7·35 (95% CI 7·11-7·58; I²=92·7%). In the meta-regression, the sexual difference was significant for HPV6 (p=0·006) and HPV11 (p=0·019) with a similar tendency for HPV16 (p=0·055) and HPV18(p=0·053). Immunogenicity was significantly higher in children (<16) than in adults (p<0·0001). Interpretation: We urge that more studies be conducted to address the gap in understanding about sex difference in viral vaccine immunogenicity, especially for the HPV vaccine. Adjusting the doses and schedule for each sex should be considered within immunization programs. Funding Statement: Maxi Foundation, Zurich, Switzerland. Declaration of Interests: The authors declare no competing interests.