Sex-based biology and the rational design of influenza vaccination strategies

Abstract

Biological (ie, sex) differences as well as cultural (ie, gender) norms influence the acceptance and efficacy of vaccines for males and females. These differences are often overlooked in the design and implementation of vaccination strategies. Using seasonal and pandemic influenza vaccines, we document profound differences between the sexes in the acceptance, correlates of protection, and adverse reactions following vaccination in both young and older adults. Females develop higher antibody responses, experience more adverse reactions to influenza vaccines, and show greater vaccine efficacy than males. Despite greater vaccine efficacy in females, both young and older females are often less likely to accept influenza vaccines than their male counterparts. Identification of the biological mechanisms, including the hormones and genes, that underlie differential responses to vaccination is necessary. We propose that vaccines should be matched to an individual's biological sex, which could involve systematically tailoring diverse types of FDA-approved influenza vaccines separately for males and females. One goal for vaccines designed to protect against influenza and even other infectious diseases should be to increase the correlates of protection in males and reduce adverse reactions in females in an effort to increase acceptance and vaccine-induced protection in both sexes.

Keywords: aging; gender; immunogenicity; influenza; reactogenicity; sex difference; sex hormone; vaccine.

Figure 1.

There are a number of determinants of sex differences, including age, reproductive status, sex hormone activity, and genetic factors. The biological differences between the sexes affect innate, adaptive, and memory immune responses as well as adverse reactions (eg, inflammatory responses) to vaccines, resulting in sex differences in vaccine efficacy. Manipulating the biological differences between the sexes is not currently feasible, so we propose sex-specific rational design of vaccines, which involves tailoring vaccines separately to males and females in an effort to increase immunogenicity in males and reduce adverse reactions (reactogenicity) in females. The long-term goal of sex-specific rational vaccine design is to increase acceptance, uptake, and protection following vaccination in both sexes. Sex-specific rational design of vaccines might involve the use of adjuvanted vaccines in males, but not females; reduced doses of vaccines in females; or modified routes of administration, such as use of intradermal routes, or modified delivery methods to reduce local adverse reactions in females.