Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens

Abstract

Vaccines are one of the greatest public health achievements and have saved millions of lives. They represent a key countermeasure to limit epidemics caused by emerging infectious diseases. The Ebola virus disease crisis in West Africa dramatically revealed the need for a rapid and strategic development of vaccines to effectively control outbreaks. Seven years later, in light of the SARS-CoV-2 pandemic, this need has never been as urgent as it is today. Vaccine development and implementation of clinical trials have been greatly accelerated, but still lack strategic design and evaluation. Responses to vaccination can vary widely across individuals based on factors like age, microbiome, co-morbidities and sex. The latter aspect has received more and more attention in recent years and a growing body of data provide evidence that sex-specific effects may lead to different outcomes of vaccine safety and efficacy. As these differences might have a significant impact on the resulting optimal vaccine regimen, sex-based differences should already be considered and investigated in pre-clinical and clinical trials. In this Review, we will highlight the clinical observations of sex-specific differences in response to vaccination, delineate sex differences in immune mechanisms, and will discuss the possible resulting implications for development of vaccine candidates against emerging infections. As multiple vaccine candidates against COVID-19 that target the same antigen are tested, vaccine development may undergo a decisive change, since we now have the opportunity to better understand mechanisms that influence vaccine-induced reactogenicity and effectiveness of different vaccines.

Keywords: X-chromosome inactivation; X-linked gene products; emerging infections; genetic; hormones; miRNAs; sex differences; vaccine.

Figure 1

Sex-specific immune responses can lead to vaccine responses that differ in safety, immunogenicity or efficacy. To evaluate the impact of sex on the specific vaccine candidate, we need to include both sexes as early as during the preclinical development stage and aim for a balanced sex ratio in clinical phase 1-3 trials. A detailed snapshot of immune responses to the vaccine can be achieved by frequent blood sampling following vaccination (1) and the application of various technologies (2). Here, we can evaluate responses to the vaccine on the transcriptome, epigenome and proteome level. Using bioinformatic tools (3), we may gain a comprehensive insight into multiple levels of immune responses that may be different in men and women (4). By comprehensively studying innate and adaptive immune responses in men and women, we may better understand how genetic or hormonal differences affect the number and functionality of immune cells.

Figure 2

A better understanding of the effect of vaccines in men and women can result in a balanced vaccine response. While NSE of vaccination may improve immune responses to pathogens, negative effects on immunity have also been described in females in specific contexts. In addition, reactogenicity is generally increased in females and may affect the safety profile of vaccines for women and girls. Immunogenicity, however, seems to also generally be increased in females and may therefore affect vaccine efficacy in this population. To achieve an equally beneficial vaccine for men and women, we may administer different doses (1), different intervals (2) or different vaccine candidates (3) (viral vector, nucleosid vaccines, inactivated viruses, proteins).