Age and sex have been identified as vital indicators of immunity to infectious diseases in addition to vaccinations throughout the lifetime of a person. Based on some reports, women’s immune systems are stronger than men’s. The next level of inflammation has been reported in older individuals as a consequence of impaired immune function. The impact of interactions between sex and age might be observed through clinical manifestations and epidemiology of respiratory infections resembling COVID-19 and influenza.

Each COVID-19 and influenza comprise the most important population of diseases that might be prevented by vaccines and occur in older individuals. Nevertheless, despite high vaccine coverage against seasonal influenza, roughly 4 million cases occur in older individuals annually in the USA, resulting in 90 percent of influenza-related deaths. Moreover, it has been reported globally that males experience the next risk of influenza infection, hospitalization, and mortality with old age. The same commentary was made within the case of COVID-19, where males suffered from severe disease with old age.

Vaccines help to forestall mortality and morbidity related to influenza and COVID-19 in older individuals. Nevertheless, the impact of age and sex on vaccine responses isn’t thoroughly analyzed.

A review published in Frontiers in Aging analyzed the sex differences in the protection, effectiveness, and immunogenicity of influenza and COVID-19 vaccines in older individuals. It also analyzed the best way sex brings in regards to the modification of the impact of age-related aspects on vaccination.

Study: Roadmap for Sex-Responsive Influenza and COVID-19 Vaccine Research in Older Adults. Image Credit: Rost9 / Shutterstock

Sex differences following influenza vaccination in older individuals

Previous studies have highlighted that older females vaccinated with several varieties of inactivated influenza vaccines (IIV) have higher influenza-specific memory B cells, post-vaccination antibody titers, specific memory B cells, rates of seroconversion, fold-rises in titers, and rates of seropositivity. Moreover, for high-dose IIV that comprises 4 times the antigen in comparison with the usual dose, older females have shown the next rate of seroconversion and post-vaccination titers than older males.

Sex differences concerning vaccine effectiveness (VE) have also been observed in older individuals. Previous research has reported VE to be higher amongst older females than older males across seven influenza seasons. Also, older females were found to report more opposed events (AE) in comparison with older males for each high and standard vaccine doses.

Sex differences following COVID-19 vaccination in older individuals

For COVID-19 mRNA vaccines, female long-term care facility residents (LTCFR) were reported to have more significant functional antibodies and IgG titers as in comparison with males following the primary dose of vaccine but not after the second dose. Amongst recovered LTCFR, higher antibody levels have been observed in females in comparison with males. Nevertheless, the sex differences concerning immunogenicity in addition to vaccine effectiveness (VE) amongst older individuals who’ve received the mRNA vaccines will not be entirely evident yet.

Few studies on COVID-19 vaccine safety have reported that systemic, local, and medically attended AE are more common amongst older females in comparison with older males. Older individuals have also been found to report lower AE as in comparison with younger individuals.

Roadmap for sex-responsive vaccinology research in older adults. Sex-responsive vaccine research in older adults requires careful thought and on the study planning, data collection, evaluation, and dissemination phases. Motion items for every phase are provided.

The intersection of age and sex

Age-related changes in immunity are observed to be accompanied by changes within the hormonal environment for each females and males, thereby resulting in a sex-specific impact on aging. Furthermore, a decrease in naïve T cell activity together with a rise in monocyte function with age has been observed more extensively in males as in comparison with females. That is further related to a male-specific decrease in B cell transcriptional activity.

Moreover, older females have been reported to enter each season of influenza with greater immunity in comparison with older males with high-dose IIV. Nevertheless, for the pH1N1 vaccine, a decline in immunogenicity with age was observed in older females but not older males. For COVID-19 vaccines, studies on the VE and antibody response have indicated old age as a risk factor, however the sex-specific effects of aging haven’t been analyzed.

The intersection of frailty and sex

Frailty might be defined as a decrease in physiological function that results in a rise in vulnerability. It is usually related to immune dysregulation, which thereby affects vaccine responses in a sex-specific manner. Prevalence of frailty has been observed to be higher in older females in comparison with older males.

Previous research has indicated that frailty isn’t related to either pre- or postvaccination HAI titers or antibody responses in each women and men for influenza. Furthermore, the data on the impact of frailty on influenza VE was also found to be conflicting.

For COVID-19, frailty was analyzed without the consideration of biological sex. Frailty was not found to affect vaccine-induced antibody responses against the BNT162b2 vaccine. Nevertheless, it was found to extend the chance for severe outcomes post-vaccination, and the VE of frail individuals was found to be lower and wane faster.

The intersection of comorbidity and sex

High occurrence of comorbidity in older adults can impact each the epidemiology of infectious diseases in addition to response to vaccines. The chance of influenza-related complications in addition to COVID-19-related complications was observed to be higher in older males with comorbidities in comparison with older females. Nevertheless, the modification of the effect of multimorbidity on vaccine responses through the impact of sex continues to be not understood.

Conclusion

Although sex differences in influenza and COVID-19 vaccine outcomes have been identified in older individuals, a major gap within the literature exists regarding the impact of sex-specific effects on age-related aspects. Subsequently, an efficient roadmap is required to know the impact of sex-responsive vaccinology in older adults. Implementation of the roadmap requires engagement amongst regulatory agencies, funders, academic institutions, and vaccine manufacturers. Although the present review focuses on influenza and COVID-19 vaccines, its conclusion might be implemented for other vaccines which can be administered to older individuals. Further sex-responsive research is required for understanding the heterogeneity of older populations in addition to providing optimal protection against diseases that vaccinations can prevent.