Sex differences in the efficacy and safety of SARS-CoV-2 vaccination in residents of long-term care facilities: insights from the GeroCovid Vax study

Since the COVID-19 pandemic outbreak in 2020, more than 6 million people have died, mainly male, older, and vulnerable people with concomitant chronic non-communicable diseases [1, 2]. Undoubtedly, the advent of vaccines against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) has strongly affected the course of the COVID-19 pandemic, mitigating the incidence and the severity of the infection in all settings. However, some knowledge gaps still exist in the immunogenicity of vaccines in some population categories, such as residents in long-term care facilities (LTCFs), undoubtedly the most vulnerable ones [3]. In this regard, an age-dependent decline in immune responses has been reported and could result in increased susceptibility to the infection and compromised vaccine immunogenicity in older, frailer individuals [4].

In addition to age, it is unclear whether sex may represent another impactful modifying factor in the efficacy and safety of SARS-CoV-2 vaccination. The presence of disparities between male and female individuals in vaccination outcomes is a well-known topic, and extensive literature has demonstrated that from childhood to adult age, females are more likely to have higher humoral and cell-mediated responses and report adverse effects than their male counterparts [5‐7]. This picture may change in advanced age. Indeed, although older women showed a greater immune response to influenza vaccination, a male advantage in terms of effective response has been observed for other vaccines, such as those against pneumococcal infection and tetanus/diphtheria/pertussis [5, 7]. These differences seem to be mediated by biological (i.e., sex-related) and psycho-socio-cultural (i.e., gender-related) aspects, including genetic, hormonal, and environmental factors, that may change with aging [6, 7].

To tackle the many unknowns regarding the response to SARS-CoV-2 vaccination in female and male older people, we assessed the existence of sex differences in the efficacy (i.e., humoral response and incident SARS-CoV-2 infections) and safety (i.e., frequency and types of adverse effects) of these vaccines among older residents of LTCFs.

Among older and multimorbid residents of LTCF, SARS-CoV-2 vaccination had similar efficacy in males and females. Yet, sex-related differences emerged in the safety profile and the factors associated with the antibody response to the vaccination. In fact, the frequency of local adverse effects after the first vaccine dose was higher in female participants than in males. Moreover, although LTCF residents showed similar antibody kinetics over 12 months, some of the chronic conditions associated with humoral response differed by sex.

Although vaccination had an impact on the restraint of the SARS-CoV-2 infection, the duration of protection, the optimal timing of the vaccination, and the identification of the factors associated with an effective antibody response have still to be fully clarified. Understanding clinical factors that impact the strength and duration of the immune response to vaccines represents a goal of preventive strategies, particularly among those mostly affected by the fatal consequences of the disease, such as older people living in LTCFs. As broadly reported, people in advanced age have been the category of individuals the most hit by the COVID-19 pandemic in terms of incident cases and fatality rate, so they have been the first target of the vaccination campaign [10].

While some studies have reported the effect of isolated or few conditions on the immune response after the vaccination among middle-aged individuals [13‐15], data on older people are scarce. The lack of information on the most vulnerable people also concerns the adverse effects of SARS-CoV-2 vaccines and their differences by sex. Overall, although several community-based studies found that younger and female individuals were more likely to report mild adverse effects, others recorded more serious reactions among older people and in men, or no sex-related differences [16‐18]. In the present work, it was evidenced that 23% of the enrolled people had adverse effects after the first vaccine dose, with women being more likely than men to present local reactions. The frequency of adverse effects decreased after the second and subsequent booster doses and did not show any other substantial difference by sex.

Our findings align with and reinforce the higher prevalence of adverse effect reactions after vaccination in women. It is well known that older females are generally more likely to report adverse reactions than males in response to different vaccines, regardless of the reaction type (local vs systemic) [7]. As emerged from information of the Vaccine Adverse Event Reporting System (VAERS) in the U.S. for seasonal influenza, the frequency of local erythema and induration, markers of local inflammation, at the site of injection was higher in aged females. Whether differences in adverse reactions reflect a sex-based reporting bias or a real sex difference in inflammatory response has not been clearly understood. Furthermore, the increased incidence of local reactions, including tenderness and pain at the injection site after the first dose of SARS-CoV-2 vaccination, has been reported in both retrospective and prospective studies [19, 20].

In our sample, we did not observe any difference in antibody titer changes over time in males and females, nor the risk of SARS-CoV-2 breakthrough infection after vaccination. This issue contrasts with the results of studies including individuals with a younger age and a better health status than our participants [21]. Instead, one previous work involving also older adults showed that the slight sex disparities in antibody titers after the primary vaccine cycle disappeared after the booster dose administration [22].

Thanks to the large set of variables collected for each participant, the GeroCovid Vax study allowed us to explore this issue and answer whether functional and clinical factors can affect the magnitude of immune response to SARS-CoV-2 vaccination. Moreover, we could investigate if the pattern of these factors varies by sex, as actually demonstrated by our findings. The sex-stratified analyses on the factors associated with a lower and heterogenous antibody response after vaccination revealed some intriguing findings. Among older male residents, those with CVD were more likely to have a lower antibodies response compared to CVD-free participants. As far as CVD are concerned, previous studies provide results similar to ours since antibody titers were found to be decreased in individuals with chronic heart disease or those with more severe congenital cardiopathies [23, 24]. Conversely, another work did not see any apparent difference in response to influenza vaccination between patients with coronary artery diseases and controls [25]. In our study, the negative impact of CVD on humoral immune response was observed only among men. The reasons behind a poor humoral response to the SARS-CoV-2 vaccine are still unclear. In a small retrospective analysis, lower antibodies titer was documented among subjects with CVD in response to the BNT162b2 mRNA SARS-CoV-2 vaccine after the first and second doses independently by sex, and the authors suggested an interaction with the cardiovascular medications of these patients [26]. Nevertheless, our findings might be influenced by the higher prevalence of CVD in the male population.

Among female residents, we found a negative influence on the vaccine humoral response from diabetes and cognitive disorders. The greater impact of diabetes on vaccine immunogenicity in female participants has already emerged from a previous study in the same population [27]. In that work, while admitting a possible residual confounding due to the generally worse health status in older male residents compared to females, we underlined the need for further studies evaluating whether biological factors, e.g. sex hormones variations, drive such differences. Regarding cognitive disorders, our findings align with a previous study observing lower antibody levels after influenza vaccination in people with dementia [28]. For instance, Ward et al. found that individuals affected by neurological diseases were less likely to present adequate antibody production against SARS-CoV-2 after 21 days of vaccination completion [29]. One of the explanations for this result concerns the high co-existence of poor nutritional status and depressive symptoms in people with neurocognitive disorders, which have both been associated with a weaker antibody production [30‐32]. Moreover, the changes in the immune system occurring with aging and exacerbated in people with dementia could further attenuate the adaptive immunity and, therefore, antibody response [33].

Finally, in both sexes, depressive disorders were associated with lower antibody titers, in accordance with a large amount of literature that underlined a link between depressive mood and dysfunctions of innate and acquired immune responses [30]. For instance, a weaker cellular-mediated response to the herpes zoster vaccine was observed in older individuals suffering from major depression [34]. This finding corroborates previous studies and underlines a link between psychological stress and immune response to influenza vaccination, especially in older people [35, 36]. Vaccine-induced immunity is a complex response involving humoral and cellular responses that simultaneously orchestrate the protection against the infection. Despite only a few works evaluating possible sex-related differences, the detrimental effect of states of psychological distress on vaccination response in the current literature seems similar in men and women [37]. Conversely, the results about the increased antibody levels at 12 months among those with a low mobility level are not of univocal interpretation. Indeed, results on the influence of functional status on the immune response to vaccines are contrasting, with some studies reporting weaker responses in people with disabilities and others showing no significant associations [38, 39]. Furthermore, our results could be driven by survival bias, which led to selecting the “healthiest” ones among vulnerable individuals at the 12-month follow-up. Therefore, this issue needs to be verified in other works that better explore the influence that inflammaging-related changes [40‐42] can play on the efficacy and safety of common vaccines. In this regard, inflammation should be seen as an adaptive phenomenon that tries to limit pro-inflammatory processes occurring with aging through continuously stimulating anti-inflammatory responses. Therefore, maintaining an optimal balance between inflammation and anti-inflammation represents the crucial point in determining the effectiveness of immune systems against the onset of acute or chronic diseases in advanced age [43]. Whether the intersection between the ability to keep an immune balance and sex may further impact the immune response to vaccination in older individuals is still a matter of debate [44, 45].

The strengths of the present analyses are the sample size of older male and female residents and the large set of collected variables. However, our findings should be carefully interpreted in light of several limitations. First, evaluating the factors associated with a higher/lower efficacy and safety of the vaccination in LTCF residents was one of the study’s aims but not the primary objective. Therefore, despite including a representative number of older male and female residents, the study sample size was not computed based on pre-planned sex-stratified analyses. Second, we described the antibody titers at specified time points and limited the observation to 12 months after the first vaccine dose; therefore, we cannot exclude that the kinetics and magnitude of antibody response might have varied at different time points between older females and males. Third, we did not consider data on the severity of the diseases that might have interfered with an effective immune response. Finally, the higher incidence of local adverse events among female participants might result from a reporting bias, as it was previously documented that female subjects are more likely to report adverse drug reactions [46].

SARS-CoV-2 vaccination seems to have similar efficacy in older male and female LTCF residents. However, some sex-specific differences emerged in the occurrence of local adverse effects of the vaccination and in patterns of factors that influence antibody levels including functional and medical characteristics. Overall, this supports the need for a sex- and gender-specific approach when conducting research on vaccination response, also in older age.