Sex-specific effects of aging on humoral immune responses to repeated influenza vaccination in older adults

Shapiro, Janna R.; Li, Huifen; Morgan, Rosemary; Chen, Yiyin; Kuo, Helen; Ning, Xiaoxuan; Shea, Patrick; Wu, Caiying; Merport, Katherine; Saldanha, Rayna; Liu, Sui-Feng; Abrams, Engle; Chen, Yan; Kelly, D.; Sheridan-Malone, Eileen; Wang, Lan; Zeger, Scott L.; Klein, Sabra L.; Leng, Sean X.

doi:10.1038/s41541-021-00412-6

Cited by 30 publications

(39 citation statements)

References 64 publications

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“…For influenza, frailty is not associated with pre-or postvaccination HAI titers in either males or females, nor is a sex difference in the impact of frailty observed (Moehling et al, 2018;Shapiro et al, 2021b). In addition, no association between frailty and antibody responses is observed either when controlling for sex in statistical analysis (Narang et al, 2018;Moehling et al, 2020) or when ignoring sex altogether (DiazGranados et al, 2015;Bauer et al, 2017;Epps et al, 2017).…”

Section: The Intersection Of Sex and Frailtymentioning

confidence: 92%

Roadmap for Sex-Responsive Influenza and COVID-19 Vaccine Research in Older Adults

et al. 2022

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Sex differences in the immune system are dynamic throughout the lifespan and contribute to heterogeneity in the risk of infectious diseases and the response to vaccination in older adults. The importance of the intersection between sex and age in immunity to viral respiratory diseases is clearly demonstrated by the increased prevalence and severity of influenza and COVID-19 in older males compared to older females. Despite sex and age biases in the epidemiology and clinical manifestations of disease, these host factors are often ignored in vaccine research. Here, we review sex differences in the immunogenicity, effectiveness, and safety of the influenza and COVID-19 vaccines in older adults and the impact of sex-specific effects of age-related factors, including chronological age, frailty, and the presence of comorbidities. While a female bias in immunity to influenza vaccines has been consistently reported, understanding of sex differences in the response to COVID-19 vaccines in older adults is incomplete due to small sample sizes and failure to disaggregate clinical trial data by both sex and age. For both vaccines, a major gap in the literature is apparent, whereby very few studies investigate sex-specific effects of aging, frailty, or multimorbidity. By providing a roadmap for sex-responsive vaccine research, beyond influenza and COVID-19, we can leverage the heterogeneity in immunity among older adults to provide better protection against vaccine-preventable diseases.

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Section: The Intersection Of Sex and Frailtymentioning

confidence: 92%

Roadmap for Sex-Responsive Influenza and COVID-19 Vaccine Research in Older Adults

et al. 2022

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“…8,9 COVID-19 susceptibility and the risk for severe disease are strongly influenced age and sex, with older males having higher rates of infection and significantly worse outcomes. 10 These major immunological disparities, while common to a broader range of viral infections and vaccines, 11 are being studied in an effort to personalize and improve COVID-19 treatment and vaccination strategy. [12][13][14] In this study, we measured the concentration of SARS-CoV-2 RBD-specific serum antibodies in an Israeli cohort, composed of BNT162b2 vaccine recipients, patients recovering from COVID-19 and unvaccinated patients from the general population.…”

Section: Introductionmentioning

confidence: 99%

Population differences in antibody response to SARS‐CoV‐2 infection and BNT162b2 vaccination

Shapira

Hamad²,

Weiner

et al. 2022

The FASEB Journal

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The concentration of SARS‐CoV‐2‐specific serum antibodies, elicited by vaccination or infection, is a primary determinant of anti‐viral immunity, which correlates with protection against infection and COVID‐19. Serum samples were obtained from 25 897 participants and assayed for anti‐SARS‐CoV‐2 spike protein RBD IgG antibodies. The cohort was composed of newly vaccinated BNT162b2 recipients, in the first month or 6 months after vaccination, COVID‐19 patients and a general sample of the Israeli population. Antibody levels of BNT162b2 vaccine recipients were negatively correlated with age, with a prominent decrease in recipients over 55 years old, which was most significant in males. This trend was observable within the first month and 6 months after vaccination, while younger participants were more likely to maintain stable levels of serum antibodies. The antibody concentration of participants previously infected with SARS‐CoV‐2 was lower than the vaccinated and had a more complex, non‐linear relation to age, sex and COVID‐19 symptoms. Taken together, our data supports age and sex as primary determining factors for both the magnitude and durability of humoral response to SARS‐CoV‐2 infection and the COVID‐19 vaccine. Our results could inform vaccination policies, prioritizing the most susceptible populations for repeated vaccination.

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“…Particularly for age-based analyses, however, the consistency of trends between assays and timepoints, coupled with statistically significant sex differences in the effect of aging at 3M_PD2, lend credibility to the conclusion that the effects of age on antiviral antibody responses are driven by males. Further supporting these findings are similar sex-specific effects of age observed following seasonal influenza vaccination in both younger and older adults [17, 46]. While it is important to not over-interpret ‘within-sex’ differences as ‘between-sex’ differences [47], there is considerable value in studying differences within males or feamles [48, 49].…”

Section: Discussionmentioning

confidence: 83%

“…Older adults (75-98 years) were recruited from the Johns Hopkins Longitudinal Influenza Immunization Study of Aging over 75 years of age (JH LIISA 75+) cohort [17] (Table 1).…”

Section: Cohortsmentioning

confidence: 99%

“…There is extensive evidence that the effects of aging on the immune system differ between the sexes, including that immunosenescence occurs at a slower rate in females than males [15, 16]. The implications of biological sex are evident in the response to repeated seasonal influenza vaccination in older adults, where pre-vaccination titers decrease with age in males but not in females, suggesting that older females enter each influenza season with greater immunity than their male counterparts [17]. In the context of SARS-CoV-2 vaccines, however, studies have failed to provide sex-disaggregated data within each age group [18, 19], and little is known about how biological sex may modify the effects of age, and age-related factors like frailty, on vaccine immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

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Association of frailty, age, and biological sex with SARS-CoV-2 mRNA vaccine-induced immunity in older adults

Shapiro

Park

Aytenfisu

et al. 2022

Preprint

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Background: Male sex and old age are risk factors for severe COVID-19, but the intersection of sex and aging on antibody responses to SARS-CoV-2 vaccines has not been characterized. Methods: Plasma samples were collected from older adults (75-98 years) before and after three doses of SARS-CoV-2 mRNA vaccination, and from younger adults (18-74 years) post-dose two, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S-receptor binding domain [S-RBD], and nucleocapsid [N]) and functional activity against S were measured against the vaccine virus and variants of concern (VOC). Results: Vaccination induced greater antibody titers in older females than males, with both age and frailty associated with reduced antibody responses to vaccine antigens in males, but not females. ACE2 binding inhibition declined more than anti-S or anti-S-RBD IgG in the six months following the second dose (28-fold vs. 12- and 11-fold decreases in titer). The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOC were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOC than females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with disparities being greater in males than females. Conclusion: Older and frail males may be more vulnerable to breakthrough infections due to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.

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Sex-specific effects of aging on humoral immune responses to repeated influenza vaccination in older adults

Cited by 30 publications

References 64 publications

Roadmap for Sex-Responsive Influenza and COVID-19 Vaccine Research in Older Adults

Roadmap for Sex-Responsive Influenza and COVID-19 Vaccine Research in Older Adults

Population differences in antibody response to SARS‐CoV‐2 infection and BNT162b2 vaccination

Association of frailty, age, and biological sex with SARS-CoV-2 mRNA vaccine-induced immunity in older adults

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