The SARS-CoV-2 pandemic has underscored the critical importance of effective vaccination strategies to mitigate severe disease and mortality, particularly among vulnerable populations such as the elderly^{1, 2–3}. Aging is associated with profound changes in the immune system, including diminished adaptive immune responses and alterations in innate immune function^{4, 5–6}. These changes, collectively termed “immunosenescence,” have been implicated in reduced vaccine efficacy and poorer outcomes in older individuals following viral infection^{7, 8–9}. Despite the widespread administration of COVID-19 vaccines, the extent to which aging influences the immune responses elicited by vaccination remains incompletely understood^{10, 11, 12–13}.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein are a central component of vaccine-induced immunity, preventing viral entry and replication^{14, 15–16}. However, the role of Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), in vaccine protection has garnered increasing attention during the pandemic^{17, 18–19}. These effector functions, mediated through the interaction of antibody Fc regions with Fc gamma receptors (FcγRs) on immune cells, contribute to the clearance of infected cells and the modulation of antiviral immunity. Notably, Fc-mediated effector functions have been shown to correlate with protection in animal models and convalescent individuals, highlighting their importance in combating SARS-CoV-2^{20, 21–22}. In murine models deficient in functional Fcγ receptors, protection against SARS-CoV-2 was lost underscoring the essential role of FcγRs in mediating antiviral immunity²¹. The importance of Fc effector functions extends beyond SARS-CoV-2 and has been extensively studied in other viral infections, including respiratory syncytial virus (RSV), influenza, and HIV^{23, 24–25}.

Recent studies suggest that the quality of vaccine-induced antibody responses, including Fc effector functions, may decline with age^9,26. IgG1, the predominant antibody subclass responsible for mediating ADCC, has been shown to exhibit reduced functionality in older adults²⁷. Given the increasing reliance on booster doses to maintain protective immunity, understanding how aging impacts Fc-mediated responses after repeated vaccination is critical for optimizing vaccine strategies in this population.

Here, we sought to evaluate the age-dependent effects of SARS-CoV-2 vaccination on immune parameters, including neutralization, Fc effector functions, and antibody isotype-specific responses. We analyzed immune responses in a cohort of elderly individuals (mean age: 79 years; age range: 65–92 years) who had received six doses of SARS-CoV-2 vaccines. By stratifying participants into younger (≤80 years) and older (>80 years) groups, we identified age-related differences in Fc-mediated ADCC activity and IgG1 binding to the SARS-CoV-2 spike protein. These findings reveal a critical vulnerability in vaccine-induced immunity among the elderly and underscore the need for tailored approaches to enhance immune responses in this high-risk population.

We enrolled a cohort of 50 individuals (54% male and 46% female) who had received their sixth dose of a SARS-CoV-2 vaccine, with blood samples collected one-month post-vaccination (Table 1). The median age of the participants was 79 years, and individuals were stratified into two groups: younger (≤80 years [65–80]) and older (>80 years [81–92]). This cohort had an age range of 65–92 years old. Of this cohort, 25 individuals had the Sanofi/GSK AS03-adjuvanted (VidPrevtyn Beta) subunit vaccine, and 25 individuals had the Pfizer-BioNTech mRNA (Comirnaty Original/Omicron BA. 4–5) bivalent vaccine. This vaccine regimen represented the most common schedules among participants, although some individuals did receive mixed vaccine types across different doses. To assess vaccine-induced humoral immunity, we measured comprehensive total immunoglobulin G (IgG) responses against the SARS-CoV-2 spike (S) protein, alongside nucleocapsid (N) total IgG, using a Luminex-based flow cytometry assay. Participants with evidence of active SARS-CoV-2 infection were excluded from the study. Notably, N-specific antibody titers can decline over time, in some cases within relatively short intervals²⁸ underscoring the importance of stratifying individuals based on infection status to accurately evaluate vaccine-induced immunity.Table 1

Demographics of the cohort

To assess the impact of aging on neutralizing antibody responses, we compared neutralization titers (NT50) among younger (≤80 years) and older (>80 years) individuals following their sixth SARS-CoV-2 vaccine dose (Fig. 1A). Neutralization was evaluated against wild-type (WT) SARS-CoV-2 as well as key SARS-CoV-2 variants, including BA.1, BA.2, XBB.1.5, BA.2.86, and JN1 (Fig. 1B). Across all tested variants, we observed no significant differences in NT50 values between the two age groups, indicating that neutralizing antibody responses remained comparable at dose 6 regardless of age (Fig. 1C). This suggests that repeated vaccination may effectively preserve neutralization capacity among elderly and very elderly individuals; however, comparisons to younger cohorts (under 50 years) were not assessed in this analysis and younger individuals may show higher neutralization titers.Fig. 1

A Top, Study design. Schematic of vaccine timeline highlighting the sixth dose. Fifty-one individuals vaccinated against SARS-CoV-2 with mRNA-based vaccines and/or AZD1222 and/or sub-unit vaccine. B Schematic design of pseudovirus neutralization assay. C Neutralization titers (pNT50) stratified by age against Wu-1 D614G WT, BA.1, BA.2, XBB1.5, BA.2.86, and JN.1. D pNT50 stratified by vaccine-type at dose 6. E pNT50 stratified by sex. Multiple Mann-Whitney compare rank tests with Holm-Šídák corrections were performed to determine significance. *p < 0.05, **p < 0.005, ***p < 0.0005. NS, not significant.

To investigate how aging affects vaccine-elicited antibody responses, we then analyzed the distribution of antibody subclasses in our cohort. Using a Luminex bead-based assay, we measured total IgG, IgA, IgG1, IgG2, IgG3, and IgG4 titers towards various regions of the wild-type and omicron SARS-CoV-2 virion including, nucleocapsid (N), omicron receptor-binding domain (RBD), RBD2, spike (S), S1, and S1 omicron (Fig. 2A). Among all subclasses, only IgG1 exhibited a significant decline in individuals aged >80 years compared to younger participants (≤80 years), suggesting a potential age-dependent reduction in the maintenance or production of this antibody subclass (Figs. 2B and S2C and S3C). In contrast, total IgG, IgA, IgG2, IgG3, and IgG4 levels against spike remained comparable between age groups, indicating a selective impairment in IgG1 response with aging (Figs. S2–S6). Similarly, when correlated with age, only IgG1 demonstrated a significant negative correlation with age (Fig. 2C–F). Importantly, anti-spike IgG3, which is the other antibody isotype known to activate ADCC, remained consistent between both age cohorts (Fig. S2E)²⁹. Anti-S1 and anti-S1 Omicron IgG1 titers however, followed a similar relationship as anti-spike IgG1, as the older participants had significantly lower titers (Figs. S3C and S5C).Fig. 2

A Total anti-spike IgG binding antibody responses (multiple Mann-Whitney compare rank test with Holm-Šídák corrections: ***p < 0.0005). B Anti-spike IgG1 binding stratified by age. C Correlation coefficient between IgG1 S correlated with age. D Correlation coefficient between IgG2 S and age, non-significant. E Correlation IgG3 S and age, non-significant. F Correlation coefficient between IgG4 S and age, non-significant. Scatter plots show linear correlation line, and statistical significance was assessed by Pearson’s Correlation.

To determine if the observed decline in spike-specific IgG1 levels correlated with Fc-mediated immunity, we next assessed ADCC signaling activity in our cohort. Using an ADCC signaling assay with a CD16-expressing reporter cell line, we observed a striking age-dependent decrease in ADCC activation, measured as signaling units, with individuals aged >80 years demonstrating significantly lower ADCC responses than younger participants ( ≤ 80 years), (Fig. 3A, B). This disparity suggests that, despite comparable neutralizing antibody titers, older individuals may have diminished Fc-mediated effector functions, potentially limiting their ability to eliminate virus-infected cells.Fig. 3

A Schematic of the antibody-dependent cellular cytotoxicity (ADCC) assay. B Antibody-dependent cellular cytotoxicity assay stratified by age. Mann-Whitney test was used. ***p < 0.0005. C log(ADCC signaling units) correlated with age. **p < 0.005 . D Correlation coefficients between log(ADCC signaling units) and anti-spike IgG1. **p < 0.005. Scatter plots show linear correlation line, and statistical significance was assessed by Pearson’s Correlation.

Our findings reveal a key deficiency in vaccine-induced immunity among elderly individuals, with potential implications for future vaccine design, particularly for those at highest risk of severe COVID-19 outcomes. Despite maintaining comparable neutralization capabilities, older individuals exhibit significantly lower levels of spike-specific IgG1, which likely contributes to the observed reduction in ADCC responses, an essential mechanism for clearing infected cells, controlling viral spread, and playing a role in modulating disease severity. While neutralization activity remains consistent between age groups, the ability to neutralize emerging SARS-CoV-2 variants, such as XBB1.5 and JN.1, remains suboptimal, potentially increasing susceptibility to breakthrough infections. Interestingly, the bivalent mRNA and adjuvanted subunit vaccines elicited similar levels of neutralization, which we hypothesize may be due to prior infection (imprinting) or heterologous epitope boosting, however more in-depth analysis would be required to prove this. Given that IgG1 plays a critical role in Fc-mediated effector functions, its diminished presence in older adults may impair the antibody-mediated activation of FcγRIIIa (CD16) on effector cells, thereby reducing their capacity to eliminate virally-infected cells^17,30,31. This age-related decline in IgG1-mediated immunity may reflect broader immunosenescence patterns, including both qualitative and quantitative shifts in humoral immunity, with implications for protection against severe disease and death^{32, 33–34}. These findings underscore the importance of tailoring vaccine strategies for elderly populations, ensuring that immunization approaches not only elicit strong neutralizing antibody responses, but also antibodies that enable Fc-mediated effector functions, critical for comprehensive disease protection. Whether this reduction in IgG1 reflects a diminished capacity to produce spike-specific antibodies that mediate cellular immunity or an overall shift in isotype or antigen-specificity distribution warrants further investigation.

Importantly, this age-dependent immune decline is not unique to SARS-CoV-2 vaccination. Similar declines in IgG have been reported in the context of pneumococcal disease with elderly individuals demonstrating lower total antibody titers and a reduction in IgG1 compared to younger adults^35,36. Likewise, influenza is particularly severe among people aged more than 65 years, with elderly accounting for 90% of all influenza-related deaths outside of pandemic seasons^37,38. It is possible that the increase in influenza-related mortality among elderly individuals is related to the impaired antibody response, and corresponding blunted Fc-mediated immunity³⁹. This decline in IgG1 likely plays a role in impaired Fc-mediated effector functions, including ADCC, which is critical for the clearance of virus-infected cells, as IgG1 and IgG3 are the main isotypes for mediating ADCC²⁹. Although the direct link between reduced IgG1 production and increased influenza mortality in the elderly has not been firmly established, the decline in IgG1 and corresponding impaired ADCC response could be a contributing factor to higher influenza-related mortality. Given the established role of ADCC in influencing influenza disease severity and enhancing viral clearance, an impairment in the SARS-CoV-2 setting could indicate a broader deficiency in antibody-mediated effector function with aging.

One possible explanation for the lower IgG1 levels in elderly individuals is a decline in class-switching efficiency, reduced production of B and T cells in the bone marrow, and diminished function of mature lymphocytes^{40, 41–42}. Alternatively, it is possible that elderly individuals produce similar amounts of total IgG but exhibit skewed subclass distribution, favoring isotypes such as IgG2 or IgG4 that do not induce ADCC-activation^29,43. The extent to which this altered subclass balance affects other Fc-mediated immune functions beyond ADCC, such as antibody-dependent cellular phagocytosis (ADCP) or complement activation, remains of interest.

Another potential contributor to the reduced spike-specific IgG1 levels and impaired ADCC responses in elderly individuals is clonal hematopoiesis (CH), a phenomenon common with aging. CH, particularly involving lymphoid-biased clones, can influence B cell repertoire, diversity, and function^{44, 45–46}. As B cell development is highly regulated by clonal selection processes, the expansion of certain clones at the expense of others may lead to an altered antibody profile. If elderly individuals exhibit increased clonal expansions of B cells that produce non-specific, lower-affinity, or functionally impaired antibodies, this could potentially lead to reduced production of high-quality antigen-specific IgG1 post-vaccination. Furthermore, CH-associated mutations can also be involved in immune cell signaling and inflammatory states, which may skew B cell differentiation pathways away from optimal IgG subclass switching^47,48, as antibody isotype switching is largely mediated by cytokine expression^{49, 50–51}. Investigating the intersection of CH and vaccine-induced immunity may provide crucial insights into age-related immune responses and strategies to enhance these antibody responses in older adults.

Similar to CH, age-associated B cells (ABCs), or atypical B cells, have been demonstrated to accumulate with increasing age and may contribute to reduced production of ADCC-activating antibodies^{52, 53–54}. These cells are characterized by higher expression of the inhibitory FcγRIIB receptor, which is known to impair B cell activation and function^{55, 56, 57–58}. Similarly, individuals that present with higher baseline percentages of ABCs have correlated with decreased levels of antigen-specific memory B cells and reduced antigen availability for immune stimulation⁵⁸. This mechanism may contribute to the diminished vaccine responses in elderly individuals, including lower spike-specific IgG1 levels and impaired ADCC responses. Likewise, studies have linked the expansion of ABCs to chronic antigen exposure and inflammation, both of which are more prevent in aging populations, further supporting their potential role in age-associated immune dysfunction^{59, 60–61}.

Understanding the mechanisms underlying the reduced ADCC observed in our cohort is critical in developing methods and approaches to better protect elderly populations from severe COVID-19. If the deficit is driven by impaired IgG1 production, enhancing germinal center responses through adjuvants or tailored booster formulations may help restore ADCC activity. However, if this decline is rooted in effector cell dysfunction and decreasing NK cell populations or functionality, focusing solely on enhancing antibody responses may be insufficient. Addressing this gap requires further studies evaluating Fc-mediated antibody responses alongside effector cell functionality in elderly populations. These insights will be essential in the development of strategies to prevent severe COVID-19 in the elderly.

This study has limitations that should be considered when interpreting the findings. Firstly, the sample size was relatively small, which may limit the generalizability of our results. Likewise, we recognize unequal distribution of vaccine types across age groups. However, we consistently observed lower ADCC signaling with increasing age, regardless of vaccine type. In addition, we did not assay spike specific B cells to explore whether there was an atypical phenotype or other abnormality in the elderly group. Additionally, the cross-sectional nature of the study prevents us from assessing longitudinal changes in ADCC over time as other timepoints were unavailable for analysis. Future studies with longitudinal design and pre-vaccination baseline serum could clarify how these immune responses evolve upon repeated SARS-CoV-2 exposure or vaccination. Unfortunately, PCR-confirmed infection data and hospitalization records were not available for all individuals, limiting our ability to interpret the results in the context of prior infection. Second, we used a lentiviral-based pseudotyped virus system rather than live SARS-CoV-2 to evaluate neutralization and viral entry⁶². While pseudoviruses are well-established tools for studying viral entry and antibody-mediated neutralization, they may not fully replicate the complexities of infection with replication-competent virus. Additionally, ADCC was assessed using a surrogate reporter assay rather than cytotoxicity assays with live autologous NK cells. However, previous studies have demonstrated that this surrogate assay strongly correlates with functional ADCC responses^13,63,64. Despite these limitations, our study provides important insights into the age-dependent differences in immunity following repeated vaccination. Importantly, these findings may reflect both vaccine response differences and age-associated immunoglobulin shifts.