Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4⁺ and CD8⁺ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019.

Age-related changes in the immune system are thought to underlie the vulnerability of elderly individuals to emerging viral diseases, such as coronavirus disease 2019 (COVID-19). In this study, we used a fully validated in vitro approach to determine how age impacts the generation of de novo CD8⁺ T cell responses against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. Our data revealed a generalized deficit in the ability of elderly individuals to prime the differentiation of naïve precursors into effector CD8⁺ T cells defined by the expression of interferon (IFN)-γ and the transcription factor T-bet. As a consequence, there was an age-related decline in the diversity of newly generated CD8⁺ T cell responses targeting a range of typically immunodominant epitopes derived from SARS-CoV-2, accompanied by an overall reduction in the expression frequency of IFN-γ. These findings have potential implications for the development of new strategies to protect the elderly against COVID-19.

SARS-CoV-2-specific immunity has been shaped in recent years by a combination of natural infection, complicated by ongoing viral evolution, and vaccination. However, it has remained unclear to what extent combined antigen challenge, which elicits so-called hybrid immunity, impacts clinical outcomes and subsequent protection against COVID-19. In this study, we evaluated spike-specific humoral and cellular immune responses elicited by hybrid antigen exposure versus vaccination alone, considering the order of challenge and disease severity after infection with SARS-CoV-2. Hybrid antigen exposure was characterized by enhanced humoral and cellular immune responses compared with vaccination alone. CD8⁺ T cell responses were also more cross-reactive and displayed skewed epitope targeting hierarchies in the context of hybrid immunity. These features were maintained in older adults, who typically exhibit age-related deficits in de novo immunity, especially after breakthrough infections (BTIs). BTIs were further associated with more coordinated adaptive immune responses compared with those elicited by vaccination after infection with SARS-CoV-2. We also found that humoral immune responses, specifically IgG antibody titers targeting the spike protein receptor-binding domain, were better maintained after mRNA vaccination and that cellular immune responses were better maintained after vectored vaccination in the wake of BTIs. Moreover, vaccination was associated with mild disease after subsequent infection, especially among individuals who had received a booster dose. These results suggest that vaccine-induced memory responses, which generally wane over time, can be reactivated and reshaped by BTIs, amplifying features associated with enhanced immunity against SARS-CoV-2.

The mucosal immune response is recognized to be important in the early control of infection sustained by viruses with mucosal tissues as the primary site of entry and replication, such as SARS-CoV-2. Mucosal IgA has been consistently reported in the mouth and eye of SARS-CoV-2 infected subjects, where it correlated inversely with COVID-19 symptom severity. Yet, there is still scarce information on the comparative ability of the diverse SARS-CoV-2 vaccines to induce local IgA responses at the virus entry site. Thus, the aim of this study was to assess the presence of anti-SARS-CoV-2 IgA in the saliva of 95 subjects vaccinated with a booster dose and different combinations of vaccines, including mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and Vaxzevria (AstraZeneca). The results showed the presence of a mucosal response in 93.7% of vaccinated subjects, with a mean IgA titer of 351.5 ± 31.77 U/mL, strongly correlating with the serum anti-SARS-CoV-2 IgG titer (p < 0.0001). No statistically significant differences emerged between the vaccine types, although the salivary IgA titer appeared slightly higher after receiving a booster dose of the mRNA-1273 vaccine (Moderna) following two doses of BNT162b2 (Pfizer-BioNTech), compared to the other vaccine combinations. These data confirm what was previously reported at the eye level and suggest that monitoring salivary IgA may be a useful tool for driving forward vaccine design and surveillance strategies, potentially leading to novel routes of vaccine administration and boosting.