Vaccination protects against fatal courses of SARS-CoV-2 infection, also in the elderly1,2. Induction of neutralizing serum antibodies was observed after two intramuscular applications of the BNT162b2 mRNA COVID-19 vaccine in people > 80 years of age3. However, recent outbreaks among elderly vaccinees4, and antibody responses inferior to those observed in younger vaccinees3, prompt discussion on the necessity of a third vaccination.
Herein, we compared vaccine-induced humoral and cellular immune responses to SARS-CoV-2 in 51 individuals aged > 80 years (elderly) and in 46 control individuals (young) (45 aged 20–44 years, plus one 53 year old woman, Table S1). All participants were vaccinated twice, at day 0 and day 21 with BNT162b2 in a vaccination center (elderly) or a doctor’s practice (young) in Marburg, Germany, March-May 2021. Analysis of spike-specific IgG and CD40L + IFNγ + CD4 T cells in peripheral blood revealed strong induction of humoral and cellular immunity in response to vaccination (Fig. 1A,B). This finding confirms previous data on antibodies3. As for spike-specific CD4 T cells, our data vary from this report3, as young and elderly groups demonstrated a further increase (10-fold average), between first and second dose (Fig. 1B, day 21 versus day 35). This was previously not noted3, potentially due to the different method used for their quantification (FluroSpot), as compared to the herein applied multi-parameter flow cytometry (Fig. S1).
Several important differences were noted between young and old vaccinees’ immune responses. First, the overall antibody and CD4 T cell response was lower in elderly vaccinees at a high level of significance (Fig. 1A,B, day 35). Secondly, while responses were comparable across young donors, substantial heterogeneity was observed in elderly donors, both in antibody and CD4 T cell responses, whereby several elderly showed scarce or even no reaction. Thirdly, some elderly had high frequencies of responding CD4 T cells before vaccination (Fig. 1B, day 0), likely reflecting cross-reactive activities gained during previous encounters with other corona viruses, as demonstrated before5,6.
By combining results for antibodies and CD4 T cells for each vaccinee (Fig. 2A,B), we identified five elderly individuals retaining very low levels of specific serum IgG together with almost absence of spike-reactive CD4 T cells (Fig. 2B, red triangles). Remarkably, these elderly were potentially not protected by the previous two doses of the vaccine. Among them, donor #31 received methotrexate for rheumatoid arthritis, while no history of immune modulating medication or disease was evident in the remaining four. No similar non-responder was found within the young cohort (Fig. 2A). Notably, our local authorities (Regional Counsil of Giessen, Hesse, Germany) informed us about breakthrough infections in several retirement homes. These infections occurred between one and three months after second vaccination with BNT162b2 and 5 out of 45 infected inhabitants > 80 years succumbed to infection. Thus, the lethality of these breakthrough infections is remarkably similar to the frequency of non-responders in our elderly study cohort. No COVID-19 infections were recorded in our cohorts until August 2021.
Aiming to enhance SARS-CoV-2 immunity, all five elderly non-responders received a third dose of the BNT162b2 mRNA vaccine during week 16 after the first dose. At that day, blood analyses demonstrated absence of specific immunity to SARS-CoV-2. The third vaccination was well tolerated. Most importantly, two weeks later four out out of five vaccinees, including #31, demonstrated robust spike-specific T cell and antibody responses, comparable to that detectable in responders after two-dose vaccination (Fig. 2C,D). In donor #54, a healthy man without obvious morbidities, specific serum IgG and T cell frequency also increased, however only to low levels. He was meanwhile vaccinated a fourth time, again with BNT162b2 and without obvious side effects.
Our data shows that the elderly initially hardly responding to two-dose vaccination can mount a virus-specific adaptive immune response after a third BNT162b2 dose. While the reason for primary unresponsiveness in our elderly cohort remains unclear, BNT162b2 unresponsiveness in the elderly is not fateful, and can be overcome by repeated vaccination. To confirm overall intact adaptive immune competence in initial non-responders, we tested for antibody and CD4 T cell reactivity towards control pathogens unrelated to SARS-CoV-2. Measles virus (MV)- or varicella-zoster virus (VZV)-specific IgG did not differ between non-responsive donors and all other aged donors at baseline (day 0, Fig. 2E). Additionally, the T cell responsiveness towards staphylococcal enterotoxin B (SEB) was comparable to that seen in the other elderly vaccinees throughout the observation period (Fig. 2F, Fig. S1). A similar response was observed in the young cohort (exemplified by their data on day 0), or in elderly (> 80 years) having recovered from COVID-19 infection several months before (Fig. S1). These results demonstrate that kinetics of T cell activation in our assay conditions are similar throughout participants and evaluated time points. Furthermore, initial unresponsiveness to vaccination is not indicative of an overall lack of immune competence; consequently, elderly who previously did not respond to vaccination, would likely benefit from a third dose of BNT162b2. Accordingly, in very recent studies of patients after allogeneic HSCT or on hemodialysis, only a subgroup of vaccinees reacted by a rise of antibody levels after a third vaccination, while T cell reactivity was not analyzed7,8. A third vaccination was recently shown to increase protection against COVID-19 in people > 60 years (Bar-On et al., 10.1101/2021.08.27.21262679). Likely, this effect combines overcoming of the herein described primary non-responsiveness, and a booster effect in primary responders, whose antibody titers may have gradually declined.
Overall, we show lower immune responses against SARS-CoV-2 in aged versus young vaccines, a finding which in preliminary analyses is also reflected in the antibody neutralization capacity against the SARS-CoV-2 delta variant (data not shown). Nevertheless, 90% of individuals aged > 80 years established adaptive SARS-CoV-2 specific immunity after receiving two doses of the BNT162b2 mRNA vaccine. However, non-responders can be identified. Therefore, our data are suggestive of routine screening for spike-specific immunity in this population at risk, to assess the extent of immunity after two doses of BNT162b2. Screening should be unbiased and not limited to conditions of immunodeficiency or targeted immunosuppression. Should such tests reveal lack of specific immunity, re-vaccination should be considered.