Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8 + T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response, but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.

Vaccines remain the cornerstone for containing the SARS-CoV-2 pandemic. mRNA vaccines provide protection in clinical trials using a two-dose approach, separated by a three-week gap. Here we assessed real world immune responses following vaccination with mRNA-based vaccine BNT162b2. Following the first and second doses of the BNT162b2 vaccine, we measured IFNgamma; T cell responses, both total IgG Spike, IgG Spike RBD and neutralising antibody responses to Spike in sera using a lentiviral pseudotyping system. Median age was 82 amongst 26 participants. Three weeks after the first dose a lower proportion of participants over 80 years old achieved adequate neutralisation titre of >1:4 for 50% neutralisation as compared to those under 80 (8/15 versus 11/11, p<0.05). Mean neutralisation titres in this age group after the first dose were lower than in younger individuals (p<0.05). Following the second dose, neutralising antibody response 50% titres were above 1:4 in all individuals and there was no longer a difference by age grouping. A significant proportion of individuals over 80 appear to require a second dose of vaccine, given in this study at three weeks, to achieve virus neutralisation.

B cells are important in immunity to both SARS-CoV-2 infection and vaccination, but B cell receptor (BCR) repertoire development in these contexts has not been compared. We analyse serial samples from 171 SARS-CoV-2-infected individuals and 63 vaccine recipients, and find the global BCR repertoire differs between them. Following infection, IgG1/3 and IgA1 BCRs increase, somatic hypermutation (SHM) decreases and, in severe disease, IgM and IgA clones are expanded. In contrast, after vaccination the proportion of IgD/M BCRs increase, SHM is unchanged and expansion of IgG clones is prominent. VH1-24, which targets the N-terminal domain (NTD) and contributes to neutralization, is expanded post-infection except in the most severe disease. Infection generates a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein, whilst a more focused response after vaccination mainly targets the spike’s receptor-binding domain. Thus the nature of SARS-CoV-2 exposure differentially impacts BCR repertoire development, potentially informing vaccine strategies.