www.medrxiv.orgAtypical B cells and impaired SARS-CoV-2 neutralisation following booster vaccination in the elderlyAge is a major risk factor for hospitalization and death after SARS-CoV-2 infection, even in vaccinees. Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here we show that individuals 70 or older who received a primary two dose schedule with AZD1222 and booster third dose with mRNA vaccine achieved significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared to those younger than 70. One month after the booster neither the concentration of serum binding anti spike IgG antibody, nor the frequency of spike-specific B cells showed differences by age grouping. However, the impaired neutralization potency and breadth post-third dose in the elderly was associated with enrichment of circulating “atypical” spike-specific B cells expressing CD11c and FCRL5. Single cell RNA sequencing confirmed an expansion of TBX21-, ITGAX -expressing B cells in the elderly that enriched for B cell activation/receptor signalling pathway genes. Importantly we also observed impaired T cell responses to SARS-CoV-2 spike peptides in the elderly post-booster, both in terms of IFNgamma and IL2 secretion, as well as a decrease in T cell receptor signalling pathway genes. This expansion of atypical B cells and impaired T cell responses may contribute to the generation of less affinity-matured antibodies, with lower neutralizing capacity post-third dose in the elderly. Altogether, our data reveal the extent and potential mechanistic underpinning of the impaired vaccine responses present in the elderly after a booster dose, contributing to their increased susceptibility to COVID-19 infection.
### Competing Interest Statement
The authors have declared no competing interest.
### Funding Statement
The Wellcome Trust Addenbrookes Charitable Trust BRC
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The study was approved by the East of England Cambridge Central Research Ethics Committee (17/EE/0025). PBMC from unexposed volunteers previously recruited by the NIHR BioResource Centre Cambridge through the ARIA study (2014-2016), with ethical approval from the Cambridge Human Biology Research Ethics Committee (HBREC.2014.07) and currently North of Scotland Research Ethics Committee 1 (NS/17/0110).
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