Atypical B cells and impaired SARS-CoV-2 neutralisation following booster vaccination<br>in the elderly.

Age 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.