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

This research has not been peer-reviewed. It is a preliminary report that should not be regarded as conclusive, guide clinical practice or health-related behaviour, or be reported in news media as established information.

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.

Author list



  1. Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Cambridge, UK.
  2. Department of Medicine, University of Cambridge, Cambridge, UK.
  3. Molecular Immunity Unit, Department of Medicine, Medical Research Council
  4. Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK.
  5. Wellcome Sanger Institute, Cambridge, UK.
  6. Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, UK.
  7. Division of infection and immunity, UCL, London, UK
  8. National University of Singapore, Singapore


Isabella A.T.M. Ferreira1, 2**, Colin Y.C. Lee3, 4**, William Foster5**, Adam Abdullahi1, 2, Zewen Kelvin Tuong3, 4, Benjamin J Stewart3, 4, John R. Ferdinand3, Stephane Guillaume5, Martin O.P. Potts1, 2, Marianne Perera1, 2, Benjamin A. Krishna1, 2, Ana P. Alonso3, Mia Cabantous3, Steven A. Kemp1, 2, Lourdes Ceron-Gutierrez6, Soraya Ebrahimi6, The CITIID- NIHR BioResource COVID-19 Collaboration, Paul Lyons1, 2, Kenneth GC Smith1, 2, John Bradley1, 2, Dami A. Collier1, 2, Sarah A. Teichmann4, Laura E. McCoy7, Paul A. MacAry8, Rainer Doffinger6, Mark R. Wills1, 2, Michelle Linterman5*, Menna R. Clatworthy 1, 3, 4*, Ravindra K. Gupta1, 2*

    Novel Coronavirus SARS-CoV-2