The SARS-CoV-2 genome is subject to constant mutations. Some of these mutations reduce the effectiveness of RNA-based vaccines, which consequently have to be adapted regularly. Until now, however, it was unclear how the immune system reacts to new virus variants. Are mainly pre-existing memory B cells reactivated, or are new naive B cells also activated on a larger scale? This question is particularly relevant for people whose immune response has already been shaped by previous vaccinations and infections.
An interdisciplinary team of medical and scientific researchers from TWINCORE, Centre for Experimental and Clinical Infection Research in Hannover, the Hannover Medical School (MHH) and the German Primate Centre in Göttingen has therefore investigated the antibody and B-cell responses in a cohort of pre-immunised individuals following vaccination with an mRNA vaccine adapted to the JN.1 variant. TWINCORE is a joint institution of the Helmholtz Centre for Infection Research (HZI) and the MHH.
“Following the booster vaccination, we observed increased antibody binding and improved neutralisation of JN.1 and subsequent virus variants,” says Dr Metodi Stankov. He is a research fellow in Prof. Georg Behrens’s research group at the Department of Rheumatology and Immunology at the MHH and one of the two first authors of the study.
Initially, the researchers found only B cells that either recognised exclusively the earlier Wu01 variant or were cross-reactive against both Wu01 and JN.1. “In contrast, B cells specific only to JN.1 increased only slowly, reaching their peak 21 days after vaccination,” says Dr Matthias Bruhn, a postdoctoral researcher at the Institute for Experimental Infection Research at TWINCORE and also a co-first author of the article.
Subsequent single-cell RNA sequencing of the antigen-specific memory B cells and functional analyses of the corresponding monoclonal antibodies revealed that so-called somatic hypermutation drives specialisation towards improved binding to JN.1 and more effective neutralisation. Somatic hypermutation is a natural maturation process of the immune system. It involves targeted changes in the gene segments of antibodies responsible for antigen binding. Through the subsequent selection of antibodies with particularly strong binding affinity, the immune system can specifically refine its defence against already known pathogens.
The researchers conclude from these results that it is primarily pre-existing memory B cells that adapt to the new viral variant following a booster vaccination. The activation of naive B cells, by contrast, does not appear to be the dominant mechanism. “The JN.1-adapted booster vaccination is associated with the adaptation of an existing memory B-cell repertoire to JN.1, as well as with improved neutralisation of circulating and antigenically closely related viral variants,” says Prof. Ulrich Kalinke, Director of the Institute for Experimental Infection Research at TWINCORE.
“This study is a first step towards better understanding how the adaptation of vaccines to new virus variant influences the immune response,” says Georg Behrens. “Using the methods available today, we can track much more precisely how adapted vaccines modulate the immune response.”
The work was funded by, amongst others, the RESIST Cluster of Excellence and the German Centre for Infection Research (DZIF).
