Weaving the Threads of Memory: How Pre-existing Immunity Shapes B Cell Responses to Influenza A Virus

Abstract

Influenza A virus (IAV) poses a persistent global health threat due to its ability to evolve rapidly, requiring annual updates to seasonal vaccines. Despite significant advancements, a universal vaccine capable of providing long-term and broad protection has not been developed yet. It was investigated here, how pre-existing immune components—antibodies (Abs), memory B cells (MBCs), and CD4 T cells—shape B cell responses to drifted IAV haemagglutinin (HA). We also explored innovative immunogen design strategies, targeting a conserved epitope to overcome immunodominance (ID) and enhance vaccine efficacy. While pre-existing CD4 T cells accelerated Ab and GC responses, pre-existing Abs were shown to mask epitopes and exhibit feedback mechanisms, thereby reshaping ID patterns of B cell responses. The valency of antigens used for vaccination influenced the extent of Ab-mediated modulation, with multivalent antigens showing greater effects compared to monovalent counterparts. Whereas MBC rapidly differentiated into antibody-secreting cells (ASC) rather than re-entering secondary germinal center reactions (GCs), this localized Ab secretion contributed to secondary responses rather than the presence of serum-Abs. Finally, MBC and naïve B cells were regulated differently after vaccination with a multivalent particle. To address challenges posed by antigenic variability and to induce broad immunity against IAV, a computationally designed HA stem mimetic was developed. This immunogen selectively engaged MBCs of IAV-experienced individuals and induced cross-reactive Ab responses against both group 1 and group 2 IAV strains after vaccination in mice. By combining insights into ID, the effect of pre-existing immunity on secondary B cell responses and rational antigen design, this work highlights key mechanisms driving protective and broad B cell responses to IAV, thereby providing valuable insights to inform the development of a universal IAV vaccine. These findings also offer broader implications for combating other highly variable pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV).