Why does this pronounced neutralizing breadth occur? Memory B cells are a primary reason. They have two major functions: one is to produce identical antibodies upon reinfection with the same virus, and the other is to encode a library of antibody mutations, a stockpile of immunological variants. These diverse memory B cells, created in response to the original infection, appear to be pre-emptive guesses by the immune system as to what viral variants may emerge in the future. This brilliant evolutionary strategy is observed clearly for immunity to SARS-CoV-2: A substantial proportion of memory B cells encode antibodies that are capable of binding or neutralizing VOCs, and the quality of those memory B cells increases over time. Thus, the increase in variant-neutralizing antibodies after vaccination of previously SARS-CoV-2-infected persons reflects recall of diverse and high-quality memory B cells generated after the original infection.
T cells are required for the generation of diverse memory B cells. The evolution of B cells in response to infection, or vaccination, is powered by immunological microanatomical structures called germinal centers, which are T cell–dependent, instructed by T follicular helper (TFH) CD4+ T cells. Thus, T cells and B cells work together to generate antibody breadth against variants. Additionally, T cells appear to be important at the recall stage. Memory B cells do not actively produce antibodies; they are quiescent cells that only synthesize antibodies upon reinfection or subsequent vaccination. Memory B cells are increased 5- to 10-fold in hybrid immunity compared with natural infection or vaccination alone. Virus-specific CD4+ T cells and TFH cells appear to be key drivers of the recall and expansion of those SARS-CoV-2 memory B cells and the impressive antibody titers observed.
T cell responses against SARS- CoV-2 in natural infection are quite broad, and most T cell epitopes are not mutated in VOCs, indicating that the contributions of T cells to protective immunity are likely to be retained. Most of the COVID-19 vaccines in use consist of a single antigen, spike, whereas 25 different viral proteins are present in SARS-CoV-2. Thus, the epitope breadth of both the CD4+ and CD8+ T cell responses is more restricted in current COVID-19 vaccines than in natural infection, whereas hybrid immunity consists of both spike and non-spike T cell memory.
Overall, hybrid immunity to SARS-CoV-2 appears to be impressively potent. The synergy is primarily observed for the antibody response more so than the T cell response after vaccination, although the enhanced antibody response depends on memory T cells. Will hybrid natural/vaccine-immunity approaches be a reproducible way to enhance immunity? The Shingrix vaccine to prevent shingles, which is given to people previously infected with the varicella zoster virus, is impressively effective (~97% efficacy), and elicits much higher antibody responses than viral infection alone. It has long been observed that combining two different kinds of vaccines in a heterologous prime-boost regimen can elicit substantially stronger immune responses than either modality alone - depending on the order in which they are used and on which vaccine modalities are combined. This may occur with combinations of COVID-19 vaccines, such as mRNA and adenoviral vectors, or mRNA and recombinant protein vaccines. These recent findings about SARS-CoV-2 immunology are pleasant surprises and can potentially be leveraged to generate better immunity to COVID-19 and other diseases.