Instructing durable humoral immunity for COVID-19 and other vaccinable diseases

Abstract

Many aspects of SARS-CoV-2 have fully conformed with the principles established by decades of viral immunology research, ultimately leading to the crowning achievement of highly effective COVID-19 vaccines. Nonetheless, the pandemic has also exposed areas where our fundamental knowledge is thinner. Some key unknowns are the duration of humoral immunity post-primary infection or vaccination and how long booster shots confer protection. As a corollary, if protection does not last as long as desired, what are some ways it can be improved? Here, I discuss lessons from other infections and vaccines that point to several key features that influence durable antibody production and the perseverance of immunity. These include (1) the specific innate sensors that are initially triggered, (2) the kinetics of antigen delivery and persistence, (3) the starting B cell receptor (BCR) avidity and antigen valency, and (4) the memory B cell subsets that are recalled by boosters. I further highlight the fundamental B cell-intrinsic and B cell-extrinsic pathways that, if understood better, would provide a rational framework for vaccines to reliably provide durable immunity.

Keywords: COVID-19; SARS-CoV-2; antibodies; durable immunity; plasma cells; vaccines; viruses.

Figure 1

Duration of antibody production varies widely across vaccines Most vaccines lead to a sharp rise and partial decline in antibody levels after the final dose of the primary series (black line). Afterwards, the rate of decline varies greatly. Human papillomavirus, yellow fever, and smallpox vaccines induce durable antibody production (green line), whereas the malaria and influenza vaccines lead to very transient antibody levels (red line). The kinetics of antibody production for the COVID-19 vaccines differ from each other. Whereas the BNT162b2 and mRNA-1273 vaccines induce a sharp rise in antibodies, this is followed by a prolonged decline phase (blue line). Ad26.CoV2.S yields lower initial titers, but more stable maintenance (purple line).

Figure 2

Germinal center persistence depends on the nature of the antigen, innate signals, and kinetics of delivery Bolus immunizations with suboptimal inflammatory signals lead to transient germinal centers that export predominantly short-lived plasma cells (top). In contrast, slow antigen delivery or multimerized innate signals lead to persistent germinal centers (bottom). In the early phases of the response, plasma cells are predominantly short-lived, yet those exported from later germinal centers tend to be much longer lived and possess elevated secretory capacity.

Figure 3

Early imprinting of memory B cells Primary immunizations with suboptimal innate signals may lead to qualitatively distinct memory B cells than those generated with more optimal inflammatory mediators. Upon booster immunization with the same immunogen, these two types of memory B cells mediate markedly distinct responses. Those that were generated under suboptimal responses may produce shorter-lived plasma cells than those generated under more optimal conditions.