First Impressions Matter: Immune Imprinting and Antibody Cross-Reactivity in Influenza and SARS-CoV-2

Abstract

Many rigorous studies have shown that early childhood infections leave a lasting imprint on the immune system. The understanding of this phenomenon has expanded significantly since 1960, when Dr. Thomas Francis Jr first coined the term "original antigenic sin", to account for all previous pathogen exposures, rather than only the first. Now more commonly referred to as "immune imprinting", this effect most often focuses on how memory B-cell responses are shaped by prior antigen exposure, and the resultant antibodies produced after subsequent exposure to antigenically similar pathogens. Although imprinting was originally observed within the context of influenza viral infection, it has since been applied to the pandemic coronavirus SARS-CoV-2. To fully comprehend how imprinting affects the evolution of antibody responses, it is necessary to compare responses elicited by pathogenic strains that are both antigenically similar and dissimilar to strains encountered previously. To accomplish this, we must be able to measure the antigenic distance between strains, which can be easily accomplished using data from multidimensional immunological assays. The knowledge of imprinting, combined with antigenic distance measures, may allow for improvements in vaccine design and development for both influenza and SARS-CoV-2 viruses.

Keywords: SARS-CoV-2; antigenic distance; cross-reactivity; immune imprinting; influenza; memory B cells; multidimensional assay.

Figure 2

Variability in the speed and intensity of B cell immune responses as a result of imprinting. (A) B cells may follow one of two pathways when dealing with antigenic threats: the naive pathway or the memory pathway. Upon exposure to new epitopes, B cells will follow the naive, I pathway, responding to these epitopes with a lower binding affinity using IgM. Subsequent exposures to recognized epitopes will cause B cells to follow the memory pathway with a higher binding affinity using IgG. Memory responses to epitopes will result in the expansion of MBC pools, leading to a greater number of MBCs and plasma cells specific to that epitope [40]. These responses to recognized epitopes will be faster and larger due to the preexistence of MBC colonies that have already undergone selection and affinity maturation [41]. (B) B cell immune responses resulting from multiple exposures to related antigens with shared epitopes (black) or unique antigens with no shared epitopes (red, blue, green) showing the possible back boosting of preexisting antibodies associated with multiple exposures to conserved, previously recognized epitopes. The memory response to the related antigens, with recognized epitopes, is a faster, more robust response than that observed for novel antigens that follow the naive pathway, responding to new epitopes. Created with BioRender.com.

Figure 1

Antigens, Epitopes, and Imprinting of viruses. (A) Antigens contain many B cell epitopes, generally 3–15 amino acids and glycans clustered together on the protein surface that can be recognized by B cell surface immunoglobulin (i.e., B cell receptors) and trigger B cell immune responses. An example using the SARS-CoV-2 spike protein trimer with several epitopes, without glycans, is highlighted. (B) Antibody cross-reactivity occurs when antibodies bind to an epitope present on two different variants of the same protein, or a mixture of antibodies bind to different epitopes present on each variant. (C) Immune imprinting and B-cell memory. Primary exposure to a viral surface antigen leads to the production of antibodies against antigenic epitopes, and memory B cells. Exposure to a related antigen leads to a mixed primary and recall “imprinted” immune response. The primary response is less efficient and is overwhelmed by the rapid and robust memory B cell recall response to the imprinted antigens. The resulting response produces high levels of IgG to the imprinted epitopes and much lower levels of IgG against the new epitopes.