Decoding immunological imprinting in the context of COVID-19

In a recent article published in the journal immunity, researchers described the concept of immunological imprinting and its underlying principles. They also discussed its potential role in the context of coronavirus disease 2019 (COVID-19) vaccines.

Primer: Immunological Imprinting: Understanding COVID-19Image Credit: Lightspring/Shutterstock

Immunological imprinting is a phenomenon in which prior exposure to a viral strain (antigen) induces B-cell memory that confers protection against future relevant antigens. In other words, the initial exposure to an antigen (e.g., a viral pathogen) leaves a permanent “trace” on the naive immune system. Other names for immunological imprinting are antigen imprinting, immune imprinting, and original antigenic sin (OAS).

Noted scientist Thomas Francis Jr coined the term OAS in the 1960s in relation to the influenza virus. This is because many epidemiological studies have linked his exposure to influenza A virus at an early age to the effect of later susceptibility to severe influenza infection and immune imprinting. However, it has recently received more attention due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The original antigenic term “sin” seems to have a negative connotation. This indicates that lifelong antigenic bias develops after the first antigen exposure in childhood. Although reactivity to the original strain is higher than reactivity to the new strain, it is still feasible to exploit his OAS using appropriate vaccine formulations. In addition, the researchers discussed the published scientific literature on OAS, a seemingly contradictory observation that essentially focused on the influenza virus.

Sampling time after reexposure is a confounding factor when examining OAS as a bias in antibody levels after a second exposure to antigen. Furthermore, ‘bias’ can vary widely and refer to variation in antibody affinity for original and recall antigens, or measurable variation in antibody titers, a potential confounding factor for quantification assays ( e.g. neutralization versus binding assay).

In rare cases, it also refers to OAS. live Antibody recall by secondary antigen.However, these are not quantifiable in vitro They bind to the original antigen, but to the secondary antigen. For decades, the meaning of the word “sin” in OAS has limited its usefulness. Therefore, we recommend that you avoid this term and use other, less misleading, consistently defined terms.

Another notable feature of immunoimprinting is that all immunological reactivity differences caused by it could not be translated into epidemiological differences. Therefore, variable susceptibility to infectious diseases can be easily considered as an ‘epidemiological imprint’ left at the population level by initial antigenic exposure.

Some additional terms help describe or explain the patterns observed in antibody titers or the immunological effects of OAS described above. The first is “antigenic seniority.” This refers to a quantitatively stratified hierarchy of antibody titers elicited in response to antigen-associated viral encounters during a lifetime.

As the name suggests, earlier-encountered antigens occupy higher positions in this hierarchy than later-encountered antigens. In cross-sectional studies, the term is used in the context of ‘steady-state’ antibody titers, capturing a phenomenon very similar to Francis’s OAS, but with no negative connotations.

Another term is “backboosting”. This refers to increased antibody titers against previously encountered antigens. Longitudinal studies have used the term to describe antibody responses following exposure to antigenically related pathogens, e.g., modified influenza virus strains used in vaccines or new strains that cause reinfection.

Titer boosts, i.e., fold differences in pre- and post-exposure titers, are greater for new antigens, whereas back-boosts retain absolute neutralizing antibody titers against previously encountered antigens at higher levels than new ones. increase. These terms describe two major immunological processes: cross-reactivity and memory retrieval.

Published literature often suggests that immune imprinting is a barrier for generating protective immunity.For example, there is evidence that childhood exposures adversely affected vaccines. effectiveness of Influenza A virus. On the contrary, exposure to H1N1 during childhood greatly reduced the risk of H1N1-induced influenza and her fatal H5N1 infection. However, given the mixed beneficial and detrimental effects of some of the previous exposures, generalizing the effects of immune imprinting is not recommended.

Immunological data may help to understand the observed epidemiological patterns, but also vice versa. Thus, it is not realistic to extrapolate immunological results to clinical outcomes. Considering the classical seroprotection curve, one of two possibilities arises.

i) Exceeding the antibody threshold does not increase the conferred immune protection.

ii) comparable antibody titer Fold variation can have markedly different protective effects.

Both scenarios depend on the relationship between actual antibody titers and immune protection.

Importantly, with respect to disease severity, immunoprotection is multifactorial and cannot be quantified by a single immunological assessment. Thus, although immunological data may be useful, interpreting clinical and epidemiological inferences of exposure history entirely from variations in antibody response patterns can lead to misinterpretation.

recently, Neutralizing antibody is a well-established correlate of COVID-19 vaccine protection. However, that does not detract from the importance of cell-mediated immunity, which is relatively immune to history of exposure, when considering protection from disease.

Studies have shown a back-boost of antibodies with cross-reactivity to the spike (S) protein of several hCoVs after COVID-19 vaccination or SARS-CoV-2 infection. However, evidence to suggest that these antibodies modulate susceptibility to severe disease is sparse.

On the contrary, people sensitized with an ancestral SARS-CoV-2 strain (Wuhan-Hu-1-like) by vaccination or infection and infected with an antigenically drifted showed higher neutralizing antibody titers.like antigen (by backboosting) and new infectious variants.

However, when infected with antigenically distant variants, such as Omicron, they maintained higher antibody titers against Wuhan-Hu-1 than Omicron, indicating antigen predominance. Both scenarios are indications for recall of cross-reactive memory B cells induced by Wuhan-Hu-1 priming.

Surprisingly, bivalent vaccines based on Omicron BA.1/BA.5 antigens elicit higher neutralizing activity against more antigenically advanced variants. Also, the Omicron antigen-based bivalent vaccine is again Reactivity to mutated epitopes indicates recruitment of naive B cells to sites of antigen exposure.

It is not yet possible to fully understand and generalize the effects of previous antigen exposure on subsequent B cell responses through cross-reactivity and recall. However, increasing the dose of antigen or adding adjuvants to vaccine formulations may interfere with some of the limitations imposed by pre-existing memory.

Conclusion

The effects of previous antigen exposure influence immunity to disease. In the analysis of antibody reactivity, immunological patterns, such as antigenic seniority, appeared to be important, whereas epidemiological patterns appeared to be important determinants of disease susceptibility in people with varying exposure histories. Careful consideration of these effects while extrapolating to clinical outcomes using consistent terminology is therefore urgent. Nonetheless, this study provided insights that could greatly aid the development of a COVID-19 vaccine against antigenically aggressive SARS-CoV-2 variants.