Recent findings on original antigenic sin and SARS-CoV-2

In a recent article published in Journal of Clinical Investigation, researchers collated findings on the evolution of primitive antigenic sin (OAS) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, they showed the impact of this phenomenon on coronavirus disease 2019 (COVID-19) outcomes and vaccine design.

Background

Thomas Francis first used the term OAS to describe the adverse clinical consequences of influenza virus infection. It has varying degrees of clinical impact in the context of other viruses, including SARS-CoV-2, human immunodeficiency virus (HIV), dengue virus, and some bacterial infections.

In general, recall of immunological memory is a positive process, antigen Memory immune cells (B and T cells) faster, at a larger scale, and better protection from infection.

Memory B and T cells also initiate responses to neoepitopes, but B and T cell clones that provide broad protection against previously encountered and related infections are favored by the natural selection process. is selected to This phenomenon is called immunoimprinting. Imprinting gradually narrows the immune response to new antigens.

However, it also has the potential to turn OAS into a positive phenomenon called buckboost and has been proposed for designing preventive vaccines against future influenza strains. Therefore, we should be able to develop a similar COVID-19 vaccine that has a positive effect on back-boosting. However, more intensive investigation of the effects of heterologous priming and boosting by current COVID-19 vaccines will be required.

Antigen evolution of SARS-CoV-2

New subspecies of SARS-CoV-2 continuously evolve, supplanting their predecessors and becoming virtually extinct. For example, new omicron (sub)strains such as BA.4 and BA.5 establish global dominance in pre-immune populations against SARS-CoV-2 through vaccination or prior infection with previous strains. doing. They have an unexpectedly high mutational burden, thanks to which they evade pre-existing immunity, and their origin is largely unknown. Detailed insight into the genetic alterations that caused these immune escape mutations in these viruses is important for understanding the alterations. effectiveness of SARS-CoV-2 vaccine.

Studies have demonstrated that antigenic evolution of the SARS-CoV-2 spike (S) resembles influenza HA, although both bind to different host cell receptors, angiotensin-converting enzyme 2 (ACE2) and glycans, respectively. To do. Perhaps it distinguishes between the rate of their evolution and the rate at which emerging SARS-CoV-2 variants incorporate them into the S protein.

Nevertheless, the accumulation of mutations in S of these new omicron (sub)variants indicates antibody neutralization that drives antigenic evolution of SARS-CoV-2 S. Therefore, infection with antigenic drift variants may preferentially induce non-neutralizing antibody clones. It may increase the risk of OAS.

Different levels of serum antibody cross-neutralizing titers help define antigenic drift variants, especially how “antigenically” distant they are, and can be visualized using antigen maps. Combined with whole-genome sequencing data, antigen maps may yield information on the molecular determinants of antigenic variation. Similarly, plaque reduction neutralization tests have helped confirm the antigenic relevance of different coronavirus (CoV) variants.

An antigen map of SARS-CoV-2 variants revealed that Omicron is currently the most distant lineage from Wuhan-Hu-1. Perhaps this is why Omicron and its subspecies continue to evade vaccine immunity. It therefore appears to be one of the most important aspects to consider when designing next-generation universal vaccines against his CoV, including SARS-CoV-2.

Another thing that antigen mapping can help decipher is the potential for cross-neutralization. The sequence and type of exposure (infection or vaccination) induces a characteristic antibody repertoire called the antibody landscape. This may change upon exposure to new antigenically related strains. The antibody landscape induced by individuals infected with new virus variants can affect OAS, immune imprinting and backboosting.

OAS in SARS-CoV-2 Immunity and its Impact on COVID-19 Outcomes and Vaccine Development

With OAS, neutralizing antibody (nAb) titers sufficient to cross-neutralize SARS-CoV-2 variants that have not yet emerged are achieved in the short term after vaccination or after boosting with the original S antigen. may occur. Furthermore, a homogenous boost of S-antigen-specific responses by repeated vaccination or reinfection with an ancestral strain could trigger immune imprinting that results in an OAS-like response upon exposure to new variants. Similarly, the relatively attenuated response of vaccinated individuals infected with the delta/alpha variant upon exposure to variant-specific epitopes could be due to OAS.

On the other hand, hybrid immunity acquired by vaccination and infection increases overall nAb titers neutralizing SARS-CoV-2 variants, including omicron, compared to vaccination. Therefore, mild breakthrough infections may provide sufficient immune protection against circulating and future SARS-CoV-2 variants. However, relying on this protection alone poses risks for high-risk populations such as immunocompromised individuals.

It is also worth noting here that most of the studies evaluating neutralization potential of SARS-CoV-2 variants in individuals with hybrid immunity were conducted early after infection. Processes such as the germinal center (GC) reaction, clonal expansion of plasmablasts, and antibody maturation are typically ongoing at this stage. Moreover, memory B cell responses during immune recovery may take at least 6 months or more. Therefore, longer follow-up is needed to determine the precise long-term impact of hybrid immunity on protection against SARS-CoV-2 variants.

Conclusion

Future vaccination strategies address the potential negative impact of OAS amid the continuing emergence of SARS-CoV-2 antigen-drift variants with potential for vaccination- and infection-induced immune evasion is needed. The messenger ribonucleic acid (mRNA) vaccine platform currently in use is very flexible. Therefore, it can be conveniently used to evaluate vaccine dose combinations to minimize immune imprinting effects and maximize efficacy against SARS-CoV-2 variants with complex antigenic signatures. sexuality increases.

But so far, many such aspects remain unexplored. For example, the potential of mRNA vaccine platforms to activate dendritic cells, which influences imprinted immunity, has not yet been compared. More importantly, studies have not evaluated how to better position homologous and heterologous COVID-19 vaccines in time to improve the quality of the immune responses elicited.

Understanding the potential interference effects of the SARS-CoV-2 vaccine on human CoV immunity is critical before using a vaccine that offers broad protection against all variants. Antigenic mapping may help design vaccines that cover all prevalent SARS-CoV-2 variants as adjuvanted antigens.