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

By Neha MathurReviewed by Danielle Ellis, B.Sc.Jan 13 2023

In a recent article published in The Journal of Clinical Investigation, researchers collated the findings of studies relating original antigenic sin (OAS) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution. 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 negative clinical impact of influenza virus infection. It exerts a varying degree of clinical impact(s) in the context of other viruses, such as SARS-CoV-2, human immunodeficiency virus (HIV), dengue virus, and some bacterial infections.

In general, immune memory recall is a positive process wherein reexposure to antigens (from pathogens or other sources) encountered earlier in life induces memory immune cells (B and T cells) faster and in a larger magnitude, increasing the protection from infection.

Though the memory B and T cells also initiate a response to neoepitopes, B and T cell clones that offer broad protection against previously encountered and related infections are selected on priority by natural selection processes, a phenomenon termed immune imprinting. Immune imprinting progressively narrows immune response toward a new antigen.

However, it also raises a possibility of turning OAS into a positive phenomenon termed back-boost, suggested for designing preemptive vaccines against future influenza strains. Thus, it should be possible to develop similar COVID-19 vaccines that exert positive effects on back boost. However, it would require a more intensive investigation into the effects of heterologous priming and boost by the current COVID-19 vaccines.

Antigenic evolution of SARS-CoV-2

New variants of SARS-CoV-2 have continuously evolved and replaced their predecessors, making them virtually extinct. For instance, new Omicron (sub)lineages, like BA.4 and BA.5, have established global dominance in populations preimmune to SARS-CoV-2 due to vaccination or prior infection with preceding strains. They carry an unexpectedly high mutation load, thanks to which they evade pre-existing immunity, and their origins are largely unknown. Detailed insights into the genetic changes that have caused these immune escape mutations in these viruses are crucial to understanding the changing efficacy of SARS-CoV-2 vaccines.

Studies have evidenced that the antigenic evolution of SARS-CoV-2 spike (S) resembles influenza HA, though both bind to different host cell receptors, angiotensin-converting enzyme 2 (ACE2) and glycans, respectively. Perhaps that distinguishes their speed of evolution and the rate at which emerging SARS-CoV-2 variants have incorporated them in their S proteins.

Nevertheless, the accumulation of mutations in S of these new Omicron (sub)variants points to antibody neutralization driving the antigenic evolution of SARS-CoV-2 S. Thus, an infection with an antigenic drift variant might preferentially induce non-neutralizing antibody clones, which could increase the risk of OAS.

Different levels of serum antibody cross-neutralization titers could help define antigenic drift variants, especially how farther apart they are "antigenically," visualized using antigenic maps. When combined with whole genome sequencing data, antigenic maps could yield information about the molecular determinants of antigenic change. Likewise, plaque reduction neutralization tests have successfully helped ascertain the antigenic relatedness of different coronavirus (CoV) variants.

Antigenic maps of SARS-CoV-2 variants have revealed that Omicron is currently the most distant lineage from Wuhan-Hu-1. Perhaps, this is why Omicron and its subvariants continue to escape vaccine-induced immunity. Thus, it appears to be one of the most important aspects to consider while designing next-generation universal vaccines against CoVs, including SARS-CoV-2.

Another thing that antigenic cartography helps decipher is cross-neutralization potential. The order and type of exposure (infection or vaccination) induce a hallmark antibody repertoire termed antibody landscape. It is susceptible to change with exposure to a new antigenically related strain. The antibody landscape evoked by an individual upon infection with a new variant virus potentially affects OAS, immune imprinting, and back-boost.

OAS in SARS-CoV-2 immunity and its effect on COVID-19 outcomes and vaccine development

Due to OAS, neutralizing antibody (nAb) titers adequate to cross-neutralize yet-to-emerge SARS-CoV-2 variants might be attained for a brief period, post-vaccination or boosting with original S antigens. Moreover, homologous boosting of S antigen-specific responses by recurrent vaccination or reinfections by ancestral strains might trigger their immune imprinting resulting in an OAS-like response upon exposure to new variants. Likewise, the relatively attenuated response of vaccinated individuals infected with the Delta/Alpha variants upon exposure to variant-specific epitopes might be due to OAS.

On the other hand, hybrid immunity acquired by vaccination and infection raises the overall nAb titers that neutralize SARS-CoV-2 variants, including Omicron, compared with vaccination. Thus, mild breakthrough infections might offer adequate immune protection against circulating and future SARS-CoV-2 variants. However, relying alone on this protection poses risks for high-risk populations, such as immunocompromised individuals.

Here it is also noteworthy that most of the research evaluating the SARS-CoV-2 variant's neutralization potential in individuals with hybrid immunity has been performed early after infection. The processes like germinal center (GC) reactions, plasmablasts clonal expansion, and antibody maturation are usually ongoing at this stage. Moreover, memory B cell response at immune convalescence potentially takes at least six months or longer. Thus, longer follow-ups are required to determine the exact effects of hybrid immunity on protection against SARS-CoV-2 variants in the long term.

Conclusions

Amid the continuous emergence of antigenic drift variants of SARS-CoV-2 with immune evasion potential elicited by vaccination and infection, future vaccination strategies must accommodate the potentially negative effects of OAS. The currently used messenger ribonucleic acid (mRNA) vaccine platform is highly flexible. Thus, raising the possibility of conveniently using it to evaluate combinations of vaccine doses to minimize immune imprinting effects and maximize effectiveness against SARS-CoV-2 variants with complex antigenic properties.

However, so far, many such aspects remain unexplored. For instance, the potential of mRNA vaccine platforms to activate dendritic cells, with implications for imprinted immunity, has not been compared yet. More importantly, studies have not evaluated how to better temporally space the homologous and heterologous COVID-19 vaccines to improve the quality of triggered immune response.

Understanding the effects of the potential interference of SARS-CoV-2 vaccines with human CoV immunity is crucial before using vaccines that offer broad protection against all variants. Antigenic cartography could help design vaccines that cover all circulating SARS-CoV-2 variants as antigens with adjuvants.