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. Moreover, they showed the impact of this phenomenon on coronavirus disease 2019 (COVID-19) outcomes and vaccine design.

Study: Impact of antigenic evolution and original antigenic sin on SARS-CoV-2 immunity. Image Credit: Corona Borealis Studio/Shutterstock

Background

Thomas Francis first used the term OAS to explain the negative clinical impact of influenza virus infection. It exerts a various degree of clinical impact(s) within the context of other viruses, reminiscent of SARS-CoV-2, human immunodeficiency virus (HIV), dengue virus, and a few bacterial infections.

Normally, 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 bigger 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 supply broad protection against previously encountered and related infections are chosen on priority by natural selection processes, a phenomenon termed immune imprinting. Immune imprinting progressively narrows immune response toward a latest antigen.

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

Antigenic evolution of SARS-CoV-2

Latest variants of SARS-CoV-2 have constantly evolved and replaced their predecessors, making them virtually extinct. For example, latest Omicron (sub)lineages, like BA.4 and BA.5, have established global dominance in populations preimmune to SARS-CoV-2 resulting from vaccination or prior infection with preceding strains. They carry an unexpectedly high mutation load, because of which they evade pre-existing immunity, and their origins are largely unknown. Detailed insights into the genetic changes which 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 each bind to different host cell receptors, angiotensin-converting enzyme 2 (ACE2) and glycans, respectively. Perhaps that distinguishes their speed of evolution and the speed at which emerging SARS-CoV-2 variants have incorporated them of their S proteins.

Nevertheless, the buildup of mutations in S of those latest 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 danger of OAS.

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

Antigenic maps of SARS-CoV-2 variants have revealed that Omicron is currently probably the most distant lineage from Wuhan-Hu-1. Perhaps, this is the reason Omicron and its subvariants proceed to flee vaccine-induced immunity. Thus, it appears to be one of the crucial essential elements to contemplate while designing next-generation universal vaccines against CoVs, including SARS-CoV-2.

One other thing that antigenic cartography helps decipher is cross-neutralization potential. The order and kind of exposure (infection or vaccination) induce an indicator antibody repertoire termed antibody landscape. It’s liable to change with exposure to a latest antigenically related strain. The antibody landscape evoked by a person upon infection with a latest 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

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

Then again, hybrid immunity acquired by vaccination and infection raises the general 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. Nonetheless, relying alone on this protection poses risks for high-risk populations, reminiscent of immunocompromised individuals.

Here additionally it is noteworthy that almost all 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 frequently ongoing at this stage. Furthermore, memory B cell response at immune convalescence potentially takes at the very least six months or longer. Thus, longer follow-ups are required to find out the precise effects of hybrid immunity on protection against SARS-CoV-2 variants in the long run.

Conclusions

Amid the continual emergence of antigenic drift variants of SARS-CoV-2 with immune evasion potential elicited by vaccination and infection, future vaccination strategies must accommodate the possibly negative effects of OAS. The currently used messenger ribonucleic acid (mRNA) vaccine platform is very flexible. Thus, raising the potential for conveniently using it to judge mixtures of vaccine doses to reduce immune imprinting effects and maximize effectiveness against SARS-CoV-2 variants with complex antigenic properties.

Nonetheless, to date, many such elements remain unexplored. For example, the potential of mRNA vaccine platforms to activate dendritic cells, with implications for imprinted immunity, has not been compared yet. More importantly, studies haven’t evaluated the way to higher temporally space the homologous and heterologous COVID-19 vaccines to enhance the standard of triggered immune response.

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