Is There an Act of Contrition for Original Antigenic Sin?

I suppose it is appropriate to begin with a confession; I was drawn to the study by the phrase “original antigenic sin.”  I stayed for the content, which taught me more about our immune responses. Antibody responses to antigens is a complex symphony of responses by B cells to different components of the antigens over various time frames. The critical science of the study, performed in mice, was how the scientists could tag antibodies to tease out which antigens were being responded to, at what point in the temporal sequence after infection, and how strong their effect was.

I will leave the explanations of those tags and their verification to others who have a far more profound understanding of immunology than I do. For our purposes, it is perhaps better to understand the impact of that initial exposure to an antigen, the original antigenic “sin,” especially in the context of vaccination for COVID.

OAS, as the scientists determined, suppresses the formation of antibodies against variations in the original antigen. The more similar the antigens are, the greater the suppression of new antibodies. To speak of it in terms of the COVID vaccine, the original series aimed against the “Wuhan” version of COVID didn’t create antibodies against new antigen components because the antigen in doses 1 and 2 was identical. Still, the combination of two doses spread a few weeks apart boosted antibody levels and the protection they afforded.

The suppressive effect wanes as we are exposed to antigens that increasingly vary from our initial exposure. In this study, the researchers used two strains of influenza that differed by about 10% in their amino acid sequences. [1] The strain for the second exposure contributed about 10% to the antibody response; the predominant response was from the antigen given originally. As a generalization, the OAS effect diminishes as strains become more divergent and more divergent antibodies are produced.  

“We conclude that increased antigenic distance between priming and boosting antigens …[enables] the generation of new, variant-specific antibody responses.”

The researchers also looked for OAS in exposure to the original “Wuhan” COVID strain and the Omicron strain. Depending upon what portions of the virus are targeted, the two strains share over 90% similarity; to the spike component, 98% similarity. The researchers found, in this instance, that exposure to the Omicron variant after infection by the “Wuhan” version resulted in no loss of response to Wuhan and a significantly increased response to Omicron. Despite their apparent structural similarities, our immune system saw them as divergent enough to create new antigenic targets. “Boosting” with a different antigen broadens our immunologic coverage.

The Act of Contrition

As it turns out, to continue the title’s analogy, the bivalent vaccine, now available, is an act of contrition for those who received the original vaccine series. As the FDA is now considering an annual "booster" similar to the yearly influenza vaccine, it might also be helpful to clear up the use of the term booster. All of the vaccines were used to provide some degree of protection. The original series of two was felt to be necessary to achieve a rapid immune response. For those with difficulty remembering those times, in January 2021, when the vaccines were first introduced, roughly 3,000 people were dying daily.

The boosters subsequently offered were identical in terms of the antigens. From the point of view of original antigenic sin, they indeed boosted or increased our immunologic response. But if you did not have the original series, it was not a booster; it was your first antigenic exposure. [2] Booster is a relative term referencing prior antigenic exposures. 

The bivalent booster contains antigens against both the “Wuhan” and Omicron strains. Calling it a booster is technically incorrect. It boosts your response to the original strain but also broadens your antigenic coverage to include Omicron. Hopefully, an annual COVID vaccination, like the influenza vaccination, will consider the variants out and about when they are produced, “boosting” our original protection and broadening it.  

[1] Because the sequence of amino acids will impact the folding of a protein, the 10% difference in amino acid sequence may have a greater or lesser impact on antigenicity.

[2] Unless you had acquired exposure the natural way by a COVID infection.

Source: Molecular fate-mapping of serum antibody responses to repeat immunization Nature DOI: /10.1038/s41586-023-05715-3