Original Antigenic Sin: the Downside of Immunological Memory and Implications for COVID-19

I enthusiastically recommend this paper to my physician colleagues (or anyone) who desire a more detailed and nuanced understanding of primary vs secondary immune responses and how those responses, particularly from B-cells, might enhance OR diminish the effectiveness of a vaccine.

The importance of antigenic distance and the concept of Original Antigen Sin is vital to unraveling the complexities of the COVID19 vaccines.

An understanding primary memory B-cells and how they interplay with GCR B-cells activated to a specific new epitope that is similar, yet antigenically distinct, to the original primary antigen is essential knowledge to understand modern vaccinology.
~ Forum for Healthcare Freedom

“…immunological memory that keeps us safe from reinfection with the same pathogen if neutralizing immunity is elicited following primary exposure or vaccination.

The problems with OAS (Original Antigen Sin) begin following exposure to a related strain of a pathogen that possesses a similar but not identical panel of antigens (

It is important to remember that OAS cannot occur without the Germinal Center Reaction: OAS exists because B cells surviving the GCR express B-Cell Receptors (BCR) of such high affinity that naive B cells with specificities to new antigens receiving activating signals via their BCR for the first time will stand little chance of competing successfully against seasoned memory B cells that activate at lower signaling thresholds following reexposure to their cognate antigen, independent of the fact that the memory and naive B cells in this scenario likely have BCRs with different specificities (
4, 19).

Therefore, if memory B cells respond to an infection with a related but antigenically distant pathogen, the memory response can not only be ineffective but possibly diminish the effectiveness of naive B cells capable of producing neutralizing antibodies (5). This potential downside of memory must be considered when attempting to design vaccines lest a vaccine formulation induce an immunological setback that precludes the elicitation of protective immunity or to understand the production of protective or nonprotective immunity to a new strain of a pathogen.

This scenario recently played out following the release of the human papillomavirus (HPV) vaccine Gardasil 9 that contains four antigens present in the original Gardasil vaccine plus an additional five new antigens. Individuals previously immunized with Gardasil who were later vaccinated with Gardasil 9 mounted poor responses to the five new antigens present in the Gardasil 9 vaccine compared to individuals vaccinated with Gardasil 9 who had no prior exposure to Gardasil (

In the context of vaccine design, the antigenic distance hypothesis was put forth to explain how differences in vaccine efficacy were impacted by the distance or relatedness of prior vaccine strains (22). That is, if the antigenic distance of respective vaccines is greater than that of circulating virus strains, efficacy is compromised (3, 22). A recent example occurred during the 2014–2015 influenza season when a new glycosylation site acquired by the circulating H3N2 strain was absent from the vaccine strains (3). Adults previously infected during childhood with influenza strains deficient in this glycosylation elicited strong responses against the vaccine strain but were poorly equipped immunologically to prevent infections with the glycosylated 2014–2015 H3N2 isolate (23,–25).


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s