‘Original Antigenic Sin’ Mentioned in the New England Journal of Medicine

Suppose an individual is infected with a novel pathogen, and then sometime later is infected with a related version of the same pathogen. If ‘original antigenic sin’ is present, the individual’s immune system will respond to the antigens carried by the original version of the pathogen, resulting in weaker immunity.

The idea is that, for certain classes of pathogen, the immune system’s response to any particular exposure depends on an individual’s first exposure. If two versions of a pathogen, A and B, are circulating in a population, individuals who were first exposed to A may develop weaker immunity against B, and vice versa.

There is substantial evidence that original antigenic sin applies to influenza: those who gain immunity to one strain of influenza may develop weaker immunity to other strains.

It can also apply to vaccines. As a recent review notes, “if we only immunise to a single strain or epitope, and if that strain/epitope changes over time, then the immune system is unable to mount an accurate secondary response.”

At the end of last year, ‘mainstream’ commentators began discussing the possibility that original antigenic sin applies to the Covid vaccines. If it does, we may have vaccinated millions of young people against a version of Covid that poses little risk to them, at the cost of weakening their immunity to subsequent variants.

Now ‘original antigenic sin’ has been mentioned in the context of Covid vaccines in the pages of the New England Journal of Medicine – the world’s most ‘prestigious’ medical journal.

Noting that boosters are “not risk-free”, the American immunologist Paul Offit writes: “all age groups are at risk for the theoretical problem of an ‘original antigenic sin’ – a decreased ability to respond to a new immunogen because the immune system has locked onto the original immunogen.”

He cites a recent preprint by Matthew Gagne and colleagues, who carried out an experiment on nonhuman primates. They began by giving two groups of primates the Moderna vaccine. After 41 weeks, they gave each group a booster shot. One group received the Moderna vaccine again, while the other group received an Omicron-specific booster.

Finally, both groups were exposed to Covid. The researchers measured memory B cells and found that the Omicron-specific booster “provided no advantage” over the original Moderna vaccine. Indeed, they “did not observe a population of Omicron-only memory B cells before or after the boost that was clearly distinct from background staining”.

This means the Omicron-specific booster did not produce any detectable Omicron-only memory B cells at all, though it did trigger the production of more memory B cells specific to the original SARS-CoV-2 strain. It’s important to note, however, that both boosters did increase memory B cells (and neutralising antibodies) to some extent. (Neither was totally ineffective.)

As Gagne and colleagues note, the fact that memory B cells were no higher in the group that received the Omicron-specific booster “likely stems from the principle of original antigenic sin”. How serious this problem turns out to be will depend on several factors, not least subsequent viral evolution.

Offit writes in the NEJM that it “could limit our ability to respond to a new variant”.