What is original antigenic sin?
When one is exposed to a new pathogen, memory B cells respond and form antibodies to this pathogen. So when the same pathogen comes around again, the body is adequately ready and produces antibodies quickly to keep us safe. Great stuff.
However, not all pathogens remain the same.
Viruses, as we know, have a tendency to mutate. More specifically, viruses may undergo a process called ‘antigenic drift’, in which the proteins on their surface become altered enough to escape the immune system.
When we encounter this ‘virus 2.0’, the body, instead of forming fresh antibodies, may respond by reactivating previously formed antibodies to the first version of the virus. If this happens then problems occur, as these antibodies aren’t able to neutralise this pathogen and this process may also diminish the effectiveness of naive B cells capability of producing neutralising antibodies.
This process is called “original antigenic sin” (OAS), and was first used in the 1960s to describe how one’s first exposure to influenza virus shapes the outcome of subsequent exposures to antigenically related strains.
OAS is also known as antigenic imprinting or the Hoskins effect, and is of particular importance in the application of vaccines.
As one study concerning the influenza vaccines states, “In the present study, we studied the immune responses to the 2009 H1N1 vaccine in subjects who either received the seasonal influenza virus vaccination within the prior 3 months or did not. Following 2009 H1N1 vaccination, subjects previously given a seasonal influenza virus vaccination exhibited significantly lower antibody responses, as determined by hemagglutination inhibition assay, than subjects who had not received the seasonal influenza virus vaccination. This result is compatible with the phenomenon of “original antigenic sin,” by which previous influenza virus vaccination hampers induction of immunity against a new variant.”.
Other than influenza vaccines, a similar scenario has 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. It was found that individuals previously immunised 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 1960’s the first generation of vaccines against Respiratory Syncytial Virus (RSV) were produced, however when these vaccines were given to children who hadn’t encountered RSV, a large proportion of those who later became naturally infected with RSV developed enhanced respiratory disease, in some cases with a fatal outcome.
OAS has also been described for dengue, feline coronaviruses, suggested for HIV and for several other viruses too.
What about SARS-CoV-2?
Well we now know that OAS can be elicited naturally by previous common cold coronaviruses, and that this likely plays a role in severe COVID-19. But like anything, it gets slightly more complicated as OAS here may also depend on which region of the common cold coronavirus spike your body has dominant antibody responses to.
When it comes to the mRNA shots, one study noted that memory B cells in those who were never infected with SARS-CoV-2 were similar 5 months after inoculation to those that dominate the initial response. They also noted that individual memory antibodies selected over time by natural infection had greater potency and breadth than antibodies elicited by these shots. And so combining those together, it may mean that those who have received the shots and continue to get jabbed with boosters may be at higher risk of developing OAS.
Observations from UK Health Security Agency (UKHSA) surveillance data showed that N antibody levels appear to be lower in individuals who acquire infection following two doses of these mRNA agents. One reason for this has been hypothesised as being down to a stronger response to the spike than nucleocapsid protein, through OAS-like mechanisms.
In a way, you could see OAS as a form of trauma - certain vaccines may “scare” the immune system so badly during the first round that it responds to all similar pathogens the same way. Rooting in immunological memory, this becomes learned behaviour and “traps” the immune response into the first ineffective response it makes to the pathogen. A similar phenomenon has been described in cytotoxic T cells, and possibly why attempted vaccines for HIV have failed.
When the immune system is turned into a one trick pony against a rapidly mutating virus, bad things happen. Viral mutations are not only more likely to occur, but also less likely to be controlled by future vaccines, even if they are changed to tackle new variants. In fact, we might already be seeing this with evidence of certain Omicron subvariants being 4.2 times more resistant than variants in those who have had the jabs.
OAS is a problem rooted in immunological memory, and thus by toying with it one can also possibly prevent optimal naturally occuring immunity from occurring later down the line. That’s a life of repeated infections and subsequent bodily damage. A life of repeated illness.
So what may be the answer?
OAS is a phenomenon affecting the adaptive immune response (primarily B cells, but also cytotoxic T cells), and so those with a higher risk of OAS (but also everyone) may need to optimise first line defences including mucosal secretory antibodies and tissue resident memory T cells to prevent both infection and OAS.
The innate and mucosal immune system again. Funny how we always come back to the same thing.
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