‘Original Antigenic Sin’ Is a Real Problem with COVID-19 Vaccines

Introduction

There is a phenomenon in immunology known as “original antigenic sin” that studies have now confirmed to be a real problem with COVID‑19 vaccines.

In brief, what can happen is that an initial viral infection or vaccination can result in an individual’s immune system becoming fixated on generating responses to the original antigen even during subsequent infection with different strains characterized by different epitopes, or molecular structures capable of being recognized and responded to by the immune system. Thus, the immune response to a new strain can result in an inferior immune response in immunologically experienced people relative to the immune response induced by the new strain in immunologically naïve individuals.

Other terms that are sometimes used to describe this phenomenon include “viral interference”, “immune interference”, “antigenic fixation”, and “immune imprinting”.

Of course, the imprinting of an immune response to a virus is not in itself a bad thing. On the contrary, the induction of immunological “memory” to a virus is what provides long-term protection. It is only when a previously primed immune system fails to adequately adapt its responses to a newly infecting strain that the effect can be detrimental.

It is also not necessarily a question of whether original antigenic sin occurs or not; the more relevant question might be to what degree it occurs. For example, it has been observed with both natural immunity to influenza and with flu shots, but since infection induces a broader repertoire of immune responses than vaccination, natural immunity still represents an opportunity cost of vaccination.

In other words, priming the immune system by vaccination comes at the cost of the lost opportunity to prime the immune system by infection, resulting in a fixation of the immune response to subsequent infections with mutated strains that is suboptimal relative to superior natural immunity.

In fact, original antigenic sin has been hypothesized as a mechanism that could explain observations of an increased risk of illness due to the 2009 pandemic influenza A(H1N1) virus, also known as the “swine flu”, among individuals who received the seasonal flu shot.[1]

Policymakers eager to get jabs into arms perpetually fail to consider natural immunity as an opportunity cost of vaccination. I have long been warning that if original antigenic sin turns out to be a problem with COVID‑19 vaccines, the policy aim of achieving a high vaccination rate could result in a prolonging of the pandemic and worsening of mortality outcomes in the long run.[2]

For instance, three months before the first COVID‑19 vaccine received emergency use authorization from the US Food and Drug Administration (FDA), the UN published a written statement to the UN Human Rights Council that I authored on behalf of the non-governmental organization Planetary Association for Clean Energy, Inc. (PACE). Published on September 14, 2020, as General Assembly document A/HRC/45/NGO/43, the document included the following warning about the potential risks of forcing COVID‑19 vaccines on the population:

There are many legitimate concerns about vaccines in addition to their non-specific effects. Policymakers do not consider the opportunity costs of vaccination, such as the superiority of immunity acquired naturally compared to that conferred by vaccination.

For example, studies have found that having a flu shot annually could increase the risk of infection with novel influenza strains, as well as with non-influenza viruses, in part due to the lost opportunity to acquire the cross-protective, cell-mediated immunity conferred by infection.

A complementary hypothesis is the phenomenon of “original antigenic sin”, whereby the first experience of the immune system with an antigen determines future responses. Priming the immune system with antigen components of the influenza vaccine could potentially cause a mismatched antibody response to strains that the vaccine is not designed to protect against, thereby increasing the risk of infection as compared to an immune response in which naive T and B cells are instructed to fight off the infecting virus.

This phenomenon might help explain an increased risk of serious dengue infection among Filipino children who received the dengue vaccine and who had not already experienced a prior infection. This finding led the Philippines to the withdrawal of the vaccine, which the government had implemented into its childhood schedule upon the recommendation of WHO, despite earlier data having indicated that the vaccine might cause precisely that outcome.[3]

Unsurprisingly, the phenomenon of original antigenic sin has received scant attention in the mainstream media, which generally do policy advocacy rather than journalism when it comes to the topic of vaccines.

A rare early exception was an article in The Conversation on March 8, 2021, written by Matthew Woodruff, an instructor at the Lowance Center for Human Immunology at Emory University whose research is funded by the National Institutes of Health (NIH). The current COVID‑19 vaccines are designed to elicit an immune response to the spike protein of the original Wuhan strain of SARS‑CoV‑2 (the coronavirus that causes COVID‑19), which is no longer circulating. Woodruff anticipated that attempts to update the vaccines to generate antibodies specific to newer variants of SARS‑CoV‑2 might fail due to original antigenic sin.[4]

Woodruff’s cautionary remarks, like my own, have proven prescient.

Indeed, it has been demonstrated that a booster dose of an mRNA vaccine modified to express the spike protein of the Beta variant still results in generation of neutralizing antibodies more specific to the original Wuhan strain than to the Beta variant. As the authors of a study published in the journal Cell on January 24, 2022, pointed out, this suggests that “some degree of immune imprinting, or preferential responses to the viral variants initially encountered by the immune system, may affect the development of antibodies against new viral variants.”[5]

Similarly, a study comparing the antibody response in macaques from either the Moderna mRNA COVID‑19 vaccine or an updated vaccine designed to induce antibodies specific to the Omicron variant of SARS‑CoV‑2 found no protective advantage of the Omicron-matched vaccine compared to the vaccine designed to induce antibodies to the ancestral Wuhan strain, which is now extinct outside of laboratories.[6]

These findings help to explain why, despite the acknowledgment that the vaccines are much less effective against Omicron, and despite early promises from “public health” officials that the mRNA vaccines could be easily updated to match new variants, there remains no Omicron-specific vaccine.

Since very early into the mass vaccination campaign, there were indications in the scientific literature that original antigenic sin would turn out to be a major obstacle for policymakers intent on getting the population to accept COVID‑19 vaccines. Several recent studies have now confirmed that this is a real problem, with startling implications for the long-term protection of vaccinated individuals.