Evidence of Covid-related Original Antigenic Sin Has Finally Surfaced


Prior immunity — especially from natural infection — may backfire instead when it comes to Omicron.

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In the late 1900s, scientists discovered that antibodies generated against a particular influenza virus strain were deployed again even when the person got infected with a different influenza virus strain.

Not only are such old antibodies ineffective, but they sometimes hinder the formation of newer, more effective antibodies. In essence, the immune system insists on doing what it has learned initially, despite that the same trick may not work twice.

This phenomenon is called the original antigenic sin or immune imprinting.

As the Covid-19 virus, SARS-CoV-2 mutates from the original 2019 Wuhan variant to multiple variants — such as Alpha, Beta, Gamma, Delta, and Omicron — scientists have consistently voiced concerns of possible original antigenic sin occurring since early last year.

Now, evidence of Covid-related original antigenic sin has surfaced, which may also explain how Omicron has become so successful at dominating all the other Covid variants we thought would dominate indefinitely.

What recent studies show

The paper, “Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure,” was recently published in Science. Herein, Reynolds et al. from Imperial College London analyzed the immune responses of healthcare workers (n=731) who were vaccinated and either infected by one of the SARS-CoV-2 variants or never infected.

And here are their results:

  • Among triple vaccinated individuals, those with prior Wuhan or Delta variant infection had a greater reduction in antibody and T-cell responses against Omicron compared to never-infected individuals.
  • Among triple vaccinated individuals who got infected with Omicron, those never-infected before mounted greater antibody and T-cell responses than those with prior Wuhan variant infection.

So, previous Covid actually hampered the immune defenses against the next Covid from a different variant among triple vaccinated individuals.

Reynolds et al. also studied immune responses longitudinally, showing that:

  • Among single-vaccinated individuals, those with prior infection made greater antibody responses against Omicron than those never infected — indicative of hybrid immunity.
  • But among double-vaccinated individuals, those with and without prior infection made similar antibody responses against Omicron — suggesting that the hybrid immunity got nullified. The same trend was noted among triple-vaccinated individuals, where those with and without prior infection made similar antibody responses against Omicron.
  • But 14 weeks later, during the Omicron wave, triple-vaccinated individuals with prior Wuhan variant infection made weaker antibody responses against Omicron than triple-vaccinated, never-infected individuals who just got Omicron.

The last point here is important, which the authors wrote, “indicates that prior [Wuhan variant] infected individuals were immune imprinted to not boost antibody binding responses against [Omicron] despite having been infected by [Omicron] itself.”

In other words, Wuhan + triple vaccination + Omicron showed weaker antibody responses than triple vaccination + Omicron.

Prior infection with the Wuhan variant, thus, hampered immune reaction against Omicron due to immune imprinting or original antigenic sin.

(The same trend was noted in triple-vaccinated individuals with prior Alpha variant infection, but the anti-Omicron antibody responses were not as weak as those with prior Wuhan variant infection.)


Moving on, in another related study, “Imprinted antibody responses against SARS-CoV-2 Omicron sublineages,” Park et al. from the University of Washington analyzed the efficacy of antibodies isolated from different groups of individuals.

Park et al. found that over 80% of antibodies of Omicron breakthrough cases (i.e., vaccinated + Omicron infection) reacted with older variants of SARS-CoV-2. But unvaccinated, never-infected individuals who just caught Omicron had more Omicron-specific antibodies.

This finding can easily be misused to say vaccination increases susceptibility to Omicron infection. But previous studies have already shown that current Covid-19 vaccines do protect against Omicron-related infection and disease.

One possible reason for this discordance is that even though vaccinated individuals generate antibodies that are not Omicron-specific, there are still deployed faster than unvaccinated individuals with no immunity.

“These findings illustrate how immunological imprinting from prior exposure, i.e., ‘original antigenic sin’, can strongly affect the response to antigenically novel antigens,” Park et al. wrote. “Collectively, these findings demonstrate that infection with Omicron preferentially expanded existing B cell pools primed by vaccination and elicited cross-reactive plasma cells and antibodies, supporting the concept of immunological imprinting.”

What these studies indicate

Most of us already have some level of immunity against Covid, vaccinated or not. SARS-CoV-2 is so globally ubiquitous that even unvaccinated individuals who never got sick are likely exposed to Covid at some point in their lives.

The weakened anti-Omicron immunity among us may help explain Omicron’s success at becoming the most dominant variant ever, displacing previous dominating variants like Alpha and Delta. Even now, Omicron sublineages BA.4 and BA.5 are displacing the previous Omicron variants.

And not to mention that Omicron is inherently more immune-evasive than most other variants. The added disadvantage of original antigenic sin or immune imprinting would further make Omicron thrive.

“The high global prevalence of [Omicron] infections and reinfections likely reflects considerable subversion of immune recognition at both the [B cell], T cell, antibody binding and [neutralizing antibody] level, although with considerable differential modulation through immune imprinting,” Reynolds et al. stated. “Some imprinted combinations, such as infection during the Wuhan Hu-1 and Omicron waves, confer particularly impaired responses.”

But the study of Reynolds et al. and Park et al. are confined within the limitations of laboratory settings, which may or may not translate to real-world scenarios. Even so, more often than not, antibody responses studied in laboratories do reflect the effectiveness of immunity in the real world.

As Deepti Gurdasani, Ph.D., a clinical epidemiologist at the Queen Mary University of London, said in response to Reynolds et al.’s paper:

“We do need to understand this better. These are laboratory studies, so we need to see how this affects protection from infection & severe disease among those with different past infection profiles. [Still], Neutralising antibodies have shown strong correlation with clinical protection.”

“And also important to reflect on the narrative that ‘hybrid immunity’ is always better, and infection is a ‘good booster’ to vaccination,” Dr. Gurdasani continued. “Not only does infection come with serious risk of long COVID & severe illness (despite boosting), it may impair response to future variants.”

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MSc Biology student | 7x first-author academic papers | 200+ articles on coronavirus | Freelance medical writer


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