Some people are better at fighting off seasonal flu when the strain of influenza virus is similar to the first one they encountered in childhood — a phenomenon evocatively dubbed ‘original antigenic sin’, or OAS. Now, there is increasing evidence that people’s immune responses to COVID-19 could be shaped in a similar way by previous infections with common-cold coronaviruses.
The effect could have implications for the design of future COVID-19 vaccines. However, to what extent it affects people with COVID-19 — and whether it provides enhanced protection or, in fact, hampers the immune response — is still unclear. “The debate is quite polarized at the moment,” says Craig Thompson, a virologist at the University of Oxford, UK.
OAS — also called immune imprinting — was first characterized in 1960 by US epidemiologist Thomas Francis Jr, who noticed that the immune system seemed to be permanently programmed to produce antibodies against the first strain of a flu virus that it encountered1. Immune cells reactivate when the body is infected by a flu virus that shares regions, or ‘epitopes’, with that first strain.
For SARS-CoV-2, there is growing evidence that exposure to other coronaviruses — including those that cause colds and other respiratory illnesses — plays a part in people’s immune responses. “Much like flu, most of us are infected with these common coronaviruses by the age of five or six,” says Scott Hensley, a microbiologist at the University of Pennsylvania in Philadelphia. His group discovered that blood serum samples taken from people before the pandemic contained antibodies against a common-cold coronavirus called OC43 that could bind to the SARS-Cov-2 spike protein2.
Using samples taken before and after SARS-CoV-2 infection, Hensley and his colleagues were able to show that catching SARS-CoV-2 boosted the production of OC43-binding antibodies. Their study, published in April, found that these antibodies bound to the S2 subunit of the SARS-CoV-2 spike protein — which has a similar structure to that in OC43. But the OC43 antibodies did not bind to the S1 region of the SARS-CoV-2 spike and were unable to stop the virus entering cells.
Effects of imprinting
In some cases, imprinting is known to have a positive effect on immunity. Hensley and his colleagues studied the effects of imprinting during the 2009 H1N1 flu pandemic and found that exposure to some historical flu strains provided protection against H1N1 infection3. “There were some epitopes in that virus that were conserved with past seasonal influenza strains,” Hensley says. “The recall of antibody responses against those epitopes was actually beneficial.”
But OAS also has potential downsides. Sometimes, antibodies produced as a result of imprinting are not a very good match to the virus causing an infection, but their production suppresses the activation of naive B cells that would otherwise produce more-protective antibodies. “You get a response that may be skewed towards conserved antigens versus the new antigens,” says Adolfo García-Sastre, the director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai in New York City. This can diminish the immune system’s ability to fight the new infection.
García-Sastre looked at the early immune responses of people hospitalized with COVID-19 in Spain, and observed increased levels of antibodies against both OC43 and another betacoronavirus, called HKU1, that shared epitopes with SARS-CoV-24. “We looked for a correlation between people mounting higher [levels of] antibodies against these conserved epitopes versus having less protective immunity against SARS-COV-2, and there was a slight correlation,” says García-Sastre.
Signs of OAS negatively affecting people with COVID-19 were also seen by Thompson and his colleagues, in a preprint posted earlier this year5. The analysis was based on samples taken in 2020 from people in the United Kingdom who had asymptomatic infections, and from people who were admitted to hospital with severe COVID-19, half of whom subsequently died. The researchers found that people who died produced fewer antibodies against the SARS-CoV-2 spike protein than did people who survived, but produced the same amount of antibodies to another protein found in the virus — the nucleocapsid protein.
Thompson says these results indicate that imprinted memories of the spike protein from a different coronavirus could be preventing a more effective immune response in those who did not survive. “This is a fingerprint of OAS,” he says. But he adds that it is too early to conclude this definitively.
It is difficult to tell from such early results whether OAS is beneficial or detrimental to the immune response against SARS-CoV-2, and the results of preliminary studies are open to interpretation. Hensley warns that just measuring antibody levels does not provide a full picture of a complex immune response. He also thinks the presence of OC43 antibodies in people with COVID-19 could indicate that a recent OC43 infection is helping the immune system to fight the virus. In August, a study of samples from health-care workers showed that individuals with higher OC43 antibody levels, indicating recent OC43 exposure, recovered from a SARS-CoV-2 infection faster6 than those with lower levels. Other research has shown similar protective effects.
In a study published in December 2020, George Kassiotis, an immunologist at the Francis Crick Institute in London, also found that pre-existing OC43 antibodies showed reactivity to SARS-Cov-27. At the time, he wasn’t sure of the implications, but after reviewing studies published since, he says, “most of the evidence points to a positive overall contribution, not a negative one”.
García-Sastre suggests that even if they are not able to stop SARS-CoV-2 entering cells, OC43 antibodies might trigger the immune system to kill infected cells.
A key question is whether these observations can help to inform future COVID-19 vaccination strategies. For now, vaccines based on the original version of the coronavirus — first reported in Wuhan, China, in late 2019 — protect against all known variants, says Kassiotis.
Imprinting sometimes reduces the effectiveness of flu vaccines, according to Sarah Cobey, an evolutionary biologist and flu researcher at the University of Chicago in Illinois. The flu vaccine is updated each year to protect against those strains that researchers think are the most likely to be prevalent. Some people’s immune systems are still not seeing the update, says Cobey, and still target parts of the virus that are familiar to them. “It looks like they’re not really mounting a response to the thing that we carefully updated the vaccine for.” It is possible that future COVID-19 vaccines tailored to new variants could experience similar problems.
Hensley does not think this is likely, however. In a study published as a preprint last month, he and his colleagues reported that people do not produce as many OC43 antibodies after receiving a messenger RNA vaccine as they do when infected with SARS-CoV-2 itself8. This could be because the mRNA vaccines establish such an efficient immune response that they can bypass any immune-imprinting effect. “Maybe in the context of mRNA vaccines there’s not really going to be as much of a biasing towards conserved epitopes. That’s the hope,” says Hensley.
Thompson says that the problem could also be circumvented in updated COVID-19 vaccines by removing the shared epitopes: “You could easily just chop the S2 domain off … or make a vaccine just targeting the receptor binding domain of the most recent circulating strain,” he says. “But this is really hypothetical.”
“There likely is a very complicated interplay between seasonal coronavirus infection and disease outcome upon SARS-CoV-2 infection,” says Hensley. “I don’t think anything should be pitched as complete fact at this point.”
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