One of the greatest success stories of the pandemic has been the development of mRNA vaccines. However, 2 years into the pandemic, many people’s immune systems are no longer naive to the virus, which has led to questions about how vaccines could and should evolve in the future.

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What is ‘immune imprinting,’ and what does it mean for the future of COVID-19 vaccines? Image credit: Paul Yeung/Bloomberg via Getty Images.

When AstraZeneca, Pfizer, and Moderna started to recruit participants for their first COVID-19 vaccine trials in the spring and summer of 2020, they had to find people who did not think they had previously been infected with SARS-CoV-2, the virus that causes COVID-19.

Pharmaceutical companies took this measure for a number of reasons — for example, the world had little idea how much previous infection with SARS-CoV-2 might protect against future infections.

Without this information, it was difficult to evaluate how much of the protection discovered in the trial was due to the vaccine or to previous exposure to the virus. This presented some challenges.

In fact, in areas heavily impacted by the virus in the first wave, the requirement to recruit participants with no previous infection was met with some initial reactions of disbelief.

Community testing had not been in place for months in many places, some people would have had asymptomatic infections, and it is also likely people had COVID-19 before they understood it was circulating in their region.

And of course, no trial participants had, in the beginning, received any other form of COVID-19 vaccine as they did not yet exist.

Research has since shown that previous SARS-CoV-2 infection alongside vaccination offers the strongest protection against future infection, that mixing and matching vaccines works, and that immunity from COVID-19 wanes with time.

Our understanding of the virus has improved. We know how it spreads, how to protect against it, and how to treat the disease it causes. Yet, at the same time that this body of knowledge has grown, our actual bodies have changed in how they might respond to a SARS-CoV-2 infection.

While in November 2019, very few people in the world had been exposed to SARS-CoV-2, today, over 11 billion doses of COVID-19 vaccines have been administered, and about 500 million people are likely to have had COVID-19.

Of those individuals, some will have contracted the original Alpha variant of the virus, some Delta, some Omicron, and some may have had several infections with more than one variant.

Considering that, on top of that, many people will have been vaccinated with different types of vaccines and different combinations of vaccines, the ways in which our immune systems may have been exposed to SARS-CoV-2 markers are myriad.

While many of us will be able to stage an immune response to SARS-CoV-2 that we would not have been able to 2 years or even 1 year ago, the individual response may vary considerably between people, depending on the nature of previous exposure.

This phenomenon is known as immune imprinting, Prof. Danny Altmann, professor of immunology at Imperial College London explained to Medical News Today in an interview:

“All those things push and pull your immune repertoire, your antibodies and things in different directions, and make you respond differently to the next vaccine that comes along […] So that’s what’s called immune imprinting.”

Along with colleagues at Imperial College London and St Mary’s University, London, United Kingdom, he carried out a detailed, longitudinal study of a cohort of 731 healthcare professionals.

Their individual immune responses were measured after vaccination with the Pfizer vaccine, and stratified according to who had been previously infected with SARS-CoV-2 and those who had not, and which strain they were likely to have had depending on when they contracted the virus.

The results appeared in the journal Science in December 2021, and they outline how the exact spike protein an individual is exposed to during infection or vaccination affects that individual’s ability to stage an immune response to other spike proteins.

Since then, research by other teams has confirmed their findings.

“Some people want to be very exotic and sort of biblical about it, call it ‘original antigenic sin,’ you know, the idea that […] your immune system is born with some sin on board already, and you can’t go change it back to a blank sheet. So that’s not the kind of academic nuance, that’s a real thing and a big thing,” Prof. Altmann said.

So how are the pharmaceutical companies factoring these different responses into their vaccine trials?

First of all, Janssen (Johnson & Johnson), which held its first vaccine trials months after the other pharmaceutical companies, allowed people who had previous infection with SARS-CoV-2 into their trials, outlined in its results. Instead, they excluded people who had received other vaccinations.

Pfizer, Moderna, and AstraZeneca are holding current vaccine trials with their existing vaccines. A spokesperson for Pfizer told MNT:

“In our ongoing studies of COVID-19 vaccines we include both vaccinated and previously unvaccinated participants. Additionally, in our landmark phase 3 study we had seropositive and seronegative participants. So to summarize, people who have previous vaccination/ infection are included in our current trials.”

AstraZeneca responded similarly, with Fiona Cookson, director of global media relations telling MNT: “We do take into account previous infection in our studies as part of the stratification process.”

The use of original vaccines based on the original variant was still valid, said Prof. Monica Gandhi, professor of medicine at the University of California, San Francisco, and medical director of the UCSF Center for AIDS research.

This was because attempts to develop variant-specific vaccines showed that it was not possible to develop them quickly enough to be of use in each wave.

She told MNT: “This study [in Science] shows that the well-described phenomenon of a breakthrough infection enhancing vaccine responses is less effective if the infection involves a variant of concern since the variant has a different (heterologous) spike protein — with mutations that distinguish it from the ancestral state — than that encoded by the vaccine.”

“Clinically, this likely means that there is no reason to develop variant-specific boosters since they may not be more effective against a variant in the future and that we can likely stick with the original booster — with the Wuhan-Hu-1 sequence — for now,” she added.

While the original vaccines are still effective, the finding also raises questions about whether mRNA vaccines, which were designed to make the body launch an immune response to the original spike protein, would have been better designed to help the body stage a response against a different, less frequently mutating part of the viral RNA.

Originally, researchers had hoped that designing mRNA vaccines to help our bodies recognize the spike protein would mean variants would not matter, as they assumed that variants that featured mutations on the spike protein that were not recognized by existing antigens would be less virulent.

Since these vaccines were first designed we have learned more about the virus and why some of these assumptions were incorrect. For example, the virus mutates more rapidly than previously assumed.

Prof. Altmann suggested that researchers could use this knowledge to develop new vaccines in the future, which target the parts of the virus genome that do not mutate, or at least do not do it as rapidly:

“We’re intelligent people, we know the structure of the spike and which bits are conserved and which bits are different. So surely, you know where on the virus we can hone in on for a vaccine. That’s against the bits that it can’t mutate.”

We are already seeing mRNA vaccine technology harnessed to target other viruses, such as HIV, and even experimental vaccines against cancer.

The development of a next generation of mRNA vaccines that target non-mutating parts of the virus genome could help us tackle the COVID-19 pandemic and lay the path for innovative vaccines that take on board our growing understanding of genomics and our immune systems.