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Immune imprinting causes varied patterns of protection against COVID-19 variants

New research shows that the first SARS-CoV-2 spike protein a person encounters, be it by vaccination or infection, shapes their subsequent immune response against current and future variants.

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SARS-CoV-2 virus particle surrounded by antibodies. Credit: koto_feja/
SARS-CoV-2 virus particle surrounded by antibodies. Credit: koto_feja/

That is, it imparts different properties that have an impact on the immune system’s ability to protect against variants, and also affects the rate of decay of protection.

The study, published in Science, was led by a team from Imperial College London and Queen Mary University of London and is funded by UKRI.

Understanding protective responses

It is known that antibody levels wane over time following infection or vaccination, but the new research shows that an individual’s protective immune responses are also affected by which strain or combination of strains they have been exposed to.

At 23 months into the pandemic, people across the world have very different patterns of immunity to the SARS-CoV-2 virus, based on their exposure. Globally, people have been exposed to the original strain and/or Alpha, Beta, Gamma, Delta variants and now Omicron. In addition, people may be unvaccinated or have had one to three vaccine doses (which are programmed using the spike of the original strain).

Each SARS-CoV-2 variant has different mutations in the spike protein, and the researchers found that these shape the subsequent antibody and T cell responses (the immune repertoire).

Professor Rosemary Boyton, from Imperial’s Department of Infectious Disease, says: “Our first encounter with spike antigen either through infection or vaccination shapes our subsequent pattern of immunity through immune imprinting. Exposure to different spike proteins can result in reduced or enhanced responses to variants further down the line. This has important implications for future-proofing vaccine design and dosing strategies.”

Immune imprinting

The new study looks at ‘immune imprinting’ in healthcare workers after 2 doses of Pfizer vaccine to understand their immune response to infection by variants of concern. It involves a detailed, longitudinal follow-up of the ‘Barts COVIDsortium’ healthcare worker cohort of 731 individuals, who have been followed since March 2020.

The researchers compared protective immunity between people infected in the first wave with the original strain, or in the second wave with the Alpha variant.

In second wave infected people, three encounters with mixed spike proteins (i.e. with sequences following Alpha infection and two vaccine doses) resulted in lower protective (neutralizing) antibody responses against the original strain and the Beta variant, yet higher responses against Delta when compared to encounters with three of the same spike sequences (i.e. all with the original, first-wave sequence through infection and two vaccine doses). 

The study also showed that neutralising antibody responses against variants decay differentially over time after these mixed spike encounters.

There were several cases of Delta breakthrough infection in two dose vaccinated individuals in the study. Levels of spike antibodies measured three weeks after the second vaccine dose were high, yet the actual levels of protective neutralizing antibody responses against Delta had fallen to zero five months after their second dose.  

However, a third dose of the original spike from a booster vaccine uplifts the antibody response.

“These findings highlight the importance of third dose booster vaccination to reduce viral transmission,” says Professor Boyton.

The researchers stress that, despite breakthrough infections being seen, immune responses to vaccination are still effective in preventing severe disease and death from COVID-19 in the face of Alpha, Beta, Gamma and Delta variants.


Based on their findings, the researchers say that vaccine design and dosing strategies need to be future-proofed to take maximum advantage of immune imprinting. This will involve enhancing the breadth of protection rather than tweaking the vaccines with the latest variant spike sequences.

“Modelling the future course of the pandemic is becoming increasingly complicated,” explained Professor Áine McKnight, Professor of Viral Pathology at Queen Mary.

Dr Joseph Gibbons from Queen Mary added: “The emergence of new variants with the potential to evade immunity has shown that we must future-proof the next generation of vaccines. We studied immunity over time in people infected with different variants and found that vaccine responses are highly variable depending on the infecting strain. These findings can be used to ensure vaccine design is optimal. This work highlights the importance of continually monitoring the effectiveness of vaccines against new variants such as Omicron.”  

More information

  • The COVIDsortium is a collaborative partnership between researchers at Imperial College London, Queen Mary University of London, Bart’s and the London School of Medicine and Dentistry, University College London, Barts NHS Trust, Royal Free London NHS Trust and UK Health Security Agency, Porton Down.
  • Research publication: ‘Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants’ by Reynolds, Gibbons and Pade et al published today in Science:
  • This story was adapted from the press release published by Imperial College London


For media information, contact:

Sophie McLachlan
Faculty Communications Manager (Science and Engineering)
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