New research shows that the first SARS-CoV-2 spike protein a person encounters shapes their subsequent immune response against current and future variants.
This encounter could be by vaccination or infection.
The spike protein 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 is published in Science by a team from Imperial College London and Queen Mary University of London. It is funded by UK Research and Innovation.
Antibody levels wane over time
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.
Global exposure to variants
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.
Understanding immune responses
The new study looks at ‘immune imprinting’ in healthcare workers after two doses of Pfizer vaccine to understand their immune response to infection by variants of concern.
It involves 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.
Comparing antibody responses
In second wave infected people, three encounters with mixed spike proteins (with sequences following Alpha infection and two vaccine doses) resulted in lower protective (neutralising) antibody responses.
This was compared against the original strain and the Beta variant.
However, there were higher responses against Delta when compared to encounters with three of the same spike sequences (all with the original, first-wave sequence through infection and two vaccine doses).
Decaying differently over time
The study also showed that neutralising antibody responses against variants decay differentially over time after these mixed spike encounters.
There were a number of 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 neutralising antibody responses against Delta had fallen to zero five months after their second dose.
Booster vaccine uplifts antibody response
However, a third dose of the original spike from a booster vaccine uplifts the antibody response.
Professor Boyton says:
These findings highlight the importance of third dose booster vaccination to reduce viral transmission.
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:
- Delta variants.
Future proofing vaccine design and strategies
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.
Professor Fiona Watt, Executive Chair of the Medical Research Council, which co-funded the study, said:
This important research demonstrates the importance of considering the natural infection and vaccination history of a population when prioritising new vaccines.
It is particularly timely as the world confronts the emergence of a new variant of concern, Omicron.
Broadening the population’s immunity
Professor Danny Altmann from Imperial’s Department of Immunology and Inflammation said:
We’ve recently had some very large studies making the point that vaccine immunity wanes quite rapidly.
This leaves us vulnerable to Delta breakthroughs, and protection can generally be rescued by a third dose.
This study now offers considerable new detail about who is susceptible and when.
You can be someone who made a great response to the vaccine and still fall prey to Delta breakthrough if you haven’t had a booster.
The really surprising news was finding that people infected with the Alpha variant had such different patterns and waning of immunity to other variants.
Immune imprinting means we’re now all walking around programmed slightly differently for our future protection.
The challenge is how to broaden the population’s immunity in the right way as we need to ensure the widest coverage possible.
Currently, with the Omicron variant emerging, it’s vital that people get their booster vaccines.
But in the future, we should consider how we can create vaccines that broaden our immune response even more to protect against other new variants of concern.
Modelling the future is complicated
Professor Áine McKnight, Queen Mary University of London added:
Modelling the future course of the pandemic is becoming increasingly complicated.
Dr Catherine Reynolds, Imperial College London, said:
Our study highlights the importance of understanding the immune responses to the different SARS-CoV-2 variants in the context of existing vaccines, in order to make informed decisions about future vaccine design, strategy and timescales.
Dr Joseph Gibbons, Queen Mary University of London said:
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.
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
- UK Health Security Agency, Porton Down.
Read the research paper, published on 2 December in Science: ‘Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants’ by Reynolds, Gibbons and Pade et al.
Top image: Credit: solarseven, Getty Images