Friday, December 03, 2021

Science: Heterologous Infection and Vaccination Shapes Immunity Against SARS-CoV-2 Variants


Credit NIAID


We've a new study, published yesterday by researchers from Imperial College London and Queen Mary University of London, that looks at the long-term immune impacts of a person's 1st exposure (via infection of vaccination) to SARS-CoV-2. 

This is admittedly a lengthy, and quite technical, report.  Luckily, we have a press release summarizing their results, and have previously seen similar impacts described with influenza subtypes, which should make it easier to digest.

First a a link to the study, and the Abstract, after which we'll begin to break it down.

Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants

SCIENCE • 2 Dec 2021 • First Release • DOI: 10.1126/science.abm0811


The impact of initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infecting strain on downstream immunity to heterologous variants of concern (VOC) is unknown. Studying a longitudinal healthcare worker cohort, we found that after three antigen exposures (infection+two vaccine doses), S1 antibody, memory B cells and heterologous neutralization of B.1.351, P.1 and B.1.617.2 plateaued, while B.1.1.7 neutralization and spike T cell responses increased. Serology using Wuhan Hu-1 spike receptor binding domain poorly predicted neutralizing immunity against VOCs. Neutralization potency against VOCs changed with heterologous virus encounter and number of antigen exposures. Neutralization potency fell differentially depending on targeted VOCs over 5-months from the second vaccine dose. Heterologous combinations of spike encountered during infection and vaccination shape subsequent cross-protection against VOC, with implications for future-proof next-generation vaccines.

          (Continue . . . )

Five years ago, in Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting, we looked at research which suggested the influenza HA Group type (1 or 2) you are first exposed to makes a significant, and lasting, impression on your immune system. 

The process behind this is called OAS -  or Original Antigenic Sin - a term coined in 1960 by Thomas Francis, Jr. in his article On the Doctrine of Original Antigenic Sin that postulates that when the body’s immune system is exposed to and develops an immunological memory to one virus, it may be less able to mount a defense against a subsequent exposure to a second slightly different version of the virus.

With influenza, if your first flu exposure was prior to 1968 (H1N1 or H2N2), your immune system `remembers' Group 1 influenza viruses better than Group 2 viruses which you may have been subsequently exposed to.  

Those born between 1968 and 1977 - when H3N2 (Group 2) first emerged - are likely better protected against Group 2 viruses.  Those born after 1977 could have been first exposed to either H3N2 or H1N1. 

This has practical applications, since theoretically those who were first exposed to a Group 1 flu virus would fare better during an H5 avian flu pandemic, while those first exposed to a Group 2 flu virus would have an advantage during an H7 avian flu pandemic.  

We've revisited this topic a number of times in recent years, including:

Nature Comms: Middle-Aged Individuals May Be in a Perpetual State of H3N2 Flu Virus Susceptibility

PLoS Path.: Childhood Immune Imprinting to Influenza A

Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression

While the mechanics of OAS remain poorly understood, we've seen examples with other viruses, perhaps most famously with Dengue, which has multiple serotypes. 

Most people's first exposure to Dengue is mild, but a second exposure (to a different serotype) often is more serious or even fatal (i.e. Hemorrhagic Dengue). Instead of recognizing the new serotype and creating fresh antibodies, the body's immune system often dispatches ineffective antibodies based on the first infection. 

With these facts in mind, the question then becomes "Does the COVID variant you are first exposed to determine your immune system's response to future variants?"  And if so, how should that affect future vaccine formulations?

According to today's study, and press release, the authors believe it does. 

‘Immune imprinting’ by different SARS-CoV-2 spike sequences from variants and vaccines means we now have diverse patterns of protection against new variants

Peer-Reviewed Publication


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. 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 is published today in Science by a team from Imperial College London and Queen Mary University of London. It is funded by UKRI.

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.”

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 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 different spike proteins (ie, 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 (ie, 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 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 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.

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.”

Professor Áine McKnight, from Queen Mary University of London, added: “Modelling the future course of the pandemic is becoming increasingly complicated.”

Dr Catherine Reynolds, from 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, from 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 and UK Health Security Agency, Porton Down.


‘Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants’ by Reynolds, Gibbons and Pade et al published today in Science:

Assuming these findings are correct, COVID may be a much tougher nut to crack than we first hoped. 

Stay tuned.