Researchers reveal a strategy for next-generation COVID-19 vaccines

A study led by the Garvan Institute of Medical Research has revealed a guide to developing COVID-19 vaccines that both prevent the coronavirus from infecting human cells and that are more resistant to evolving viral strains.

The team’s key criteria for antibodies generated by future vaccines are to target regions of the SARS-CoV-2 viral surface that are unlikely to mutate and share key features that the researchers found could block the virus from infecting human cells.

Remarkably, the researchers found in experimental models that immunising with surface proteins from related viruses, such as SARS-CoV-1, the virus responsible for the original 2003 SARS epidemic, generated antibodies that met these criteria. The findings, published today in the journal Immunity, provide a new direction for vaccine development.

"Current COVID-19 vaccines, which target the SARS-CoV-2 spike protein, are highly effective at reducing disease severity and reducing transmission. Future variant strains, which will emerge due to the virus’s mass spread, may escape the current strategy," says co-senior author Professor Chris Goodnow, Executive Director of the Garvan Institute and Head of the Immunogenomics Laboratory.

"Research into next-generation vaccines with increased resistance to future variants is therefore warranted. Our work provides a guide for developing such future-proofed vaccines," says co-senior author Professor Daniel Christ, Director of the Centre of Targeted Therapy at Garvan.

Strategy to reduce future virus threat

Existing variants of coronavirus, such as the Delta strain, have already partially reduced the efficacy of antibodies generated by current vaccines to prevent COVID-19 infection, although they remain highly effective at preventing death and hospitalisations.

"Our research aimed to identify a vaccination strategy that would target a key site of vulnerability on the virus surface that is unlikely to change over time. This site is unchanged in different coronavirus strains, meaning that the virus may be less likely to mutate to escape from an antibody immune response targeting this site," says Dr Deborah Burnett, first author of the paper.

The team tested different immunisations in mice that had been specialised to produce human antibody responses. Specifically, the researchers aimed to generate antibodies that target the ‘class 4 epitope' region, which is conserved among coronaviruses (does not genetically vary between different strains) and may therefore be less likely to mutate in the future.

"Surprisingly, when we immunised with a protein from SARS-CoV-1, 80% of antibodies that were formed bound to the class 4 epitope. In contrast, when we used the SARS-CoV-2 protein, the mice generated antibodies that targeted regions of the coronavirus spike protein that are prone to mutations that allow the virus to easily escape," she adds.

"What this leads us to propose is that targeting SARS-CoV-2 may not be the most effective vaccination strategy moving forward, and that immunising against a related virus may produce an antibody response that has greater resistance against emerging strains."

A path towards a next-generation COVID-19 vaccine

The researchers next set out to identify antibodies that not only bind to the SARS-CoV-2 class 4 epitope but can also block its entry into human cells. They analysed thousands of individual antibody-producing B cells and pinpointed a rare subset of these ‘class 4’ antibodies that were able to neutralise the virus.

"When we analysed the 3D structure of these antibodies, they all had several features in common," explains co-senior author Professor Christ.

"They bound to the same section of the class 4 epitope and oriented the rest of the antibody to physically block access to the ACE2 binding site. ACE2 is the receptor on human cells that the virus needs to dock to before it can infect. We confirmed antibodies capable of blocking this interaction were able to neutralise the SARS-CoV-2 virus in laboratory assays, performed at the Kirby Institute, which traced the ability of the virus to enter human cells."

As part of this work, the researchers isolated a subset of antibodies effective at neutralising SARS-CoV-2, which they hope to advance to clinical trials as an antibody therapy.

"To progress our proposed vaccine approach, we are now aiming to test next-generation vaccines in our preclinical models, to determine if they can generate these antibodies, which can protect against different strains of the virus," says Professor Goodnow.

"We now know what to look for in an antibody response. Our goal for this research is to help develop a vaccine that that would need no updating and that could ultimately lead to better control of COVID-19."

Deborah L Burnett, Katherine JL Jackson, David B Langley, Anupria Aggrawal, Alberto Ospina Stella, Matt D Johansen, Harikrishnan Balachandran, Helen Lenthall, Romain Rouet, Gregory Walker, Bernadette M Saunders, Mandeep Singh, Hui Li, Jake Y Henry, Jennifer Jackson, Alastair G Stewart, Franka Witthauer, Matthew A Spence, Nicole G Hansbro, Colin Jackson, Peter Schofield, Claire Milthorpe, Marianne Martinello, Sebastian R Schulz, Edith Roth, Anthony Kelleher, Sean Emery, Warwick J Britton, William D Rawlinson, Rudolfo Karl, Simon Schäfer, Thomas H Winkler, Robert Brink, Rowena A Bull, Philip M Hansbro, Hans-Martin Jäck, Stuart Turville, Daniel Christ, Christopher C Goodnow.
Immunizations with diverse sarbecovirus receptor binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability.
Immunity, 2021. doi: 10.1016/j.immuni.2021.10.019

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