What is science doing to redesign COVID-19 vaccines against new variants

All the evidence suggests that the newer variants of SARS-CoV-2 progress in their ability to bypass immunity produced by vaccination or previous infections, therefore scientists are starting to consider redesigning the vaccines that are distributed around the world.

The debate continues on the possible decrease in the effectiveness of this first generation of vaccines in the fight against COVID-19 due to the new variants. But some developers have published plans to update their injections to work on emerging variants as well. These strains carry mutations which appear to reduce the effect of antibodies essential to repel infection. It is also envisioned that COVID-19 vaccines will need to be updated regularly, as is the case with influenza.

For Mani Foroohar, a biotechnology analyst at the investment bank SVB Leerink in Boston, the best and most immediate way to combat the threat of emerging variants “will probably still be to quickly vaccinate as many people as possible with the current doses. .s. You have to prick a lot of arms to drown this virus before it explodes again in our face ”.

Will the vaccines need to be updated?

Virologist Kanta Subbarao, of the Peter Doherty Institute for Infection and Immunity in Melbourne, thinks that “everything is going in this direction”.

Laboratories around the world are vying to expose the threat emerging variants of the coronavirus pose to vaccines. But the first data from these studies appear patchy and incomplete. Among the more worrying variants is the one identified in late 2020 in South Africa, called 501Y.V2 (also known as variant B.1.351). In lab tests, he was found to carry mutations that attenuated the potency of the virus-inactivating “neutralizing antibodies” made by those who received the Pfizer or Moderna RNA vaccines.

“It is not clear that these changes are enough to decrease the effectiveness of these vaccines,” says Subbarao. That’s the million dollar question, because we don’t know how many antibodies are needed”. Vaccines elicit other immune responses that may help protect against the effects of the variants.

Last January, biotech company Novavax released clinical trial data showing that its investigational vaccine, designed to fight the original virus, was around 85% effective against the variant identified in the UK, but l efficiency has fallen to 50%. 501Y.V2. This drop worries researchers, as it indicates that 501Y.V2 and similar variants will result in a significant loss of vaccine efficacy.

Virologist Paul Bieniasz of Rockefeller University in New York, who co-led one of the antibody neutralization studies, believes that “The update seems inevitable to keep the effectiveness of vaccines in top form. The unknowns are how often and when ”.

How should you decide when to update them?

Scientists, healthcare professionals and vaccine manufacturers are starting to tackle the problem. We are beginning to see how the response of vaccines is altered according to the different mutations, and how these mutations are propagated thanks to evolutionary forces.. “Of course, I won’t update them now.”said Bieniasz.

Subbarao, from the head of the World Health Organization’s Collaborating Center for Influenza Reference and Research, Melbourne, suggests that the seasonal flu vaccine be the model for updates to the vaccine against influenza. COVID-19. In centers like yours, they monitor whether there are genetic changes in emerging strains of the influenza virus that could influence the effectiveness of vaccines. It is being studied with ferret and human antibodies to determine if the new strain manages to bypass the vaccine from the previous season and therefore needs an update. Subbarao comments that “these exams are done annually during the flu season of each hemisphere, and changes are only implemented when a strain that bypasses vaccine immunity has spread. If it is located in a region or a country, the composite will not be modified for the whole hemisphere ”.

Usually, the threshold magnitude for updating influenza vaccines is the same as for changes in the neutralizing antibody response that researchers have linked to the 501Y.V2 variant. But it is not yet clear how this drift, as well as the geographic distribution of the different variants and mutations, will warn when the COVID-19 vaccine will need to be updated. For Subbarao, “these debates are just beginning. We can’t go after every variation that comes up. “

How will the vaccines be updated?

This is another unknown. Some anti-ovoid vaccines, including those manufactured by Moderna, Pfizer, and AstraZeneca, carry instructions for cells to synthesize the virus spike protein, which is the key target of the immune system against them. Variants such as 501Y.V2 carry mutations in the tip that alter certain regions recognized by neutralizing antibodies.

One possibility is change vaccines containing old versions of the spicule (mainly based on the first virus identified in Wuhan) by an updated molecule that has specific amino acid changes that hamper the antibody response. But first, researchers will need to determine whether such changes alter or affect the response of the immune system to the vaccine. Another possibility would be to include in the same puncture the new and the old form of the spike protein, i.e. to convert it into a polyvalent vaccine.

In Moderna, they started work on updating their mRNA vaccine to contain the mutated spike as in 501Y.V2. In a conference with investors, Tal Zaks, chief scientist at the Cambridge, Massachusetts-based biotechnology company, said they were also testing the effectiveness of a third dose with the original coronavirus, and that ‘they were considering a versatile vaccine. But Subbarao says, “Before deciding on any of these options, they will need to study how animals, and possibly humans, respond to a possible vaccine update. It will not be enough to change the amino acid of a position and assume that it will be successful. “

How will vaccines be studied and licensed?

The developers have tested the vaccines so far in Phase III trials with tens of thousands of participants before regulatory agencies allow the drugs to be used for them. “But this kind of testing for a repackaged vaccine would be slow and difficult now that the first generation of vaccines are deployed around the world –says immunologist Drew Weissman, of the University of Pennsylvania in Philadelphia. I can’t imagine how a phase III trial would be done for a variant. “

It is not known how much clinical data will need to be provided to standardize an update. Although new seasonal influenza vaccines generally do not need further testing, health officials do not have decades of experience and clinical data for COVID-19 vaccines. According to Weissman, “since this is totally new, we will have to mount some clinical trials.”

The size and duration of these tests will depend on whether or not the researchers find indicators of protection: measurable characteristics of an immune response (for example, a specific concentration of neutralizing antibodies) that serve as markers of protection against the disease. COVID-19. With them, You wouldn’t have to wait until trial participants are infected with the coronavirus to know if the vaccines are working, as it would be enough to measure the immune response after each dose.

“We have no guarantee that a robust indicator will emerge,” says vaccine specialist Paul Offit of Children’s Hospital in Philadelphia, Pa. “But even without a clear marker, it would be possible to show that the new vaccine produces an amount of antibodies similar to those of the first generation.” From Moderna, they report that they hope clinical trials involving hundreds or even thousands of people, will help them continue their vaccine against the 501Y.V2 variant. Foroohar imagines it will take about five months for the company to move from producing the new vaccine to submitting its trial data to health authorities.

How will people who are already immune react to updated vaccines?

It is not yet clear how a person immunized with a first generation vaccine will react to a new vaccine against an emerging variant. Immunologists have long observed that people tend to develop a more robust immune response against the first variant of a pathogen than against subsequent ones. This phenomenon would indicate that the updated vaccines may elicit more suppressed immune responses than those of the first vaccine. Weissman fears that “the dose against a variant does not provide a new response against it, and that only the first response is improved”. But he also argues that “there is some evidence that RNA vaccines are not falling prey to this trend. For reasons that are not clear, some RNA vaccines elicit surprisingly complex responses that result in antibodies that act on regions of viral proteins that are often undetected in response to other classes of vaccines. And that could mean that RNA vaccines will also have a greater capacity to act on changes present in a variant ”.

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