How to redesign COVID-19 vaccine that can resist new variants?

How to redesign COVID-19 vaccine that can resist new variants?  With the development of vaccines and global promotion, the COVID-19 epidemic seems to be contained, but more and more evidence shows that new variants of the new coronavirus (SARS-CoV-2) can escape vaccines or previous infections Immunity. In response to this problem, scientists are exploring redesigning vaccines to protect against the mutated new coronavirus.

Whether the new virus variants will weaken the effectiveness of the first-generation COVID-19 vaccine is still controversial, but some vaccine developers are advancing plans to update the vaccine, hoping to better deal with the emerging variants, such as those found in South Africa and Brazil Mutant virus strains. These genetic mutations seem to inhibit the effects of antibodies, which are essential in preventing viral infections. Researchers are also considering another possibility, which is to regularly update the vaccine against the new coronavirus, just like the flu vaccine.

People are waiting for the COVID-19 virus vaccine in a hospital in Glasgow, UK People are waiting for the COVID-19 virus vaccine in a hospital in Glasgow, UK.

Mani Frouhal, an analyst at SVB Leerink Investment Bank in Boston, Massachusetts, said that the best and most direct way to deal with the new variants of the new coronavirus is to vaccinate as many people as possible as soon as possible. He said: “We need Vaccination on the arm will smother the virus before it touches our face.”

However, many people, including Foruhar, believe that there will be a bunch of new vaccines in the future to deal with the variants of the new coronavirus. Recently, “Nature” (Nature) magazine has discussed some open issues in redesigning the new coronavirus vaccine.

Do we need to update the COVID-19 vaccine?

Kanta Subbarao, a virologist at the Peter Doherty Institute of Infection and Immunity in Melbourne, Australia, said: “I think the situation has started to move in this direction.”

Laboratories around the world are working hard to study the threat of new coronavirus variants to vaccines, but the early results from these studies are mixed and incomplete. A variant named 501Y.V2 (also known as B.1.351) was discovered in South Africa at the end of 2020 and is one of the most worrying variants. Laboratory tests have found that the mutations carried by this variant will weaken the effectiveness of “neutralizing antibodies”, and these antibodies are produced after receiving Pfizer or Moderna mRNA vaccination and can inhibit the virus.

Canta Subbarao said whether these changes are sufficient to reduce the effectiveness of these vaccines is unclear. She said: “This is an important question because we don’t know how many antibodies you need.” Other immune responses caused by the vaccine may help protect the body from the new coronavirus variants.

There have been several mutations in the new coronavirus, and these mutations are changing its behavior The new coronavirus has appeared in several mutations, and these mutations are changing its behavior.

However, on January 28, the biotechnology company Novavax released clinical trial data, showing that its experimental vaccine designed to fight the original virus is about 85% effective against a virus variant found in the UK, and against 501Y. The effectiveness of the variant is less than 50%. The researchers said that this result is worrying because it shows that 501Y.V2 and other similar variants can cause a significant decrease in vaccine efficacy.

Paul Viñas, a virologist at Rockefeller University in New York and one of the leaders of one of the neutralizing antibody studies, said: “I think if vaccines are to maintain their best effectiveness, they will need to be updated. . The only question is how often to update and when to update.”

How should we decide when to update the vaccine?

Scientists, health officials and vaccine manufacturers have already begun to discuss this issue. Researchers are just beginning to understand how different mutations change vaccine responses, and how evolutionary forces cause mutations to spread. Viñas said: “I will definitely not update them now.”

Subalao is also the director of the World Health Organization’s Influenza Reference and Research Cooperation Center. She pointed out that the update of the new coronavirus vaccine can follow the pattern of seasonal influenza vaccine. Many research institutions, including her research center, are monitoring emerging influenza strains, looking for genetic changes that may affect vaccine effectiveness.

Researchers use ferrets and human antibodies to determine whether new influenza strains are likely to escape the previous season’s vaccine, and then evaluate the need for its renewal. Subalao said that for each hemisphere flu season, such an assessment will be carried out every year, but only when the vaccine-evading virus is spreading widely, “If it is confined to one region and one country, we It will not replace the vaccine for the entire hemisphere.”

Generally speaking, the threshold for updating the flu vaccine is similar in magnitude to the threshold for researchers to associate the 501Y.V2 variant with the neutralizing antibody response. But it is not yet clear how these changes-and the geographical distribution of different variants and mutations-will affect the update of the COVID-19 vaccine. “These discussions have just begun,” Subalao said. “It is impossible for us to track every variant that appears.”

How will the vaccine be updated?

This is another open question. Some new coronavirus vaccines, including mainstream vaccines produced by Moderna, Pfizer, and AstraZeneca, instruct cells to produce the virus’s spike protein, which is the main surface protein that the new coronavirus binds to the receptor and is a key target of the immune system. The mutations carried by variants including 501Y.V2 change the target area of ​​the neutralizing antibody.

One possible update method is to replace the original spike protein of the vaccine with a new molecule that has specific amino acid changes that hinder the antibody response. However, researchers first need to determine whether these changes will have a knock-on effect, changing the way the immune system responds to the vaccine. Another possibility is to include both the new form and the old form of spike protein in a single injection, which scientists call a multivalent vaccine.

Moderna has begun to update its mRNA vaccine to match the spike protein mutation of the 501Y.V2 variant. Moderna’s Chief Scientific Officer, Tal Zak, said in a conference call with investors on January 25 that the company also intends to test the original new coronavirus vaccine to determine the effectiveness of the third dose. The possibility of developing a multivalent vaccine is being studied. Subalao said that before deciding on any method, scientists need to conduct animal tests and possibly human tests to understand the impact of any potential vaccine updates. She said, “It’s not as simple as (changing) a certain amino acid position and saying, ‘okay, we found it’.”

How will the vaccine be tested and approved?

Before regulatory approval for use, vaccine developers have tested the currently available COVID-19 vaccine in phase three clinical trials, involving tens of thousands of participants. However, since the first-generation vaccines have been popularized all over the world, such testing of improved vaccines will be very slow and difficult. Drew Weisman, an immunologist at the University of Pennsylvania in Philadelphia, said: “I can’t imagine how they would conduct a three-phase trial on a variant.”

It is not clear how much clinical data is needed to approve the new coronavirus vaccine update. New seasonal flu vaccines usually do not require new tests, but for the COVID-19 vaccine, regulatory agencies have not accumulated decades of experience and clinical data like flu vaccines. “They might say, ‘this is a brand new vaccine, let’s do a few clinical trials,’” Weisman said.

The scale and duration of these trials may depend on whether researchers can find “correlates of protection”, that is, immunological indicators related to the clinical endpoint of the study, such as specific neutralizing antibody levels, which can be used for COVID-19 . The protective efficacy of the vaccine provides a marker. With these markers, researchers can simply measure the immune response after each injection, without waiting for test participants to be infected with the new coronavirus to know whether the vaccine is effective.

Paul Offett, a vaccine researcher at the Children’s Hospital in Philadelphia, Pennsylvania, said there is no guarantee that there will be a clear correlation between the two. But even if there is no clear correlation, researchers can still prove that the new vaccine produces antibody levels similar to the first-generation vaccine. Moderna has stated that they hope to rely on clinical trials involving hundreds of people instead of thousands of people to promote the development of vaccines that can resist the 501Y.V2 variant. Forujal predicts that it will take about 5 months for the company from the production of a new vaccine to the submission of test data to regulatory agencies.

How will people who have been vaccinated respond to the newer vaccine?

Researchers do not yet know how people who have been vaccinated with the first-generation new coronavirus vaccine will react to the new vaccine against the new variant. Immunologists have long observed that people tend to have a stronger immune response to the first variant of a pathogen than subsequent variants. This phenomenon may mean that, compared with the first vaccine, the newer vaccine may trigger a weaker immune response. “Our concern is that vaccinating a person infected with a variant of the virus may not have a new response to the variant,” Weisman said, “but only stimulate the old response.”

But Weisman pointed out that there is evidence that RNA vaccines may not be affected by this tendency. For some unclear reasons, some RNA vaccines can trigger a surprisingly complex immune response, producing antibodies against certain viral protein regions that are usually not detected by other types of vaccines. Weisman said this may mean that RNA vaccines can better deal with the mutations carried by the variant.

Paul Offett also pointed out that an immune response to the variant may not be necessary. He pointed out that even if a newer vaccine mainly enhances the response to an earlier new coronavirus vaccine, it may be sufficient to resist the variant. Some researchers hope that the regularly updated COVID-19 vaccine can become a way of life like the flu vaccine.

What are vaccine manufacturers doing?

Like Moderna, other manufacturers of new coronavirus vaccines have also stated that they are studying how to update the vaccine. Among them is Johnson & Johnson in New Brunswick, New Jersey, which is developing a single-dose vaccine for the new coronavirus.

Some aspiring vaccine manufacturers have noticed the possible threat of virus variants from the beginning. Andrew Allen, president of American Gritstone Oncology Company (located in Emeryville, California), said that a team of the company tried to solve this potential problem by designing a vaccine that targets multiple sites of several viral proteins. The first-generation vaccines only target spike proteins. The vaccine will begin clinical trials soon, and the developers hope it will increase the difficulty for the virus to evade immunity-the virus needs to change many genes to do this. Allen said: “You can chase various virus variants like playing a mole, or you can try to walk in front of them.”

Weisman estimates that due to the relatively simple structure of updating existing vaccines, a new RNA vaccine can be designed and manufactured within 6 weeks for clinical trials. But this is only the beginning. “It is difficult to produce vaccines on a large scale. It will be a challenge to start all over again,” Offfit said

(source:internet, reference only)

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