Experimental COVID-19 vaccine could outcompete future coronavirus variants

A nurse prepares a syringe of vaccine against COVID-19. An experimental vaccine aims to get ahead of new variants by preparing the immune system to recognize a stable part of the coronavirus. (Brian van der Brug/Los Angeles Times)

The new COVID-19 booster shots being sent to arms across the country are prized for their ability to recognize the distinctive spike protein shared by BA.4 and BA.5, the Omicron strains that currently represent almost 90% of the coronavirus specimens currently circulating in the US

But sooner or later, mutations in the spike protein will allow the virus to slip past the antibodies that are trained to recognize its predecessors. The boosters can still protect people from serious illness, but they will be less effective at preventing infections in the first place.

An experimental vaccine aims to solve this problem by preparing the immune system to recognize both the spike protein and a second, much more stable viral protein.

When tested in small animals, this bivalent vaccine provided stronger protection than alternatives that only targeted one of the proteins. And while the vaccine design was based on an early strain of coronavirus from Wuhan, China, it remained effective against the Delta and Omicron variants.

The new vaccine will have to be tested in larger animals before it is tested in people, and there is no guarantee that the results will be the same. Still, the scientists said the approach could lead to a single vaccine that offers longer-lasting protection against a virus with a proven track record of spawning new variants.

“We think it’s a one-size-fits-all solution for all variants of COVID,” Haitao Hu, an immunologist at the University of Texas Medical Branch and lead author of a study describing the vaccine, said in Wednesday’s edition of the journal Science Translational Medicine.

Other scientists not involved in the study agreed that if the vaccine works as well in humans as it does in mice and hamsters, it could help us stay one step ahead of the coronavirus.

“It’s a great idea,” said Dr. Paul Offit, a virologist and immunologist at the University of Pennsylvania who was not involved in the study. “You could have argued that we should have done this in the first place.”

Current vaccines against COVID-19 have saved an estimated 19.8 million lives worldwide. However, as the virus has evolved, its effectiveness at preventing infection has declined, meaning more illnesses, more time away from work and school, and more people at risk of developing COVID long-term.

The situation has forced scientists to catch up with variants, Hu said: “You’re always one step behind.”

The spike protein of the SARS-CoV-2 virus is in some ways the double-edged sword of the pandemic. It is the key target of the four COVID-19 vaccines currently available in the US, but it is also the part of the virus most likely to take advantage of the random mutations that allow it to evade the immunity these vaccines are intended to provide.

There’s a reason why the spike protein, or “S” for virology, is so susceptible to evolutionary pressure: It’s the part of the virus that initiates an infection by entering a host cell. If the spike can’t do its job, the virus can’t survive.

The second target of the experimental vaccine is the nucleocapsid protein, known as “N”. It is located at the core of the virus and has little reason to change. But once inside a host cell, it plays an essential role in allowing the coronavirus to make copies of itself.

Hu and colleagues used the same mRNA technology as the Pfizer-BioNTech and Moderna vaccines to encode instructions for making harmless copies of the S and N proteins. Once these copies are made, the immune system recognizes them as threats and learn to respond accordingly.

The researchers began their tests by injecting small groups of mice with vaccines targeting only the N protein. The animals mounted an immune response, but only a modest one, Hu said.

Exposure of cells to N did not trigger the production of neutralizing antibodies. The study authors expected this, since N is not involved in helping the virus enter a host cell. The exposure, however, induced a strong T-cell response, which helps clear the virus from the cell.

The researchers then injected animals with a bivalent vaccine targeting S and N at the same time. The immune response was much stronger: no viral RNA was detected in the lungs of the eight mice that received the bivalent vaccine. Conversely, among eight mice immunized with a shot targeting only S, seven had detectable amounts of viral RNA.

Additional tests were performed on hamsters that were exposed to the Delta variant. The results were similar: the viral load was undetectable in the animals that received the combined vaccine and their lung pathology was clear. Compared to hamsters that received the S-only vaccine, they also had less virus in their upper respiratory tracts, which could make them less likely to spread the virus to others.

Hamsters exposed to the Omicron variant also did better with the bivalent vaccine. Four of five hamsters that received it had no detectable virus, compared with only one of five hamsters that were vaccinated with a shot targeting only S. Animals that received the bivalent vaccine had no lung damage, while those who received only the S. vaccine developed lesions in their lungs. The bivalent vaccine also reduced viral loads in the upper respiratory tract of the hamsters.

The Texas team is not the first to go after spike and nucleocapsid proteins at the same time. ImmunityBio of Culver City has developed a COVID-19 vaccine with a similar structure that is currently in clinical trials in South Africa.

The new study “confirmed that when you have S plus N, you can have multivariate protection,” said Dr. Patrick Soon-Shiong, executive chairman of ImmunityBio. (Soon-Shiong also owns the Los Angeles Times.)

Protein S “gives you good antibodies and N gives you amazing T cells,” he said. “It’s the interaction between the antibodies and the T cells — by having both, you get the best of both worlds.”

One thing the new study didn’t address is how long the benefits of the combination vaccine would last, said Stanley Perlman, a microbiologist and immunologist at the University of Iowa. The animals were tested two weeks after receiving the final dose, and the study authors acknowledged that longer experiments were needed to measure the vaccine’s longevity.

Hu said his team’s next step is to study the vaccine in non-human primates. If all the funding and approvals come through, that could be completed in six months, and if the results are good, human trials would be next, he said.

This story originally appeared in the Los Angeles Times.

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