As the coronavirus evolves, scientists seek a new generation of vaccines

More than two years into the COVID-19 pandemic, and even with highly effective vaccines that protect people against severe disease, the coronavirus has continued to evolve and disrupt lives.

The Omicron variant, which is currently the dominant strain of the virus worldwide, is more transmissible and is now better at evading protection conferred by vaccination and prior infection. At the same time, protection from our current vaccines has been shown to wane over time. This has given the virus a tremendous advantage, and explains why breakthrough infections from Omicron have become more common.

Even though vaccinated people who get a mild case of COVID-19 don’t need hospitalization in most cases, catching the virus can be quite disruptive. Mild COVID-19 symptoms can include sore throat, cough, fever, fatigue and shortness of breath, and can last anywhere from a few days to a week or more. This means people who test positive have to miss school or work, among other things. It also means they can spread the virus to others.

Furthermore, experts predict that reinfections are likely to increase as emerging Omicron subvariants continue to evade immunity.

Dr. Monica Gandhi, an infectious disease doctor and professor of medicine at the University of California, San Francisco, told Yahoo News that all of these challenges brought on by the Omicron variant highlight the need for new vaccines: ones that are longer-lasting, that can protect us against future variants, that stop transmission and offer protection against all symptoms, including mild ones.

“Minor symptoms disrupt society,” she said, adding that the current mRNA vaccines, such as those manufactured by Pfizer and Moderna, have successfully protected people from pneumonia caused by COVID-19 and severe disease but “are not working as well in generating an adequate antibody response to protect us against all symptoms and to stop transmission.” New vaccine design approaches, she said, are needed to keep up with the virus.

A syringe is inserted into a Moderna COVID-19 vaccine.
A health worker in London prepares a Moderna COVID-19 shot at a vaccination clinic. (Dinendra Haria/SOPA Images/LightRocket via Getty Images) (SOPA Images via Getty Images)

Vaccine experts agree that our current vaccines should be updated, but there isn’t yet general agreement on what the best approach is moving forward. However, a Food and Drug Administration panel of outside experts, the Vaccines and Related Biological Products Advisory Committee, is expected to meet on June 28 to discuss whether the strain composition of the current COVID-19 vaccines should be modified and, if so, which variant they should target next.

There are currently multiple Omicron sublineages circulating in the U.S., although BA.2.12.1, accounts for the most cases, 64% at the moment.

Besides Novavax, a new vaccine candidate approved by an FDA advisory committee last week and expected to receive full approval by U.S. regulators soon, next in the COVID-19 vaccine pipeline is a COVID booster candidate developed by Moderna.

The booster shot is designed to target Omicron specifically and could be available this fall. The company announced last week that its "bivalent" vaccine, a combination of the old booster targeting the ancestral strain and a formula targeting the Omicron variant, generated "superior neutralizing antibody response" against the coronavirus, compared with its original vaccine.

But Gandhi and other experts worry that by the time the Omicron-specific booster becomes available it will not be as effective, because it was designed to target Omicron BA.1, which is now extinct in the U.S.

“We're already on BA.2, BA.2 12, and BA.4 and BA.5 are coming. So it's hard to keep up if you're only targeting the spike protein,” Gandhi said.

The spike protein is the part of the virus that helps it attach to cells. All vaccines currently being used in the U.S. target this specific location of the virus. The problem with that, Gandhi explained, is that this is the part of the virus that mutates the most. The current vaccines are designed to target the spike protein of the ancestral strain that began circulating in the spring of 2020, but the spike protein of the virus today looks very different. Researchers have found that Omicron’s spike protein has at least 42 new mutations.

Gandhi believes that a better vaccine against Omicron and future variants would be one that looks beyond the spike protein and helps the immune system take multiple shots at the coronavirus. “We need a vaccine that actually doesn't just give us the spike protein of the virus, because that is the part of the virus that's changing the most,” she said.

“We need to see the whole virus, I think, and that way we have antibodies against the nucleocapsid [protein] against the cell membrane, not just against that pretty mutated spike protein,” she added.

One such vaccine that holds promise, she said, is the Covaxin vaccine — a shot originally developed in India by Bharat Pharmaceuticals but that now has a U.S. manufacturer named Ocugen.

Gandhi explained that the Covaxin vaccine shows the immune system the entire virus in an inactivated form and because of this, it generates a broader immunological response against not only the spike protein but other parts of the virus. She also said the vaccine elicits “strong cellular immune responses,” which could make it longer-lasting.

More than 350 million doses of Covaxin have been administered around the world. It is India’s second most used shot and it has been approved for use in 24 other countries so far, according to Fierce Pharma.

A woman in a blue sari wearing a green mask bares her arm for a shot in a medical office, with another health worker in white scrubs sitting at a desk behind her.
A health worker in New Delhi in April administers a booster dose of Covaxin vaccine at a local dispensary. (Naveen Sharma/SOPA Images/LightRocket via Getty Images) (SOPA Images via Getty Images)

In addition, Gandhi said, Covaxin has been shown to be safe and effective and could soon be available in the U.S. “They are just doing a small, 400-person trial in the U.S., and then they are going to file to the FDA. … That's going to be the soonest we could get a whole virus inactivated vaccine,” she said. In a post on the medical website Medscape, Gandhi said she hopes it will be available later this year.

Another vaccine approach that scientists are pursuing is a nasal spray. Dr. Benjamin Goldman-Israelow, an instructor at Yale School of Medicine, is part of a research team currently working on an intranasal vaccine. He explained that our current vaccines generate systemic immunity, meaning that once you receive the shot, circulating antibodies and T cells — important parts of the immune system — help you fight the virus.

But the vaccines don’t generate much protection in the respiratory tract, which is where the coronavirus enters the body.

“We wanted to create a vaccine that didn't just boost antibody levels systemically, but induce the formation of antibodies, as well as T cells, within the respiratory tract that's the site of infection of SARS CoV-2,” Goldman-Israelow told Yahoo News. “Our hypothesis, which is, you know, shared by many in the field, is that by inducing immunologic memory within the respiratory tract, we could better prevent both infection as well as transmission of the virus.”

The intranasal vaccine that the Yale group is developing would complement the “systemic preexisting immunity” conferred by intramuscular vaccines, Goldman-Israelow said, so it is designed to act as a booster.

Nasal vaccines are not a new idea. The U.S. has a nasal vaccine called FluMist that was designed to prevent influenza, but it has not always performed as well as the regular flu shot. It has also been approved only for people ages 2 through 49, which means that a vulnerable portion of the population, such as older adults and younger children, can’t benefit from it.

Goldman-Israelow, however, says he’s confident his group’s nasal vaccine will be different, because it uses a different vaccine design that he believes will be more effective. “If everything goes as quickly and as well as we hope, we're hoping to be able to start phase one clinical trials in the next 12 to 15 months,” he said.

Finally, and perhaps the most popular idea, is to develop a so-called pan-coronavirus vaccine, a shot that could protect against different COVID-19 variants and even work against other coronaviruses. The virus responsible for COVID-19 is part of a family of coronaviruses called betacoronaviruses. The coronaviruses that cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), for example, are part of this family.

About a dozen vaccine makers, nonprofits and government agencies are focused on the development of such variant-proof vaccines, according to the journal Nature. Some researchers have received funding from the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health. Last September, NIAID awarded approximately $36.3 million to three different institutions — the University of Wisconsin, Brigham and Women's Hospital in Boston and Duke University — to conduct research and develop the all-in-one coronavirus shot.

Scientists from these and other groups working on pan-coronavirus vaccines are exploring different vaccine designs and technologies, including messenger RNA, or mRNA, used in the Moderna and Pfizer COVID-19 vaccines, and protein-based nanoparticle technologies, which have been used in vaccines targeting influenza and shingles. Some groups are focusing on targeting the spike protein only, while others, like the Duke University vaccine candidate, are looking to target other parts of the virus that don’t mutate as much.

So far, experts have said that some of these vaccines have shown great promise in animal experiments and that they could be available in the next few years. “There's no doubt, I would say in two years' time. Not this winter. It's going to be too soon for a whole virus vaccine, but next winter I think we're going to have it,” Gandhi said.