Why Covid Nasal Vaccines May Make Better Boosters

HYDERABAD, India — On the outskirts of this centuries-old Indian city, a world away from its congested roads and cacophony, the gleaming...


HYDERABAD, India — On the outskirts of this centuries-old Indian city, a world away from its congested roads and cacophony, the gleaming modern labs of Bharat Biotech are producing a Covid vaccine that would be sprayed into the nose rather than injected into the some blood.

Currently available vaccines produce potent and long-lasting immunity against serious diseases, as several studies have recently shown. But their protection against coronavirus infection is transient and may falter as new variants of the virus emerge – a failure that has prompted talk of regular boosters.

Nasal vaccines may be the best way to prevent long-term infections because they provide protection exactly where it’s needed to ward off the virus: the mucous membranes of the respiratory tract, where the coronavirus first lands.

Bharat Biotech is one of the world’s leading vaccine manufacturers. Its best-known product, Covaxin, is licensed to prevent Covid in India and many other countries. But his experimental nasal vaccine could turn out to be the real game-changer.

Immunizing entire populations with a nasal or oral vaccine would be faster in the middle of an outbreak than injections, which require skill and time to administer. A nasal vaccine is likely to be more palatable to many (including children) than painful injections, and would prevent shortages of needles, syringes and other materials.

Intranasal vaccines “can be administered easily in mass vaccination campaigns and reduce transmission,” said Krishna Ella, president and CEO of Bharat Biotech.

There are at least a dozen other nasal vaccines in development worldwidesome of them now in phase 3 trials. But Bharat Biotech may be the first to be available. In January, the company got the approval to begin a phase 3 trial of the nasal spray in India as a booster for people who have already received two injections of a Covid vaccine.

The Omicron variant has shown all too clearly that even three doses of a vaccine, while providing potent protection against serious disease, may not prevent infection. Indeed, injected vaccines produce antibodies in the blood, relatively few of which reach the nose, the entry point for the virus.

Ideally, so-called mucosal vaccines would coat the mucous surfaces of the nose, mouth and throat with long-lasting antibodies and be much more effective. better to prevent infection and the spread of the virus. It’s the difference between planting sentries at the gates to keep intruders out and trying to drive them out after they’ve already stormed the castle.

Nasal vaccines are “the only way to really bypass person-to-person transmission,” said Jennifer Gommerman, an immunologist at the University of Toronto. “We can’t live forever sheltering vulnerable people and stimulating them to keep their antibody levels artificially high.”

Nasal vaccines have been show at protect mouse, ferrets, hamster and monkeys against the coronavirus. A new study last week offered strong evidence in support of their use as a booster.

An intranasal boost induced immune memory cells and antibodies in the nose and throat, and enhanced protection against the initial vaccination, the researchers reported. The study has not yet been published in a scientific journal.

“Our approach is not to use a nasal vaccine as a primary vaccination, but to reinforce with a nasal vaccine, because then you can take advantage of the existing immunity that has already been created,” said Akiko Iwasaki, an immunologist at the University of Yale who conducted the study.

When she and her colleagues used a mixture of proteins from the novel coronavirus as well as the related SARS virus, their experimental nasal vaccine appeared capable of fending off a wide range of coronavirus variants.

“There is some flexibility, and there could be more resilience against the virus,” said Dr Gommerman, who was not involved in the work. “And because we don’t know what the virus will do next, it’s awfully appealing.”

Current Covid vaccines are injected into the muscles and excel at forming immune cells to fight the virus after it enters the body. They produce antibodies called IgG which circulate in the blood and can be collected when needed.

But few of these antibodies travel to the nose and throat, and even those that wane rapidly.

In contrast, nasal vaccines produce a special set of antibodies, called IgA, which grow on mucous surfaces like the nose and throat. And these antibodies may decline more slowly.

A vaccine delivered with a nebulizer could coat the entire airway, including the lungs, with IgA antibodies. “It’s not just the tip of the nose that’s protected,” Dr. Iwasaki said.

A growing body of evidence supports that IgA antibodies are the key to preventing infection. In one study, Dr. Gommerman and his colleagues found that only about 30% of people had detectable IgA antibodies after receiving a second dose of vaccine.

Those who had lower IgA levels less than a month after the second dose were more likely to develop breakthrough infection. IgG levels seemed to have no impact on the outcome.

“Location really matters, and mucosal immunity is really important for protection against infection,” said Michal Tal, an immunologist at Stanford University who was involved in the work.

People who acquire immunity due to infection with the virus – rather than an injected vaccine – tend to have a strong mucosal immunity, at least for a while. This may help explain why they seemed fare better against the Delta variant than those who had been vaccinated, Dr. Tal said.

But she warned it was dangerous to try to achieve mucosal immunity by getting infected. “The way to get that kind of mucosal protection should really, really, really be with a nasal vaccine,” she said.

Injected vaccines are the right approach to generate the systemic immunity needed to prevent death and disease, the urgent goal at the start of the pandemic, Dr Tal said. And the Trump administration has introduced several candidates as part of Operation Warp Speed.

“It was a good first step, but we needed to have intranasal vaccines ready to boost right after,” she added. “What I really wish I had was a Warp Speed ​​​​2.0 for nasal vaccines.”

But developing nasal vaccines is complicated. Measuring mucosal antibodies is much more difficult than quantifying antibodies in blood. The amounts are often small and can fluctuate wildly. For example, the aroma of a delicious meal can flood the mouth with saliva, diluting mucosal antibody levels.

“It’s like a stepchild for vaccine development, because it’s difficult,” Florian Krammer, an immunologist at the Icahn School of Medicine at Mount Sinai in New York, said of mucosal vaccines.

The only nasal vaccine approved in the United States for respiratory diseases is FluMist, and even that has been fraught with pitfalls. FluMist relies on a weakened flu virus, so it works well in children who have never been exposed. But in many adults, existing immunity to the flu killed the weakened virus and left the vaccine ineffective.

Trying to enhance the vaccine with an additional ingredient, called an adjuvant, has inflamed the nasal lining and led to Bell’s palsy in some people.

But those issues wouldn’t affect a nasal vaccine that uses a viral protein, Dr Iwasaki said: “Our approach is so different, I don’t think it suffers from that kind of limitation.

Yet there has been little talk of nasal vaccines for Covid in the United States, which has embraced mRNA vaccines made by Pfizer-BioNTech and Moderna.

“A lot of these developments are happening in other parts of the world,” said Dr. Krammer, who is involved in an effort to create a nasal vaccine. “The appetite for new vaccines in the United States is very low.”

One reason for the hesitation is that no one yet knows how strong the immunity from a mucosal vaccine against Covid might be and how long it might last, Dr Gommerman said.

But mRNA vaccines were also a gamble early in the pandemic, she noted: “I don’t think that’s reason enough not to try.”

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