HYDERABAD, India – On the outskirts of this centuries-old Indian city, a world away from its congested roads and cacophony, Bharat Biotech’s shiny modern laboratories are in the process of secreting a COVID vaccine that would be injected into the nose instead. to be injected into blood.
Currently available vaccines produce strong, long-lasting immunity to serious disease, as several recent studies have shown. But their protection against coronavirus infection is temporary and can falter as new variants of the virus emerge – a failure that has led to regular booster shots.
Nasal vaccines can be the best way to prevent infections in the long run because they provide protection exactly where it is needed to ward off the virus: the mucous membranes of the airways where the coronavirus first lands.
Bharat Biotech is one of the world’s leading vaccine manufacturers. Its best known product, Covaxin, is approved to prevent COVID in India and many other countries. But its experimental nasal vaccine may prove to be the real game changer.
Immunization of entire populations with a nasal or oral vaccine would be faster in the middle of a wave than injections, which require skill and time to administer. A nasal vaccine is likely to be more palatable to many (including children) than painful shots and would bypass the lack of needles, syringes and other materials.
Intranasal vaccines “can be easily administered in mass immunization campaigns and reduce transmission,” said Krishna Ella, President and CEO of Bharat Biotech.
There are at least a dozen other nasal vaccines under development worldwide, some of which are now in Phase 3 trials. But Bharat Biotech’s may be the first to become available. In January, the company won approval to embark on a Phase 3 trial of the nasal spray in India as a booster for people who have already received two shots of a COVID vaccine.
The Omicron variant made it all too clear that even three doses of a vaccine, although providing strong protection against serious illness, may not prevent infection. This is because injected vaccines produce antibodies in the blood, of which relatively few get to the nose, the entrance to the virus.
So-called mucosal vaccines will ideally coat the mucous membranes of the nose, mouth and throat with long-lasting antibodies and would be much better at preventing infection and spread of the virus. That’s the difference between planting sentries at the gates to block uninvited guests and trying to evict them after they had 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 not live forever by protecting vulnerable people and boosting them so that their antibody levels remain artificially high.”
Nasal vaccines have been shown to protect mice, ferrets, hamsters and monkeys from coronavirus. A new study last week offered strong evidence to support their use as a booster.
An intranasal booster induced immune memory cells and antibodies in the nose and throat and strengthened 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 boost 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 Yale University who led the study.
When she and her colleagues used a mixture of proteins from the new coronavirus as well as the related SARS virus, their experimental nasal vaccine seemed able to ward off a wide range of coronavirus variants.
“There is some flexibility and there may be more resistance to the virus,” said Gommerman, who was not involved in the work. “And because we do not know what the virus will do next time, it is very appealing.”
The current COVID vaccines are injected into muscles and are distinguished by training immune cells to tackle the virus after it enters the body. They produce antibodies called IgG that circulate in the blood and can be collected as needed.
But few of these antibodies travel to the nose and throat, and even those that do decline rapidly.
In contrast, nasal vaccines produce a special set of antibodies, called IgA, that thrive on mucosal surfaces such as the nose and throat. And these antibodies can slow down more slowly.
A vaccine delivered with a nebulizer can coat the entire airway, including the lungs, with IgG antibodies. “It’s not just the tip of the nose that is protected,” Iwasaki said.
Mounting evidence supports IgA antibodies as the key to preventing infection. In one study, Gommerman and her colleagues found that only about 30% of people had detectable IgA antibodies after receiving a second dose of vaccine.
Those who had lower levels of IgA within one month of the second dose were more likely to develop a breakthrough infection. IgG levels did not appear to have any effect 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 gain immunity due to an infection with the virus – rather than from an injected vaccine – tend to have strong mucosal immunity, at least for a while. That may help explain why they seemed to do better against the delta variant than those who had been vaccinated, Tal said.
But she warned that it was dangerous to try to get mucosal immunity by getting infected. “The way to get people that kind of mucus protection really, really, really should be with a nasal vaccine,” she said.
Injected vaccines are the right approach to create the systemic immunity needed to prevent death and disease, the urgent goal at the beginning of the pandemic, Tal said. And the Trump administration heralded several candidates through Operation Warp Speed.
“It was a good first step, but we had to have intranasal vaccines ready to boost right after that,” she added. “What I really wish we 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 the blood. The amounts are often low and can fluctuate wildly. For example, the smell of a delicious meal can flood the mouth with saliva, diluting the antibody levels of the mucous membranes.
“It’s like a stepchild to vaccine development because it’s difficult,” said Florian Krammer, an immunologist at the Icahn School of Medicine at Mount Sinai in New York, about mucosal vaccines.
The only nasal vaccine approved in the United States for respiratory diseases is FluMist, and even that has been fraught with problems. FluMist is dependent on a weakened influenza virus, so it works well in children who have never been exposed to it. However, in many adults, existing immunity to influenza killed the weakened virus and rendered the vaccine ineffective.
Attempts to improve the vaccine with an additional ingredient, called an adjuvant, inflamed the nasal mucosa and led to Bell’s palsy in some people.
But these problems would not plague a nasal vaccine that uses a viral protein, Iwasaki said, “Our approach is so different, I do not think it suffers from that kind of restriction.”
Yet there have been no nose vaccines against COVID in the US that have embraced the mRNA vaccines made by Pfizer and Moderna.
“Much of this development is taking place in other regions of the world,” said Krammer, who is involved in an attempt to create a nasal vaccine. “Appetite for new vaccines in the United States is very low.”
One reason for the hesitation is that no one yet knows how strong immunity can be from a mucosal COVID vaccine and how long it can last, Gommerman said.
But mRNA vaccines were also a gamble at the beginning of the pandemic, she noted, “I do not think that is a good enough reason not to try.”