Are nasal sprays the future of COVID-19 vaccines? That’s certainly the hope of many researchers working on new kinds of inoculation. Nasal vaccines were recently approved in China and India for use as a booster dose. The Chinese vaccine is inhaled through the mouth and nose, whereas the Indian vaccine is delivered through nasal drops.

These vaccines are just two of more than 100 oral or nasal vaccines in development around the world, according to a report in Nature. The German Association of Research-Based Pharmaceutical Companies (VFA) has provided a good overview of the next generation of COVID vaccines.

Sterilizing Immunity

SARS-CoV-2 enters the body via the mucous membranes in the mouth and nose. In theory, oral or nasal vaccines could prime the immune cells in these mucous membranes and quickly stop the virus in its tracks before it spreads. It is hoped that these vaccines will prevent even mild cases of illness and block transmission to other people.

Vaccines that generate a sterilizing immunity would be crucially important for the pandemic. In the estimation of Leif Erik Sander, PhD, vaccine researcher from the Charité University Hospital in Berlin, Germany, nasal vaccines would have a significant effect on transmission and infection. “In my opinion, not enough has been invested in their development,” Sander tweeted last August.

Preventing infection and transmission is a high bar for any vaccine. However, studies of SARS-CoV-2 mucosal vaccines in animals suggest that it is possible. For example, a study in mice found that an intranasal booster induced mucosal immunity and completely protected the animals from a lethal level of exposure to the virus, whereas an intramuscular booster did not.

In the opinion of Christian Drosten, PhD, a virologist at Charité, nasal vaccines may even provide longer protection against transmission. In an interview with the German newspaper Süddeutsche Zeitung, Drosten referred to a study with rhesus macaques that was published at the end of May. In this study, an intranasal vaccine completely protected the animals from SARS-CoV-2 infection.

Virus replication was undetectable in the macaques’ airways and lung tissues, says Ursula Buchholz, chief of the RNA viruses section at the National Institute of Allergy and Infectious Diseases (NIAID), which led the study. “In preclinical models, we get something that’s very close to sterilizing immunity. We’ll have to see how this translates into clinical studies,” she said.

In China and India, nasal vaccines are already in use. “These authorizations confirm the need for mucosal vaccines,” commented Marty Moore, PhD, cofounder of Meissa Vaccines in Redwood City, California. His company is developing a COVID-19 vaccine that will be administered nasally. “This is the direction we must take globally, and the United States has to catch up,” Moore emphasized.

The current COVID-19 vaccines provide effective protection against severe illness and prevent hospitalizations. They do very little to prevent transmission, however, and they are also not particularly good at protecting against mild illness.

One reason for this observation is that the vaccines are injected into the muscle. Intramuscular injection triggers an immune reaction that includes T cells, which destroy infected cells, and B cells, which produce antibodies to neutralize the pathogens, binding to them to stop them from entering healthy cells.

These cells and antibodies circulate through the bloodstream. However, they are not present at high enough levels in the nose and lungs to provide rapid protection. In the time it takes them to journey there from the bloodstream, the virus spreads, and the infected person gets ill.

Mucosal vaccines can trigger an immune reaction throughout the body, including by activating immune cells in the mucous membranes of the nose and airways. Mucosal vaccines are being tested as first doses for unvaccinated people and as booster vaccinations.

Previous Experiences

Nine mucosal vaccines are approved for use in people against pathogens including poliovirus, influenza, and cholera. Eight of these vaccines are taken orally, and one, against flu, is administered intranasally. The oral polio vaccine is successful at inducing immunity in the gut and comes close to achieving sterilizing immunity. In rare cases, however, this live attenuated vaccine will mutate and cause illness.

For other diseases, mucosal vaccines have not been successful. It is sometimes because the vaccine does not generate a sufficiently strong immune response and sometimes because it triggers side effects. The Swiss company Berna Biotech pulled its intranasal flu vaccine off the market in 2001, for instance, after discovering that it increased the risk of temporary facial paralysis.

FluMist, a live attenuated intranasal vaccine against influenza that is approved in the United States and Europe, outperforms the intramuscular vaccination in young children. FluMist has not worked as well in adults.

That is because many adults have had years to build up some immunity to flu viruses. Even if this immunity is not strong enough to prevent the disease, adults’ mucosal immune reactions might still prevent the attenuated vaccine from infecting nasal cells or clear it before it can take full effect.

“It’s a balancing act between making sure the vaccine doesn’t cause illness and yet replicates enough to elicit mucosal immunity in people who have had some experience with the virus,” said Kanta Subbarao, director of the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia. Researchers do not know yet if this issue might also affect intranasal COVID-19 vaccines.

Indicators of Effectiveness

There is a quick way to predict whether an intramuscular COVID-19 vaccine will be effective: measure the neutralizing-antibody levels circulating in the blood. Higher levels generally mean better protection. For mucosal vaccines, no clear-cut correlate exists. Many developers are measuring immune responses in the airways, including secretory immunoglobulin A (IgA), other antibodies, and tissue-resident memory T cells. These probably contribute to protection, but it is unclear what levels are necessary to prevent infection and transmission.

Until the basic research is completed, the efficacy of mucosal vaccines must be determined in other ways. The Indian company Bharat Biotech measured systemic neutralizing antibodies in blood serum in its study of an intranasal COVID-19 vaccine. If these antibody levels match or exceed the antibody levels of intramuscular vaccines, the study will achieve its primary endpoint and be considered a success. But it will not determine the vaccine’s ability to prevent infection or transmission.

CanSino, the manufacturer of the Chinese vaccine, tracked efficacy using a similar strategy: measuring the concentration of neutralizing antibodies in blood serum and comparing it with that from existing vaccines. A phase 2 study of the company’s aerosolized mucosal vaccine reported in January that, when given as a booster vaccination, the vaccine raised serum antibody levels significantly more than a booster with CanSino’s intramuscular vaccine did.

In July, the company noted in a further report that antibody levels waned over time but were still higher than those elicited through the intramuscular administration. The company is also measuring T cells and antibodies in saliva, but the strength of response needed to provide sterilizing immunity is not known.

The Chinese company Beijing Wantai Biological Pharmacy also has a mucosal vaccine in phase 3 trials, but the company did not respond to Nature‘s request for comment.

Another option is to conduct efficacy studies by comparing a mucosal vaccine against a placebo group. Codagenix in Farmingdale, New York, and the Serum Institute of India in Pune are taking this approach in a phase 2/3 study of an intranasal vaccine in 20,000 unvaccinated people, about half of whom will receive a placebo in their noses. Efficacy will be determined by comparing the number of confirmed cases in each group and measuring the rate of protection from the vaccine, says Robert Coleman, chief executive at Codagenix.

Codagenix’s phase 2/3 study is part of the WHO’s Solidarity Trial for vaccines, which brings several studies together to share one placebo group. Sandy Douglas, who is developing an intranasal SARS-CoV-2 vaccine at the University of Oxford, United Kingdom, thinks that it is completely possible to determine efficacy. “It’s just a bit trickier than testing first-generation intramuscular vaccines in an infection-naive population,” he says.

Coming Soon?

According to information from Airfinity, a health-analytics company in London, United Kingdom, 20 of the around 100 COVID-19 mucosal vaccines in development globally are currently being tested in clinical studies. At least four — in India, Iran, and two in China — have been completed or are undergoing phase 3 studies to test safety and efficacy compared with other vaccines.

Iran gave emergency approval in October 2021 for a nasal vaccine, and at least 5 million doses have been delivered to the Ministry of Health, reports Ali Es-haghi. He is a chemist at the Razi Vaccine and Serum Research Institute in Karaj, Iran, which developed the vaccine. But the institute has not yet published data on efficacy in humans. Russia is said to have approved a mucosal vaccine for its market but has not published data, and the vaccine manufacturers did not respond to Nature’s request for details.

Large-scale human study data on mucosal vaccines in the US and Europe will take another year or 2. “There’s not the same sense of urgency now, compared with at the beginning of the pandemic,” said Louise Blair, head of the vaccines department at Airfinity. “We are in an abundance of vaccines. Countries at the moment seem to be satisfied with protection against hospitalization rather than infection. So, funding and resources are very different, and I don’t think we’ll see the same speed of development,” says Blair.

This article was translated from the Medscape German edition.

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