The U.S. led the world in quickly developing COVID-19 vaccines—one of the few bright spots in the country’s otherwise criticized response. But while injectable vaccines are effective in protecting people from getting sick with COVID-19, they are less able to block infection. In order to put the pandemic behind us, the world will need a way to stop infections and spread of the virus. That’s where a different type of vaccine, one that works at the places where the virus gets into the body, will likely prove useful.
Here, though, the U.S. is losing its edge. In September, India approved a nasal COVID-19 vaccine, and in October, China began administering an inhalable one—the world’s first such vaccine against any disease. Both countries conducted their own clinical safety and efficacy tests in humans (but have not yet published the complete and latest results).
U.S. researchers have created several nasal vaccines that have been tested in animals, and some—like the booster Dr. Akiko Iwasaki and her Yale University colleagues developed—look promising; their group published encouraging results in the journal Science on Oct. 27. But such vaccines are at least several years away in the U.S. Moving to the next step—human testing—is stalled for several big reasons, including a lack of funding.
“There is a lot of science that needs to be done to see if developing mucosal vaccines against COVID-19 is possible,” says Dr. Richard Hatchett, CEO of the Coalition for Epidemic Preparedness Innovations (CEPI), an organization that funds research into innovative solutions to responding to disease outbreaks. CEPI helped to fund Moderna’s mRNA vaccine and is currently supporting several nasal-vaccine programs around the world. “But we ought to make major investments in understanding the immunology of COVID-19, understanding the immune response, and testing various approaches to delivering vaccines with the goal of producing mucosal immunity.”
The challenges of nasal vaccines
Creating a nasal vaccine that proves effective may be difficult, as AstraZeneca executives learned when they announced disappointing results in October from their trial of a nasal vaccine. The company turned its injected COVID-19 vaccine, which was developed with researchers from Oxford University, into a mucosal version given through the nose, but early trials in 30 people showed weak antibody responses in their nasal mucosa, where the vaccine was expected to have its greatest effect. They also found lower immune responses in the rest of the body when compared to injected vaccines. AstraZeneca scientists speculated that much of the vaccine, which uses a disabled virus to deliver SARS-CoV-2 genes, might have bypassed the lungs and ended up in the digestive tract, where it was destroyed before it could adequately activate the immune system. Another pitfall of this approach is that people might already have significant immunity built up to the disabled virus, weakening the effect (although AstraZeneca used a virus that normally infects chimps in an effort to avoid this problem).
AstraZeneca’s experience shows how unpredictable vaccine development can be and why the U.S. has so far have favored existing, proven shots based on mRNA technology. These first-generation vaccines against SARS-CoV-2 were about 95% effective at reducing the risk of severe disease, and though efficacy has diminished as SARS-CoV-2 has mutated into more transmissible variants, they continue to protect people from hospitalizations and deaths. Health officials are hopeful that the updated Omicron booster shots currently being administered will rebuild waning immunity. With so much invested in the mRNA platform—money, time, and considerable public-health messaging to get people to trust these specific vaccines—it’s a challenge to shift to a different type.
There is also the perception, among both political leaders and the public, that COVID-19 is no longer an urgent health threat, and that the current strategy of boosting with mRNA vaccines will be enough to protect people. But that false sense of security could be shattered this winter, as more people gather indoors and respiratory viruses like SARS-CoV-2 tend to spread more efficiently. “I am concerned that the relaxed attitude toward COVID-19 is going to lead to further spread, more disease, and more Long COVID-19 among people who do get infected,” says Iwasaki, professor of immunobiology, molecular, cellular and developmental biology at Yale University. “All of these things point toward the need for a next generation vaccine.” With many people around the world vaccinated against SARS-CoV-2 but experiencing waning immunity, nasal vaccines could be the next step in building up that protection again.
Why nasal vaccines make sense as a booster
There’s a reason why scientists are pursuing a nasal vaccine that works through the mucosal tissues in the nose, mouth, and lungs. SARS-CoV-2 is a respiratory virus that preferentially finds and infects cells in the respiratory tract, from the nose and throat all the way down to the lungs. A vaccine that works in these tissues might do more to hamper the virus from infecting cells than one that’s injected into the arm and needs to travel throughout the body’s circulatory system to do its work.
“If you give a vaccine in the nasal cavity, then you create a localized immune response, and that is fundamentally different from what you get with an intramuscular vaccine,” says Iwasaki. “Being local has the advantage of capturing the virus before it even enters our body. By limiting the amount of replication at the site of entry, you can also prevent infection, and the potential consequences of infection, including Long COVID. If you limit the amount of virus in the body, you also prevent transmission and spread of disease.”
The type of immune response generated by cells in the mucosal passages of the nose, mouth, and airways also differs from that produced by a vaccine given in the muscle. Nasal vaccines produce a type of antibody called IgA, which injected vaccines don’t produce as much of; vaccines injected in the muscle tend to generate more IgG antibodies. One is not necessarily better than the other, but the two antibodies have different functions. IgA antibodies are more localized—they live in areas like the respiratory tract, reproductive system, or the gut—and are produced in the mucous layer in parts of the body where viruses are most likely to invade. IgG molecules are systemic, and trigger the body to bind and inactivate viruses circulating in the blood. When IgG antibodies are produced, they create systemic immunity, and the body is better prepared to fight back if those viruses or bacteria return to cause infection again.
There may be some advantages to generating a more localized, IgA-heavy response—especially at this point in the pandemic, when blocking people from getting infected with the virus in the first place has become more of a priority. Antibody-producing cells in tissues like the mucosa tend to produce IgA antibodies that clump viruses like SARS-CoV-2 together, making them easier to neutralize en masse. An international group of scientists also reported in December 2020 that IgA antibodies dominate the first wave of people’s immune response in their saliva, blood, and lungs, in an effort to block the virus from infecting more cells. In a study published in June, researchers at the National Institute of Allergy and Infectious Diseases (NIAID) found that intranasal COVID-19 inoculation dramatically lowered the amount of virus detected in animals’ respiratory tract. “We couldn’t find virus in either the upper or lower respiratory tract, and we know the intranasal vaccine either prevented infection or eliminated infection within two days,” says Bernard Moss, distinguished investigator at NIAID and senior author of the paper. Studies also show that people who have had COVID-19 tend to have high levels of IgA in the nose, and they are less likely to get infected if exposed to SARS-CoV-2 than people who haven’t had COVID-19. That further suggests the importance of generating IgA antibodies to protect people from getting infected.
Because much of the world’s population now has some type of immunity to SARS-CoV-2, whether from vaccination or infection, Iwasaki believes it’s time to use nasal boosters instead of injected ones, in what she describes as the “prime and spike” strategy. Her latest results support this strategy, as she and her team reported in Science that mice given an intranasal vaccine after receiving mRNA vaccination produced higher levels of IgA antibodies in the nose and mouth than either mRNA shots or a dose of the nasal vaccine alone. The prime and spike model also produced robust immune responses, involving more immune T cells, which are more durable than antibodies.
That belief is gaining ground among immune-system experts. “We are at a different stage in the pandemic,” says Stephanie Langel, instructor in the department of surgery at Duke University who developed a nasal COVID-19 vaccine based on a modified cold virus and tested it in hamsters. “Boosting people with a nasal vaccine could help to reduce things like infection and transmission, which is going to be beneficial at a time when we are all going to be spending more time indoors in poorly ventilated spaces during the winter.”
CanSino Biologics’ vaccine was approved by Chinese health authorities as a booster dose for this reason. It’s the same vaccine as the company’s injected shot—which is about 60% effective in protecting against COVID-19 symptoms one month or more after vaccination—but in liquid-turned-mist form that is sprayed using a nebulizer in the mouth. Both vaccines use a disabled cold virus engineered to no longer be infectious, to deliver genes coding for the SARS-CoV-2 spike protein for the immune cells to recognize and target. While the results from late-stage human studies of the mucosal vaccine aren’t available, the company published early-stage data that showed people receiving the inhaled dose generated similar levels of virus-fighting antibodies as people getting the injected form of the booster. An October release summarizing later stage trials said these levels of antibodies were higher among the people receiving the inhaled dose compared to the injected one.
Indian health officials approved a nasal vaccine for primary vaccination in two doses given through the nose, but also have not yet published the results of the human studies supporting that decision. Its nasal vaccine also uses another modified virus to deliver SARS-CoV-2 spike genes. Iran and Russia also reportedly approved nasal vaccines developed by researchers in their respective countries, but without publicly available data.
Will nasal vaccines work?
Whether these vaccines will reduce infections won’t be clear until more people have taken them. Real-world analysis of how well vaccinated people can fend off infections is likely going to be the most efficient way to measure whether nasal vaccines are working.
That’s because there are no widely accepted ways to document the effects that a mucosal vaccine is having on the immune system. Scientists have much less experience with mucosal vaccines, and only a handful are approved, including one for influenza and the oral polio vaccine. That makes it difficult for health authorities to measure what the vaccines are doing and to know whether they’re providing protection above and beyond existing vaccines. Most people make more IgA than any other major antibody, and these levels can vary among people, so it’s hard to determine a standard level, which makes tracking changes nearly impossible.
“For intranasal vaccines, we don’t have good biological correlates of immunity,” says Hatchett, the CEO of CEPI. “There are other questions of whether mucosal immunity against COVID-19 will be protective against disease, and whether that immunity will be enduring.” That was also true of the other mRNA-based COVID-19 vaccines before they were approved, but regulators relied on measuring levels of neutralizing antibodies circulating in the blood, because those could be documented more easily than levels in tissues in the mucosa. It’s impossible to answer such questions without testing nasal vaccines in people in clinical trials.
That uncertainty has dissuaded biotech and pharmaceutical companies from investing in mucosal-based vaccines. While unprecedented financial support from the U.S. government fueled the development of mRNA vaccines, no such public sector resources are available for companies trying to develop a nasal vaccine. About a dozen companies have completed or are nearly finished with preliminary animal studies of various nasal vaccines, but they lack the funding needed to test their candidates in people through expensive clinical trials. “They have no financial support, no de-risking, nothing. They are in their own orbit,” says Dr. Eric Topol, director of the Scripps Research Translational Institute; along with Iwasaki, Topol wrote an editorial in July supporting the need for broader vaccine research, including on nasal vaccines.
Next steps for nasal vaccines
Philanthropic organizations including CEPI, the Wellcome Trust, and the Bill and Melinda Gates Foundation are convening a workshop in early November to formulate ways to bridge the gap between animal and human studies of nasal vaccines. The groups are focused on finding sustainable and broadly applicable vaccine strategies for fighting infectious diseases—including a pan-coronavirus vaccine that targets multiple and potentially future strains—and a nasal-based approach is one of them.
CEPI partnered with the U.S. National Institutes of Health to support more basic research on mucosal COVID-19 vaccines, and in October it also announced a partnership with Dutch biopharmaceutical company Intravacc to develop a SARS-CoV-2 nasal vaccine that would protect against a broad range of coronaviruses, including the latest SARS-CoV-2 variants. Intravacc developed a technology that exploits the fact that some bacteria shed non-infectious components called vesicles, which trigger the immune system. Intravacc’s vaccine is designed to neutralize the bacteria so they can’t cause harm, while taking advantage of their ability to alert immune cells by packing the vehicles with SARS-CoV-2 spike protein. In animal studies in rodents and rabbits, the vaccine lowered the viral load in the animals’ respiratory tract and generated high levels of IgA antibodies. Forty volunteers are now testing the vaccine in Australia in the company’s first human intranasal trial, and those results are expected in early 2023.
Dozens of other nasal vaccines in development are showing promise in animal studies. To avoid the potential challenges of vaccines such as AstraZeneca’s, which used another virus to deliver the SARS-CoV-2 genes, Iwasaki is exploring two other strategies for a nasal vaccine. One involves introducing a modified viral spike protein to awaken the immune system, the method described in the latest Science paper, while the other uses mRNA from SARS-CoV-2, but in a delivery system distinct from the intramuscular vaccine that’s more tailored to the nasal cavity. “These are fundamentally different approaches, and we need to test them,” she says. The approach is promising in animal studies, and Iwasaki co-founded a company, Xanadu Bio, to test the vaccine further and look for industry partners to test it in people.
If successful, nasal vaccines could also help to improve vaccination rates in lower-resource countries where vaccination with the current vaccines, which require proper storage at ultra-low temperatures, has hampered immunization rates. Increasing vaccination with a shot that significantly decreases transmission is the only way to lower spread of the virus and ultimately contain it.
“This is going to be a decades-long engagement with this virus,” says Hatchett. “Having easy-to-administer intranasal vaccines to reduce transmission will help us in terms of global access to vaccines. It’s way too early to talk about eradication of COVID-19, but we’re never going to eradicate COVID-19 if we can’t prevent transmission.”
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Contributor: Alice Park