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September 23, 2024

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Nasal Vaccine: Building a Bulwark Against COVID-19

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By Steve Sternberg

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Overview

Vaccine experts say nasal vaccines directly target the respiratory tract, where the virus that causes COVID-19 enters the body and replicates.

It’s hard to imagine a bigger milestone during a pandemic than developing a vaccine that can prevent severe disease and death. COVID-19 vaccines have done both, sparing millions of lives.

But standard mRNA vaccines, which are injected into muscle, fall short in two key respects. They cannot block infection or halt community spread of the SARS-CoV-2 virus.

Vaccine experts say nasal vaccines may be a powerful adjunct to standard COVID-19 vaccination because they directly target the respiratory tract, where the virus enters the body and replicates. At the peak of COVID-19 infection, the nasal passages, throat and lungs host vast amounts of virus. A single cough or a sneeze can propel viral particles 20 feet or more.

Current COVID-19 vaccines are injected into muscle and exploit what is known as adaptive immunity, priming the immune system to recognize and destroy microbial invaders before they do too much damage. Adaptive immunity, however, only kicks in once the invaders have breached the body’s first line of defense, the skin and membranes that serve as barriers to entry.

That’s why even people who have been vaccinated multiple times remain susceptible to the waves of infection that have surged through global populations since the pandemic began. It’s also why those surges continue.

“Nasal vaccines are appealing because they bolster immunity where pathogens enter the body,” says Pamela Wong, PhD, an immunologist and research associate professor of internal medicine at the University of Michigan School of Medicine, where FluMist, the first nasal spray vaccine in the U.S. was developed.

On Friday, Sept. 20, 2024, the U.S. Food and Drug Administration approved FluMist for sale by pharmacies directly to consumers – making it the first vaccine that can be self-administered – as long as they have a prescription from a physician. FluMist is approved for use in individuals 2 through 49 years of age.

When properly armed, the mucus membranes, packed with 80 percent of the immune cells in the body, can mount a potent immune response. But provoking that response is a challenge. The barriers that prevent germs from entering the body also obstruct the absorption of the proteins that make up the vaccine – the nasal cilia clear away particles as if they were motes of dust.

Furthermore, triggering strong immune responses in the mucosa is often difficult due to the natural immune tolerance that has evolved to ensure that we don’t over-react to the multitudes of foreign proteins and other agents we encounter in the environment. This makes developing an effective nasal vaccine a challenge.

In June 2024, the US government announced that it will award up to $500 million through its “rapid response” partnership program to study vaccines that can be delivered via nasal spray or a pill. The program is part of the $5 billion Project NextGen, a push to develop new approaches to combat COVID-19 led by The Biomedical Advanced Research and Development Authority (BARDA), and HHS, its parent agency.

“We learned a lot during the COVID-19 pandemic that we can use to better prepare for future public health crises. That includes finding new ways to administer vaccines to make it even easier for everyone to protect themselves from illness,” Health and Human Services Secretary Xavier Becerra, JD, said at the time.

A least a dozen nasal vaccines are now in development, according to the federal government database clinicaltrials.gov. BARDA announced in June 2024 that it had awarded:

  • Approximately $34 million to Castlevax, part of the Mount Sinai Health System in New York City, developing an intranasal vaccine candidate, CVAX-01.

  • Approximately $40 million to Cyanvac of Athens, GA, developing an intranasal vaccine candidate, CVXGA.

Each of the Phase 2b clinical trials will recruit 10,000 volunteers, half of whom will be given one of the study vaccines while the other half will receive an FDA-licensed vaccine. The safety and efficacy of the study vaccines will be compared to the licensed vaccines.

Nasal vaccinations have been in use since the 1980s. Notable examples include a nasal spray flu vaccine that was developed in Russia and licensed in 2009 by the World Health Organization from its owner, Australian vaccine developer BioDiem, according to The Scientist. The vaccine has since been manufactured by companies in India, China and Thailand. A nasal vaccine approved in Switzerland in 1997, the report says, was pulled from the from the market after data revealed an elevated risk of Bell’s palsy in vaccine recipients versus controls.

The Food and Drug Administration approved FluMist in 2003, but the vaccine has also had a rocky history. In 2016 and again in the 2017-18 flu season, the Centers for Disease Control and Prevention recommended against FluMist’s use after studies showed that it was less effective than flu shots. The latest version of FluMist was endorsed by the CDC in mid-2018.

There are also a other intranasally delivered vaccine candidates in development, including one for respiratory syncytial virus. The Institut Pasteur in Paris has successfully completed an early trial of a nasal vaccine for Bordetella pertussis, or whooping cough. Veterinarians routinely prescribe a nasal Bordetella vaccine to protect dogs from the bacteria that causes kennel cough.

Now the emphasis has switched to SARS-CoV-2 and the list of candidate nasal vaccines is growing. In July 2024, researchers at Washington University School of Medicine in St. Louis demonstrated that a nasal COVID-19 vaccine can prevent community spread of COVID-19 in hamsters.

The vaccine, using technology developed by Washington University researchers, is already approved for emergency use in humans as a booster in India and is licensed to Ocugen for further development in the United States, according to a university release. The findings were published in the journal Science Advances.

“To prevent transmission, you need to keep the amount of virus in the upper airways low,” senior author Jacco Boon, PhD, a professor of medicine, of molecular microbiology and of pathology & immunology, said in a statement. “The less virus that is there to begin with, the less likely you are to infect someone else if you cough or sneeze or even just breathe on them.”

In preclinical research, a team at Yale led by Akiko Iwasaki, PhD, Waldemar von Zedtwitz Professor of Immunobiology has created a spike mRNA nasal vaccine candidate and has formed a company, Xanadu Bio, to commercialize it.

Wong says one of the most promising approaches involves following a standard COVID-19 shot with a nasal vaccine booster, a concept called prime-pull. “You’re priming the immune system and then pulling [the immune response] to the mucosa,” she says.

Wong says her team has focused on developing adjuvants, additives that can stimulate a stronger immune response.

Her lab is developing an adjuvant made from a “nanoemulsion,” combining droplets of oil and water together with an RNA-based molecule which trigger tailored immune responses that are similar to the body’s natural response to COVID-19 infection.

“We’ve been trying to broaden the immune response,” she says, so that the virus, in its many forms, has a tougher time evading it. So far, preclinical research has shown that the combination stops COVID-19 infection in young and old mice.

The intense focus on nasal vaccines for COVID-19 may yield insights that can be used to prevent other respiratory illnesses and even those elsewhere in the body. One of the most intriguing features of the mucosa is that it is all interconnected – from nose to intestine and beyond, it behaves like a single organ through crosstalk between sites. “It’s thought of as the largest immune organ system,” Wong says.

Remarkably, she says, triggering the immune system in the nose or mouth can often also activate the immune system in the gastrointestinal and reproductive tracts.

“Sexually transmitted diseases, enteric bugs and respiratory viruses are all prime targets for people working on intranasal and oral vaccines,” she says.

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