COVID-19 vaccines have helped tame some of the worst risks related to the virus, including serious illness and death. But as many people have learned the hard way — thanks to immune-evasive coronavirus variants — vaccines don’t always stop people from getting sick or from spreading illness to others.
Like the virus, COVID-19 vaccines need to evolve, experts say. Attention has now pivoted to a new generation of products, specifically nasal vaccines, that can attack the virus quickly where it first enters the body, inside the upper airway. Nasal vaccines got a lot of attention at a White House Summit on the future of COVID-19 vaccines held in July due to their potential to induce what’s known as mucosal immunity, which primes immune responders in the slippery tissues lining the respiratory tract to act quickly, making it less likely that people will get sick or spread the disease.
“I think the idea of a silver bullet that you get once and you're protected from COVID is probably not possible. And that's not because of any failings of any of the vaccines. It's the nature of respiratory viruses.”
J. Robert Coleman
CEO, Codagenix
Currently, there are at least 12 nasal spray vaccines in development, some in the preclinical stages, others as advanced as phase 3 trials. They’re being explored both as a booster for vaccinated people and a first-line option for the unvaccinated. While the vaccines are all administered through the nose, they use a variety of different technologies to prime the immune system.
It remains to be seen if one of these products is more potent than the others or if all will be effective and safe. But having a host of different products could be beneficial, because they might excel for various applications in different populations depending on their unique characteristics, says Dr. Bruce Turner, CEO of Xanadu Bio, a privately held company focused on nanoparticle delivery, which is working on an mRNA-based nasal vaccine using technology licensed from Yale University researchers.
Working toward a better option
CoviLiv, a Codagenix-developed vaccine is the furthest along in development, according to the company’s CEO, J. Robert Coleman, who is also co-founder of the Farmingdale, New York-based company focused on developing vaccines for infectious diseases and cancer virotherapys.
“We will actually show efficacy before the end of the year in a 20,000 patient trial. So, while I wish the other vaccines success, you know, a lot of them are still pre-clinic, maybe phase one, and don't necessarily have a line of sight to the market,” he says. “But Codagenix will have demonstrated efficacy against COVID infection sometime in late 2022.”
Provided all goes well, the CoviLiv vaccine may be available sometime in 2023, probably outside the U.S. market, at least initially, Coleman says. The timeline will be heavily dependent on regulators, he says. The World Health Organization recently approached the company to include the vaccine in its global, phase 2/3 efficacy trial for COVID-19.
“The reason they selected us is demonstrated potential for efficacy in clinical trials, ease of administration, ease of manufacturing, so the potential for global scalability, and ease of distribution” Coleman says. “So, unlike the [current] mRNA vaccines that require ultra-cold chains, ours requires just a standard refrigerator. It doesn’t even need a needle — it's a dropper.” The company is testing the vaccine both as a booster and a first-line inoculation in unvaccinated people.
“Our approach is really different,” says Coleman. Like some traditional vaccines, CoviLiv is made using a live attenuated — or weakened — strain of the SARS-CoV-2 virus, which causes COVID-19. But the synthetic biology company is using a different process to modify the virus. Codagenix’s manufacturing process essentially recodes the live virus to slow its replication rate.
“What our algorithm does is that we take the DNA, recode it, slow that process down, stitch that DNA back into the virus, and now it has gone from killer pathogen into a safe, live-attenuated vaccine,” Coleman says. This process allows the immune system to gain broad recognition of the virus — making it more effective against future variants, while also making it genetically impossible for the virus to revert and cause infection, he says. In the phase 1 study, T cells from participants were able to recognize and respond to the Omicron strains of COVID-19 even though the vaccine was made using an earlier strain of the virus.
The safety profile seen in the phase 1 trial exceeded that of first-generation COVID-19 vaccines, Coleman says. “We saw significant immunogenicity with a 100% seroconversion rate,” he says. “Everyone who got the vaccinating dose had at least a fourfold increase in their antibodies.”
Because the vaccine is easy to transport and store, it could reach millions of people, particularly in regions like Africa, Latin America, South America and Southeast Asia, where vaccination rates are low, Coleman says.
“I think that's important. We need to vaccinate those individuals in order to truly start to break the transmission cycle. So, the near-term goal would be to help satisfy vaccination rates as a global health issue,” he says.
But because CoviLiv is a live-attenuated vaccine, it’s not clear if the vaccine will be appropriate for all. “A lot of times live vaccines are counter indicated for immunocompromised individuals,” Coleman says. Even so, the vast majority of the global population would likely still be eligible. “I will say in the trials we're allowing people to enroll who have some immune-compromised backgrounds. So, we will get that information,” Coleman says.
Trials will also give the company a better idea of how durable vaccine protection might be.
“I think the idea of a silver bullet that you get once and you're protected from COVID is probably not possible. And that's not because of any failings of any of the vaccines. It's the nature of respiratory viruses,” he says.
Using existing vaccine technology
Other companies developing these intranasal vaccines are taking different approaches. Xanadu Bio is preparing to begin testing its mRNA-based candidate in non-primate animals. This strategy, while still in early stages, has a number of distinct advantages, Turner says. For one, the base of the vaccine is the same mRNA technology used to create the traditional COVID-19 vaccines, albeit a modified version that allows delivery through the nose as a booster for people who have already been vaccinated.
“Greater than 50% of the population has now been immunized with systemic mRNA vaccines. And so the likelihood that a majority of the U.S. population would also feel comfortable … using an intranasal mRNA vaccine, I think is likely quite high,” Turner says. But like current COVID-19 vaccines, the nasal vaccine, which is initially being formulated using an ancestral strain of SARS-CoV-2 and the BA.5 Omicron variant, could potentially need regular updates as the virus mutates. The mRNA technology does allow those updates to be accomplished relatively quickly, Turner says.
“We hope to have some nonhuman primate data available sometime during the winter, Q1 or Q2 of 2023, basically validating the concepts of mucosal immunity that the two Yale co-founders have propagated,” he says.
The path ahead
If nasal vaccines do successfully make it to market, experts say they may have another distinct advantage over traditional shots: they’re not shots. For the needle-averse or needle-phobic, the idea of a spray or drop instead of a jab holds great appeal, says Coleman — so much so that Codagenix has already been getting unsolicited letters from people who want to try it.
“I think there's just booster fatigue for injectables. You can ask people, would you want to get another shot or would you want to get a drop in your nose this time? I think the vast majority would probably say, let's try the nasal booster. I think that's a little bit of a tail wind for the product too,” Coleman says.
Aside from the science, one of the main factors determining how quickly these vaccines move forward will be funding and vaccine pricing. It remains to be seen what federal and private investments and pricing structures might look like.
“It's important that there is some profit that these companies can make. It required tens of billions of dollars in development to produce [Pfizer and BioNTech’s] Comirnaty and [Moderna’s] Spikevax. It will require trials that will be large and expensive, and a lot of manufacturing, to get an intranasal vaccine to market,” Turner says. “And so, the fact that there is a mechanism at the moment that the government can buy these, that there can be some profit to the pharmaceutical and biotech companies, allowing the further development of these vaccines, I think will be important.”
