A novel approach to a COVID-19 nasal vaccine developed by scientists in Germany has demonstrated the potential to halt viral infections in the nose and throat, the initial sites of entry for the virus. In experiments conducted on hamsters, two doses of this vaccine, which is composed of a live but weakened strain of the coronavirus, successfully prevented the virus from replicating in the animals' upper airways. This achievement, termed "sterilizing immunity," also prevented the onset of illness, a significant objective in the ongoing fight against the pandemic.
While this experimental vaccine faces further developmental hurdles before potential availability, other nasal vaccine candidates are either in use or nearing the completion of clinical trials. China and India introduced nasal vaccines in the fall of the previous year, though their efficacy in humans remains uncertain as studies on their effectiveness have yet to be published. This leaves a global question mark regarding the true effectiveness of this delivery method in people.
The United States, like much of the world, has reached a plateau with COVID-19. Despite the pandemic's most severe days being behind us, hundreds of Americans continue to die daily from the virus, which persists as an underlying threat. The ongoing circulation of the virus among people and animals carries the inherent risk of mutation into more contagious or severe variants. While COVID-19 infections have become manageable for most healthy individuals, they continue to pose a significant danger to vulnerable populations, including the elderly and those with compromised immune systems.
Researchers are hopeful that next-generation COVID-19 vaccines, designed to neutralize the virus before it can cause sickness and ultimately prevent its spread, could diminish the threat posed by this persistent respiratory infection. One key strategy involves bolstering mucosal immunity, enhancing immune defenses within the tissues lining the upper airways, precisely where the virus first lands and begins its cellular invasion.
Emanuel Wyler, a scientist at the Max Delbruck Center for Molecular Medicine in Berlin and an author of the study, likened this strategy to "stationing firefighters underneath the smoke alarm in your house." He explained that immunity generated by traditional injectable vaccines primarily resides in the bloodstream, potentially leading to a delayed response compared to localized immunity in the airways. "If they are already on site, they can immediately eliminate the fire, but if they’re like 2 miles away, they first need to drive there, and by that time, one-third of the house is already in full flames," Wyler stated.
The new nasal vaccine employs a novel application of an established concept: weakening a virus to render it harmless while still allowing the immune system to learn to recognize and combat it. This principle dates back to the 1870s with vaccines against anthrax and rabies, where viruses were weakened using heat and chemicals. The current research team utilized genetic manipulation, specifically a technique called codon pair deoptimization, to alter the virus's genetic material. This modification makes it difficult for host cells to translate the viral code, effectively hobbling the virus so it can be presented to the immune system without causing illness.
Wyler elaborated on this technique with an analogy: "You could imagine reading a text … and every letter is a different font, or every letter is a different size, then the text is much harder to read. And this is basically what we do in codon pair deoptimization."
The findings from the hamster studies, published on Monday in the journal Nature Microbiology, indicated that two doses of the live, weakened nasal vaccine generated a significantly stronger immune response compared to two doses of an mRNA-based vaccine or one utilizing an adenovirus vector. The researchers hypothesize that the live, weakened vaccine's superior performance stems from its closer mimicry of a natural infection process.
Furthermore, the nasal vaccine exposes the body's immune system to the entire coronavirus, not solely its spike proteins as current COVID-19 vaccines do. This broader exposure allows the hamsters to develop immune responses against a wider array of viral targets.
Despite the promising results, vaccine experts urge caution. Dr. Greg Poland, a vaccine designer at the Mayo Clinic who was not involved in the research, commented that the work is "competent and thoughtful" and "impressive in the scope of what they did." However, he stressed that the vaccine must be replicated in further studies, including in primates and humans, before it can be widely deployed. "Now it just needs to be repeated," Poland added.
The research commenced in 2021, prior to the emergence of the Omicron variant, meaning the vaccine tested was based on the original strain of the coronavirus. In experiments where animals were subsequently infected with Omicron, the live, weakened nasal vaccine still demonstrated superior performance compared to other vaccines, although its virus-neutralizing capacity was diminished. Researchers believe an updated version will be necessary.
Human trials are the next crucial step, and Wyler confirmed that efforts are underway. The scientists have partnered with RocketVax, a Swiss company, to initiate Phase I clinical trials. Poland noted that progress on other vaccine candidates has been "slow and halting," attributing this to challenges in securing funding for the high costs associated with bringing a new vaccine to market, particularly in an environment where the public may perceive the vaccine development race as concluded.
Poland emphasized that this perception is misguided, stating, "That’s foolish. We should be developing a pan-coronavirus vaccine that does induce mucosal immunity and that is long-lived." He warned that another significant evolutionary shift in the virus, akin to the Omicron variant's emergence, could render current tools ineffective and return humanity to a vulnerable state.
According to the World Health Organization's vaccine tracker, at least four nasal COVID-19 vaccines have advanced to late-stage human testing. The nasal vaccines currently in use in China and India employ adenoviruses to deliver vaccine instructions, though published data on their effectiveness is lacking. Two other nasal vaccines are nearing completion of human studies. One, a recombinant vaccine that can be produced affordably in chicken eggs—similar to many flu vaccines—is being evaluated by researchers at Mount Sinai in New York City. Another, developed by Codagenix, also utilizes a live, weakened version of the virus and is undergoing trials in South America and Africa, with results anticipated later this year. The German research team is keenly awaiting the Codagenix data, as Wyler stated, "They will be very important in order to know where whether this kind of attempt is basically promising or not."
Developing effective inhaled vaccines for respiratory infections has historically presented challenges. FluMist, a live, weakened influenza vaccine, shows good efficacy in children but is less effective in adults. This difference is thought to be due to pre-existing immune memory in adults for influenza, which may interfere with the vaccine's intended response when administered nasally. Nevertheless, some of the most potent vaccines, such as the measles, mumps, and rubella (MMR) vaccine, utilize live attenuated viruses, suggesting the approach holds significant promise.
An important consideration for live vaccines is their suitability for all individuals. People with severely compromised immune systems are often advised against live vaccines, as even highly weakened viruses could pose a risk. Wyler cautioned, "Although it’s strongly attenuated, it’s still a real virus," highlighting the necessity for careful administration.
