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German scientists say they have successfully developed a nasal vaccine that can stop Covid-19 infection in the nose and throat, where the virus first gets its foothold in the body.
In experiments on hamsters, two doses of the vaccine — made from a live but weakened form of the coronavirus that causes Covid-19 — prevented the virus from copying itself in the animals’ upper respiratory tracts, achieving “sterilizing immunity” and preventing disease, a long-sought goal in the pandemic.
Although this vaccine still has several hurdles to clear before it reaches a doctor’s office or pharmacy, other nasal vaccines are in use or are about to be developed in clinical trials.
China and India both rolled out nasally administered vaccines last fall, but it’s not yet clear whether they’re effective. Studies on the vaccines’ effectiveness have yet to be published, leaving much of the world wondering whether this protective approach actually works in humans.
The United States is in a sort of impasse over Covid-19. Even though the darkest days of the pandemic are behind us, hundreds of Americans are still dying every day as the infection continues to fester in the background of our return to normal life.
As long as the virus continues to spread among humans and animals, it is always at risk of mutating into a more contagious or dangerous version of itself. And while Covid infections have become manageable for most healthy people, they can still pose a danger to vulnerable groups such as the elderly and people with compromised immune systems.
Researchers hope that next-generation Covid-19 vaccines, which aim to neutralize the virus before it has a chance to make us sick and ultimately prevent the infection from spreading, could make our new resident respiratory infection less of a threat.
One way scientists are trying to do this is by boosting mucosal immunity, by strengthening immune defenses in the tissues that line the upper respiratory tract, where the virus would land and begin infecting our cells.
It’s a bit like posting firefighters under the smoke alarm in your house, says study author Emanuel Wyler, a scientist at the Max Delbruck Center for Molecular Medicine at the Helmholtz Association in Berlin.
The immunity created by the shots works throughout the body, but it resides primarily in the blood. This means it may take longer for a response to occur.
“If they’re already there, they can put out the fire right away, but if they’re about 2 miles away, they have to drive there first, and by that time a third of the house is already on fire,” Wyler said.
Mucosal vaccines are also more effective than shots at preparing another type of first responder. They are better at mobilizing IgA antibodies, which have four arms to latch onto invaders instead of the two arms of Y-shaped IgG antibodies. Some scientists think IgA antibodies may be less picky about their targets than IgG antibodies, making them better equipped to deal with new variants.
The new nasal vaccine takes a novel approach to an old idea: weaken a virus so it no longer poses a threat, then give it to people so their immune systems learn to recognize and fight it. The first vaccines using this approach date back to the 1870s, for anthrax and rabies. Back then, scientists weakened the agents they used with heat and chemicals.
The researchers manipulated the virus’s genetic material to make it harder for cells to translate. This technique, called codon pair deoptimization, hampers the virus so it can be shown to the immune system without making the body sick.
“You can imagine reading a text… and each letter is a different font, or each letter is a different size, so the text is much harder to read. And that’s essentially what we’re doing in codon pair deoptimization,” Wyler said.
In the hamster studies, published Monday in the journal Nature Microbiology, two doses of the live but weakened nasal vaccine created a much stronger immune response than two doses of an mRNA vaccine or a vaccine that uses an adenovirus to deliver the vaccine’s instructions into cells.
Researchers believe the weakened live vaccine probably worked better because it closely mimics the process of a natural infection.
The nasal vaccine also previews the entire coronavirus for the body, not just its spike proteins as current Covid-19 vaccines do, so the hamsters were able to build immune weapons against a broader range of targets.
As promising as it sounds, vaccine experts are advising caution. The vaccine still needs to undergo further testing before it’s ready for use, but the results appear encouraging, they say.
“They’ve done a very good job. It’s clearly a competent and thoughtful team that’s done this work, and the magnitude of what they’ve accomplished is impressive. It just needs to be repeated,” perhaps in primates and certainly in humans before it can be used widely, said Dr. Greg Poland, a vaccine developer at the Mayo Clinic. He was not involved in the new research.
The study began in 2021, before the Omicron variant emerged, so the vaccine tested in these experiments was made with the original strain of the coronavirus. In the experiments, when they infected animals with Omicron, the live but weakened nasal vaccine still performed better than the others, but its ability to neutralize the virus was reduced. The researchers believe it will need to be updated.
The product also needs to be tested in humans, and Wyler says researchers are working on it. The scientists have partnered with a Swiss company called RocketVax to launch Phase I clinical trials.
Other vaccines are further along, but progress is “slow and halting,” Poland said. Groups working on these vaccines are struggling to raise the high costs of bringing a new vaccine to market, and they’re doing so in an environment where people tend to assume the vaccine race is won and over.
In reality, Poland said, we are far from that. Just one more Omicron-level change in the evolution of the virus would be enough, and we could be back to square one, with no effective tools against the coronavirus.
“This is stupid. We should develop a vaccine against all coronaviruses that induces mucosal immunity and lasts a long time,” he said.
At least four nasal COVID-19 vaccines have reached advanced stages of human testing, according to the World Health Organization’s vaccine tracker.
Nasal vaccines used in China and India rely on harmless adenoviruses to deliver their instructions to cells, although data on their effectiveness has not been published.
Two other nasal vaccines are currently in human studies.
A recombinant vaccine, which can be produced cheaply from chicken eggs, in the same way as many flu vaccines, is currently being tested by researchers at Mount Sinai in New York.
Another vaccine, like the German one, uses a live but weakened version of the virus. It is being developed by a company called Codagenix. The results of these studies, which have been conducted in South America and Africa, could be known later this year.
The German team says it is looking forward to the data from Codagenix.
“They will be very important in knowing whether this kind of attempt is fundamentally promising or not,” Wyler said.
They have reason to be concerned. Respiratory infections are proving to be difficult targets for inhaled vaccines.
FluMist, a live but weakened form of the flu virus, works quite well in children but doesn’t help adults as much. The reason is thought to be that adults already have an immune memory for the flu, and when the virus is injected into the nose, the vaccine mostly strengthens what’s already there.
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However, some of the most powerful vaccines, such as the measles, mumps, and rubella vaccine, use live, attenuated viruses, which is a promising approach.
It should also be taken into account that live vaccines cannot be given to everyone. People with very weakened immunity are often warned against using live vaccines, because even these very weakened viruses can be dangerous for them.
“Although it is highly attenuated, it is still a real virus,” Wyler said, so it should be used with caution.
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