Sniffling instead of poking: Researchers are developing nasal corona vaccines

Corona viruses are known to spread primarily through the air and usually first reach the nose, throat and lungs.

Sniffling instead of poking: Researchers are developing nasal corona vaccines

Corona viruses are known to spread primarily through the air and usually first reach the nose, throat and lungs. It's only logical to start fighting the pathogens right there, in the mucous membranes, and at best to avoid an infection altogether. In fact, researchers have been working on mucosal vaccines since the early days of the pandemic. Unlike the previous vaccines, they should not be injected into the muscle, but administered directly into the nose or inhaled.

"If the vaccine is injected into the muscle, the immunity builds up primarily in the blood or distributed throughout the body. This means that the corona viruses, which penetrate through the surface of the mucous membranes of the nose and throat, are only recognized relatively late by the immune system noticed and thus combated," explains Emanuel Wyler, molecular biologist at the Max Delbrück Center for Molecular Medicine in Berlin. "It's too late to prevent infection or the spread of the virus."

Preparations already approved in India and China

The mucosal vaccines, on the other hand, should build up immunity directly at the point of entry of Sars-CoV-2 and then fight the pathogens quickly. At the beginning of September, two preparations were approved in India and China. Dozens of other candidates are in development, and some are already being tested in clinical trials.

The vaccine from the Chinese manufacturer CanSinoBIO is inhaled and approved as a booster. The Indian preparation, developed by the company Bharat Biotech, is also approved for primary immunization and is given in the nose. Both preparations are based on weakened adenoviruses, a group of viruses that can cause different diseases. The weakened viruses cannot multiply themselves, or only poorly, and therefore cannot cause diseases. However, they transport genetic material from Sars-CoV-2 into the cells of the mucous membrane, whereupon the body forms antibodies and other antibodies against the corona virus.

The hope is that the immunity built up in the mucous membranes will protect against infection for a longer period of time and slow down the transmission of the pathogen. "At the moment, however, we don't know how well this works, because so far only a few data from the underlying studies have been published," says Leif Erik Sander, immunologist and vaccine researcher at the Berlin Charité.

Many questions still open

So far there is comparatively little experience with measuring immunity in mucous membranes. For example, how high does the antibody level in the mucous membrane have to be in order to actually be able to assume protection against infection? Many questions like these are still open. In principle, however, exactly such vaccines are needed, says Sander. It is regrettable that research is not being carried out with the same intensity in Europe or the USA.

However, some studies on mucosal vaccines are also underway outside of Asia. In the USA, for example, the pharmaceutical company Codagenix has made good progress. According to its own statements, it is testing its preparation in a more advanced phase II/III clinical study in cooperation with the Serum Institute of India as part of a WHO project.

In Germany, the biologist Wyler is working in a team with scientists from the Charité under the leadership of the FU Berlin on a nasal spray vaccine that, like the Codagenix vaccine, is based on weakened corona viruses. The advantage here is that a complete virus is presented to the immune system - and not just individual proteins as in most of the other corona vaccines currently available. It is hoped that this will provide better protection against newly emerging variants. Wyler considers it extremely unlikely that the vaccine virus itself will regain the ability to multiply massively and cause disease. "We changed 200 of the virus' 30,000 building blocks to mitigate it - that's a big hurdle."

Results from animal experiments were therefore successful: the vaccine elicited an effective immune response in hamsters, after two doses the animals showed almost no signs of disease and very low levels of inflammation after a targeted infection with the coronavirus. As a booster after a previous mRNA vaccination, the nasal vaccine protected better than two mRNA vaccine doses alone. "In cooperation with the company Rocket Vax, the project is now moving towards a clinical study," explains Wyler. "First of all, the tolerability of the preparation is to be proven in a phase 1 study on around 100 test persons and the dosage is to be checked."

Nasal flu vaccine withdrawn from the market

A safety issue specific to an intranasally administered vaccine relates to proximity to the facial nerves. A Swiss pharmaceutical company's nasal flu vaccine was withdrawn from the market in 2001 after a rise in cases of facial paralysis among those who had been vaccinated. "This is a possible side effect of such products that we need to look at carefully," says Wyler. At the moment, only one nasal mucosal vaccine is approved in Europe for children and adolescents against influenza.

But do we still need such vaccines in the corona pandemic? After all, in many countries the immunity of the population has increased significantly thanks to vaccinations and as a result of infections. Klaus Stöhr, epidemiologist and, among other things, a member of the Corona Expert Committee, which independently evaluated the federal government's corona measures, is skeptical.

"Nasal vaccines have nothing to do with the outcome of the pandemic and if they were approved in industrialized countries in a few years' time, they would have no significant impact on the emergence of escape variants or virus circulation," Stöhr recently wrote on Twitter. According to Stöhr, approval in all age groups is "extremely unlikely" - but widespread use is necessary to stop the virus circulation or to prevent the development of immune escape variants.

Administration as a nasal spray is comparatively easy

Doctor Sander, on the other hand, can well imagine a targeted use of the vaccines in special groups of people or special situations. "I think a scenario is conceivable that high-risk groups, such as residents of nursing homes, might refresh their immunity with a nasal spray like this every three months." In such a situation, the comparatively simple administration as a nasal spray pays off. Intranasal vaccines are also interesting for the not so small group of people who suffer from a strong fear of needles, adds biologist Wyler.

However, he also points out the high hurdles that a mucosal vaccine has to overcome in order to be approved. "We are no longer in the same situation as in 2020," says Wyler. "Any potential new vaccine has to outperform all vaccines currently on the market - it just has to be better." However, everything that is now being researched is also helpful for the development of other mucosal vaccines - "against flu, viral respiratory diseases or anything else that may come up."