Mr. Wyler, together with colleagues from the Free University of Berlin and the Charité, you are developing a Covid-19 vaccine that is to be sprayed into the nose. Do nasal vaccines work better than those given by injection? Injectable corona vaccines result in a good antibody response and are also effective against the virus. However, they have a systemic effect, which means that the antibodies circulate primarily in the blood. There, however, they only recognize the virus when it has long since penetrated the body.

In order to catch a respiratory virus early on, local immunity is required where the virus attaches. And nasal vaccines are better at that because the infection starts in the mucous membranes of the upper respiratory tract. There they stimulate, among other things, the formation of so-called IgA antibody dimers, which ideally do not even allow an infection.

They tested the effect of the drug candidate on hamsters. Successful? On the one hand, we were able to determine the basic effectiveness. If the vaccine was given twice, the virus could no longer multiply in the hamsters. The immune memory was very well stimulated and the mucous membranes were also very well protected by a high concentration of antibodies. Better even than after a natural infection. The nerve cells responsible for the sense of smell were also protected.

Therefore, we hope that a nasal vaccine could better protect against the loss of smell typical of corona infections. On the other hand, we compared the effectiveness in combination with an mRNA vaccine previously injected into the muscle. The combination of the nasal vaccine and the Biontech vaccine was more effective than giving two doses of the mRNA vaccine alone. This could make a nasal vaccine particularly interesting as a booster.

Can the vaccine candidate nip infections in the bud and thus end the pandemic? With such sterile immunity, the vaccinated person would be completely protected, would not develop any symptoms and would not be able to infect others. However, we will not achieve lifelong sterile immunity with nasal vaccines because antibodies in the mucous membranes do not last as long. However, we hope that we can achieve near-sterile immunity for three or five years and thus be able to avoid infections much better.

For example, there are vaccines against measles that achieve sterile immunity. Why is it so difficult to develop such vaccines?Measles multiplies in the blood vessels. It is much easier to achieve sterile immunity in the blood because there are generally many more antibodies circulating there. A virus that is in the blood usually has no chance of remaining undetected for a long time. However, mucous membranes, such as those of the nose, are not as accessible to the immune system. Therefore, there will hardly be any real lifelong sterile immunity against respiratory viruses.

They are testing a live vaccine, which means that weakened but reproducible corona viruses are vaccinated. How do you prevent infection? This is something to watch closely for live vaccines. For example, we know from a live vaccine against measles that about five percent of those vaccinated become infected with the vaccine measles. The symptoms of the disease are then much weaker than with a real infection. Nevertheless, live vaccines are therefore not suitable for people with an immune deficiency, for example after cancer therapy or an organ transplant.

The live vaccine against polio has occasionally caused the vaccine virus to spread. How great is the risk of weakened corona viruses? In the past, weakened live vaccines were bred in the laboratory almost by chance. So sometimes people waited for years for mutations that produced a weakened virus. On the other hand, we have specifically and systematically changed the genetic code. In this way we want to prevent weakened vaccine viruses from mutating back into a more aggressive variant.

To do this, we changed the Sars-Cov-2 genome at 200 of the 30,000 existing positions. Of those 200, maybe 150 would have to mutate back to pose a threat. For comparison: That would be more mutations than between the original virus and omicron. It is extremely unlikely that this would happen in a single human being.

The US company Altimmune had also carried out promising animal experiments with the “AdCOVID” nasal vaccine spray. But in the phase 1 trial, many human subjects did not respond to the vaccine. Altimmune relied on an adenovirus as the carrier for its nasal vaccine. So it’s a vector vaccine that, like the Astrazeneca vaccine, introduces the spike protein of the coronavirus into the body with a carrier virus. This is only a small part of the whole pathogen. This principle did not work in the nose, perhaps because the carrier viruses cannot easily penetrate the nasal mucosa, or because the immune system is not activated enough. A live vaccine seems to be able to do this better.

Their vaccine has yet to be shown to be safe and effective in large-scale human trials. When do you expect approval? The vaccine will certainly not be available next winter. In any case, we gain important insights for the development of nasal vaccines, which could then also be used against other respiratory viruses.

Together with the Swiss company RocketVax, we are now preparing the phase 1 study on humans, which could start at the turn of the year. However, further studies are then required. The researchers at the US company Codagenix, who could already show the phase 3 data of their nasal vaccine at the end of the year, have made further progress. This would at least make it possible for Codagenix to receive market approval in the first half of 2023.