A new vaccination strategy could fundamentally change the course of the pandemic. Spray and oral vaccinations should soon provide immunity where the viruses land first: mainly in the mucous membranes (mucosa) of the nose, mouth and respiratory tract. They put the border guards on alert, so to speak, and allow antibodies to develop directly in the mucous membrane.
Only such mucosal or mucosal immunity would be truly effective in preventing contagion and significantly reducing infection and the chances of the virus mutating further and being transmitted to new hosts. So it would be the much-vaunted sterile immunity that, in addition to frequent absences from work and school, could also help prevent the long-term damage known as Long Covid.
Researchers and doctors see mucosal vaccines as a supplement to the systemic protection of classic intramuscularly administered vaccines. These often prevent severe disease progression. Ultimately, however, they cannot keep up with the ever new virus mutants, even in variant-specific form, and cannot contain their spread, as Akiko Iwasaki from Yale University and Eric Topol, director of the Scripps Research Translational Institute in California, write in an appeal in the journal Science Immunology. ‘The only way to do that will be through nasal or oral vaccines,’ the researchers said.
Operation lightning speed
However, in order for them to be available as quickly as possible, a similarly large-scale funding program is necessary, such as the US government’s “Operation Warp Speed” for the development of regular corona vaccines. Such an “Operation Nasal Vaccine – Lightning Speed” would actually significantly increase the chances that some of the more than 100 mucosal vaccine candidates worldwide will make it to approval faster. Xanadu Bio, a startup co-founded by Iwasaki, could also benefit. It is also developing a novel intranasal Covid-19 booster, but is only in pre-clinical animal testing.
So far, companies like yours have hardly been the focus of government or other support programs. Many countries seem to be content with the fact that traditional vaccines have lowered the risk of severe disease progression. The sense of urgency has disappeared in many places. Iwasaki, Topol and many other experts are therefore trying to raise awareness of the importance of the new vaccines.
Four mucosal vaccines are already approved in their home countries, but none of them have published clinical trial results. So it’s unclear how effective and how safe they are. The latest two were approved in China and India in early September. CanSino Biologics’ Convidecia Air booster is sprayed into the nose or mouth as a fine mist, while Bharat Biotech’s Incovacc is dripped into the mouth as a two-dose primary series. Both are non-replicating vector vaccines. They contain “viral taxis” that carry the genome instructions for the spike protein and cause it to be produced so that the immune system recognizes it on the pathogens.
Syringe becomes spray version
The Russian Mukosal vaccine, which was locally approved in April, also works according to this scheme and, like the Chinese vaccine, is the spray version of the previously injected vaccine. The Iranian nasal spray vaccine approved by the Razi Vaccine and Serum Research Institute in October last year is a protein subunit vaccine. He trains the defense with the finished antigen.
In addition to these four, there are currently almost 20 other mucosal vaccines in clinical trials. They range from live attenuated virus vaccines to vector vaccines to protein subunit vaccines.
Many are new developments. Some, such as AstraZeneca’s candidates, are lower-dose spray versions of the intramuscular vaccine. Some candidates are planned at the same time for the basic immunization and as a booster.
development with obstacles
Their development is in many ways more difficult than that of classic vaccines. For example, according to Florian Krammer from the Icahn School of Medicine at Mount Sinai, there are no standardized tests to assess mucosal immunity. They would reveal whether and what amounts of antibodies were formed in the mucous membrane. So far, this test has only been available for antibodies in the blood. The immunologist has also co-developed a Covid-19 nasal vaccine, which is currently going through the middle phase 2 study.
Mucosal vaccines also lead to antibodies in the blood, but often only in small amounts. However, this does not necessarily mean that a vaccine works badly. Until these tests are available, the mucosal vaccines will probably be measured by their blood antibody levels. According to the company, CanSino Biologics’ spray vaccine causes higher values than the intramuscular variant, even after the usual removal. The company also measured antibody and T-cell levels in saliva, but it’s currently unclear what levels would indicate sterile immunity.
Another difficulty is to find suitable enhancers (adjuvants) so that the immune system kicks in properly. It is also not easy to measure how effective mucosal vaccines are in disrupting virus transmission. Last but not least, the question arises as to how long the protection would last and whether variant-specific boosters would be necessary. But even if so, Iwasaki says these sprays could potentially be sold in pharmacies because anyone can self-administer them like an allergy spray.
How well do previous mucosal vaccines work?
Previous examples of mucosal vaccines also show how trivial the generation of mucosal immunity is. In total, just over ten of them are available for various diseases. These include the only nasal spray vaccine LAIV for children and adolescents against influenza (called FluMist in the US and Fluenz in the UK), as well as a number of oral vaccines, for example against cholera and the former polio vaccine. However, the weakened flu pathogen of the LAIV vaccine only protects children well against the disease, but has little effect on adults. This may be due to the fact that adults have acquired a certain immunity through previous contact with the pathogens, which also clears away the vaccine viruses.
The oral polio vaccine, on the other hand, provided almost complete sterile immunity in the intestinal mucosa, but is no longer used in Europe. Because its weakened viruses can occasionally mutate and produce infectious virus particles again, which are then excreted in the stool. This phenomenon is behind the recent poliovirus finds in the sewage of London and New York. They probably go back to children who came into the country and were immunized with the oral vaccine in other countries.
According to experts, without large-scale funding, it will take up to two years before the next mucous membrane vaccines are available. But despite the remaining hurdles, it is worth the effort: the profit would be huge if successful.
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