Corona vaccines have prevented many serious illnesses and deaths. However, the injected inactivated vaccines do not provide long-term protection against infection. Therefore, researchers led by Thomas Klimkait at the University of Basel are developing a live vaccine that is administered as nasal drops and is intended to draw the line of defense against the Sars-CoV-2 virus in the nasal mucosa instead of in the blood.
In this way, he should prevent an infection from the outset and also prevent the virus from being passed on to others. Such “sterile immunity” against Covid-19 does not yet exist. The researchers have now demonstrated it in a pilot animal study on 12 hamsters. They published their results in a preprint that is still going through the review process.
In fact, none of the experimental hamsters that received vaccine nasal drops became ill even after subsequent exposure to a high dose of wild-type virus. In addition, they did not infect any unvaccinated conspecifics with whom they were brought together the day after real corona viruses were administered.
Live vaccine without risk of reproduction
The Basel vaccine is a “single-cycle live vaccine” with modified corona viruses. Although these can penetrate the nasal mucosa, they cannot multiply there. This is ensured by two genetic interventions in their genome. The scientists excised the so-called envelope gene “E”. Without these building instructions for the virus envelope, infiltrated cells do not build complete virus particles.
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Explanation of the new vaccine (Video: Uni Basel).
The virus also has at least four genes that inhibit virus defenses in the infected cells. So the researchers removed several of these genes from the vaccine virus with the aim of making the immune protection particularly effective and long-lasting. All other viral components are manufactured by the cells and presented to the immune system on their surface. This not only gets to know the spike protein as before, but also many much less changeable components.
The vaccine could thus also protect against new Sars-CoV-2 variants, since new mutations particularly often affect the spike protein.
Genetic trick for vaccine virus construction
However, in order for the vaccine viruses to be able to penetrate the mucous membrane, they themselves need an envelope, including the E gene. To do this, the researchers created special production cells that have the missing gene in the cell nucleus and thus produce the required shell component. Because the remaining virus blueprints are read in a strictly spatially separate manner, namely outside the nucleus in the cell plasma, “the virus genome cannot complete itself back to the original version,” emphasizes Klimkait. So it cannot become disease-causing again, as happened with the polio vaccine virus.
Nor could the vaccine viruses produced absorb the E gene from a natural virus. “We don’t offer any overlap points with which the virus could manage such a repair,” Klimkait continues. The vaccine candidate also proved to be quite stable and can be stored at refrigerator temperatures.
In fact, the safety of the method – that the vaccine virus cannot multiply – has also convinced the Swiss Federal Office of Public Health. “We got permission to do that [Impf-] To take virus out of the security lab because it’s completely safe. This allows us to carry out further animal experiments in laboratories that do not have biosafety level 3,” says Klimkait. The researchers have applied for a patent for their method and are working together with the Swiss startup RocketVax to bring the vaccine into the first clinical test phase.
In addition, Klimkait’s team is working on applying the new vaccination strategy against other viral diseases. “I’m thinking above all of the dengue and chikungunya viruses, which we are waiting for in our latitudes, because we now have the tiger mosquitoes with us that transmit such viruses,” says the virologist.
Vaccine viruses must not be too weak
Compared to other live vaccine candidates, the developers of the Basel vaccine “went a step further in weakening the virus so that the virus can no longer multiply at all,” says Emanuel Wyler from the Max Delbrück Center for Molecular Medicine in Berlin. “Nevertheless, this live vaccine candidate also protected the hamsters very well from disease after infection with SARS-CoV-2 in animal experiments.”
Because how much you weaken viruses is always a matter of consideration. It must not be too strong, otherwise you may have too little vaccination effect. While weaker viruses used to arise by chance during cultivation, targeted methods of impairment are now used, such as the targeted removal of entire genes, as in the Basel vaccine, or “codon de-optimization”. The base triplets in the genome that encode amino acids are called codons. They are like words in the overall genetic material.
During de-optimization, triplets are modified at certain points in such a way that the words become much more difficult to read. “You can think of it like text where each letter is a different size, different font, different color,” says Wyler. The goal: The vaccine viruses should hardly multiply so that they do not cause any disease themselves, but still have an adequate immunizing effect.
Wyler is working himself, together with scientists from the Berlin Charité and the Freie Universität Berlin, on a live vaccine against Covid-19 administered by nasal spray. According to Wyler, they use a “slightly more sophisticated method” in which codons are changed in pairs.
In animal studies with hamsters, the vaccine candidate elicited stronger mucosal immunity and better protection against infection and severe disease than compared injected inactivated vaccines such as BioNTech/Pfizer’s mRNA vaccine and a spike antigen-transporting adenovirus vector vaccine candidate from Charité. The researchers write in the journal Nature Microbiology.
Double immunization with the nasal spray vaccine produced the best protection. If the hamsters were exposed to natural Sars-CoV-2 viruses, they could no longer multiply in the animals’ mucous membranes. The researchers are currently preparing a first clinical study with humans, also together with RocketVax.
The most advanced of the live intranasal vaccines against Covid-19 is Codagenix’s candidate. The US company relies on simple codon de-optimization and has announced the results of its final phase 3 study for the second quarter.
So far, India and China have each approved an intranasal vaccine against Covid-19. Both contain weakened adenoviruses that bring a spike variant of Sars-CoV-2 into the mucosal cells to immunize. However, data on the effectiveness of these vaccines are scarce.
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