COVID: nasal vaccines will be much more effective than injections

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Currently, it is the Omicron variant (and its derivatives) that mainly circulates among the population. These viral forms appear to be more transmissible than the original virus and are better at suppressing immune defenses. As a result, the effectiveness of existing vaccines is reduced: they protect against severe forms of COVID-19, but cannot completely prevent infection and transmission of the infection. To increase their effectiveness, the researchers suggest administering these vaccines via a nasal spray.

Nearly a dozen nasal vaccines are currently in development, and three of them are already in Phase 3 clinical trials (so they are being tested in large populations and compared to a placebo or a reference vaccine). SARS-CoV-2 is transmitted mainly by airborne droplets, it enters the body mainly through the nose. Therefore, administering the vaccine exactly at this site can be much more effective, in particular because it will stimulate the protection associated with the so-called mucosal immunity.

As the name suggests, the mucosal immune system is the part of the immune system responsible for protecting the mucous membranes (including the gastrointestinal tract, urinary and respiratory systems). As the body’s first line of defense against antigens, its action essentially involves the production of secretory immunoglobulins A (IgA), which only modestly activate the complement system (innate immune proteins) and thereby limit inflammation. Thus, these antibodies are the first to fight SARS-CoV-2 before it causes a more serious infection. “Increasing” the immunity of the mucous membranes will enhance its effect.

More localized, faster and more effective action

Among the nasal vaccines currently being studied, some consist of tiny droplets containing SARS-CoV-2’s spike protein (through which the virus binds to human cells). Others contain genetically modified (and disabled) conventional viruses, to which a gene has been added that expresses the coronavirus spike protein. Still others rely on a synthetic form of attenuated SARS-CoV-2 (the so-called live attenuated virus, a technique also used for MMR or BCG vaccines, for example).

Akiko Iwasaki, an immunologist at Yale University, has been working on nasal vaccines for some time. His team recently found that nasal spray vaccines were more effective in protecting mice against the flu than vaccines injected into a muscle. “We found that the local mucosal immunity that is created by intranasal vaccination elicits much stronger and cross-reactive cross-protective immunity than the conventional vaccine, which uses intramuscular injection,” she said in an interview in December.

The specialist explains that intranasal vaccination stimulates the production of IgA, which then coats the surface of the mucus (in the nose, mouth and throat), preventing the virus from penetrating deeper into the host body. Conventional arm vaccines elicit a systemic type of immune response: Immunoglobulins G are produced, then circulate in the blood system, ready to intervene if they encounter a pathogenic agent. On the other hand, nasal sprays stimulate IgA directly where the virus is located: therefore, their action is much faster and more effective.

This vaccination strategy could be applied to several other viruses, in particular SARS-CoV-2, Iwasaki said. “We are facing a different threat than in 2020. If we’re going to contain the spread of the virus, the only way to do that is through mucosal immunity,” she told Scientific American.

This approach seems all the more interesting since nasal vaccines can simultaneously cause mucosal and systemic reactions. A study published last year in the journal Science Translational Medicine compared the effectiveness of the ChAdOx1 nCoV-19/AZD1222 vaccine (developed by AstraZeneca and the University of Oxford) in hamsters by route of administration (nasal spray versus muscle injection). The experiment showed that intranasal vaccination caused an increased level of neutralizing antibodies compared to intramuscular vaccination, although both routes were effective in reducing viral load.

Good addition to intramuscular vaccines

Iwasaki notes that intranasal vaccination not only provides better protection, but also leads to longer lasting immunity. Indeed, T- and B-lymphocytes that penetrate the mucous membrane remain there and become the so-called memory cells.

However, the development of a nasal vaccine remains a challenge because scientists have not yet understood all the processes involved in mucosal immunity. Given the proximity of the nose to the brain, injected substances have the potential to lead to neurological complications. Indeed, this approach carries risks: in 2000, after the introduction of an inactivated intranasal influenza vaccine (which was used only in Switzerland), 46 cases of Bell’s palsy (temporary facial paralysis) were reported.

In addition, the development of a spray is more difficult than it seems: the product must enter the nasal cavity correctly (without immediate rejection when sneezing), then pass through the mucus in order to activate the immune cells located there. On this last point, live attenuated viruses have proven to be the most effective, and several laboratories are currently investigating this option. Codagenix, whose intranasal vaccine CoviLiv contains an attenuated version of SARS-CoV-2, recently reported the results of its phase 1 trial: researchers report high potential for immunogenicity against Omicron and future variants.

Meanwhile, Iwasaki and his colleagues have developed a nasal spray that acts as a “booster” for the standard vaccine, a vaccination strategy the team calls “Prime and Spike.” This approach involves using existing immunity created by primary vaccination to trigger immune memory of the airway mucosa. This vaccine, tested in mice, effectively protected against severe forms of COVID-19 while significantly reducing the viral load in the nose and lungs.

In addition, when they added the SARS-CoV-1 spike protein to their nasal formula, they found that it elicited a broad-spectrum immune response. Based on this preliminary study, Iwasaki hopes to develop an effective vaccine against all forms of the coronavirus. “I think mucus vaccines will give us a tool to develop a universal flu vaccine, or maybe a universal coronavirus vaccine. [les vaccins contre] many other respiratory infections,” she says.

T. Mao et al., bioRxiv.

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