Despite an arsenal of highly effective injectable vaccines, drugmakers are looking into products that will be easier to store, transport, and administer in the global crisis -- particularly, intranasal vaccines.

Could these vaccines also hold an advantage when it comes to blocking transmission? While more data has suggested the vaccines authorized in the U.S. cut transmission, some experts have argued that intranasal vaccines may do an even better job of this.

MedPage Today surveyed the global landscape of intranasal vaccines in development, the majority of which are in early stages.

Rationale for COVID-19 Mucosal Vaccines

The mucosal immune system represents the body's first line of defense against outside pathogens at surfaces like the nose, lungs, mouth, eyes, and GI tract. Because the nasopharynx is the primary entry point for SARS-CoV-2, targeting the nasal cavity could be one of the best lines of defense for vaccines, according to Michael Russell, PhD, an emeritus professor of microbiology and immunology at the University at Buffalo in New York.

"By generating effective mucosal immune responses, it should be possible to forestall coronavirus infection from the outset, and also more effectively reduce transmission of the virus," Russell told MedPage Today. "Nasal immunization aims to replicate this natural immunization process in a more effective manner."

Current injectable vaccines induce a systemic immune response by generating circulating IgG antibodies that neutralize pathogens before they can cause severe tissue damage. But IgG is not very good at controlling viral entry into the body. To do that, the mucosal immune system is needed. It produces secretory IgA at the site of viral entry, and in larger quantities than any other type of immunoglobulin in the body.

"The major advantage of mucosal vaccines would be to create a strong immune response at the initial site of virus entry. If you can stop the virus here, it won't be able to get into the lungs to cause damage," said Richard Kennedy, PhD, who studies the development of immune responses after vaccination at the Mayo Clinic.

IgA also seems to be important in early infection. In one study, researchers measured immune responses in 159 patients with COVID-19. They found that IgA dominated the early stage of infection, peaked 3 weeks after symptom onset, and neutralized virus better than IgG. The results suggest that IgA-mediated mucosal immunity may decrease infectivity of the virus in human secretions and decrease viral transmission, according to the authors.

Mucosal Vaccines in the Pipeline

While mucosal vaccines may hold promise, clinical trials have only recently begun. Among 96 vaccine candidates in clinical trials, just eight are intranasal vaccines. Clinical trials are being conducted in the U.S., U.K., China, India, Cuba, and Iran, according to World Health Organization data released on May 5.

Two intranasal vaccine candidates are in phase II clinical trials. One uses a live-attenuated influenza virus adapted to express the spike protein of SARS-CoV-2, and is being developed by the University of Hong Kong, Xiamen University, and the Beijing Wantai Biological Pharmacy Enterprise, in partnership with the Coalition for Epidemic Preparedness Innovations (CEPI). The second is a protein subunit vaccine that is being developed by Razi Vaccine and Serum Research Institute in Iran.

In the U.S., two intranasal vaccine candidates are in phase I trials. The first is Altimmune's nonreplicating adenoviral vector vaccine called AdCOVID. On March 25, the company released preclinical results in mice suggesting that the vaccine was protective against illness, decreased levels of replicating virus in the nose and respiratory tract, and produced a "robust" IgG response. Past results in mice had shown that IgA antibodies were maintained for at least 6 months after a single dose of the vaccine.

The second is Meissa's live-attenuated candidate. Preclinical data in nonhuman primates have suggested that the candidate induced mucosal IgA and serum neutralizing antibodies, and was "highly protective" against infection with SARS-CoV-2 in the upper and lower respiratory tract.

Other intranasal vaccine candidates in clinical trials include: Cuba's Center for Genetic Engineering & Biotech protein subunit vaccine (phase I/II); the University of Oxford/AstraZeneca's Covishield, a nasal spray version of its ChadOx1 vaccine (phase I); Codagenix/Serum Institute of India's live-attenuated SARS CoV-2 COVI-VAC vaccine (phase I); and India's Bharat Biotech's non-replicating adenoviral vector vaccine.

Recently, China's CanSino Biologics announced plans to start a phase I/II trial of another inhaled vaccine, according to an emailed news release from the data and analytics company Global Data.

Because SARS-CoV-2 also infects the GI tract, another potential site of mucosal immunity, oral vaccines are also in clinical trials. Maryland's Vaxart recently announced that it will be advancing one oral vaccine candidate to a phase II trial, and two oral vaccine candidates to phase I/II trials. California's Immunity Bio has a nonreplicating human adenoviral vector vaccine in a phase Ib trial, and Symvivo/Merck's DNA-based vaccine is in a phase I trial in Australia.

Advantages and Drawbacks

Both oral and intranasal vaccines offer the advantage of being stable at room temperature, making them easier to ship and potentially improving access to vaccination in remote or resource-poor settings. Both offer the advantage of easier administration, in the form of a nasal spray, pill, or drop on the tongue. That, in turn, may help improve acceptance, especially among children and the needle-shy, Russell said.

Nevertheless, mucosal vaccines do have drawbacks. While they can produce both systemic and local immunity, one stumbling block is producing effective, long-lasting immunity. Mucosal surfaces contain various barriers to pathogens -- high acidity in the upper GI tract, sticky layers of mucous in the respiratory system -- which may interfere with the ability of vaccines to access and activate the mucosal immune system. That could contribute to poor immunogenicity and faster waning immunity.

For instance, the intranasal flu vaccine FluMist has had a rocky road, in part because of lower effectiveness compared to injectable flu vaccines.

"There are not many licensed mucosal vaccines," Kennedy said. "These vaccines are effective for certain pathogens, but this may or may not be true for SARS-CoV-2."

Safety is another consideration. The majority of mucosal vaccines licensed in the U.S. are delivered via the oral route. Perhaps because of closer proximity to the brain, vaccine regulators appear to have shied away from the intranasal route. For example, Berna Biotech's inactivated intranasal influenza vaccine was discontinued in Switzerland after it was found to be associated with increased risk of Bell's Palsy.

Still, because oral vaccination tends to produce an antibody response that is not so strong in the respiratory tract, Russell contends that intranasal immunization "makes the most sense" for a respiratory pathogen like SARS-CoV-2.

"If similar resources can be made available for the accelerated development of intranasal vaccines, as have been deployed for the existing vaccines, my guess is that we might see some of them becoming available within about a year," he said.



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