Illustration of several SARS-CoV-2 virus particles in blue on a red background
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Protection against COVID-19 may be improved by delivering booster shots directly to the respiratory tract—the primary site of entry for SARS-CoV-2 infection, research from Beth Israel Deaconess Medical Center (BIDMC) suggests. In a study using macaques, this team found that boosters given via inhaler, which delivers treatment straight to the trachea, were much more effective than those given intranasally or by traditional intramuscular shots.

The team’s findings were published in the journal Nature. The senior author is Dan H. Barouch, MD, PhD, director of the Center for Vaccine and Virology Research at BIDMC.

Current COVID-19 vaccines provide protection against developing severe disease, but they do little to prevent infection and transmission and provide minimal protection against Omicron variants. 

One theory says enhanced mucosal immunity is required to block infection and onward transmission. But intranasal administration of current vaccines has proven inconsistent, possibly because the drug is quickly cleared from the system via sneezing etc. 

“The failure of the current generation of SARS-CoV-2 vaccines delivered by the intramuscular route to block infection likely relates to their inability to induce robust mucosal immune responses at the portal of entry,” said Barouch.

“In this study, we demonstrated that novel immunization strategies can markedly increase mucosal immunity in nonhuman primates and improve protective efficacy against a mucosal virus challenge,” he added.

Barouch and colleagues primed 40 adult rhesus macaques with the Ad26 COVID-19 vaccine (Janssen/Johnson & Johnson) administered intramuscularly. Approximately a year later, the animals received a booster. Three groups received either a dose of the Ad26 vaccine via the intramuscular route, the intranasal route (delivered via nasal spray), or intratracheal route (delivered by nebulizer or inhaler). A fourth group received a dose of the bivalent mRNA vaccine (Pfizer-BioNTech) by the intranasal  route. A sham group received no boosters.

When the macaques were later challenged with a high dose of the virus, the investigators sampled the animals’ blood, nasal, and lung fluids to monitor their immune responses. They found that the Ad26 booster administered via the intratracheal route provided near complete protection against a high-dose SARS-CoV-2 challenge and induced greater mucosal immunity than it did via the intranasal or intramuscular route. In contrast, mRNA intranasal  boosting proved ineffective, suggesting that improved formulations will likely be required for effective mucosal delivery of mRNA vaccines.

“Taken together, these data demonstrate that novel immunization strategies can markedly increase mucosal immunity in nonhuman primates and improve protective efficacy against a mucosal virus challenge,” said Barouch. “These data suggest the feasibility of developing vaccines that block respiratory viral infections.”

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