Researchers Pave the Way for Next Generation COVID-19 Immunization Strategies

Vaccine Booster Delivered Directly to Mucosal Site of Infection Enhances Protection Against COVID-19 Infection in Non-human Primates

BOSTON – The global COVID-19 vaccination campaign saved an estimated 20 million lives. However, while current COVID-19 vaccines provide protection against developing severe disease, they do little to prevent infection and transmission.

Findings published in the journal Nature by physician-scientists at Beth Israel Deaconess Medical Center (BIDMC) and colleagues suggest that it may be possible to improve protection against COVID-19 by delivering the vaccine directly to the respiratory tract— the primary site of entry in SARS-CoV-2 infection.

“The failure of the current generation of SARS-CoV-2 vaccines delivered by the intramuscular (IM) route to block infection likely relates to their inability to induce robust mucosal immune responses at the portal of entry,” said corresponding author Dan H. Barouch, MD, PhD, director of the Center for Vaccine and Virology Research at BIDMC. “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.”

Barouch and colleagues primed 40 adult rhesus macaques with the Ad26 COVID-19 vaccine (Janssen/Johnson & Johnson) administered intramuscularly (IM)--like the shot in the arm adults typically receive. Approximately a year later, the animals received a booster. Three groups received either a dose of the Ad26 vaccine via the IM route, the intranasal (IN) route (delivered via nasal spray) or intratracheal (IT) route (delivered by nebulizer or inhaler). A fourth group received a dose of the bivalent mRNA vaccine (Pfizer-BioNTech) by the IN 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 IT route provided near complete protection against a high-dose SARS-CoV-2 challenge and induced greater mucosal immunity than it did via the IN or IM route. In contrast, mRNA IN 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.”

Co-authors included co-first authors Katherine McMahan, Malika Aid, Michaela Sciacca, Jinyan Liu, Nicole P. Hachmann, Jessica Miller, Catherine Jacob-Dolan, Olivia Powers and David Hope, as well as Cindy Wu, Juliana Pereira, Tetyana Murdza, Camille R. Mazurek and Amelia Hoyt of BIDMC; co-first author Frank Wegmann, as well as Jeroen Tolboom, Jan Serroyen, Laura Solforosi, Lea M.M. Costes, and co-senior author Roland C. Zahn of Janssen Vaccines and Prevention B.V.; Adrianus C.M. Boon of Washington University School of Medicine, Saint Louis; Meredith Davis-Gardner and Mehul S. Suthar of Emory School of Medicine; Amanda J. Martinot of Tufts University Cummings School of Veterinary Medicine; and Mona Boursiquot, Anthony Cook, Laurent Pessaint, Mark G. Lewis, Hanne Andersen of Bioqual.

This work was supported by Janssen, Gates Foundation (INV-027406, INV619 041469), National Institutes of Health (CA260476), the Massachusetts Consortium for Pathogen Readiness, and the Ragon Institute of MGH, MIT, and Harvard.

Barouch, Wegman, and Zahn are co-inventors on provisional SARS-CoV-2 vaccine patents 635 (63/121,482; 63/133,969; 63/135,182). Wegman, Tolboom, Serroyen, Solforosi, Costes and Zahn are employees and may hold equity in Janssen. The rest of the authors report no other conflict of interest.