Intranasal influenza-based booster induces mucosal immunity against SARS-CoV-2 in animal model

Research from the University of Hong Kong (HKU) demonstrates that intranasal influenza-based booster vaccination following PD1-based receptor-binding domain (RBD) DNA vaccine induces mucosal and systemic immunity for effective prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in both upper and lower respiratory systems of mice.

“Nasal turbinate [NT] in the upper respiratory tract [URT] is one of the most important portals of SARS-CoV-2 entry into humans. Ciliated nasal epithelial cells in NT have the highest expression of angiotensin-converting enzyme 2 [ACE2] and transmembrane serine protease 2 [TMPRSS2], supporting rapid and robust SARS-CoV-2 infection, indicating that prevention of SARS-CoV-2 infection in NT is critical for curbing the spread of the infection,” wrote the researchers. [Emerg Microbes Infect 2020;9:1664-1670]

“While most currently available vaccines have shown excellent efficacy in the lungs of vaccinated animals, SARS-CoV-2 infection in URT cells of vaccine recipients has not been investigated. Although currently available vaccines significantly reduce hospitalization and death rates, recent studies report that fully vaccinated individuals can still be infected and their breakthrough infections have viral transmission efficiency similar to unvaccinated cases, which is a great challenge for pandemic control,” they added. [Lancet Infect Dis 2021;doi:10.1016/S1473-3099(21)00648-4; BMJ 2021;372:n296]

To focus the immune response on the most critical region of SARS-CoV-2 spike protein, the researchers used RBD as the vaccine immunogen and constructed an intramuscular PD1-RBD-DNA vaccine in the hopes of eliciting enhanced antibody and CD8 T-cell responses. [J Clin Invest 2013;123:2629-2642] In addition, since intramuscular administration of mRNA or inactivated vaccines induces mainly systemic immunoglobulin G (IgG) and some T-cell immune responses without secretory immunoglobulin A (IgA) or tissue-resident memory T cells, the researchers added a live attenuated influenza-based vaccine (LAIV) booster to the regimen to enhance mucosal immunogenicity. [Nature 2020;586:516-527; Trends Immunol 2006;27:235-243]

Vaccine-induced antibody responses were determined on day 9 (acute phase) and day 69 (memory phase) after the second dose. The PD1-RBD-DNA/LAIV heterologous regimen elicited and sustained significantly higher amounts of RBD-specific IgG than controls or homologous regimens. In addition, substantially higher numbers of systemic and mucosal IgA/IgG antibodies and lung resident polyfunctional memory CD8 T cells were induced vs the other regimens. [EBioMedicine 2021;doi:10.1016/j.ebiom.2021.103762]

The heterologous vaccine regimen-induced antibodies were able to cross-neutralize global SARS-CoV-2 variants of concern, including Alpha, Beta and Delta – although the Beta and Delta variants were more resistant to neutralization. “While animals who received the booster regimen showed a mean 1.69-fold reduction against Beta or Delta variants, their mean neutralizing antibody IC₅₀ titre remained high and was superior or comparable to those of homologous-vaccinated mice and to the titres of approved vaccines tested against the wild-type virus in murine models,” noted the researchers. [Nature 2020;586:567-571; Nat Commun 2021;12:372; NPJ Vaccines 2020;5:69]

“Clinical development of HKU vaccines remains a top priority for eliminating uncontrolled spread of SARS-CoV-2. We are currently testing the influenza-based nasal spray vaccine and the DNA vaccine in humans,” shared Professor Kwok-Yung Yuen of the Department of Microbiology at HKU.

“We believe that using nasal spray vaccination to build up protection in the URT is key to reducing SARS-CoV-2 transmission and could be part of the solution for the ultimate pandemic control,” said Professor Honglin Chen of the Department of Microbiology at HKU.