Study shows efficacy of a heterologous vaccine regimen to induce mucosal protection against COVID-19

Fast-tracked genomic research has allowed several vaccines to be approved for emergency use in various countries in an effort to protect individuals against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19). However, not many of these vaccines have been evaluated for inducing mucosal protection, especially in their ability to prevent robust SARS-CoV-2 infection in nasal turbinate (NT).

Study: Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination. Image Credit: WESTOCK PRODUCTIONS /


NT in the upper respiratory tract (URT) consists of ciliated nasal epithelial cells with the highest expression of angiotensin-converting enzyme 2 (ACE2) receptors and transmembrane serine protease 2 (TMPRSS2). These receptors support rapid and robust SARS-CoV-2 infection.

Rapid impairment of host innate and adaptive immune responses enables robust viral replication and asymptomatic viral spread. These findings indicated that the prevention of SARS-CoV-2 infection in NT is critical for pandemic control.

Current systemic vaccination and passive immunization therapies are less effective or suboptimal for preventing SARS-CoV-2 in NT. Although the Pfizer BioNTech BNT162B2 messenger ribonucleic acid (mRNA) vaccine, as well as the Moderna mRNA-1273, AstraZeneca Oxford-ChAdOx1, and Novavax's NVX-CoV2373 vaccines have shown efficacies of 95%, 94.1%, 70.4%, and 89.3%, respectively, in Phase III trials in preventing COVID-19, none could substantially address asymptomatic cases. The efficacy of the Oxford-ChAdOx1 vaccine against asymptomatic SARS-CoV-2 infection was only 3.8% among human vaccinees receiving double doses.

A total of 2,800 milligrams (mg) of a receptor-binding domain (RBD)-specific human neutralizing antibody (NAb) LY-CoV555 has been evaluated to accelerate the natural decline of viral loads in nasopharyngeal swaps by day 11 of infection, thus conferring passive immunity. These results indicate that vaccine-induced or passive NAbs were suboptimal in preventing SARS-CoV-2 infection in human NT.

In a recent study published on the preprint server bioRxiv*, the researchers emphasize that an effective vaccine should induce mucosal immunity and prevent the nasal entry of SARS-CoV-2. This should help in controlling the silent spread of SARS-CoV-2 due to asymptomatic infection and sub-protection conferred by vaccines that allow the virus to cause breakthrough infections. To test their hypothesis, the authors of this study mixed doses of nasal influenza vaccines (LAIV-HK68-RBD and LAIV-CA4-RBD) with a deoxyribonucleic acid (DNA) vaccine (PD1-RBD-DNA) for SARS-CoV-2 in animal models and compared the changes in immune reactions to other vaccines like Sinovac and Pfizer.

About the study

In the current study, the researchers studied the effects of combining an intramuscular program death 1 (PD1)-based RBD DNA vaccine (PD1-RBD-DNA) and two intranasal live attenuated influenza virus (LAIV)- based vaccines (LAIV-HK68-RBD and LAIV-CA4-RBD) to assess their impact on mucosal immunity.

The results showed substantially higher systemic and mucosal immune responses, including bronchoalveolar lavage immunoglobulin A (IgA)/IgG and lung polyfunctional memory CD8 T-cells, induced by the heterologous PD1-RBD-DNA/LAIV-HK68-RBD combination as compared to heterologous combinations with the Sinovac and Pfizer vaccines.

In vaccinated animals challenged at the memory phase, the heterologous vaccine regimen showed equally efficient prevention of robust SARS-CoV-2 infection in the nasal mucosa, as well as in the lungs. The NAbs induced by this heterologous regimen cross-neutralized variants of concerns.

Importantly, the bronchoalveolar lavage (BAL) fluid from LAIV-CA4-RBD boost groups was able to neutralize the SARS-CoV-2 Beta and Delta variants, both of which are highly transmissible variants. Furthermore, LAIV-CA4-RBD was able to boost the capability of the Pfizer-BioNTech vaccine in improving mucosal immunity.


The current study highlighted the possibility of using nasal influenza vaccines with existing approved vaccines for optimal protection against the nasal entry of SARS-CoV-2. Considering the existing mass-production for influenza vaccines in the industry, it would be a feasible solution to combine vaccine doses.

The current study also highlighted that the PD1- RBD-DNA vaccine may prime stronger mucosal CD8 T-cells responses by inducing potent NAbs, as well as providing better stability than the mRNA vaccine. Although intramuscular electroporation delivery is a potential limitation for DNA vaccination in large populations, this approach is associated with a safe, tolerable, and immunogenic profile for SARS-CoV-2 DNA vaccines from clinical trials.

Future work is needed to develop non-invasive delivery techniques for DNA vaccination in humans. In cases of simultaneous or sequential co-infection by SARS-CoV-2 and A(H1N1) pdm09, which can cause more severe disease than infection by either virus, this LAIV could potentially be used against both COVID-19 and influenza.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information

Journal reference:
Sreetama Dutt

Written by

Sreetama Dutt

Sreetama Dutt has completed her B.Tech. in Biotechnology from SRM University in Chennai, India and holds an M.Sc. in Medical Microbiology from the University of Manchester, UK. Initially decided upon building her career in laboratory-based research, medical writing and communications happened to catch her when she least expected it. Of course, nothing is a coincidence.


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