Scientists from Germany and Italy recently demonstrated the benefits of intramuscular/intranasal heterologous prime-boost vaccination regimen against coronavirus disease 2019 (COVID-19). They have shown that intranasal administration of adenovirus vector-based booster vaccine following prime immunization with a DNA- or mRNA-based vaccine induces robust mucosal and systemic antibody and T cell responses in mice. The study is currently available on the bioRxiv* preprint server.

Study: Protective mucosal immunity against SARS-CoV-2 after heterologous systemic RNA-mucosal adenoviral vector immunization. Image Credit: Leo Altman / Shutterstock


Sufficient real-world data are now available to highlight the importance of COVID-19 vaccines in bringing an end to the pandemic. Of all available vaccines, mRNA-based and adenoviral vector-based COVID-19 vaccines have shown the highest efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19.

In addition, to protect against infection, these vaccines may reduce the risk of viral spread by reducing viral load and shedding duration. In this context, studies have shown that intramuscular administration of the 1st dose of COVID-19 vaccines can reduce the risk of household transmission by 40 – 50%. However, there is evidence indicating that a small proportion of vaccinated individuals can still acquire SARS-CoV-2 infection and can transmit the virus to others.   

Despite inducing robust systemic antibody and T cell responses, these vaccines may not always induce mucosal immunity in the form of secretory IgA antibodies and tissue-resident memory T cells. In the case of respiratory infection, secretory IgA antibodies play a vital role in neutralizing the virus at the mucosal surface, which significantly prevents the further spread of the virus. As evidenced in several preclinical and clinical trials, intranasal administration of protein-based vaccines is highly effective in inducing robust mucosal immunity and providing immediate protection against respiratory infection.

In the current study, the scientists have described the immunogenicity and protective efficacy of heterologous prime-boost immunization with an intramuscular DNA- or mRNA-based vaccine (prime) and an intranasal adenovirus vector-based vaccine (boost).

Immunogenicity of DNA – adenoviral vector prime-boost immunization

The scientists immunized mice with an intranasal adenoviral vector-based vaccine either as a single shot or four weeks after intramuscular prime immunization with a DNA vaccine. In both vaccines, full-length SARS-CoV-2 spike and nucleocapsid proteins were incorporated as vaccine antigens.

The analysis of antibody responses 2 weeks after immunization revealed that the prime-boost immunization strongly induced IgG-specific anti-spike antibodies in serum; however, a single shot of intranasal vaccine failed to induce mucosal antibody responses. A similar trend was observed for neutralizing antibody responses. Furthermore, the estimation of anti-spike IgA response in respiratory samples revealed that the intranasal vaccine-induced antibody response was benefited from the systemic response induced by DNA prime vaccination.

Regarding cellular immunity, the highest number of spike-specific, IFNγ-producing CD8+ T cells was observed in the lungs of prime-boost immunized mice. Similarly, high levels of Spike- and nucleocapsid-specific polyfunctional CD4+ T cells were observed in mice following prime-boost immunization.      

Immunogenicity of mRNA – adenoviral vector prime-boost immunization

The mRNA-based COVID-19 vaccine developed by Pfizer/BioNTech was used to prime immunize the mice. For analysis, the scientists immunized the mice with three different regimens: intramuscular mRNA vaccine followed by intranasal adenoviral vector vaccine; two intramuscular shots with mRNA vaccine; and two intramuscular shots with adenoviral vector vaccine.

The analysis revealed that the homologous mRNA vaccination-induced significantly higher anti-spike IgG antibody levels in serum compared to other vaccination regimens. However, the heterologous prime-boost immunization caused comparatively higher induction of anti-spike IgGs in respiratory samples. Similarly, higher levels of IgA-specific anti-spike binding and neutralizing antibodies were observed in respiratory samples following heterologous prime-boost immunization.

Regarding neutralization of SARS-CoV-2 variants, the findings revealed that compared to the intramuscular – intranasal heterologous prime-boost immunization, only intramuscular administration of two vaccine doses induced 4 – 32-fold lower neutralizing antibody titers against the B.1.1.7, P1, and B.1.351 variants, with no neutralizing efficacy against the B.1.617.2 variant.         

Regarding lung-resident memory T cell response, the findings revealed that prime-boost immunization with mRNA and adenoviral vector vaccines had the highest efficacy in inducing robust T cell memory response in the form of both circulatory and tissue-resident T cells.

Protection against SARS-CoV-2 infection

The scientists infected immunized mice with SARS-CoV-2 four weeks after boost immunization. Compared to unvaccinated control mice, all vaccinated mice displayed protection against body weight loss, severe COVID-19, and mortality. Moreover, no viral RNA and infectious virus were detected in the lungs of vaccinated mice. Importantly, no significant difference in the level of protection was observed between different vaccination regimens.

Study significance

The study findings reveal that intramuscular RNA prime – intranasal adenoviral vector boost immunization regimen is highly effective in inducing both mucosal and systemic adaptive immune responses against SARS-CoV-2 and its variants. The protective efficacy of this vaccination regimen against acute infection is equivalent to the currently approved regimen of intramuscular homologous prime-boost immunization.

*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.

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