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Intranasal mRNA-lipid nanoparticle vaccines elicit significant protection against SARS-CoV-2 in hamsters

In a recent study posted to the bioRxiv* preprint server, researchers from the United States evaluated the efficacy and immunogenicity of an intranasal messenger ribonucleic acid (mRNA)-lipid nanoparticle (LNP) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a hamster model.

Study: Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection. Image Credit: An13nA/Shutterstock


Although the coronavirus disease 2019 (COVID-19) pandemic has been one of the most serious respiratory virus-related global emergencies, with over 661 million cases worldwide and 6.7 million deaths, respiratory viruses and bacteria have been a constant cause for concern.

Before the emergence of SARS-CoV-2, respiratory viruses such as influenza virus and respiratory syncytial virus and bacteria such as Streptococcus pneumoniae caused close to 2.5 million deaths and over 17.7 billion upper and lower respiratory tract infections globally.

The current respiratory disease vaccines are administered through the intramuscular route, which largely induces systemic immunity and a lower level of mucosal immunity. Since most respiratory viruses enter through the mucosal route, intranasally administered vaccines that induce localized mucosal immunity and systemic immunity present the advantage of targeting the viruses at the site of entry, establishing protection, and limiting the infection early. Furthermore, the ease of administration of intranasal vaccines through aerosolized sprays makes it a non-invasive and simple method that could potentially increase vaccine uptake rates.

About the study

In the present study, the researchers used Syrian golden hamsters to investigate the protective efficacy and immunogenicity of the mRNA-LNP intranasal vaccine. Two LNP compositions were used to formulate the vaccine. Both LNPs were similar to that used in the Moderna vaccine mRNA-1273, but LNP1 had ionizable lipids that were chemically distinct, and LNP2 was modified for improved delivery to the respiratory tract. The vaccines carried an mRNA segment coded for the prefusion stabilized SARS-CoV-2 spike protein.

Each group of 10 hamsters was intranasally immunized with either two doses of 5 μg or 25 μg mRNA-LNP vaccine or tris/sucrose buffer (control group) at a three-week interval. Two additional groups were also intramuscularly immunized with a vaccine composed of the same mRNA segment as the mRNA-LNP vaccine combined with the LNP from the mRNA-1273 vaccine for comparison.

Enzyme-linked immunosorbent assay (ELISA) was used to determine the binding antibody levels of spike-specific serum immunoglobulin G (IgG) or IgA. In contrast, the plaque reduction neutralization test (PRNT) was used to measure the serum-neutralizing antibody titers to evaluate the immunogenicity of the vaccine.

The hamsters in the vaccinated and control groups were intranasally challenged with SARS-CoV-2 three weeks following the second vaccine dose. The USA-WA1/2020 isolate was selected for the viral challenge as hamsters are more susceptible to the ancestral SARS-CoV-2 strain than the recent Omicron variant. Three and 14 days after the viral challenge, the viral load in the lungs and nasal turbinates were assessed, while body weight measurements were taken daily.

Additionally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify the subgenomic viral RNA levels in respiratory tissue to determine the viral load. Since SARS-CoV-2 infections are known to cause severe lesions in the lungs of Syrian golden hamsters by the third day of infection, a histopathological exam of the lungs was conducted on days three and 14 following infection to understand the effectiveness of the mRNA-LNP vaccine in reducing lung pathology. Lung tissue samples were also immunohistochemically stained for SARS-CoV-2 nucleocapsid protein to identify infected cells.


The results indicated that the SARS-CoV-2 spike-specific IgA and IgG antibodies and the neutralizing antibody levels induced by the mRNA-LNP intranasal vaccine were comparable to those induced by the intramuscular vaccine. The antibody titers elicited by the mRNA-LNP2 vaccine were significantly higher than those induced by the mRNA-LNP1 vaccine. Furthermore, the IgA titers elicited by the mRNA-LNP2 vaccine at 25 μg dosage were higher than those induced by the intramuscular vaccine at 0.4 μg and 1 μg dosages after the first and the second vaccine dose.

Compared to the control group, the viral loads in the nasal turbinates and lungs of the hamsters in the vaccination groups were significantly lower three days after the viral challenge. In the mRNA-LNP2 vaccinated group, the viral loads were below detection levels in four hamsters.

High doses of the mRNA-LNP intranasal vaccines and the intramuscular vaccine reduced the severity of bronchial and bronchiolar inflammation. However, the pulmonary parenchymal infection levels were similar to that of the control group.


Overall, the results suggested that intranasally administered mRNA-LNP vaccines, especially when the LNP is modified to improve vaccine delivery to respiratory tissue, can induce comparable binding IgA and IgG and neutralizing antibody levels against the SARS-CoV-2 spike protein as intramuscular vaccines.

Given the ease of administration of intranasal vaccines and the comparable efficacy in protecting against severe disease, these intranasal mRNA-LNP vaccines could potentially be used as booster doses to complement the primary intramuscular vaccines.

*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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