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

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

Background

Although the coronavirus disease 2019 (COVID-19) pandemic has been one of the most severe global respiratory virus emergencies, with more than 661 million cases worldwide and 6.7 million deaths, viruses and respiratory bacteria have been a constant source of 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 nearly 2.5 million deaths and more than 17.7 billion upper and lower respiratory tract infections worldwide.

Current vaccines against respiratory diseases are administered intramuscularly, 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 have the advantage of targeting viruses at the site of entry, establishing protection and to limit infection early. Additionally, the ease of administering intranasal vaccines through aerosol sprays makes them a noninvasive and simple method that could potentially increase vaccination rates.

About the study

In the present study, researchers used Syrian golden hamsters to investigate the protective efficacy and immunogenicity of the intranasal mRNA-LNP vaccine. Two LNP compositions were used to formulate the vaccine. The two 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 better airway delivery. The vaccines carried a segment of mRNA encoded for SARS-CoV-2 stabilized by prefusion spike protein.

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

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

Hamsters in the vaccinated and control groups were challenged intranasally with SARS-CoV-2 three weeks after the second vaccine dose. The USA-WA1/2020 isolate was selected for the viral challenge because 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 subgenomic viral RNA levels in respiratory tissues to determine viral load. Since SARS-CoV-2 infections are known to cause severe lesions in the lungs of Syrian golden hamsters on day three of infection, histopathological examination of the lungs was performed on days three and 14 post-infection. infection to understand the efficacy of the mRNA-LNP vaccine in reducing lung pathology. Lung tissue samples were also stained by immunohistochemistry for SARS-CoV-2 nucleocapsid protein to identify infected cells.

Results

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

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

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

conclusion

Taken together, the results suggest that mRNA-LNP vaccines administered intranasally, particularly when the LNP is modified to improve vaccine delivery to respiratory tissues, can induce IgA and IgG levels of comparable binding and neutralizing antibody levels against the SARS-CoV-2 spike protein as intramuscular vaccines.

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

*Important Notice

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