Nasal SARS-CoV-2 vaccine outperforms existing vaccines in preclinical trial

By Bhavana KunkalikarReviewed by Benedette Cuffari, M.Sc.Apr 6 2023

In a recent study published in the journal Nature Microbiology, researchers assess the role of the live-attenuated vaccine (LAV) sCPD9 in inducing systemic and mucosal immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants.

Study: Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Image Credit: TopMicrobialStock / Shutterstock.com

Introduction

Coronavirus disease 2019 (COVID-19) vaccines, currently administered through the intramuscular route, effectively stimulate the production of neutralizing antibodies, effector and central memory T-cells, germinal center B-cells, long-lived plasma cells, and nasal-resident CD8+ T-cells. The intramuscular route has lower efficacy in promoting long-lasting mucosal immunoglobulin A (IgA) and IgG responses, as well as pulmonary tissue-resident memory cell responses.

Notably, mucosal antibodies are important in reducing viral infectivity and transmission at the site of entry. Tissue-resident memory cells have faster recall responses and can recognize cognate antigens earlier due to their local positioning.

About the study

In the present study, researchers compare the immune responses and preclinical efficacy of the Pfizer-BioNTech BNT162b2 messenger ribonucleic acid (mRNA) COVID-19 vaccine, adenovirus-vectored spike vaccine Ad2-spike, and LAV sCPD9 in Syrian hamsters.

The efficiency and mechanism of action of the evaluated vaccines were evaluated in a heterologous SARS-CoV-2 Delta variant challenge condition. To this end, Syrian hamsters received one vaccine dose and were exposed to the SARS-CoV-2 Delta variant 21 days after vaccination to evaluate its effectiveness. Hamsters were administered two vaccine doses 21 days apart and were later infected with the virus 14 days after booster administration.

Histopathology was used to examine challenged hamsters and determine any lung damage caused by infection. Single-cell RNA sequencing (scRNA-seq) was performed on lung specimens to establish a correlation between inflammation levels and cellular responses.

The humoral responses of hamsters were assessed by analyzing their sera collected before and after vaccination and determining their neutralizing ability against SARS-CoV-2 variants at different time points.

Results

All vaccinations protected hamsters from weight loss induced by SARS-CoV-2 infection. However, the vaccines did not provide complete protection against SARS-CoV-2 Delta infection after a single dose, as viral RNA was still present in the respiratory tract. The sCPD9 vaccine was the only tested vaccine that successfully reduced replicating viral titers to undetectable levels within two days post-challenge (dpc).

The overall efficacy of the SARS-CoV-2 vaccine was enhanced through prime-boost vaccination. Despite a significant reduction after prime-boost vaccination, all groups exhibited detectable viral RNA in oropharyngeal specimens and lungs. Nevertheless, sCPD9-based vaccination was more effective in decreasing viral RNA levels.

Vaccinated animals exhibited a significant reduction in replication-competent vial levels in their lungs two days post-challenge (dpc). Only the sCPD9 booster vaccine effectively reduced replicating virus proportions below the detection threshold, irrespective of whether the entire vaccination series was heterologous or homologous.

Furthermore, sCPD9 was highly effective in preventing inflammation and pneumonia after a single vaccination. This was demonstrated by the reduced levels of consolidated lung areas, along with lower scores for bronchitis, edema, and lung inflammation.

Animals with different vaccination schedules showed more significant bronchial hyperplasia. Prime-boost regimens showed a similar trend, with the mRNA vaccine displaying better histological outcomes with a homologous boost.

Homologous sCPD9 prime-boost vaccination offered better lung protection against inflammation. Both heterologous and homologous sCDP9 vaccinated hamsters exhibited reduced inflammation- and infection-related genes in their lung transcriptome.

Sera from sCPD9 vaccine recipients showed higher neutralization capacity against the ancestral SARS-CoV-2 variant B.1 compared to other groups. The sCPD9 sera effectively neutralized the Beta and Delta variants, as well as the Omicron BA.1 sublineage.

The neutralization capacity against Omicron BA.1 was reduced in all cohorts, with sCPD9 sera associated with significant neutralization. Neutralizing antibodies increased over time in all cohorts by five dpc due to challenge infection.

Hamsters that received the sCPD9 or mRNA vaccine, along with the prime-only vaccination, produced more neutralizing antibodies than those that only received the prime-only vaccination. Booster vaccination improved the serum neutralization capacity for various variants, with Omicron BA.1 exhibiting the highest neutralization evasion capacity among the tested variants.

Hamsters vaccinated with mRNA+sCDP9 and prime-boost sCDP9 produced notable IgG antibody responses against the SARS-CoV-2 spike, nucleocapsid protein, and open reading frame (ORF)-3a. Comparatively, hamsters vaccinated with prime-boost mRNA and Ad2 only exhibited IgG reactivity against the spike protein.

Conclusions

The study findings presented a comparison of vaccines across different platforms, including a novel LAV that provided better protection against SARS-CoV-2 infection than other types of COVID-19 vaccines. Importantly, these findings on enhanced immunity through heterologous prime-boost vaccination align with other recent studies that utilize systemic priming and intranasal boosting with Ad-2 vector or mRNA vaccines.

Anti-SARS-CoV-2 IgA levels in the nasal mucosa are significantly higher among sCPD9-vaccinated animals. Animals vaccinated with sCPD9 showed significant improvement in protection against virus replication, lung inflammation, and tissue damage. Animals that received sCPD9 had a broader antigen recognition, likely due to the key features of LAV.