Enhanced mucosal immune responses and reduced viral load in the respiratory tract of ferrets to intranasal lipid nanoparticle-based SARS-CoV-2 proteins and mRNA vaccines

Abstract

Background Unlike the injectable vaccines, intranasal lipid nanoparticle (NP)-based adjuvanted vaccine is promising to protect against local infection and viral transmission. Infection of ferrets with SARS-CoV-2 results in typical respiratory disease and pathology akin to in humans, suggesting that the ferret model may be ideal for intranasal vaccine studies. Results We developed SARS-CoV-2 subunit vaccine containing both Spike receptor binding domain (S-RBD) and Nucleocapsid (N) proteins (NP-COVID-Proteins) or their mRNA (NP-COVID-mRNA) and NP-monosodium urate adjuvant. Both the candidate vaccines in intranasal vaccinated aged ferrets substantially reduced the replicating virus in the entire respiratory tract. Specifically, the NP-COVID-Proteins vaccine did relatively better in clearing the virus from the nasal passage early post challenge infection. The immune gene expression in NP-COVID-Proteins vaccinates indicated increased levels of mRNA of IFNα, MCP1 and IL-4 in lungs and nasal turbinates, and IFNγ and IL-2 in lungs; while proinflammatory mediators IL-1β and IL-8 mRNA levels in lungs were downregulated. In NP-COVID-Proteins vaccinated ferrets S-RBD and N protein specific IgG antibodies in the serum were substantially increased at both day post challenge (DPC) 7 and DPC 14, while the virus neutralizing antibody titers were relatively better induced by mRNA versus the proteins-based vaccine. In conclusion, intranasal NP-COVID-Proteins vaccine induced balanced Th1 and Th2 immune responses in the respiratory tract, while NP-COVID-mRNA vaccine primarily elicited antibody responses. Conclusions Intranasal NP-COVID-Proteins vaccine may be an ideal candidate to elicit increased breadth of immunity against SARS-CoV-2 variants.

Advances in intranasal vaccine delivery: A promising non-invasive route of immunization

“…In the case of IN administration of lipid nanoparticles with virus mRNAs high levels of antibodies were noted. These outcomes demonstrated the better performance of NP-based vaccine containing virus proteins when administered intranasally in ferrets animal model [96] .…”

Mucosal SARS-CoV-2 Nanoparticle Vaccine Based on Mucosal Adjuvants and Its Immune Effectiveness by Intranasal Administration

“…However, the preexisting immune response to adenovirus has raised serious concerns. Boley et al developed an intranasal lipid nanoparticle-based adjuvanted SARS-CoV-2 vaccine, which induced strong immune responses in the respiratory tract . In addition, SARS-CoV-2 nanoparticle vaccines based on ferritin nanocarrier, CpG ODN-squalene, and N , N , N -trimethyl chitosan nanoparticles have been developed to potentiate strong systemic and mucosal immunity. − …”

“…Boley tract. 36 In addition, SARS-CoV-2 nanoparticle vaccines based on ferritin nanocarrier, CpG ODN-squalene, and N,N,Ntrimethyl chitosan nanoparticles have been developed to potentiate strong systemic and mucosal immunity. 37−39 Alternatively, a mucosal SARS-CoV-2 nanoparticle vaccine (RBD-MP-cG) was prepared in the present study.…”

Can the Revolution in mRNA-Based Vaccine Technologies Solve the Intractable Health Issues of Current Ruminant Production Systems?

“…One approach that is used, particularly with MLVs, is intranasal vaccination. Boley et al [ 90 ] compared the capacity of LNP–protein and LNP–mRNA formulations (both the delivery of the spike receptor-binding domain and nucleocapsid proteins) in a SARS-CoV-2 ferret challenge–protection study following intranasal delivery. Each formulation was also evaluated in combination with monosodium urate encapsulated in the LNPs as an adjuvant.…”

“…Each formulation was also evaluated in combination with monosodium urate encapsulated in the LNPs as an adjuvant. The results of the study suggest that the LNP–protein formulation elicited balanced Th1/Th2 immune responses compared to the LNP–mRNA formulation, which elicited a biased antibody-mediated response based on the cytokine expression profiles in various respiratory tissues [ 90 ]. Of note in this study was that the mRNA formulation (two mRNAs plus an adjuvant) induced similar serum IgG responses with or without liposome encapsulation.…”