Skip to main content

Development of an Intranasally- and Intramuscularly-Administrable #Replicon #Vaccine Efficacious Against #H5N1 #Influenza Virus

Abstract

The risk of a respiratory viral pandemic is significant, including from the now widespread panzootic H5N1 influenza virus, highlighting the need for effective, stable, and inexpensive vaccine technologies that elicit strongly protective immunity. Intranasal vaccines can stimulate local immune responses at the site of natural respiratory viral infection, a key characteristic that can not only reduce morbidity and mortality caused by respiratory viruses but also potentially reduce viral transmissibility to limit outbreaks. Nucleic acid vaccines are now a valuable tool in pandemic responses, with high potency and rapid adaptability to target circulating or emerging viral strains; however, data are limited on which vaccine attributes are needed for efficient transmucosal delivery and immune stimulation following intranasal delivery. To demonstrate proof of concept, here we have developed a replicon vaccine expressing an H5 influenza antigen that uses a nanostructured lipid carrier (NLC) delivery system. A relationship was established between the molar ratio of positive charges on the NLC to the negative charges on the nucleic acid (N:P ratio) and the immunogenicity of the vaccine formulations, with higher N:P ratios resulting in an increase in vaccine immunogenicity. We demonstrated the ability of this replicon vaccine to be administered via intramuscular and intranasal routes with a singular vaccine formulation. The vaccine induced systemic immunity when dosed intramuscularly or intranasally in an immunocompetent mouse model, whereas intranasal dosing uniquely stimulated a strong mucosal immune response. Moreover, a mixed intramuscular/intranasal dosing strategy using this unified formulation stimulated a balanced systemic and mucosal immune response. Finally, we demonstrated the protective efficacy of this intranasally and intramuscularly/intranasally delivered H5 replicon-NLC vaccine against morbidity and mortality in a lethal H5N1 influenza challenge ferret model. This work establishes the replicon-NLC vaccine platform as a potential novel intranasal technology for rapid pandemic response.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.03.31.646478v1

____

Comments

Popular posts from this blog

#Neuroinvasive #Oropouche virus in a patient with #HIV from extra-Amazonian #Brazil

{Excerpt} A novel reassortant Oropouche virus (OROV) lineage (with medium [M], large [L], and small [S] RNA segments : M1L2S2) has driven Brazil's largest and most geographically widespread OROV epidemic , expanding beyond the endemic Amazon basin to establish local transmission across multiple Brazilian states and other previously unaffected Latin American countries . The rapid spread of this lineage underscores its evolutionary potential and reinforces its significance as a public health threat .1 Similar to chikungunya and Zika viruses, expanding arboviruses can exhibit unexpected clinical and epidemiological shifts , including vertical transmissions , neuroinvasive effects, and potentially fatal outcomes.2–4 Although OROV typically causes self-limited febrile illness, accumulating clinical and experimental evidence suggests neurotropic potential .5 This Correspondence describes the first confirmed case of neuroinvasive OROV infection caused by the emergent M1L2S2 lineage in ext...

No evidence of immune #exhaustion after repeated #SARS-CoV-2 #vaccination in vulnerable and healthy populations

Abstract Frequent SARS-CoV-2 vaccination in vulnerable populations has raised concerns that this may contribute to T cell exhaustion , which could negatively affect the quality of immune protection. Herein, we examined the impact of repeated SARS-CoV-2 vaccination on T cell phenotypic and functional exhaustion in frail older adults in long-term care (n = 23), individuals on immunosuppressive drugs (n = 10), and healthy adults (n = 43), in Canada . Spike-specific CD4+ and CD8+ T cell levels did not decline in any cohort following repeated SARS-CoV-2 vaccination, nor did the expression of exhaustion markers on spike-specific or total T cells increase. T cell production of multiple cytokines (i.e. polyfunctionality) in response to the spike protein of SARS-CoV-2 did not decline in any cohort following repeated vaccination. None of the cohorts displayed elevated levels of terminally differentiated T cells following multiple SARS-CoV-2 vaccinations. Thus, repeated SARS-CoV-2 vaccination was...

Chimeric #hemagglutinin and #M2 #mRNA #vaccine for broad #influenza subtype protection

Abstract Since multiple and unpredicted influenza viruses cause seasonal epidemics and even high-risk pandemics , developing a universal influenza vaccine is essential to provide broad protection against various influenza subtypes. Combined with the mRNA lipid nanoparticle-encapsulated (mRNA-LNP) vaccine platform and chimeric immunogen strategy , we developed a novel cocktail mRNA vaccine encoding chimeric HAs (cH5/1-BV, cH7/3) and intact M2 (termed Fluaxe), which confers broad protection against major circulating IAVs and IBVs , as well as highly pathogenic avian influenza . Two-dose intramuscular immunization of Fluaxe in mice elicited cross-reactive neutralizing antibodies , T cell responses, and long-lived immunity, resulting in robust protection against multiple lethal influenza virus infections and severe acute lung injuries . In particular, intramuscular administration stimulated systemic immunity together with a prominent lung tropism of memory cells . Moreover, Fluaxe immuniza...