Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

Abstract

Seasonal influenza is a vaccine-preventable disease that remains a major health problem worldwide, especially in immunocompromised populations. The impact of influenza disease is even greater when strains drift, and influenza pandemics can result when animal-derived influenza virus strains combine with seasonal strains. In this study, we used the SAM technology and characterized the immunogenicity and efficacy of a self-amplifying mRNA expressing influenza virus hemagglutinin ( IMPORTANCEIn this study, we describe protective immune responses in mice and ferrets after vaccination with a novel HA-based influenza vaccine. This novel type of vaccine elicits both humoral and cellular immune responses. Although vaccine-specific antibodies are the key players in mediating protection from homologous influenza virus infections, vaccine-specific T cells contribute to the control of heterologous infections. The rapid production capacity and the synthetic origin of the vaccine antigen make the SAM platform particularly exploitable in case of influenza pandemic.

Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses

“…HAI titers were low but measurable for the 15-μg dose (two of six responders) and at the 45-μg dose (three of six responders) after a single immunization. Following a boost, titers were measurable in all animals and provided protection to a homologous challenge strain 45 . In another study, mice singly immunized against H1N1 (A/WSN/33), receiving a self-amplifying mRNA, showed no IgG responses after 7 days.…”

“…Unmodified, sequence-optimized mRNA was used to generate H1-specific responses in mice, ferrets, and pigs at dose levels ∼4- to 8-fold higher than tested by us 20 . Brazzoli et al 45 . evaluated a self-amplifying mRNA that expressed H1 HA from the 2009 pandemic formulated with a cationic nanoemulsion in ferrets.…”

mRNA vaccines — a new era in vaccinology

“…As little as 100 ng of an RNA replicon vaccine encoding RSV F, complexed to LNP, resulted in potent T and B cell immune responses in mice, and 1 μg elicited protective immune responses against RSV infection in a cotton rat intranasal challenge system 19 . SAM vaccines encoding influenza virus antigens in LNPs or an oil-in-water cationic nanoemulsion induced potent immune responses in ferrets and conferred protection from homologous and heterologous viral challenge in mice 94–96 . Further studies demonstrated the immunogenicity of this vaccine platform against diverse viruses in multiple species, including human cytomegalovirus (CMV), hepatitis C virus and rabies virus in mice, HIV-1 in rabbits, and HIV-1 and human CMV in rhesus macaques 50,87,97 .…”

Biomedical applications of mRNA nanomedicine

“…An early study demonstrated that a dose as low as 0.1 μg of SAM vaccine encoding respiratory syncytial virus fusion glycoprotein (RSV-F) in an LNP delivery system produced effective cellular and humoral immune responses in mice, and 1 μg elicited potent immune responses and conferred protection from further RSV infections in cotton rats [142]. Immunization with SAM vaccines encoding influenza virus hemagglutinin (HA) in a cationic nanoemulsion protected mice from influenza virus challenges [143, 144]. In other studies, SAM vaccines encoding influenza antigens were successfully delivered to DCs by chitosan-nanoparticles and PEI-based polyplexes, which were also reported to successfully induce humoral and cellular immune responses in mice [145, 146].…”