Development of an mRNA vaccine against a panel of heterologous H1N1 seasonal influenza viruses using a consensus hemagglutinin sequence

Abstract

Seasonal influenza, causes hundreds of thousands of deaths annually, posing a severe threat to human health. Currently available influenza vaccines are targeted only at specific strains or conserved epitopes; however, these vaccines are not completely efficacious because influenza viruses can undergo mutation during circulation, leading to antigenic mismatch between recommended strains and circulating strains and elusion from the immune system. Therefore, developing an influenza vaccine that is quick, effective, and broadly protective has become crucial, and the integral part of hemagglutinin (HA) remains an ideal target for vaccine development. This study developed a lipid nanoparticle-encapsulated nucleoside-modified mRNA vaccine (mRNA-LNPs) encoding a consensus full-length HA sequence (H1c) and evaluated its protective efficacy and immunogenicity through in vitro and in vivo assays. Following two intramuscular immunizations (2, 10 µg, or 20 µg) at a 3-week interval in BALB/c mice, H1c-mRNA-LNP vaccine induced strong antibodies as shown in the hemagglutination-inhibition test and protective neutralizing antibodies against numerous heterologous H1N1 influenza viruses as shown in the microneutralization assay. Additionally, both Th1- and Th2-biased cellular immune responses were elicited, with the Th1-biased response being stronger. Two doses of the H1c-mRNA-LNP vaccine could neutralize a panel of heterologous H1N1 influenza viruses and could confer protection in mice. Taken together, these findings suggest that the H1c-mRNA-LNP vaccine encoding a consensus full-length HA is a feasible strategy for developing a cross-protective vaccine against a panel of heterologous H1N1 influenza viruses.

mRNA vaccines encoding computationally optimized hemagglutinin elicit protective antibodies against future antigenically drifted H1N1 and H3N2 influenza viruses isolated between 2018-2020

“…In recent years, the development and commercialization of mRNA vaccines has revolutionized the field of vaccinology. Large quantities of mRNA vaccines can be produced in relatively short time frames compared to traditional methods of generating influenza virus vaccines in embryonated chicken eggs ( 17 , 24 , 26 , 27 ). This is highly advantageous when designing vaccines against pathogens that undergo constant antigenic drift, like influenza viruses, where the ever-changing viral landscape can lead to reduced vaccine efficacy, if the antigens included in the vaccine are not closely related to circulating strains ( 17 , 33 , 57 , 58 ).…”

“…A2021-06-016-Y3-A6). At the beginning of the study the mice were randomly divided into 10 groups (n=11 mice/group), and vaccinated intramuscularly with 50μL of a solution containing 1μg of mRNA vaccines encoding the HA proteins of either the H1 COBRA Y2, H1 A/California/07/2009 (EPI_ISL_159428, EP3), H3 COBRA NG2 or H3 A/Kansas/14/2017 (EPI_ISL_403059, MDCK-SP2) in phosphate buffered saline (PBS) (Thermo Fisher, Waltham, MA, USA), or 50μL of PBS alone as a placebo control vaccine ( 24 , 30 , 50 ). The vaccines were administered as either a monovalent (1μg) or bivalent (H1 + H3) (1μg each) formulation intramuscularly into the hamstring of the hind leg of the mice on the first day of the study and again on day 28.…”

“…Production time to manufacture influenza vaccines can fluctuate depending on the delivery platform, such as inactivated virus, live attenuated virus, recombinant subunit, peptide, virus-like particle, mRNA, and DNA vaccines ( 24 – 26 ). Among those, mRNA vaccines are advantageous as they can be manufactured rapidly, generate protective immune responses, use no infectious material in their production, and offer advantages over other platforms, such as DNA, because there is no risk of incorporating into the host genome ( 24 , 25 , 27 ). The production speed of mRNA vaccines was exemplified in 2021, when vaccines for SARS-CoV-2 were advanced from receipt of the sequence to phase 1 clinical trials in ~2 months ( 17 , 20 ).…”

“…mRNA encoding vaccine antigens also generate protective antibodies and robust antigen specific cellular immune responses in vaccinated animals ( 18 , 28 , 29 ). As a result, the use of the mRNA platform to deliver the next generation of influenza vaccines has gained a significant amount of interest in recent years ( 24 , 26 , 27 , 30 ).…”

A Universal Aptamer for Influenza A Viruses: Selection, Recognition, and Infection Inhibition

“…In the past decade, many universal inhibitors have been developed to inhibit viral infections. − Strategies for different types of inhibitors, including conventional antibodies, − multivalent vaccines, − peptide complexes, − small molecular drugs, , molecular imprinting sensors, − etc., continue to attract much attention. For example, Guthmiller et al have developed a class of broadly neutralizing antibodies (bnAbs) that target epitopes of the heme­agglutinin (HA) protein, which can broadly neutralize H1 viruses and cross-react with H2 and H5 viruses.…”