A combined flu and COVID-19 mRNA vaccine


The coronavirus disease 19 (COVID-19) pandemic, which was caused by the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has negatively impacted the health of people around the world. To date, more than 584 million have been infected with SARS-CoV-2, of whom more than 6.4 million have died.

The clinical signs of COVID-19 can range from a cough, fever and sore throat to mild or severe pneumonia and acute respiratory distress syndrome (ARDS).

Study: Rational development of a combined mRNA vaccine against COVID-19 and flu. Image credit: taa22/Shutterstock.com

Background

The spread of other respiratory epidemic diseases during the cold season increases the risk of co-infections with two or more respiratory pathogens.

One of the most common respiratory pathogens is the influenza virus, which has previously been reported to infect along with SARS-CoV-2. Both viruses have similar transmission routes and cause similar clinical symptoms after infection.

Several recent studies have suggested that influenza infection may facilitate the entry of SARS-CoV-2 into host cells, which can then lead to severe pneumonia and lung lesions. Co-infection with influenza and SARS-CoV-2 has also been reported to cause severe weight loss and increased deaths in mammals. Therefore, there is an urgent need to develop a combined vaccine that provides protection against both SARS-CoV-2 and influenza.

Recently, messenger ribonucleic acid (mRNA) based vaccines with a lipid nanoparticle (LNP) delivery system have been used to reduce the spread of SARS-CoV-2. Several mRNA vaccine candidates against flu and other respiratory diseases are currently in different stages of development.

a new npj vaccines study describes the efficacy of an mRNA vaccine called ARIAV, which encodes the hemagglutinin (HA) antigen of the influenza A virus (IAV) H1N1. ARIAV was then incorporated into a previous LNP-encapsulated mRNA (mRNA-LNP) vaccine (ARCoV) encoding the SARS-CoV-2 receptor binding domain (RBD) to design a combined vaccine formulation called AR-CoV/IAV. named.

Design and characterization of ARIAV mRNA-LNP encoding HA protein of the influenza A (H1N1) virus as a vaccine candidate.  a schematic diagram of ARIAV, which encodes the full-length HA protein.  b Indirect immunofluorescence assay of HA protein expression in HEK293T cells 48 hours after transfection.  Scale bar, 20 m. c HA expression in HEK293T cells was determined by immunoblotting.  d HA specific IgG antibody titers were determined by ELISA.  Hemagglutination Inhibition (HAI) titers were determined 14 and 28 days after the first immunization.  Data are presented as the mean ± SEM (n = 8).  Statistical differences were analyzed using two-tailed unpaired t-tests.  *P < 0.05,**P < 0.01, ***P < 0,001.Design and characterization of ARIAV mRNA-LNP encoding HA protein of the influenza A (H1N1) virus as a vaccine candidate. a Schematic diagram of ARIAV, which encodes the full-length HA protein. b Indirect immunofluorescence assay of HA protein expression in HEK293T cells 48 hours after transfection. Scale bar, 20 m. c HA expression in HEK293T cells was determined by immunoblotting. d HA specific IgG antibody titers were determined by ELISA. e Hemagglutination Inhibition (HAI) titers were determined 14 and 28 days after the first immunization. Data are presented as the mean ± SEM (n = 8). Statistical differences were analyzed using two-tailed unpaired t-tests. *P < 0.05, **P < 0.01, ***P < 0.001.

About the study

The study involved the synthesis of mRNA encoding the complete HA of IAV and the SARS-CoV-2 RBD, followed by LNP formulation of the mRNA and transfection. Six to eight week old female BALB/c mice were immunized with equal doses of ARIAV, AR-CoV/IAV or placebo, followed by a booster dose 14 days later.

Serum samples were collected from the mice before administration of the vaccines, as well as 14 and 28 days after administration. Some of the mice were sacrificed after the challenge with one of the viruses or co-infection with both viruses for histopathological analyzes and viral detection.

The enzyme-linked immunosorbent assay (ELISA) was used for the detection of SARS-CoV-2 and IAV specific IgG antibodies. Thereafter, pseudovirus-based neutralization assay, hemagglutination inhibition (HAI) assay, enzyme-linked immunospot (ELISPOT) assay, and multiplex immunofluorescence assay were performed.

Total RNA was isolated from infected mice and quantified by the quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay, followed by on sight hybridization test. Flow cytometry was also performed, followed by histopathological, cytokine, chemokine and phylogenetic analyses.

Study findings

ARIAV was found to induce an HA-specific IgG antibody response, as well as an increase in HAI titers that continued to rise in a dose-dependent manner after booster immunization. Vaccination with two doses of AR-CoV/IAV protected against IAV and SARS-CoV-2 infection.

AR-CoV/IAV was observed to activate antigen-specific CD4+ and CD8+ T cell responses, along with the secretion of several cytokines, including interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon (IFN -γ).

Histopathological analysis revealed pathological changes in the lung sections after IAV and SARS-CoV-2 infections in the placebo group. However, no pathological changes were observed in AR-CoV/IAV vaccinated mice after infection.

High levels of viral RNA were detected in both IAV and SARS-CoV-2 infected mice that received the placebo vaccine after infection. AR-CoV/IAV immunization reduced viral RNA load after infection and conferred protection against IAV and SARS-CoV-2 infection.

In addition, AR-CoV/IAV immunization protected infected mice from severe weight loss. This vaccine was also shown to protect against infection with the SARS-CoV-2 Alpha and Delta variants. In addition, AR-CoV/IAV vaccination reduced the levels of pro-inflammatory cytokines and chemokines, and provided protection against co-infection with IAV and SARS-CoV-2.

conclusions

The present study showed that a combined mRNA vaccine is able to induce broad and durable protection against SARS-CoV-2 and IAV co-infection, as well as against multiple SARS-CoV-2 variants. Further development of universal vaccines is important to control the COVID-19 pandemic and the spread of other respiratory viruses.

Reference magazine:

  • Ye, Q., Wu, M., Zhou, C., et al. (2022). Rational development of a combined mRNA vaccine against COVID-19 and influenza. npj vaccines 84.doi:10.1038/s41541-022-00478-w.
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