March 1, 2024

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Can an universal mRNA flu vaccine be against all 20 virus subtypes?

Can an universal mRNA flu vaccine be against all 20 known influenza virus subtypes?



Can an universal mRNA flu vaccine be against all 20 known influenza virus subtypes?

The development of a universal influenza vaccine that provides broad and durable protection against a variety of circulating and emerging influenza viruses is a longstanding goal of public health and pandemic prevention.

Influenza A virus is a zoonotic virus that infects a variety of animals and has the potential to spill over from animal hosts to cause a pandemic in humans.

The main target of the protective antibody response induced by traditional influenza virus vaccines is hemagglutinin (HA) , a surface glycoprotein critical for viral attachment to respiratory epithelial cells.

However, there are currently 18 known HA subtypes of influenza A virus and 2 HA subtypes of influenza B virus, and developing a vaccine that protects against all 20 HA subtypes faces enormous technical, immunological, and regulatory challenges .

Current routine seasonal inactivated influenza vaccines target three or four hemagglutinin (HA) subtypes, namely trivalent and quadrivalent vaccines, capable of eliciting major strains targeting the hemagglutinin subtypes included in the vaccine specific immune response. But unfortunately, the seasonal flu vaccine offers little protection against new influenza subtypes, making it unsuitable for preventing pandemics.

The COVID-19 pandemic has driven innovation in vaccine development, allowing mRNA technology to stand out from various vaccine technologies.

Nucleic acid-based mRNA vaccines consist of artificially synthesized mRNA templates encoding specific viral glycoprotein antigens (such as the spike protein of the new coronavirus) , which are translated into proteins once the mRNA is delivered into cells.

To achieve efficient delivery of mRNA in vivo, mRNA needs to be chemically modified to improve its stability, prevent its degradation, and enhance translation efficiency, and then encapsulate it in lipid nanoparticle (LNP) delivery vehicles .

The rapid scalability of vaccines based on mRNA technology, combined with their proven safety, robust immunogenicity, and high efficacy, allow them to respond flexibly to the COVID-19 pandemic.

As demonstrated by the bivalent COVID-19 mRNA vaccine (which simultaneously protects against the original COVID-19 strain and the Omicron strain) , the mRNA vaccine platform has the advantage of rapidly incorporating new variants.

On November 24, 2022, researchers from the Perelman School of Medicine at the University of Pennsylvania published a research paper entitled: A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes in the journal Science .

The study developed an experimental mRNA vaccine against all 20 known influenza virus subtypes , which can provide broad protection, significantly reduce signs of disease and avoid death, and is expected to become a general measure to prevent future influenza pandemics.

Can an universal mRNA flu vaccine be against all 20 virus subtypes?

Immunization of mice intramuscularly with this “cocktail” of mRNA, each encoding a full-length hemagglutinin (HA) isoform , successfully elicited high levels of antibodies against the influenza virus, regardless of whether the mice had previously have been exposed to the flu virus.

These antibodies persisted for at least 4 months and produced a strong and specific immune response to all 20 influenza virus subtypes.

Can an universal mRNA flu vaccine be against all 20 virus subtypes?

The study also showed that the mRNA vaccine induced specific immune responses against each influenza virus subtype, rather than broadly cross-reactive antibodies against a range of hemagglutinins.

This is a clear departure from previous strategies to develop a universal influenza vaccine targeting conserved antigens of different subtypes of influenza virus .

The research team challenged mice with the virus 28 days after a single dose of the vaccine, and the results showed that the mice were fully protected (no mice died) against the matched H1N1 influenza virus ( A/California/07/2009) .

However, for the mismatched heterologous HIN1 influenza virus (A/Puerto Rico/8/1934) , the vaccine failed to completely suppress virus replication in the lungs of mice and failed to provide complete protection (20% of mice died after infection) .

These data suggest that this 20-valent mRNA vaccine cannot protect against heterologous virus challenge .

But the team then gave two doses of the vaccine to ferrets, the “gold standard” model for studying the pathogenesis of influenza viruses, and the results showed that the vaccine induced antibodies against multiple subtypes of the influenza virus in a significant manner.

Improves the severity of influenza virus infection and also protects ferrets from lethal challenges with mismatched susceptible H1N1 viruses.

The application of mRNA technology to novel influenza vaccines will allow the design of vaccines containing multivalent mRNAs that match multiple influenza virus strains, have a rapid adaptive response to virus evolution, and can also be used to develop combined vaccines against influenza and non-influenza.

The mRNA vaccine reported in this Science paper contains the hemagglutinin antigens of all 20 known influenza virus subtypes, similar to existing multivalent pneumococcal vaccines, and each antigen expressed can be used to prevent a specific subtype. The mRNA technology does not need to choose between the two.

The mRNA technology can not only achieve specific immunity against different influenza virus subtypes, but also encode conserved antigens at the same time to achieve broader reactive immunity.

Clinical trials of mRNA influenza vaccines representing both options (against combinations of influenza virus subtype antigens, and against influenza virus conserved antigens) are ongoing, and careful attention to safety assessments is critical, for example, the previous mRNA COVID-19 The vaccine has very low side effects of myocarditis, and further evaluation is needed to evaluate whether this side effect is related to the mRNA vaccine platform or only to the mRNA COVID-19 vaccine. In addition, it needs to be assessed whether the side effects are related to the type .

A major goal of pandemic prevention is to expand vaccine manufacturing capacity to countries and regions that have traditionally relied on external suppliers.

As far as the COVID-19 epidemic is concerned, the countries that have the ability to develop and produce vaccines are the countries that launched the COVID-19 vaccine early.

Vaccine inequality has always existed in countries and regions without vaccine production capacity. The mRNA vaccine platform is less demanding in production and does not require complex cell culture steps, providing new opportunities for more equitable distribution of vaccines.

Paper link :
https://www.nejm.org/doi/full/10.1056/NEJMcibr2215281
https://www.science.org/doi/10.1126/science.abm0271

Can an universal mRNA flu vaccine be against all 20 virus subtypes?

(source:internet, reference only)


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