Live vaccine
An interferon-sensitive mutant virus will help create a universal flu vaccine
Daria Spasskaya, N+1
By introducing several mutations into the influenza virus, the researchers managed to create a strain that is particularly sensitive to interferon, which in animal experiments has shown its effectiveness as a live attenuated vaccine. Infection with this strain caused a strong interferon response in experimental mice and ferrets and provided protection from subsequent infections not only by the "parent" form of the virus, but by other subtypes of the influenza A virus. The study was published in Science (Du et al., Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design).
Interferons provide innate antiviral protection of the body and modulate adaptive cellular immunity to strengthen the fight against infection. The induction of the interferon response involves the activation of hundreds of genes, many of which encode proteins with antiviral activity. However, viruses often have the ability to suppress interferon production by cells, including the flu virus.
One of the directions in the development of influenza vaccines is the creation of interferon–sensitive virus strains. Infection with such a strain as a live vaccine should stimulate both the innate interferon and T-cell immune response, not limited by antibodies to certain virus proteins that mutate at a high rate.
It is known that the multifunctional viral protein NS1 is involved in the suppression of the interferon response. In a new paper, researchers from the University of California in the USA and Zhejiang University in China conducted an exhaustive mutagenesis of influenza A virus genes and found several dozen mutations in other genes that slowed down the reproduction of the virus in cells capable of producing interferon. In interferon-deficient cells, these mutations did not reduce the rate of virus replication.
The authors selected the six best mutations, three of which got into the PB2 protein necessary for transcription of viral genes in cells, and three into the M1 matrix protein, and introduced them into the genome of the influenza A virus subtype H1N1. Two known mutations in the NS1 gene were added to these mutations. The resulting strain had a significant sensitivity to interferon and was called HIS (hyper–interferon-sensitive).
In experiments on mice and ferrets, the HIS strain did not cause visible signs of the disease (which were assessed by weight loss by animals), even at a dose 20 times higher than the lethal dose of wild-type virus. At the same time, immunization of animals caused the appearance of antibodies to various virus proteins and antigen-specific CD8 T cells of immunity in the blood serum.
To test how "broad" immunity is produced with such a vaccine in animals against the influenza virus, mice previously immunized with the HIS strain were infected with "unrelated" strains of subtypes H1N1 and H3N2. It turned out that even against these strains, animals develop a secondary T-cell response, increased survival and improved various clinical indicators compared to mice that were not vaccinated.
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