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Influenza candidate vaccine viruses improved by amino acid substitution in hemagglutinin

Scientists at the U.S. Food and Drug Administration (FDA) developed two candidate vaccine viruses (CVVs) that may be used as the starting material for production of inactivated influenza vaccines. These CVVs protected laboratory animals against a highly pathogenic strain of Influenza A (H7N9), a potentially pandemic virus. CVVs are influenza viruses that can be used commercially to produce vaccines to prevent influenza disease.

The FDA scientists developed these CVVs by genetically modifying hemagglutinin (HA), a viral protein the influenza virus uses to bind to cells that it infects. The study also demonstrated that this modification could facilitate large-scale production of these viruses in chicken eggs and animal cells through its effects on the activity of both HA and a second viral protein, neuraminidase (NA). These two proteins are located on the surface of influenza viruses and give influenza strains their main identity and form the basis of most influenza vaccines.

Influenza A (H7N9) is an avian influenza virus, and since 2013 has caused more than 1,560 laboratory-confirmed human infections in several countries, primarily in China, of which nearly 40% were fatal. Most of the cases of human infection with this avian H7N9 virus have reported recent exposure to live poultry or potentially contaminated environments, especially markets where live birds have been sold. Therefore, developing CVVs for highly pathogenic H7N9 that could be used to produce safe and effective vaccines is essential for providing timely protection in the event of a H7N9 pandemic.

To produce enough vaccine quickly in case of a pandemic, scientists must develop CVVs that grow well in both eggs and animal cells, while ensuring they retain their low pathogenicity in animals and the ability to stimulate the immune system effectively. In particular for avian CVVs, a major obstacle to developing such vaccines is that avian CVVs do not readily grow well in mammalian cells or chicken eggs. This makes it difficult to produce enough vaccine during an emergency or in the event of a H79N pandemic.

The FDA scientists overcame this challenge by substituting an amino acid glycine with a glutamic acid at position G218E in HA, a change that affected the activity of both HA and NA during virus amplification in cells. Influenza viruses use HA molecules to bind to molecules of sialic acid on the cell surface in the initial step of infecting the cell.  However, these CVVs that FDA scientists developed facilitated the release of influenza viral particles from infected cells by cutting off sialic acid molecules on the viral surface. This could enhance viral replication for yielding more vaccine.

The FDA scientists found that the poor replication of the original, unmodified CVVs occurred because the binding of the viruses HA to the sialic acid on the cells was too strong, while cleavage of the sialic acid by NA of the newly made viruses exiting the cell was relatively weak.  Modifying the HA with the G218E amino acid substitution, however, succeeded in balancing out HA binding to sialic acid and NA cleavage this molecule. This suggests that such a modification could improve the production of vaccines using H7N9 influenza CVVs by retaining their ability to improve their ability to replicate while retaining the ability of the original virus to stimulate the immune system.

Title

A Single Amino Acid Substitution at Residue 218 of Hemagglutinin Improves the Growth of Influenza A(H7N9) Candidate Vaccine Viruses

J Virol. 2019 Jul 3. pii: JVI.00570-19. https://jvi.asm.org/content/93/19/e00570-19.

Authors

Xing Li1*, Yamei Gao1, and Zhiping Ye1*

1 Division of Viral Products, Center for Biologics Evaluation and Research, Silver Spring, Maryland USA

 *Address correspondence to: Xing Li, xing.li@fda.hhs.gov or Zhiping Ye, Zhiping.ye@fda.hhs.gov