Why is egg-based production making the flu shot ineffective?

A small substitution in the egg-based production of the flu vaccine has unexpectedly become a major cause of the vaccine’s ineffectiveness, according to researchers in a recent article in PLOS Pathogens. This finding should encourage vaccine producers to use other, non-egg approaches for making vaccines, the researchers advised.

Manufacturers typically use chicken eggs for the large-scale production of vaccines. But as the influenza virus replicates in chicken eggs, it mutates to adapt to that environment, the researchers explained. This can reduce antigenicity and, in turn, lower the vaccine’s effectiveness.

Indeed, the yearly flu vaccine’s effectiveness against H3N2 viruses has been particularly low in the past decade—only 33%, by some estimates.

In this study, scientists at The Scripps Research Institute (TSRI), La Jolla, CA, structurally characterized an egg-adaptive substitution—L194P—in the H3N2 virus subtype. They found that the L194P mutation dramatically alters the structure of a region commonly targeted by antibodies, which significantly decreases the vaccine’s antigenicity.

“Now we can explain—at an atomic level—why egg-based vaccine production is causing problems,” said first author Nicholas Wu, PhD, research associate, Department of Integrative Structural and Computational Biology, at TSRI.

Dr. Wu and colleagues used high-resolution X-ray crystallography to show that the H3N2 subtype mutates a key protein, hemagglutinin glycoprotein (HA), to better attach to receptors in bird cells. To do so, the L194P mutation disrupts the region on the protein commonly recognized by the human immune system.

“Any influenza viruses produced in eggs have to adapt to growing in that environment and hence generate mutations to grow better,” explained study senior author Ian Wilson, DPhil, Hansen Professor of Structural Biology at TSRI.

Consequently, a vaccine grown in chicken eggs and containing the L194P mutation of the HA protein will not be able to trigger an effective immune response in humans, which reduces the flu shot’s protection against circulating strains of H3N2.

“Vaccine producers need to look at this mutation,” Dr. Wu advised.

Further research is needed to replace the egg-based production of vaccines, the researchers noted.

“Other methods are now being used and explored for production of vaccines in mammalian cells using cell-based methods and recombinant HA protein vaccines,” Dr. Wilson said.