Previously Banned Flu Research Yields New Vaccine Model

    A controversial technique to create flu viruses, now effectively banned, led to the discovery of a flu vaccine model that could be more reliable than today’s main method using chicken eggs, according to a study by UW-Madison scientist Yoshihiro Kawaoka. In 2011, researchers published a study showing that a simple “gain-of-function” mutation in the highly virulent H5N1 influenza strain allowed the virus to be transmitted by aerosol or respiratory droplet to a mammalian species—an ability it did not have prior to the site-directed mutagenesis studies. Naturally, this caused concern in both the scientific community and the general public.

    Three years later (October 2014), the National Institutes of Health placed a moratorium on all gain-of-function mutation studies involving influenza, SARS, and MERS viruses. This research “pause” was designed to allow administrators time to put proper policies in place in order to regulate this controversial research.

    Now, findings from a recently published study, all of the research for which was conducted before the 2014 moratorium, describes new technology that could allow influenza vaccines to be mass-produced more quickly and efficiently.

    Currently, most flu vaccines are manufactured using fertilized chicken eggs as vessels to grow vaccine viruses—those that are a good match for anticipated seasonal or pandemic flu strains. Flu viruses are grown in the eggs, deactivated with chemicals, and purified to create the raw material for a vaccine.

    However, the current method has several drawbacks that make it vulnerable in times of serious outbreaks. For example, since avian influenza can strike the flocks used to produce the millions of eggs required to generate the vaccines, any outbreaks could seriously impede global production rates. Furthermore, there are growing numbers of individuals that are allergic to eggs and egg byproducts who cannot receive the vaccine—putting themselves and others at risk.

    In the current study, researchers from the University of Wisconsin-Madison devised new methods to produce flu vaccines in mammalian cells much more efficiently than had been performed previously. The investigators engineered the influenza virus to replicate more efficiently in mammalian cells by looking for genetic mutations that fostered more efficient grow—leading to constructs that were able to produce the vaccine viruses in high-yield.

    “We simply looked for strains that grow well in mammalian cells and picked those mutations that contribute to high yield,” explained principal investigator Yoshihiro Kawaoka, professor of pathobiological sciences at the University of Wisconsin-Madison. “Depending on the strain, we can get between a twofold and tenfold increase in production using mammalian cells, even a twofold increase is substantial for vaccine production.”

    The findings from this study were published recently in Nature Communications through an article entitled “Development of high-yield influenza A virus vaccine viruses.”

    In addition to circumventing the limitations of egg-based vaccine production, the advances described by the researchers are more versatile, as vaccine production can be altered or ramped up more easily. “You can scale up cell-based vaccine production very quickly,” Dr. Kawaoka noted.

    Dr. Kawaoka and his colleagues hope that new NIH guidelines will allow for a controlled amount of research to be performed on influenza strains, as their current study approach showed that not only could mammalian cell-based vaccine production be dramatically improved, but increased yields in currently used egg culture systems were also observed.

    “Existing strains of flu vaccine virus don’t grow well in cells and there is only one company in the United States currently using cell-based production methods,” stated Dr. Kawaoka. “But there is a trend toward cell-based production and we think this work can contribute to that.”