Research ArticleVaccines

Synthetic Generation of Influenza Vaccine Viruses for Rapid Response to Pandemics

Science Translational Medicine  15 May 2013:
Vol. 5, Issue 185, pp. 185ra68
DOI: 10.1126/scitranslmed.3006368

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Unlike the public health successes of polio and smallpox vaccines, the flu vaccine has not been so effective. Part of the reason is that there are thousands of influenza virus strains and they evolve rapidly, even to the point of switching hosts, most alarmingly from animals to humans. To keep up with this ever-evolving target, a new flu vaccine is manufactured every year. However, the conventional process is slow, requiring isolation of the flu virus, cloning or reassortment steps and bulk growth in eggs, so that by the time the vaccine is available for use, the circulating flu virus is different or, worse, in the case of a pandemic, the peak of disease incidence is past. Now, Dormitzer et al. have streamlined the process considerably by synthesizing the genes needed for the vaccine directly from the sequence and designing more productive vaccine viruses. In a simulated response to a pandemic with a H7N9 bird flu—similar to the one that has recently killed numerous people in China—they show that their new procedure could shave weeks off the time needed for vaccine manufacture and put us in a much better position to respond quickly to a sudden pandemic.

The authors started with the gene sequences for the two flu proteins needed for the vaccine: hemagglutinin and neuraminidase. A custom software program calculated the sequences of needed oligonucleotides; these were generated and then the genes were built enzymatically in cell-free reactions that also included a critical error correction step. Transfection of these synthetic genes into Madin-Darby canine kidney cells, along with an assortment of improved flu backbones that coded for the other necessary viral genes, allowed the authors to select the combination that yielded the most vaccine antigen. Inoculation of ferrets with the synthetic vaccine virus produced the same immune reaction as did the natural virus.

Although the process will still need to be optimized further—it must perform in a large-scale manufacturing setting—the greatest remaining bottleneck is to convince the regulatory agencies that the method is safe and effective.