



Novartis Vaccines and Diagnostics’ Philip Dormitzer, Ph.D., and his colleagues today report in Science Translational Medicine that they have successfully started and completed a synthetic flu vaccine virus in just one week.

This achievement emanated from what Dormitzer et al., called “lessons learned” from previous inadequate and less-than timely vaccine manufacture and delivery responses during past influenza pandemics—most notably, they said, the 2009 H1N1 pandemic, during which substantial vaccine quantities were available only after the second pandemic wave had peaked.

Based on these events, the authors explained, and the U.S. government’s interest in improving the influenza vaccine manufacturing enterprise, NV&D, the J. Craig Venter Institute, Synthetic Genomics Vaccines, and the Biomedical Advanced Research and Development Authority (BARDA), U.S. Department of Health and Human Services, initiated a collaboration to develop a rapid process for synthetic vaccine generation. The Science Translational Medicine report summarizes the results of that effort.

The scientists set out to address three major technical barriers to more rapid and reliable pandemic responses: the speed of synthesizing DNA cassettes to drive production of influenza RNA genome segments, the accuracy of rapid gene synthesis, and the yield of HA from vaccine viruses.

Having received parts of the genetic code of an unknown flu virus from the U.S. Centers for Disease Control (CDC) via the internet, the team got to work. The genetic code turned out to be a strain of the avian influenza H7N9. The researchers used enzymes to assemble synthetic DNA into genes and then corrected errors in the resulting gene sequences.

To produce the synthetic vaccine, the authors started with the gene sequences for hemagluglutinin and neuraminidase, two requisite antigens for the vaccine. A custom software program calculated the sequences of needed oligonucleotides to build the gene sequences. From there, the genes were built enzymatically in cell-free reactions that included a critical error correction step. The investigators then transfected the synthetic genes into Madin-Darby canine kidney cells, along with an assortment of improved flu backbones that coded for the other necessary viral genes, allowing them to select the combination that yielded the most vaccine antigen.

Dormitzer and colleagues sent the resulting vaccine virus to the CDC, which confirmed that key parts of the needed for an effective immune response matched the disease-causing virus.

The vaccine virus also triggered the correct immune response in ferrets, the primary mammalian model for human influenza.

Using this synthetic technology, a lab near the site of an outbreak could obtain genetic information about a new virus by sequencing, and then post the information to the internet. A vaccine manufacturer could then download the genetic code of the key parts of a virus and use that information to create a tailor-made vaccine.

The investigators showed that the new procedure could potentially save weeks of development and manufacturing time needed in response to flu pandemics.

Although synthetic vaccine technology has shown promise in the lab, further work is needed to prove effectiveness in manufacturing and field implementation before the technique can be routinely used.

The study, “Synthetic generation of influenza vaccine viruses for rapid response to pandemic,” appeared May 15 in Science Translational Medicine.



























