Synthetic Influenza Vaccine Viruses

Philip R. Dormitzer, MD, PhD

Global Head of Virology and US Head of Research, Novartis Vaccines
National Academy of Sciences Symposium on Potential Risks and
Benefits of Gain of Function Research. Session 5.
December 15, 2014

2009 pandemic vaccine response fastest ever, but

still came after the disease peak

Substantial vaccine quantities only available after the 2nd pandemic wave peaked
Every week of acceleration in vaccine supply would have prevented an additional ~300,000
to 430,000 US cases (Borse et al., EID 19, 2013, 439-48)

2 | NAS GoF Symposium | P. Dormitzer | Dec 2014

With SGVI and JCVI, established a process for rapid

generation of synthetic influenza viruses

Synthetic biology improves the speed of vaccine seed generation

Enzymatic error correction improves the accuracy of seed generation
Optimized backbones produce superior virus and HA yield
Process robustness shown by making >50 synthetic flu A and B virus strains

3 | NAS GoF Symposium | P. Dormitzer | Dec 2014

Chronology
Novartis H7N9 response the first days
March 31 China reports the first 3 human infections with H7N9 influenza, 2 of
them fatal. The China CDC posts sequences on GISAID.
Viral coding
region sequences
posted online

March 31 April 1
HA and NA
gene
synthesis
started

Genes received at NVD

Virus rescue started
Genes shipped to CDC

April 2

April 3

Gene
assembly
completed

April 4

Genetic identity of
viruses confirmed

April 5

April 6

April 7

April 8

First evidence of
virus rescue!

April 11 US CDC receives wild type virus from China, enabling the start of
reassortment to generate a conventional vaccine virus

4 | NAS GoF Symposium | P. Dormitzer | Dec 2014

The Novartis H7N9 influenza vaccine response

The science is there, the systems and policies must catch up

March

April

May

June

Synthetic virus rescue in collaboration with

Synthetic Genomics Vaccines Inc.
5 | NAS GoF Symposium | P. Dormitzer | Dec 2014

Lessons from vaccine responses for GoF regulation

Must craft carefully to avoid impeding rapid vaccine supply
Useful finding of H5N1 GoF experiments for vaccine development
existing H5N1 vaccines likely cover the transmissible strains

USDA permitting to protect poultry slowed the US H7N9 vaccine response

and forced Novartis to move vaccine development to Germany

Select Agent regulations could delay the vaccine response to a high path
H5N1 avian flu pandemic by weeks to months

Even predictably attenuated vaccine viruses ( 26 strains tested) presumed to be

select agents until attenuation confirmed experimentally in chickens
Cant start vaccine production under select agent conditions meeting
requirements could make sites non-viable for seasonal vaccine manufacturing

In a high path influenza pandemic, every day of delay for permitting and
deliberation could cost 10s of thousands of US lives

If adaptation of vaccine viruses to increased growth and HA yield in

manufacturing captured by GoF regulations, an additional unintended

impediment to a timely vaccine supply would be created
6 | NAS GoF Symposium | P. Dormitzer | Dec 2014