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Zika virus infection is the latest global health crisis spurring the biopharma industry to hone its vaccine development processes. The mosquito-borne illness, which caused hundreds of babies in Brazil to be born with microcephaly and a host of concomitant disabilities, could impact families for decades to come. Thousands of cases of microcephaly and other brain malformations have been reported in Brazil in the last year, with babies showing a variety of unique symptoms, including small heads, seizures, limb deformities and trouble swallowing.

More troubling, many babies whose head sizes were within what is considered to be normal range at birth are now showing signs of brain abnormalities, suggesting the impact of Zika infection is wider reaching than initially thought. This is leading researchers to explore how timing of the infection during the mother’s pregnancy affects the severity of its impact.

Like many sudden and catastrophic healthcare crisis – think Ebola in 2014 – Zika has rallied efforts across the public and private sector to rapidly develop a vaccine that will prevent future birth defects. The World Health Organization is also in the process of finalizing what it calls a “target product profile” — in essence, telling industry what kind of vaccine is likely to find the shortest path to regulatory approval. Some early clinical trials are already underway. The US Food and Drug Administration (FDA) approved human trials for two DNA-based Zika virus vaccines earlier this summer – one developed by the National Institute of Allergy and Infectious Diseases, which is currently running a phase 1 trial through the Emory Vaccine Center; and another by Inovio Pharmaceuticals, which is working with GeneOne Life Science in Seoul, South Korea and running its first trials in Miami. It is exciting progress, but these are early-stage trials, exploring whether the experimental vaccine is safe and can generate immune responses in healthy volunteers. A fully tested safe and effective Zika virus vaccine may not be available for several years. That can be frustrating for developers, regulators, and the communities hardest hit by this infection.

Go fast, but stay safe

The need for speed is of the essence in any health crisis, but it adds a new obstacle to the already complicated endeavor. Rapidly developing a vaccine for a disease that appears to be evolving – Zika virus was not known to be the cause of birth defects prior to the recent outbreak – is challenging. The novelty of this condition means there is little historic data to shape trial decision making.

Traditional clinical trials would measure prevention of infection, but 80% of infections are asymptomatic. Surrogate endpoints may be required. Epidemiologic information is still being gathered but current estimates are that the risk of congenital Zika virus after infection during the first trimester ranges from 0.88 to 13.2% which would result in an unfeasibly large clinical trial if ZCS was the primary endpoint.  Simultaneous studies of real world data with clinical trials can provide important insights into the safety and efficacy profile.

These factors make it incredibly difficult to achieve a desired risk/benefit scenario for trial research. Researchers want to be able to bring a useful product to market as quickly as possible, but safety must always be the first priority. The fact that the population most vulnerable to complications are pregnant women adds complexity. Historically, investigational drugs and vaccines have been rarely tested in pregnant women and then only after trials in non-pregnant adults have been completed. Additionally, research suggests Zika virus can infect a fetus in the first trimester before many women even know they are pregnant.

As a result, a strategy could be to vaccinate teens and pre-teens before they are sexually active, though that means the ultimate vaccine will need to be long-lasting, requiring real world late phase observational studies to track its performance over time. The Center for Disease Control has already established the US Zika Pregnancy Registry and is collaborating with state, tribal, local, and territorial health departments to collect information about pregnancy and infant outcomes following laboratory evidence of Zika virus infection during pregnancy. The data from this registry will be invaluable for ongoing vaccine research.

There are a lot of obstacles in the challenge to develop a Zika virus vaccine, and unfortunately, there are no easy solutions. The best approach is for industry, academia and government agencies to work collaboratively toward common goals, to involve epidemiology early in the process, and to be flexible and transparent enough that project teams can adapt to clinical data and real-world epidemic trends as they evolve, to make better research decisions and shorten the time it takes to bring this sorely needed vaccine to market. 

 

> This post was co-authored by Susan Tansey, Vice President and Global Head, Medical Strategy and Science