A Better Test for Zika

Max Essex and Wei-Kung Wang

Wei-Kung Wang’s Work on Flaviviruses

Timing is everything. Dr. Wei-Kung Wang returned to Harvard in early March, just as the World Health Organization (WHO) declared the Zika outbreak to be a Public Health Emergency of International Concern.

Boston was a homecoming of sorts for Wang. Originally from Taiwan, he received his MD from National Taiwan University in 1986 and his doctorate in virology from the Harvard School of Public Health in 1995. As a student and postdoc at Harvard, he worked on HIV with Dr. Max Essex, Chair of the Harvard T.H. Chan School of Public Health AIDS Initiative (HAI) and Dr. Tun-Hou Lee. After Harvard, Wang returned to Taiwan and switched the focus of his research to dengue virus.

“He’s recognized as one of the world’s experts on dengue virus,” said Essex. Dengue virus is a flavivirus, in the same family as Zika, West Nile, and yellow fever viruses. About 390 million people are infected with dengue every year. Infection may cause a flu-like illness, and occasionally death. Currently, there is no FDA-approved vaccine or antiviral treatment for dengue.

Dr. Wei-Kung Wang
Dr. Wei-Kung Wang

Wang, currently a Professor at the University of Hawaii at Manoa, elected to spend his sabbatical back at Harvard. He is developing a blood test that can distinguish between different members of the flavivirus family.

In mid-February, as cases of microcephaly—a condition in which a baby’s head is significantly smaller than expected— continued to increase in Brazil, the WHO advised pregnant women to avoid traveling to areas affected by the Zika outbreak. Like dengue, Zika is transmitted primarily through infected mosquitoes.

Determining whether a pregnant woman or anyone else has been infected with Zika can be difficult. If a person is tested during the acute stage of infection, usually within two weeks of the onset of symptoms, and a sample of bodily fluid tests positive for the Zika sequence by PCR, a positive diagnosis can be made. However, many clinics in developing countries may not have access to PCR facilities. In addition, most people infected with Zika virus or other flaviviruses are asymptomatic; they show no obvious signs of infection.

After the acute stage of infection, it’s possible to tell if someone has been exposed to a flavivirus, but not which one. When the flavivirus clears, what remains are antibodies—proteins produced by the body’s immune system to recognize and neutralize the virus. The antibodies to Zika generally cross-react to other members of the flavivirus family, such as dengue, West Nile, and yellow fever viruses, making it very difficult to determine the specific flavivirus.

Wang, whose area of expertise is the antibody response to dengue virus, is making progress in solving the cross-reactivity problem. His goal is to develop a blood test that will specifically identify Zika, dengue, and other flaviviruses. Though his sabbatical ended in late September, his newly-formed collaborations with Harvard colleagues will continue. What his collaborators have in common is a background in HIV research.

This doesn’t surprise Max Essex. “Wei-Kung Wang’s thesis work was on the envelope of HIV and how it evolves through immune-selection pressure to evade immune control. It turns out that working on HIV is an ideal preparation for working on certain other diseases like dengue and Zika,” said Essex. “If you’ve seen a virus as complicated as HIV, you’ve seen a very wide range of questions and challenges that viruses can make.”

Wang agrees. “When I started working on different viruses, a lot of my knowledge and background about HIV helped me think through how we were going to study another virus.”

For his work on Zika, one of Wang’s collaborators is Dr. Carlos Brites, a Professor of Infectious Diseases and Head of the Virology Research Laboratory at Universidade Federal da Bahia in Brazil. In 1998, Brites was a Visiting Scientist conducting HIV research in the Essex Lab at Harvard.

This year, besides the alarming Zika outbreak in Brazil, there was a severe yellow fever outbreak in Angola and Congo. Working with Dr. Phyllis Kanki, a Professor of Immunology and Infectious Diseases at Harvard Chan, Wang hopes to learn more about flaviviruses in Africa. “We really don’t know much about the flaviviral seroprevalence in that population,” said Wang. Kanki has studied infectious diseases in Africa for decades, especially HIV in Nigeria, a country that also has yellow fever and dengue.

“We need to have some specific serological assay to distinguish different flaviviruses,” said Wang. “All of the outbreaks of emerging and re-emerging flaviviruses in different parts of the world reinforced my idea that this is important.”

Title image: Drs. Max Essex (left) and Wei-Kung Wang in Essex’s office. Photo by Lucia Ricci.