By Annette M. Boyle
SILVER SPRING, MD—Drawing on deep experience with flaviviruses that started with its namesake’s research on yellow fever in the 1800s, the Walter Reed Army Institute of Research (WRAIR) and collaborators brought two Zika vaccine candidates through early testing in just four months this spring.
A recently inked agreement with Sanofi Pasteur will accelerate development, even as testing on humans begins in several locations.
The WRAIR team started discussing a Zika vaccine in January 2016 as a natural outgrowth of its work developing vaccines against other flaviviruses, such as yellow fever, dengue and Japanese encephalitis. Increasing reports of a denguelike illness from an Armed Forces Research Institute of Medical Sciences’ laboratory in Thailand over the previous three years had already drawn some researchers into studying Zika.
Three weeks into WRAIR’s vaccine development process, Dan Barouch, MD, PhD, of Harvard Medical School and Beth Israel Deaconess Medical Center contacted Nelson Michael, MD, PhD, director of the U.S. Military HIV Research Program at WRAIR and co-lead of the Zika program.
“He said, ‘I have three Brazilian post-docs that have made a challenge model they would like to test.’ We had a vaccine that needed a challenge,” Michael recounted. “We started experiments in April, wrote the paper Memorial Day weekend and submitted it over the holiday.” The results of their work, a study demonstrating that two different vaccines protected mice from the virus, appeared in Nature less than a month later.1
The rapid spread of the disease through South and Central America and into the U.S. spurred the team to move quickly. For the WRAIR researchers, the potential impact on warfighters and readiness provided additional impetus.
“We’ve already had one servicemember come back from deployment with it and pass Zika on to his wife,” Michael said. Zika virus infection during pregnancy can cause serious birth defects, including microcephaly.
The two candidate vaccines work in very different ways. The one developed by WRAIR is a purified Zika inactivated virus vaccine (ZPIV) based on a strain from Puerto Rico. The Harvard team developed a DNA vaccine using a strain of the virus from Brazil. Both vaccine candidates safely elicited an antibody response and protected mice against Zika challenges at four weeks and eight weeks after only one shot. No virus replication was detected in any of the vaccinated mice.
WRAIR has continued development of ZPIV, and both the Harvard group and another team at the National Institute of Allergy and Infectious Diseases (NIAID) are proceeding with DNA vaccines. WRAIR favors the purified inactivated virus vaccine over the DNA vaccine because it builds on “a flavivirus vaccine platform WRAIR previously developed which has been proven to be safe, effective, and able to meet regulatory requirements of the U.S. FDA,” explained Stephen Thomas, MD, PhD, the WRAIR Zika program lead. That might make the path to licensing and broader distribution smoother.
Earlier this summer, WRAIR tested ZPIV on monkeys. “It worked really well, and generally that’s very predictive of how a vaccine will work in humans,” Michael told U.S. Medicine.
Human testing of ZPIV will start in October with WRAIR conducting one study at its clinical trials center and NIAID starting two others through its Vaccine Trials and Evaluation Units.
The WRAIR study will involve 75 participants divided into three groups of 25, Michael said. One group will be flavivirus naïve, a second group will be vaccinated for Japanese encephalitis, and the third will receive the yellow fever vaccine. All three groups will receive ZPIV to see if prior exposure to a flavivirus affects the vaccine’s effectiveness.
A study published in PNAS in June indicates that prior flavivirus exposure could well have an impact on the vaccine’s functioning. Researchers at Emory University in Atlanta found that individuals infected with dengue virus develop antibodies that cross-react with Zika virus, with some antibodies appearing to neutralize the virus and others seeming to enhance it.2
One of the two NIAID studies will specifically examine the possible relationship by testing ZPIV in Puerto Rico, where “everyone above the age of 5 has been exposed to dengue,” Michael said. “The study will tell us whether the vaccine will still be safe. Will it generate a good immune response? If so, we’ll proceed to efficacy studies in South America.”
The other NIAID study will test smaller doses of the vaccine for effectiveness.
WRAIR is well-positioned to take a leading role in Zika vaccine development with both an in-house development facility and a pilot bioproduction facility a short walk away. The bioproduction facility manufactured small batches of ZPIV for preclinical and initial human studies.
WRAIR has transferred ZPIV technology to Sanofi Pasteur to permit larger scale manufacturing and production of the vaccine. WRAIR and its research collaborators will share data related to assays developed to measure antibody response to the vaccine as well as biologic samples from the animal studies and early human trials.
“Sanofi Pasteur could be in position in early 2017 to pick up advanced development of the vaccine,” Michael said. “If it protects humans in Puerto Rico and Brazil clinical trial sites, we could prove efficacy in a year or so.”
1 Larocca RA, Abbink P, Peron JP, Zanotto PM, Iampietro MJ, Badamchi-Zadeh A, Boyd M, Ng’ang’a D, Kirilova M, Nityanandam R, Mercado NB, Li Z, Moseley ET, Bricault CA, Borducchi EN, Giglio PB, Jetton D, Neubauer G, Nkolola JP, Maxfield LF, Barrera RA, Jarman RG, Eckels KH, Michael NL, Thomas SJ, Barouch DH. Vaccine protection against Zika virus from Brazil. Nature. 2016 Jun 28.
2 Priyamvada L, Quicke KM, Hudson WH, Onlamoon N, Sewatanon J, Edupuganti S, Pattanapanyasat K, Chokephaibulkit K, Mulligan MJ, Wilson PC, Ahmed R, Suthar MS, Wrammert J. Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus. Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7852-7.