NIH Begins Testing Investigational Zika Vaccine in Humans

August 3, 2016

​The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has launched a clinical trial of a vaccine candidate intended to prevent Zika virus infection. The early-stage study will evaluate the experimental vaccine’s safety and ability to generate an immune system response in participants. At least 80 healthy volunteers ages 18-35 years at three study sites in the United States, including the NIH Clinical Center in Bethesda, Maryland, are expected to participate in the trial. Scientists at NIAID’s Vaccine Research Center (VRC) developed the investigational vaccine—called the NIAID Zika virus investigational DNA vaccine—earlier this year.

​The study is part of the U.S. government response to the ongoing outbreak of Zika virus in the Americas. According to the Centers for Disease Control and Prevention, more than 50 countries and territories have active Zika virus transmission. In the United States and its territories, more than 6,400 Zika cases have been reported.  Although Zika infections are usually asymptomatic, some people experience mild illness lasting about a week. However, Zika virus infection during pregnancy can cause a serious birth defect called microcephaly, as well as other severe fetal defects of the brain and other organs. There are no vaccines or specific therapeutics to prevent or treat Zika virus disease.

​A safe and effective vaccine to prevent Zika virus infection and the devastating birth defects it causes is a public health imperative,” said NIAID Director Anthony S. Fauci, M.D. “NIAID worked expeditiously to ready a vaccine candidate, and results in animal testing have been very encouraging. We are pleased that we are now able to proceed with this initial study in people. Although it will take some time before a vaccine against Zika is commercially available, the launch of this study is an important step forward.

​The NIAID Zika virus investigational DNA vaccine approach is similar to that used for another investigational vaccine developed by NIAID for West Nile virus. That vaccine candidate was found to be safe and induced an immune response when tested in a Phase 1 clinical trial.

​The investigational Zika vaccine includes a small, circular piece of DNA—called a plasmid—that scientists engineered to contain genes that code for proteins of the Zika virus. When the vaccine is injected into the arm muscle, cells read the genes and make Zika virus proteins, which self-assemble into virus-like particles. The body mounts an immune response to these particles, including neutralizing antibodies and T cells. DNA vaccines do not contain infectious material—so they cannot cause a vaccinated individual to become infected with Zika—and have been shown to be safe in previous clinical trials for other diseases.

​A team of scientists here at NIAID worked tirelessly to rapidly develop this vaccine for clinical testing,” said John Mascola, M.D., director of NIAID’s VRC. “DNA or gene-based vaccines induce antibodies, but they also can activate the cell-mediated immune response, which ultimately could yield strong and durable protection against disease.

​The Phase 1 clinical trial, called VRC 319, is led by Julie E. Ledgerwood, D.O., chief of the VRC’s clinical trials program. Volunteers will be divided randomly into four study groups of 20 people each. After enrollment, all participants will receive a vaccination at their first visit via a needle-free injector that pushes the vaccine fluid into the arm muscle. Half of the participants will receive one additional vaccination eight weeks or 12 weeks later. The remaining participants will receive two additional vaccinations: one group of 20 participants will receive a second vaccine at week four and a third at week eight; the other group of 20 participants will receive a second vaccine at week four and a third at week 20. All participants will receive the same dose at each vaccination.

​Following each vaccination, participants will remain at the study site for observation for a minimum of 30 minutes so clinicians can monitor for any adverse reactions. Participants will receive a diary card to use at home to record their temperature and any symptoms for seven days following each vaccination.

​All participants will return for follow-up visits within a 44-week time period after the first vaccination so investigators can monitor their health to determine if the vaccine is safe. The study team will review patient data daily and weekly to monitor safety. A Protocol Safety Review Team will also conduct formal interim safety reviews.

​At follow-up visits, investigators will also take blood samples for laboratory testing to measure the immune response to the vaccine. Participants will be asked to return for two follow-up visits at 18 months and two years following the initial vaccination so investigators can obtain additional blood samples to assess the durability of the immune response.

​Other study sites include the Center for Vaccine Development at the University of Maryland School of Medicine’s Institute for Global Health in Baltimore, and Emory University in Atlanta. Initial safety and immunogenicity data from the Phase 1 trial are expected by the end of 2016. If results show a favorable safety profile and immune response, NIAID plans to initiate a Phase 2 trial in Zika-endemic countries in early 2017.

For more information about the early-stage clinical trial, see ClinicalTrials.gov (identifier NCT02840487).

Question & Answer: 

Phase 1 Clinical Trial of the NIAID Zika Virus Investigational DNA Vaccine

Describe the Zika vaccine candidate that NIAID will test.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), will be testing in a Phase 1/1b human clinical trial an investigational Zika vaccine developed by scientists at NIAID’s Vaccine Research Center (VRC). The candidate, called the NIAID Zika virus investigational DNA vaccine, is intended to prevent Zika virus disease.

The investigational Zika vaccine includes a small, circular piece of DNA—called a plasmid—that scientists engineered to contain genes that code for proteins of the Zika virus. When the vaccine is injected into the arm muscle, cells read the genes and make Zika virus proteins, which self-assemble into virus-like particles. The body mounts an immune response to these particles, including neutralizing antibodies and T cells.

The NIAID Zika virus investigational DNA vaccine approach is similar to that used for another investigational vaccine developed by NIAID, to prevent West Nile Virus infection. That vaccine candidate was found to be safe and induced an immune response when tested in a Phase 1 clinical trial.

Who is the sponsor of the study, and where is it being conducted?

NIAID is leading and sponsoring the trial, called VRC 319. The trial is being conducted at three study sites in the United States: the NIH Clinical Center in Bethesda, Maryland, the University of Maryland’s Center for Vaccine Development in Baltimore and Emory University in Atlanta. Julie E. Ledgerwood, D.O., chief of the VRC’s Clinical Trials Program, will serve as principal investigator.

What is the design of the clinical trial?

The study is designed to test the safety of the NIAID Zika virus investigational DNA vaccine and its ability to generate an immune system response. Phase 1 designates the first-in-human testing of an investigational medical countermeasure; phase 1 trials are usually conducted in about 20 people. The Zika genetic insert in the candidate vaccine has never been tested in humans before, thus the Phase 1 designation. A Phase 1b designation indicates a larger enrollment (80 will be enrolled in VRC 319) and in this trial also considers that the overall plasmid DNA vaccine strategy has already demonstrated safety and immune responses against emerging pathogens in previous clinical studies.

The trial will enroll 80 healthy volunteers ages 18-35 years. Participants will be randomly divided into four study groups of 20 people each. After enrollment, all participants will receive a vaccination at their first visit via a needle-free injector that pushes the vaccine fluid into the arm muscle. Half of the participants will receive one additional vaccination eight weeks or 12 weeks later. The remaining participants will receive two additional vaccinations: one group of 20 participants will receive a second vaccination at week four and a third at week eight; the other group of 20 participants will receive a second vaccination at week four and a third at week 20. All participants will receive the same dose (4 milligrams of DNA in 1 milliliter of saline) at each vaccination.

Group ​Vaccinations
1 (20 people)​ ​2 total: day 0; week 8
​2 (20 people) ​2 total: day 0; week 12
​3 (20 people) ​3 total: day 0; week 4; week 8
​4 (20 people) ​3 total: day 0; week 4; week 20

Following each vaccination, participants will remain at the study site for observation for a minimum of 30 minutes. Participants will receive a diary card to use at home to record their temperature and any symptoms for seven days following each vaccination. All participants will return for various follow up visits within a 44-week time period after the first vaccination, so investigators can monitor their health and obtain blood samples for laboratory testing to measure the immune response to the vaccine. Participants will be asked to return for two follow-up visits at 18 months and two years following the initial vaccination, so that investigators can obtain additional blood samples to assess the durability of the immune response.

The VRC 319 trial is being conducted after expedited review and approval by the U.S. Food and Drug Administration (FDA).

Can the investigational vaccine cause a study participant to become infected with Zika virus?

No. DNA vaccines do not contain infectious material, so they cannot cause a vaccinated individual to become infected with Zika. They have been shown to be safe in previous clinical trials for other diseases.

How will the safety of the study participants in the VRC 319 trial be ensured?

The safety and well-being of study participants is always NIAID’s top priority. The study protocol was reviewed and approved by NIAID, an Institutional Review Board (IRB) and the U.S. Food and Drug Administration. All volunteers participating in the study must sign an informed consent form. A Protocol Safety Review Team made up of investigators, study coordinators, protocol specialists and clinicians will review patient data daily and weekly to monitor for harmful reactions or side effects to the vaccinations. Trial data are also regularly reported to the IRB and FDA for independent review and monitoring. If serious side effects occur, further vaccinations may be delayed or canceled.

As part of the informed consent process, volunteers are told there should be no expectation of protection from Zika virus infection after receiving the investigational vaccine. Therefore, participants are advised to take regular precautions to prevent Zika virus infection, including avoiding mosquito bites and using condoms consistently and correctly to prevent sexual transmission of the virus.

If a volunteer happens to become infected with Zika while still enrolled in the trial, the infection will be noted and the study subject may be withdrawn from the vaccination schedule, though they would continue to be followed according to the schedule of safety and immunogenicity evaluations. Investigators will refer participants to their primary care physicians for any treatment for Zika virus infection or other illnesses. All women enrolled in the trial must agree to use an effective means of birth control from least 21 days prior to enrollment through 12 weeks after the last study vaccination.

 

When do you expect to have data from the trial?

Initial safety and immunogenicity data from the VRC 319 trial are expected by the end of 2016. If results show a favorable safety profile and immune response, NIAID plans to initiate a Phase 2 trial in Zika-endemic countries in early 2017.

Is NIH testing or supporting research on other Zika vaccine candidates?

Yes. NIAID is conducting and supporting research and development of multiple Zika vaccine candidates.

NIAID’s VRC is working with GSK to evaluate a Zika vaccine candidate that uses GSK’s self-amplifying mRNA technology. This research, which will take place at the GSK Vaccine R&D Center in Rockville, Maryland, is still in the pre-clinical stage.

The NIAID Laboratory of Infectious Diseases—another laboratory on NIH’s Bethesda, Maryland campus—is developing a live-attenuated investigational Zika vaccine. The vaccine contains a live but weakened virus, so that it cannot cause disease. The platform is based on a similar vaccine approach for the closely-related dengue virus. The vaccine candidate is currently in pre-clinical development. The dengue vaccine candidate was shown to be safe and immunogenic in early-phase trials, and is currently being evaluated in a large Phase 3 study in Brazil.

NIAID also will be funding Phase 1 trials of a whole-particle inactivated Zika virus vaccine developed by scientists at the Walter Reed Army Institute of Research (WRAIR). This approach has been used against the related Japanese Encephalitis and dengue viruses. WRAIR announced a cooperative research and development agreement with Sanofi Pasteur in June 2016 to advance the vaccine candidate. Two of the Phase 1 trials, set to launch in fall 2016 and early 2017, will be conducted at NIAID-funded Vaccine and Treatment Evaluation Units.

NIAID is also supporting development of an investigational Zika vaccine that uses a genetically engineered version of vesicular stomatitis virus—an animal virus that primarily affects cattle. The VSV platform was successfully used in an investigational Ebola vaccine tested by NIAID. This Zika vaccine approach is at an early stage with plans underway to evaluate the vaccine candidate in tissue culture and animal models.

Content last reviewed on August 3, 2016