Study Will Evaluate NIH’s Experimental DNA Vaccine
March 31, 2017
Vaccinations have begun in a multi-site Phase 2/2b clinical trial testing an experimental DNA vaccine designed to protect against disease caused by Zika infection. The vaccine was developed by government scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). NIAID is leading the trial, which aims to enroll at least 2,490 healthy participants in areas of confirmed or potential active mosquito-transmitted Zika infection, including the continental United States and Puerto Rico, Brazil, Peru, Costa Rica, Panama and Mexico. The two-part trial, called VRC 705, further evaluates the vaccine’s safety and ability to stimulate an immune response in participants, and assesses the optimal dose for administration. It also will attempt to determine if the vaccine can effectively prevent disease caused by Zika infection.
Most people with Zika infection have either no or only mild symptoms, such as fever, rash, joint pain and conjunctivitis (red eyes). However, when Zika infection occurs during pregnancy, the pregnant woman can pass the virus to her fetus, which can result in a range of fetal defects known collectively as congenital Zika syndrome. Currently there is no licensed vaccine to prevent disease caused by Zika infection, which is mainly transmitted via the bite of infected Aedes aegypti mosquitoes but also can be transmitted sexually.
“We are pleased to have advanced rapidly one of NIAID’s experimental Zika vaccines into this next stage of testing in volunteers. We expect this study will yield valuable insight into the vaccine’s safety and ability to prevent disease caused by Zika infection,” said NIAID Director Anthony S. Fauci, M.D. “A safe and effective Zika vaccine is urgently needed to prevent the often-devastating birth defects that can result from Zika virus infection during pregnancy. Evidence also is accumulating that Zika can cause a variety of health problems in adults as well. This trial marks a significant milestone in our efforts to develop countermeasures for a pandemic in progress.”
Scientists at NIAID’s Vaccine Research Center (VRC) developed the NIAID Zika virus investigational DNA vaccine. It entered early-stage human testing in 2016 following extensive testing in animal models. Initial findings indicate the vaccine is safe and able to induce a neutralizing antibody response against Zika virus. The Phase 2/2b trial aims to gain more safety and immune response data and determine if this immune response protects against disease caused by natural Zika infection.
The Zika vaccine platform is based on a strategy VRC scientists used previously to develop a West Nile virus vaccine candidate. The Zika vaccine candidate being tested in this study contains a small circular piece of DNA called a plasmid into which scientists have inserted genes that encode two proteins found on the surface of the Zika virus. Once injected into muscle, the encoded proteins assemble into particles that mimic Zika virus and trigger the body’s immune system to respond. The vaccine does not contain infectious material, so it cannot cause Zika infection.
The trial is being led by protocol co-chairs Julie E. Ledgerwood, D.O., chief of VRC’s Clinical Trials Program, and Grace L. Chen, M.D., deputy chief of the same program.
The trial consists of two studies: part A and part B. Part A will build on ongoing Phase 1 trials to further evaluate the vaccine’s safety and ability to stimulate an immune response, specifically in populations where Zika could be endemic. It will also help determine the optimal dose and injection sites for administration. Part A will enroll 90 healthy men and non-pregnant women ages 18-35 years at three sites in Houston, Miami and San Juan, Puerto Rico. All participants will receive the investigational vaccine intramuscularly at three separate clinic visits each four weeks apart. Participants will be randomly assigned to receive either a standard dose or a high dose of the investigational vaccine at all three visits, and will be followed for about 32 weeks total.
Part B of the trial will enroll at least 2,400 healthy men and non-pregnant women ages 15-35 years. This part of the trial aims to determine if the vaccine can effectively protect against Zika related disease when someone is naturally exposed to the virus. Sites will include the three locations from part A (Houston, Miami and San Juan) as well as two additional sites in San Juan, two sites in Costa Rica, and one site each in Peru, Brazil, Panama and Mexico. Additional sites might be added in the future. Participants will be randomly assigned to receive either the investigational vaccine or a placebo at three separate clinic visits each four weeks apart. The trial is double-blind, meaning neither the study investigators nor the participants will know who receives the investigational vaccine.
Part B participants will be followed for nearly two years, during which time they will undergo assessments for adverse events and symptoms of Zika infection. Trial participants in both parts will be counseled on how to protect against Zika infection. Investigators will compare the rates of confirmed cases of Zika in the placebo group and the vaccinated group to determine if the investigational vaccine protects against disease caused by Zika infection.
Each site will have a principal investigator responsible for ensuring daily review of safety data as they become available. A protocol safety review team that includes the protocol chairs and other medical officers at NIAID will review safety data reports weekly. The NIAID Intramural Data and Safety Monitoring Board will also review cumulative study data at least twice per year. The study is currently expected to be completed by 2019.
VRC 705: Phase 2/2b Trial Testing the NIAID Zika Virus Investigational DNA Vaccine
Scientists at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, developed the NIAID Zika virus investigational DNA vaccine.
The trial is led by protocol chairs Julie E. Ledgerwood, D.O., chief of VRC’s Clinical Trials Program, and Grace L. Chen, M.D., deputy chief of the program
NIAID has worked closely with epidemiologists from the U.S. Centers for Disease Control and Prevention and modeling experts within and outside the US government to identify areas of confirmed or projected active mosquito transmission of Zika virus. Part A of the trial will take place at the first three sites listed below, and part B will take place at all 11 sites. Additional sites may be added.
- Baylor College of Medicine (Houston); Principal investigator: Dr. Shital Patel
- University of Miami Miller School of Medicine (Miami); Principal investigator: Dr. Margaret Fischl
- University of Puerto Rico Medical Sciences Campus (San Juan, Puerto Rico); Principal investigator: Dr. Clemente Diaz
- San Juan City Hospital Research Unit (San Juan, Puerto Rico); Principal investigator: Dr. Nicolas Rosario
- Fundación de Investigación de Diego (San Juan, Puerto Rico); Principal investigator: Dr. Grisell Ortiz-Lasanta
- ASCA CRS Iquitos (Iquitos, Peru); Principal investigator: Dr. Martin Casapia Morales
- Centro de Pesquisas Clinicas do Instituto Central da FMUSP/University of São Paulo (São Paulo, Brazil); Principal investigator: Dr. Esper Kallas
- Fundación Inciensa or FUNIN (Santa Cruz, Costa Rica); Principal investigator: Dr. Paula Gonzalez
- Costa Rican Center of Medical Research (Puntarenas, Costa Rica); Principal investigator: Dr. Gisela Herrera
- Instituto Conmemorativo Gorgas de Estudios de la Salud (Panama City, Panama); Principal investigator: Dr. Nestor Sosa
- Hospital Civil de Guadalajara “Fray Antonio Alcalde” (Guadalajara, Mexico); Principal investigator: Dr. Rayo Mortin Otero
The study will enroll adults and adolescents of reproductive age. Part A will enroll 90 healthy men and non-pregnant women ages 18-35 years, and part B will enroll 2,400 healthy men and non-pregnant women ages 15-35 years. Other protocols designed for younger children may be conducted in the future.
The effects of the vaccine on a developing fetus are unknown, and therefore women who are pregnant or plan to become pregnant will not be eligible for the trial. Women who participate in the trial will undergo pregnancy prevention counseling and will be asked to use an effective form of birth control leading up to and during the trial. If a woman does become pregnant during the trial, she will be removed from the product administration schedule but may be asked to return for some follow-up visits and blood draws.
The trial consists of two studies: part A and part B. Part A will build on ongoing Phase 1 trials to further evaluate the safety and ability of the vaccine candidate to induce an immune response in participants, specifically in populations where Zika could be endemic. Part A will also help determine the optimal dose and injection sites (arm versus thigh muscle) for vaccine administration. Part B of the trial will attempt to determine if the vaccine candidate can protect against disease caused by Zika virus infection when someone is naturally exposed to the virus.
All participants in part A will receive a total of three doses of the investigational vaccine intramuscularly at three separate clinic visits four weeks apart. Participants will be randomly assigned to receive either a standard dose (4 mg) or a high dose (8 mg). The first and second group (30 participants each) will receive the standard dose of vaccine at each visit and the third group (30 participants) will receive the high dose at each visit. Information from part A will help determine the optimal dose for part B.
Part B participants will be randomly assigned to receive either the investigational vaccine or a placebo at three separate clinic visits four weeks apart. This part of the trial is double-blind, meaning neither the study investigators nor the participants will know who receives the investigational vaccine versus the placebo. A randomized controlled trial is considered the gold standard in clinical study design.
This Zika vaccine platform is based on a strategy NIAID used previously to develop a West Nile virus vaccine candidate. The Zika vaccine candidate contains a small circular piece of DNA called a plasmid into which scientists have inserted genes that encode two proteins found on the surface of the Zika virus. Once injected into muscle, the proteins assemble into particles that mimic the Zika virus and trigger the body’s immune system to respond. The vaccine does not contain infectious material, so it cannot cause Zika virus infection.
VRC scientists developed two separate plasmids for experimental testing: VRC 5288 and VRC 5283. NIAID initiated clinical testing of the vaccine containing plasmid VRC 5288 in August 2016 following testing in animal models. In December 2016, NIAID began clinical testing of VRC 5283. Initial data showed VRC 5283 induced a stronger immune response in participants and therefore will be the plasmid in the experimental vaccine in the Phase 2/2b trial.
The vaccines will be administered intramuscularly with a PharmaJet needle-free injector. The device uses pressure to push the vaccine fluid into the arm or thigh muscle.
The trial is expected to conclude in 2019, but initial results could be available at the end of 2017. The actual timing of the trial will also depend on the intensity of Zika transmission and the efficacy of the vaccine candidate.
NIAID is developing additional vaccine candidates to prevent Zika virus infection. These include
- A purified inactivated Zika vaccine called ZPIV (Zika Particle Inactivated Vaccine), developed by the Walter Reed Army Institute of Research (WRAIR). ZPIV is based on a similar approach that WRAIR used to develop vaccines against the related Japanese Encephalitis and dengue viruses. Four of five Phase 1 trials testing ZPIV have begun at the Walter Reed Army Institute of Research (WRAIR) Clinical Trial Center in Silver Spring, Maryland; the Center for Vaccine Development at the Saint Louis University School of Medicine; the Center for Virology and Vaccine Research, part of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston; and the clinical research center CAIMED, part of Ponce Health Sciences University in Puerto Rico. NIAID is co-funding the Phase 1 clinical trials program with WRAIR, and is serving as the regulatory sponsor for several of these clinical studies and providing other support. NIAID’s VRC will also test ZPIV as a boost to its DNA Zika vaccine candidate.
- A live-attenuated (in which the virus has been weakened so that it cannot cause disease) investigational vaccine designed to protect against Zika virus and dengue virus. NIAID scientists developed the vaccine candidate, which is closely related to a dengue vaccine candidate currently being evaluated in a large Phase 3 study in Brazil. A monovalent version of the vaccine that is designed to protect solely against Zika virus disease will enter a Phase 1 trial at Johns Hopkins University in Baltimore and University of Vermont. Another chimeric version of the vaccine candidate designed to protect against Zika and all four types of dengue is planned to enter clinical testing in May 2017. NIAID is working with Brazil’s Butantan Institute and the University of Sao Paolo to plan later-stage trials for this latter candidate.
- Several investigational mRNA vaccine candidates (a gene-based platform similar to DNA vaccines). NIAID’s VRC is working with GlaxoSmithKline (GSK), University of Pennsylvania and Moderna/Valera to evaluate various mRNA vaccine technologies to identify immunogenic and scalable candidates. The Moderna/Valera candidate is being evaluated in a Phase 1 trial. The candidate developed by NIAID’s VRC and GSK could enter clinical trials in late 2017.
- An investigational Zika vaccine that uses a genetically engineered version of vesicular stomatitis virus—an animal virus that primarily affects cattle. VSV was successfully used in an investigational Ebola vaccine tested by NIAID. This vaccine approach is at an early stage with plans underway to evaluate the Zika vaccine candidate in tissue culture and animal models.
- A vaccine designed to protect against multiple mosquito-borne diseases, including Zika. The investigational vaccine, called AGS-v, was developed by the London-based pharmaceutical company SEEK, which has since formed a joint venture with hVIVO in London. AGS-v is designed to trigger an immune response to mosquito salivary proteins rather than to a specific virus or parasite carried by mosquitoes. The test vaccine contains four synthetic proteins from mosquito salivary glands. The proteins are designed to induce antibodies in a vaccinated individual and to cause a modified allergic response that can prevent infection when a person is bitten by a disease-carrying mosquito. The AGS-v candidate is being evaluated in a Phase 1 clinical trial at the NIH Clinical Center in Bethesda, Maryland.