The search is on for clinical trial participants to help verify whether two genetically based vaccines that lowered Zika virus viremia in infected primates will be effective in humans.
Although much is still unknown about the pathogenesis, immunity, and transmission of the flavivirus, its devastating effects mean developing a vaccine is imperative, wrote Kimberly A. Dowd, PhD, a virologist at the National Institute of Allergy and Infectious Diseases, and her colleagues in a paper published online in Science.
©Aunt_Spray/Thinkstock
According to Dr. Dowd and her coauthors, the quickest path to a Zika vaccine is to start with what is already known about flaviviruses and to avoid unnecessary bureaucracy.
“Advantages of DNA vaccines include the ability to rapidly test multiple candidate antigen designs, rapidly produce GMP material, and established safety profile in humans, and a relatively straightforward regulatory pathway into clinical evaluation,” Dr. Dowd and her colleagues wrote. The study details the results of two Zika vaccine candidates tested in primates. The clinical trial will now test these vaccines’ efficacy in humans (Science. 2016 Sept 22. doi: 10.1126/science.aai3197).
Starting with insights gained from DNA-based testing for a West Nile virus vaccine that showed vaccine-elicited neutralizing antibodies are associated with protection from flavivirus-mediated disease, and data showing that a single vaccine antigen will protect against all strains of Zika virus, Dr. Dowd and her coinvestigators developed two DNA-based vaccines that successfully bound to Zika subviral particles in infected mice. Then they tested the vaccines in rhesus macaques.
Six animals were injected with either 1 mg of VRC5283 at 0 and 4 weeks. Another six were injected with 4 mg of either VRC5283 or VRC5288 at 0 or 4 weeks. Another six were injected with a single 1-mg dose of VRC5288 at week 0. After the initial DNA dose, all animals were found to have detectable binding and neutralizing antibody activity, peaking at week 3. Compared with controls given the CMV-immediate early-promoter–containing vector VRC8400, all study animals had a significantly higher neutralizing antibody response (P = .022). The group given the single dose of VRC5288 had significantly lower neutralizing antibody titers, compared with macaques given two doses of either vaccine (P = .022).
Across the groups given two doses of either vaccine, there were no significant differences between titer levels, suggesting that both vaccine candidates elicit substantial Zika virus–specific neutralizing antibodies in primates. More to the point was that 8 weeks after immunization, when all animals in the study were challenged subcutaneously with the virus, viremia levels in the 18 total macaques given two doses of either amount and of either vaccine were undetectable in all but 1. Compared with controls, that had peak viral loads on day 3 or 4, the six animals given one dose of 1 mg VRC5288 were viremic on day 3, but at a significantly reduced rate (P = .041).
Taking into account one animal in the VRC5288 two-dose 4-mg group that had viral load blips above background on days 3 and 7, as well as the lowest titer levels of all the test animals, the investigators determined that 70% protection from Zika virus viremia would be possible if certain titer levels could be achieved.
Whether waning or incomplete immunity could lead to enhanced flavivirus disease is a concern when developing correct vaccination dosage, the investigators said. However, despite some breakthrough infection in the group given the single 1 mg dose of VRC5288, the animals’ illness remained subclinical, there were no signs of replication, and their viremia levels were lower than in unvaccinated controls.
Now, all eyes are on how the vaccines compare with one another while researchers try to establish an adequate serologic correlate of sterilizing immunity in humans. According to Dr. Dowd and her colleagues, the phase I trial is being designed in parallel with other trials looking into a purified, protein-based whole-inactivated Zika virus vaccine, as well as other antigens, delivery methods, and combination vaccines.
The multipronged approach improves the likelihood that enough immunogenicity data can be gathered and translated into a successful intervention for the women of child-bearing age most affected by the Zika virus, and the general population at large, Dr. Dowd and her colleagues concluded.
The research was supported by intramural funding from the National Institute of Allergy and Infectious Diseases; start-up funding from the department of diagnostic medicine and pathobiology, College of Veterinary Medicine, Kansas State University; and federal funds from the Frederick National Laboratory for Cancer Research, NIH. One of the coauthors also reported funding from Leidos Biomedical Research.