Zika Vaccine Clinical Trials to Start in Humans This Month

Janis C. Kelly

June 28, 2016

Researchers inched closer to a clinically useful vaccine against Zika virus this month with the launch of a phase 1 trial of one candidate vaccine and reports of successful trials in mice for two others.

A phase 1 study was recently approved by the US Food and Drug Administration (FDA) for GLS-5700, a synthetic DNA plasmid vaccine developed by GeneOne Life Science Inc, in collaboration with Inovio Pharmaceuticals. Inovio has a track record of having moved a candidate Ebola vaccine from bench to clinic in about 18 months, attracting $45 million in development support from the US Defense Advanced Research Projects Agency.

So far, no DNA vaccine has been approved for human use in the United States, although the DNA vaccine IMOJEV for Japanese encephalitis has been approved by regulatory authorities in Australia and Thailand.

Inovio President and Chief Executive Officer J. Joseph Kim, PhD, told Medscape Medical News that shortening vaccine development time, which typically stretches over 10 years or more, was possible because creation and production of DNA vaccines does not require the extended time needed to grow and manipulate live virus or inactivated virus vaccines, and because the companies were willing to take the financial risk of ramping up production of GLS-5700 beginning in February, before the completion of mouse and primate studies.

Dr Kim said, "A paper reporting our data from mouse and rhesus monkey preclinical trials of GLS-5700 has been submitted for publication, and the data on antibody and T-cell responses were sufficiently convincing that the FDA granted an [investigational new drug exemption]. We are proud to have obtained approval for the first Zika vaccine study in human volunteers."

He continued, "The phase 1 safety trial is an open-label study to assess the safety, tolerability, and immunogenicity of two dose levels of GLS-5700 in 40 patients. We have [institutional review board] approvals at three test sites in Philadelphia, Miami, and Canada, and expect to begin enrolling patients in a week or so, once some paperwork is completed."

Patients will receive three doses of either 1 or 2 mg of GLS-5700, with doses separated by 1 month. Primary outcomes are changes in laboratory safety measures, incidence of adverse events, and incidence of serious adverse events. Secondary outcomes are binding antibody titers to Zika envelope, neutralizing antibody response against Zika virus, and T-cell response.

The researchers expect to complete the phase 1 study in the fourth quarter of 2016 and then move into a phase 2 trial if the phase 1 data support that effort, according to Dr Kim.

He emphasized the importance of being able to achieve immune responses comparable to levels associated with effective protection against Zika infection. "We don't want to be the first but with a crumby vaccine," he said, "and we are hoping to move into field studies before the end of the year, in view of the urgent need for a Zika vaccine."

GLS-5700 is a small circular piece of DNA, called a plasmid, that encodes the Zika virus premembrane and envelope (prM-Env) proteins.

Dr Kim noted that although DNA vaccines have theoretical advantages, such as easy storage and good stability, there are challenges associated with delivery that need to be addressed.

"DNA plasmids are large, and they have to get into the cell to be effective. Injecting them into the muscle often works in mice, but many things work in mice that will not work in humans. We are coaxing the plasmids into the cells using electroporation with the CELLETRA system, in which the vaccine is given intradermally and millisecond-long low-voltage electrical pulses are applied to the skin to reversibly open cellular pores and let the vaccine in. We have used this approach with over 1000 patients so far in our studies of other [experimental] vaccines."

Two Other Experimental Vaccines Protective in Mice

A second DNA vaccine against Zika was one of two approaches reported in the June 28 issue of Nature by Rafael A. Larocca, PhD, from the Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, and colleagues. The other candidate vaccine the team tested was a purified inactivated virus (PIV) vaccine developed by coauthor Col. Nelson L. Michael, MD, director of the US Military HIV Research Program‎ at Walter Reed Army Institute of Research (WRAIR) and Col. Stephen J. Thomas, MD, deputy commander of the WRAIR and program lead for Zika vaccine research.

The researchers tested single doses of each vaccine in mice, which were than challenged with Zika virus isolates from either northeast Brazil or Puerto Rico. The Zika isolates were expanded in Vero cells to generate preclinical challenge stocks (ZIKV-BR and ZIKV-PR).

As with GLS-5700, the DNA vaccine described by Dr Larocca and colleagues is a plasmid encoding full-length Zika prM-Env proteins from the Brazil BeH815744 strain, as well as smaller portions of the envelope protein.

The investigators also tested the immunogenicity and protective efficacy of a Zika PIV vaccine derived from the Puerto Rico PRVABC59 strain. Mice were vaccinated with 50 μg DNA vaccine in saline without adjuvant intramuscularly or with 1 μg PIV vaccine with 100 μg alum adjuvant, intramuscularly or subcutaneously.

One shot of either vaccine protected mice 100% against Zika infection, according to data presented in the paper and in a June 27 press briefing.

"We show that two vaccine candidates (a DNA vaccine and a purified inactivated virus vaccine) each provided complete protection against Zika virus challenge in mice," senior author Dan H. Barouch, MD, PhD, professor of medicine at Harvard Medical School and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, Boston, said at the briefing.

"To the best of our knowledge, this is the first report of complete Zika virus protection in an animal model. The protection was striking, with all control animals showing high levels of virus replication following challenge, whereas all of the vaccinated animals showed no detectable virus after challenge with Zika virus derived either from Brazil or Puerto Rico. Importantly, protection was achieved even after a single-shot immunization."

Zika PIV Vaccine Set to Begin Phase 1 trials in October

Dr Michael told Medscape Medical News that Zika PIV vaccine is being developed in collaboration with the National Institute of Allergy and Infectious Diseases, and that phase 1 trials are expected to start in October at the WRAIR and at National Institute of Allergy and Infectious Diseases partner sites. A collaboration with industry has been set up, but not yet announced publicly, he continued.

The authors write, "Our data demonstrate that a single immunization with a DNA vaccine or a PIV vaccine provided complete protection against parenteral ZIKV challenges in mice. The [prM-Env] DNA vaccine afforded protection in three strains of mice and against both ZIKV-BR and ZIKV-PR challenges, suggesting the generalizability of these observations."

Immunogenicity studies suggest that protection with the DNA vaccine comes from vaccine-elicited Env-specific antibodies. For example, the researchers were able to provide protection to nonimmunized mice by injecting them with immunoglobulin G antibodies purified from vaccinated mice. "The adoptive transfer studies also defined the threshold of Env-specific antibody titers required for protection in this model," they write.

The authors conclude, "Taken together, our findings provide substantial optimism that the development of a safe and effective ZIKV vaccine for humans will likely be feasible."

Human Vaccine Will Take Time, Expert Cautions

Peter Hotez, MD, who was not involved in the study, told Medscape Medical News that the results in mice are impressive, but might not translate to humans.

"On the positive side, it looks like a sound study, well-controlled and thoughtfully conducted," said Dr Hotez, dean, National School of Tropical Medicine, and professor, pediatrics and molecular & virology and microbiology, Baylor College of Medicine, Houston, Texas, and director of the Sabin Vaccine Institute, Texas Children's Hospital Center for Vaccine Development. "On the down side, most DNA vaccines protect mice, but DNA vaccines so far do not reproduce their protective immunity in humans. Therefore the results here may lead to advancing the vaccine to phase 1 trials, but they will not likely have any direct impact on the development of a human vaccine."

Dr Hotez said the data suggest that if the prM protein could be produced as a recombinant protein instead of a DNA vaccine, manufactured at scale, and adjuvanted appropriately, it might provide a platform as a human vaccine.

Dr Hotez also warned against expecting a clinically usable Zika vaccine in the near future. He said that candidate Zika vaccines are likely to progress quickly to phase 1 studies, but then slow or halt because the FDA will want evidence that the vaccine does not induce Guillain-Barré Syndrome, and that the vaccine is safe in pregnancy, and those studies are likely to take years.

"The bottom line is that this is not Ebola, and we will not have a Zika vaccine ready in time for this epidemic," Dr Hotez said.

The study was supported by the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology, and Harvard; the National Institutes of Health; and the São Paulo Research Foundation. Dr Kim is president and chief executive officer of Inovio Pharmaceuticals. Dr Hotez has disclosed no relevant financial relationships.

Nature. Published online June 28, 2016. Full text

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