Cytomegalovirus Vaccine Candidate Found to Be Safe & Immunogenic in First-in-Humans Trial

In most healthy individuals, the immune system is able to prevent cytomegalovirus (CMV) from causing illness but those who are immunocompromised are not so lucky; these individuals are prone to suffer from more serious symptoms that often affect the eyes, liver, esophagus, stomach, and intestines. Furthermore, congenital CMV infection can result in severe, and sometimes permanent, neurological injury in newborns.

To date, there are no approved vaccines available to protect against the virus, but progress toward this goal has been made in recent clinical trials.

Just last week, promising findings from a first-in-human phase 1 trial evaluating VBI Vaccine’s vaccine candidate, VBI-1501A, were presented at ID Week 2018, by Soren Gantt, MD, PhD, MPH, associate professor with the division of Infectious Disease in the department of pediatrics at the University British Columbia Faculty of Medicine, BC Children’s Hospital.

“Neutralizing antibodies (nAb) to the CMV envelope glycoprotein B (gB) in natural infection are thought to confer protection, and there was a recombinant gB/MF59 vaccine that was shown to be partially protective against infection and disease,” Dr. Gantt said, “but higher, longer-lived gB nAb titers are needed for a more effective vaccine.”

Enter VBI Vaccine’s candidate, VBI-1501A, an enveloped virus-like particle vaccine (VLP), designed via VBI’s eVLP Platform. eVLPS, according to VBI, are a new, innovative class of synthetic vaccines that are developed to closely mimic the structure of viruses.

The idea is that because the vaccines are designed to be structurally similar to viruses found in nature, vaccination with a target protein expressed in an eVLP should have the potential to impart greater immunity than vaccination with the same recombinant target protein by itself.

According to Dr. Gantt, his team was pleased to see that an antigenic domain (AD) of gB—AD-2—was recognized on VBI-1501; this domain is increasingly recognized to have a functional importance when it comes to CMV.

In the first-in-humans dose-ranging, controlled, observer-blinded phase 1 trial, the investigators set out to study the safety and immunogenicity of an eVLP expressing the ectodomain of gB fused to transmembrane and cytoplasmic domains of the vesicular stomatitis virus G protein (gB-G), according to the abstract.

A total of 125 healthy CMV-negative participants between 18 and 40 years of age were enrolled in the trial, which was conducted at 3 Canadian Immunization Research Network (CIRN) sites in Canada—Vancouver, Montreal, and Halifax.

Participants were randomized to 1 of 5 treatment groups. The first group received .5 μg VBI-1501A + alum; the second received 1.0 μg VBI-1501A; the third were given 2.0 μg VBI-1501A; the fourth received 1.0 μg VBI-1501 (unadjuvanted); and the fifth group received placebo. Each participant received 3 intramuscular doses of the CMV eVLP vaccine or placebo on days 0, 56, and 168, according to Dr. Gantt.

Outcome measures for the trial were solicited and unsolicited adverse events (AEs) and serious AEs. Specifically, local and systemic AEs 7 days following each injection, any AEs 28 days following each injection and SAEs through day 336 of the trial or early withdrawal, and any laboratory abnormality at the following days: 28, 56, 84, 168, 196, 280, or 336.

Secondary outcome measures pertained to immunogenicity; specifically, gB binding antibody titers and avidity assessment, as well as nAB to CMV infection of fibroblast and epithelial cells, study authors write.

Dr. Gantt reported that the most common AEs reported were headache, infections, and fatigue. However, the vaccine was not found to be associated with any clinically significant AEs compared with the placebo group. Further, there were no significant differences observed in abnormal laboratory results compared with those who received placebo.

He added that the events reported ranged from mild to moderate in severity and none of the events resulted in withdrawal from the trial. SAEs, according to Dr. Gantt, were “relatively infrequent” and did not seem to be associated with dose.

After doses 2 and 3, a dose-dependent boosting of nAB titers was noted, with the highest titers in the third treatment group, who received the highest dose of the vaccine. Dr. Gantt said that fibroblast cell nAb were observed in 100% of subjects who received the 2.0 μg dose of the vaccine, while epithelial cell nAb was noted in 31%.

“Epithelial cell nAb was correlated with higher geometric mean gB binding titers,” the authors write, “and there was a correlation between fibroblast and epithelial cell nAb titers.”

Overall, Dr. Gantt and his team concluded that VBI-1501A was safe and well-tolerated at all the doses tested in the phase 1 trial, and that the vaccine is immunogenic.

“We saw gB binding titers induced at all dose levels, with clear evidence of dose-dependent boosting,” he said. “There was good neutralizing activity in fibroblasts in 100% of subjects at highest dose with titers comparable to CMV-positive controls. And there was modest epithelial cell neutralizing activity that correlated with higher gB binding titers.”

The next steps for the vaccine are currently under discussion. Contagion^® will provide the public with updates as more information becomes available.

DISCLOSURES

S. Gantt, VBI Vaccines: Investigator, No direct financial benefit—company provided institutional support for clinical trial; C. Quach, VBI Vaccines: Investigator, No direct financial benefit—company provided institutional support for clinical trial; D. E. Anderson, VBI Vaccines: Employee and Shareholder, Salary; F. Diaz-Mitoma, VBI Vaccines: Consultant and Shareholder, Salary; J. Langley, VBI Vaccines: Investigator, No direct financial benefit—company provided institutional support for clinical trial.