HSV-2 vaccine candidate reduces viral shedding, genital lesions up to 1 year

Issue: May 2016

BALTIMORE — The investigational herpes simplex virus-2 vaccine GEN-003 was well-tolerated and reduced viral shedding and genital lesions up to 1 year after vaccination, according to data presented at the Annual Conference on Vaccine Research.

“There have been many attempts to create a vaccine that is prophylactic, and in some instances, therapeutic. They have ultimately failed,” Seth Hetherington, MD, chief medical officer for Genocea Biosciences, said during a presentation. “The likelihood is that both T- and B-cell immunity are needed for immune control and prophylaxis for this infection.”

With this knowledge, researchers created the therapeutic GEN-003 vaccine, which contains the T-cell antigen ICP4 and B-cell antigen gD2. The safety and efficacy of the vaccine was evaluated in two randomized controlled studies. For the first study, adults aged 18 to 50 years with herpes simplex virus-2 (HSV-2) not receiving chronic antiviral therapy were assigned either placebo or 10 µg, 30 µg or 100 µg of antigens with or without 50 µg of adjuvant Matrix-M2 (Novavax; MM). The vaccines were administered in three doses spaced 21 days apart.

The “most active” regimen was 30 µg of antigens with 50 µg MM, Hetherington reported, which demonstrated the greatest reduction in viral shedding (52%) and genital lesions (48%) immediately after the third dose (P < .001). Vaccine efficacy persisted for several months, with a 40% reduction in viral shedding and 65% reduction in genital lesions at 6 months (P < .001).

The 100 µg/50 µg MM dose also reduced viral shedding and genital lesions; however, the reductions were not as elevated and were no longer significant by 6 months.

“We found that if you increased the antigen dose too high, we actually had a reduced immune response,” Hetherington said.

For the second study, the researchers compared a regimen containing 30 µg of antigens with 60 µg of antigens, in addition to either 25 µg, 50 µg or 75 µg of MM. The two most promising doses of 60 µg of antigens plus 75 µg MM and 60 µg of antigens plus 50 µg MM demonstrated the greatest sustained reductions from baseline in the primary endpoint of viral shedding (60%) in participants who received 60 µg of antigens plus 75 µg MM of up to 64% 12 month post dosing (P < .0001), Hetherington said.

Meanwhile, participants who received 60 µg of antigens and 50 µg MM reported the greatest reduction in genital lesions (P < .0001), which also continued for at least 12 months.

“What we also noticed, however, was that the placebo group also demonstrated or at least reported a reduction in lesion rates immediately after dose 3,” Hetherington said. “We think that this apparent placebo affect may be related to anticipation of this trial. Patients knew they had a six out of seven chance for getting an active dose.”

In addition, Hetherington noted an “interesting” pattern among T-cell responses from the first trial. The lowest dose of antigen, 10 µg, resulted in the highest T-cell response even though it did not have an impact on viral shedding or genital lesions.

“As you up the dose, you actually see a decrease in response,” he said. “You also see that after each subsequent dose, there’s a decline in T-cell response. Although, by 12 months, that response persists above baseline.”

In contrast, IgG antibody titers demonstrated typical responses, representing a modest increase when the antigen proteins were combined with the adjuvant and additional increases with each subsequent dose.

The number of vaccine discontinuations due to reactogenicity or adverse events was low in all groups, and no grade 4 reactogenicities or serious adverse events were reported. The frequency of grade 3 adverse events increased with higher doses of adjuvant, but decreased after subsequent doses.

“Essentially, by the third dose, you’re not that much more different than placebo,” Hetherington said.

He concluded that the studies confirmed the durable efficacy of GEN-003 and that the vaccine may be a convenient regimen for patients with HSV-2 compared with a daily pill. – by Stephanie Viguers

References:

Flechtner J, et al. Abstract S6. Presented at: Annual Conference on Vaccine Research; April 18-20, 2016; Baltimore.

Nawas Z, et al. F053. Late-Breaking Research: Clinical Trials. Presented at: American Academy of Dermatology Annual Meeting; March 4-8, 2016; Washington, D.C.

Disclosure: Hetherington reports being an employee and stockholder for Genocea Biosciences.