Immune responses to a HSV-2 polynucleotide immunotherapy COR-1 in HSV-2 positive subjects: A randomized double blinded phase I/IIa trial

Abstract

BackgroundGenital herpes simplex infection affects more than 500 million people worldwide. We have previously shown that COR-1, a therapeutic HSV-2 polynucleotide vaccine candidate, is safe and well tolerated in healthy subjects.ObjectiveHere, we present a single center double-blind placebo-controlled, randomized phase I/IIa trial of COR-1 in HSV-2 positive subjects in which we assessed safety and tolerability as primary endpoints, and immunogenicity and therapeutic efficacy as exploratory endpoints.MethodsForty-four HSV-2+ subjects confirmed by positive serology or pathology, and positive qPCR during baseline shedding, with a recurrent genital HSV-2 history of at least 12 months including three to nine reported lesions in 12 months prior to screening, aged 18 to 50 years females and males with given written informed consent, were randomized into two groups. Three immunizations at 4-week intervals and one booster immunization at 6 months, each of 1 mg COR-1 DNA or placebo, were administered intradermally as two injections of 500 μg each to either one forearm or both forearms.ResultsNo serious adverse events, life-threatening events or deaths occurred throughout the study. As expected, HSV-2 infected subjects displayed gD2-specific antibody titers prior to immunization. COR-1 was associated with a reduction in viral shedding after booster administration compared with baseline.ConclusionsThis study confirms the previously demonstrated safety of COR-1 in humans and indicates a potential for use of COR-1 as a therapy to reduce viral shedding in HSV-2 infected subjects.

Epidemiological Impact of Novel Preventive and Therapeutic HSV-2 Vaccination in the United States: Mathematical Modeling Analyses

“…Despite setbacks over three decades [ 77 , 85 , 90 , 91 , 92 ], optimism is grounded on progress in basic science and results of vaccine candidates currently in phase I and/or II trials [ 29 , 35 , 93 ]. Optimism is also grounded on several lines of evidence suggesting vaccine feasibility [ 35 ], including improved understanding of HSV immunology [ 35 , 40 , 94 , 95 ], growing knowledge of the optimal combination of antigens and adjuvants that could lead to vaccine protection [ 77 , 85 , 93 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ], success and availability of both prophylactic and therapeutic vaccines against varicella zoster virus (VZV) [ 35 , 102 , 103 ], which is a closely related alpha-herpes virus, success and availability of animal herpes vaccines such as the bovine herpesvirus-1 [ 104 ] and the suid herpesvirus-1 (pseudorabies virus) [ 35 , 105 ], demonstration that intramuscular vaccination can induce genital mucosal immunity [ 35 ], as is the case for HPV vaccination [ 106 ], and the partial protection in the Herpvac trial against HSV-1 infection and genital disease [ 35 , 85 ] given the strong homology between HSV-1 and HSV-2 viruses [ 17 , 82 ].…”

Immune Response to Herpes Simplex Virus Infection and Vaccine Development

“…The authors also report the generation of memory T cells which are being studied to evaluate whether they can mount an anti-HSV-2 immune response even after primary infection [ 147 ]. Recently, a group of researchers tested their DNA vaccine candidate—a codon-modified polynucleotide vaccine COR-1 in HSV-2 positive patients, and reported a reduction in viral shedding after administration [ 115 ]. The authors had earlier shown that COR-1 induces a balanced adaptive humoral and cell-mediated immune response in mice, and protected mice challenged with a lethal dose of HSV-2 [ 142 ], and was also shown to elicit minimal adverse effects when tried in healthy volunteers [ 116 ].…”

Assessment of Two Novel Live-Attenuated Vaccine Candidates for Herpes Simplex Virus 2 (HSV-2) in Guinea Pigs

“…This DNA plasmid-based therapeutic vaccine candidate targeting glycoprotein D of HSV-2 (gD2) elicited a gD2-specific cell-mediated response in ≈40% of patients and a gD2-specific antibody response in ≈50% of patients. Viral shedding in genital swabs was reduced by 50% compared to placebo only after a booster following a prime, boost, boost vaccination series [ 51 , 52 ]. These results demonstrate the ability of HSV-2 vaccine candidates delivered via an ID injection to elicit cellular and adaptive immune responses, as well as achieve therapeutic endpoints.…”

“…A singular polyvalent recombinant subunit vaccine was developed, shown to elicit CD4+ and CD8+ T cell responses during a Phase I trial but has yet to report results from subsequent trials [ 79 , 80 ]. Beyond subunit vaccines, DNA plasmid-based vaccines expressing various infected cell proteins (ICPs) or gD2 have also been developed [ 51 , 52 , 81 , 82 , 85 , 86 ]. None of these previous therapeutic vaccine candidates have consistently reduced viral shedding, frequency of recurrence, and duration of recurrence long-term in the majority of those vaccinated and no preventative vaccine candidates have consistently reduced rates of infection for all vaccinees regardless of sex or HSV-1 serostatus.…”