A Phase 2a Randomized, Double-Blind, Dose-Optimizing Study to Evaluate the Immunogenicity and Safety of a Bivalent DNA Vaccine for Hemorrhagic Fever with Renal Syndrome Delivered by Intramuscular Electroporation

Jay Hooper,S Norris,K M Paolino,B Somerville,M Cohen,C S Schmaljohn,M Wisniewski,M Sanchez-Lockhart,D Hannaman,S Kwilas,M Josleyn,B Hill,K Mills

doi:10.3390/vaccines8030377

Abstract

Hantaan virus (HTNV) and Puumala virus (PUUV) are pathogenic hantaviruses found in Asia and Europe, respectively. DNA vaccines targeting the envelope glycoproteins of these viruses have been constructed and found to elicit neutralizing antibodies when delivered to humans by various technologies including intramuscular electroporation. Here, we report findings from a Phase 2a clinical trial of a combined HTNV/PUUV DNA vaccine delivered at varying doses and administration schedules using the Ichor Medical Systems TriGrid intramuscular electroporation delivery technology. The study was designed to characterize the effects of DNA vaccine dose and number of administrations on the frequency and magnitude of immunological response. Subjects (n = 120) were divided into four cohorts. Cohorts 1 and 2 received a dose of 2 mg of DNA (1 mg per plasmid), and cohorts 3 and 4 received a dose of 1 mg of DNA (0.5 mg per plasmid) each vaccination. Each of the four cohorts received a series of four administrations (days 0, 28, 56 and 168). For cohorts 1 and 3, the DNA vaccine candidate was delivered at each of the four administrations. For cohorts 2 and 4, in order to maintain blinding, subjects received the DNA vaccine on days 0, 56 and 168, but on day 28 received only the phosphate buffered saline vehicle rather the DNA vaccine. Sera were collected on days 0, 28, 56, 84, 140, 168, 196, 252 and 365 and evaluated for the presence of neutralizing antibodies by PUUV and HTNV pseudovirion neutralization assays (PsVNAs). Day 84 was also evaluated by a plaque reduction neutralization test (PRNT). Overall the PsVNA50 geometric mean titers (GMTs) and seropositivity rates among cohorts were similar. Cohort 3 exhibited the highest frequency of subjects that became seropositive to both PUUV and HTNV after vaccination, the highest peak GMT against both viruses, and the highest median titers against both viruses.

Highlights

Most cases of hemorrhagic fever with renal syndrome (HFRS) are caused by infection withHantaan (HTNV) or Seoul (SEOV) viruses in Asia and by Puumala (PUUV) or Dobrava (DOBV)viruses in Scandinavian countries and other parts of Europe
This optimized DNA eliminates the requirement for an untranslated extraneous sequence upstream of the open reading frame (ORF) to be included in the plasmid as described previously [10], and eliminates interference issues that occurred with the non-optimized DNA vaccine, pWRG/HTN-M(x), in animals and humans [13,15]
178 individuals were screened at a 1:20 serum dilution for pre-existing anti-hantavirus neutralizing antibodies by Hantaan virus (HTNV) and Puumala virus (PUUV) pseudovirion neutralization assays (PsVNAs)

Summary

Introduction

Most cases of hemorrhagic fever with renal syndrome (HFRS) are caused by infection withHantaan (HTNV) or Seoul (SEOV) viruses in Asia and by Puumala (PUUV) or Dobrava (DOBV)viruses in Scandinavian countries and other parts of Europe. Most cases of hemorrhagic fever with renal syndrome (HFRS) are caused by infection with. Hantaan (HTNV) or Seoul (SEOV) viruses in Asia and by Puumala (PUUV) or Dobrava (DOBV). Viruses in Scandinavian countries and other parts of Europe. Ribavirin has been used off-label to treat HFRS, and is reported to reduce mortality when given early, but not late, in the disease course [5,6]. In addition to having limited efficacy, ribavirin causes a reversible hemolytic anemia and numerous IV injections of the drug must be given over a 7-day period [6]. Toward the goal of licensing a safe and effective vaccine for HFRS, we have developed a two-plasmid DNA vaccine expressing the envelope glycoprotein (Gn and Gc) genes of HTNV or PUUV. Neutralizing antibodies to Gn and Gc have been shown to be sufficient to confer protective immunity against infection in hamsters, and are believed to be a key component of the protective immune response in humans as well [7,8,9,10,11]

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Results

Conclusion