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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.

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.

SUBMITTER: Hooper J

PROVIDER: S-EPMC7565952 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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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.

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

Vaccines 20200711 3

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 ...[more]

PMID: 32664486

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Project description:Plasmodium falciparum circumsporozoite protein (PfCSP) and Pfs25 are leading candidates for the development of pre-erythrocytic and transmission-blocking vaccines (TBV), respectively. Although considerable progress has been made in developing PfCSP- and Pfs25-based vaccines, neither have elicited complete protection or transmission blocking in clinical trials. The combination of antigens targeting various life stages is an alternative strategy to develop a more efficacious malaria vaccine. In this study, female and male mice were immunized with DNA plasmids encoding PfCSP and Pfs25, administered alone or in combination via intramuscular in vivo electroporation (EP). Antigen-specific antibodies were analyzed for antibody titers, avidity and isotype by ELISA. Immune protection against sporozoite challenge, using transgenic P. berghei expressing PfCSP and a GFP-luciferase fusion protein (PbPfCSP-GFP/Luc), was assessed by in vivo bioluminescence imaging and blood-stage parasite growth. Transmission reducing activity (TRA) was evaluated in standard membrane feeding assays (SMFA). High levels of PfCSP- and Pfs25-specific antibodies were induced in mice immunized with either DNA vaccine alone or in combination. No difference in antibody titer and avidity was observed for both PfCSP and Pfs25 between the single DNA and combined DNA immunization groups. When challenged by PbPfCSP-GFP/Luc sporozoites, mice immunized with PfCSP alone or combined with Pfs25 revealed significantly reduced liver-stage parasite loads as compared to mice immunized with Pfs25, used as a control. Furthermore, parasite liver loads were negatively correlated with PfCSP-specific antibody levels. When evaluating TRA, we found that immunization with Pfs25 alone or in combination with PfCSP elicited comparable significant transmission reduction. Our studies reveal that the combination of PfCSP and Pfs25 DNAs into a vaccine delivered by in vivo EP in mice does not compromise immunogenicity, infection protection and transmission reduction when compared to each DNA vaccine individually, and provide support for further evaluation of this DNA combination vaccine approach in larger animals and clinical trials.

Dataset Information

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.

Publications

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.

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