Immunogenicity and safety of an investigational tetravalent recombinant subunit vaccine for dengue: results of a Phase I randomized clinical trial in flavivirus-naïve adults

Abstract

There is an unmet medical need for vaccines to prevent dengue. V180 is an investigational recombinant subunit vaccine that consists of truncated dengue envelope proteins (DEN-80E) for all 4 serotypes. Three dosage levels of the tetravalent DEN-80E antigens were assessed in a randomized, placebo-controlled, Phase I dose-escalation, first-in-human proof-of-principle trial in healthy, flavivirus-naïve adults in Australia (NCT01477580). The 9 V180 formulations that were assessed included either ISCOMATRIX™ adjuvant (2 dosage levels), aluminum-hydroxide adjuvant, or were unadjuvanted, and were compared to phosphate-buffered saline placebo. Volunteers received 3 injections of assigned product on a 0, 1, 2 month schedule, and were followed for safety through 1 year after the last injection. Antibody levels were assessed at 6 time-points: enrollment, 28 days after each injection, and 6 and 12 months Postdose 3 (PD3). Of the 98 randomized participants, 90 (92%) received all 3 injections; 83 (85%) completed 1-year follow-up. Immunogenicity was measured by a qualified Focus Reduction Neutralization Test with a 50% neutralization cutoff (FRNT 50 ). All 6 V180 formulations with ISCOMATRIX™ adjuvant showed robust immunogenicity, while the 1 aluminum-adjuvanted and 2 unadjuvanted formulations were poorly immunogenic. Geometric mean antibody titers generally declined at 6 months and 1 year PD3. All 9 V180 formulations were generally well tolerated. Formulations with ISCOMATRIX™ adjuvant were associated with more adverse events than aluminum-adjuvanted or unadjuvanted formulations.

Anti-Flavivirus Vaccines: Review of the Present Situation and Perspectives of Subunit Vaccines Produced in Escherichia coli

“…The tetravalent vaccine V180, developed by Merck & Co. (Kenilworth, NJ, USA), is the only one that is presently under clinical testing. The vaccine is based on truncated versions (DEN-80E) of the E protein from DENV1-4, produced in Drosophila Schneider-2 (S2) cells, and uses the adjuvant ISCOMATRIX TM (CSL Behring, King of Prussia, PA, USA) [ 165 ]. Preclinical tests using mice and NHPs showed the induction of Th1 biased cellular immune responses, the presence of neutralizing antibodies and protective immunity against lethal challenge.…”

Defeat Dengue and Zika Viruses With a One-Two Punch of Vaccine and Vector Blockade

“…This vaccine is comprised of four Drosophila S2 cell expressed N-terminal 395aa of envelope proteins (E80) representing four serotype of dengue viruses, and it has been demonstrated to produce neutralizing antibody and provide protection against challenge with multiple serotypes of DENV in murine and non-human primate models (Clements et al, 2010;Govindarajan et al, 2015). In a recent Phase I clinical trial, tetravalent E80 vaccines formulated with different adjuvants were shown to be well tolerated in seronegative recipients in Australia, and they elicited tetravalent neutralizing antibodies, albeit of short duration (Manoff et al, 2019). Use this protein vaccine in adults who previously received attenuated vaccines, TV003 or TV005, has also been tested in clinical trial, the results of which are pending (ID: NCT02450838).…”

“…In comparison, subunit proteins are easier for epitope selection and quality control. In most subunit candidate vaccines of DENV and ZIKV, soluble EDIII or E80 as antigens were chosen (Block et al, 2010;Liang et al, 2018;Manoff et al, 2019) to induce neutralizing antibodies that block virus attachment or/and inhibit post-entry membrane fusion. Nevertheless, fusion-loop epitope antibodies can still be induced by E80 due to the probable re-exposure of fusionloop under acidic environment even for an envelope dimer immunogen.…”

Long-Term Protection Elicited by a DNA Vaccine Candidate Expressing the prM-E Antigen of Dengue Virus Serotype 3 in Mice

“…To resolve this significant, international public health problem, considerable effort has been directed toward the development of safe dengue vaccines. A number of candidates have been reported, including inactivated vaccines, live-attenuated vaccines, DNA vaccines, and subunit protein vaccines (Eckels and Putnak, 2003;Whitehead, 2016;Bustos-Arriaga et al, 2018;Manoff et al, 2019;Prompetchara et al, 2019;Wang et al, 2019). Of great concern, the first and only licensed dengue vaccine, Dengvaxia, had been approved for use in endemic areas owing to its higher efficacy among participants vaccinated at age ≥9 years (Ferguson et al, 2016;Henein et al, 2017); however, a post-hoc analysis of safety and efficacy reported a higher risk of severe dengue attack and hospitalization in vaccinated persons who had not been exposed to dengue (Sridhar et al, 2018).…”