Immunogenicity and Safety of a Tetravalent Recombinant Subunit Dengue Vaccine in Adults Previously Vaccinated with a Live Attenuated Tetravalent Dengue Vaccine: Results of a Phase-I Randomized Clinical Trial

Abstract

New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.

Trial registration: ClinicalTrials.gov NCT00936429 NCT01477580.

Conflict of interest statement

Disclosures: M. S., A. R, J. M., D. H., J. R. S., A. W.-T. L., and L. W. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, and may hold stock in Merck & Co., Inc., Kenilworth, NJ. B. A.-C. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, and may hold stock in Merck & Co., Inc., Kenilworth, NJ. and has three issued patents related to the V180 vaccine. A. P.D. has participated in scientific advisory committee meetings for Merck & Co., Inc., Kenilworth, NJ. B. D. K. reports grants from the University of Vermont. P. G. reports employment by Johns Hopkins University, MD. while working on the study. B. P.S. reports grants from the NIAID/NIH and obtaining the vaccine from Merck & Co., Inc., Kenilworth, NJ to perform the study. M. C. reports employment at MMS Holding, Inc., Jackson, NJ on assignment to Merck & Co., Inc., Kenilworth, NJ.

Figures

Figure 1.

Longitudinal immune responses as measured by PRNT50. The geometric mean titer (GMT) of neutralizing antibody of each group is shown at days 1, 15, 28, and 180 for DENV1 (A), DENV2 (B), DENV3 (C), DENV4 (D) as measured with the plaque reduction neutralization test (PRNT50). Error bars represent the 95% CI for each group. This figure appears in color at www.ajtmh.org.

Figure 2.

Longitudinal plaque reduction neutralization test (PRNT50) seropositivity frequency. The frequency of seropositivity for each group at days 1, 15, 28, and 180 is shown for DENV1 (A), DENV2 (B), DENV3 (C), and DENV 4 (D). Seropositivity was defined as a PRNT50 ≥ 10. Error bars represent the 95% CI for each group.