Research Article: Phase I Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico

Date Published: May 05, 2018

Publisher: The American Society of Tropical Medicine and Hygiene

Author(s): Clemente Diaz, Leyi Lin, Luis J. Martinez, Kenneth H. Eckels, Maribel Campos, Richard G. Jarman, Rafael De La Barrera, Edith Lepine, Jean-François Toussaint, Irma Febo, Bruce L. Innis, Stephen J. Thomas, Alexander C. Schmidt.

http://doi.org/10.4269/ajtmh.17-0627

Abstract

The safety and immunogenicity of four adjuvanted formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV) were evaluated in a predominantly dengue-primed population in Puerto Rico. In this placebo-controlled, randomized, observer-blind, phase I trial, 100 healthy adults were randomized 1:1:1:1:1 to receive DPIV at Day (D)0 and D28 (1 μg per dengue virus [DENV] type 1–4 adjuvanted with either alum, AS01E or AS03B, or 4 μg per DENV type adjuvanted with alum) or saline placebo. Functional antibody responses were assessed using a microneutralization assay at D56, Month (M)7, and M13. All DPIV formulations were well tolerated and no safety signals were identified through M13. The M13 according-to-protocol (ATP) immunogenicity cohort included 83 participants. The ATP analysis of immunogenicity was performed only on the 78 subjects seropositive for ≥ 1 DENV type at baseline: 69 tetravalent, three trivalent, two bivalent, and four monovalent. In all DPIV groups, geometric mean antibody titers (GMTs) increased from D0 to D56 and waned modestly through M13, while remaining well above prevaccination levels. The 4 μg + alum and the AS01E- and AS03B-adjuvanted formulations were highly immunogenic, with M13-neutralizing antibody GMTs against all four DENV types above 1,000. M13/D0 GMT ratios were highest in the 1 μg + AS03B group (ranging 3.2–3.7 depending on the DENV type). These results encourage continued clinical development of DPIV (ClinicalTrials.gov: NCT01702857).

Partial Text

Dengue is a mosquito-borne viral disease found in tropical and subtropical climates worldwide. Dengue is caused by any of the four single stranded, positive-sense enveloped RNA viruses (dengue virus [DENV]-1, -2, -3, and -4) from the genus Flavivirus. Global dengue incidence has increased 30-fold in the last 50 years,1 with 390 million dengue infections estimated to occur every year, of which 96 million are clinically apparent.2 Dengue fever is endemic in Puerto Rico and transmission intensity varies geographically and by season.3,4 A recent vaccine study in Puerto Rico found that the vast majority of young adults were seropositive for dengue and 89% of 21–50-year-olds were tetravalent seropositive.5 In 2010, Puerto Rico experienced the largest dengue outbreak in its history, with more than 26,000 suspected cases reported.3 Although endemic dengue cases are seen every year, cycles of epidemic outbreaks have been reported with increasing intensity during the last decades.

Results from this first phase I study of a new vaccine candidate with inactivated DENV in a dengue- primed population showed that all four DPIV vaccine formulations were well tolerated and immunogenic. Transient mild to moderate injection site pain was more frequently reported in active treatment groups, but all other solicited local and general solicited AEs were balanced between active and control groups. Although one could have speculated that more reactogenicity will be observed in a young dengue-primed population, reactogenicity in this study population was similar to that observed in a similar trial in naive subjects (NCT01666652).16 Of note, only one grade 3 fever (duration of 1 day) was reported and elevated temperatures were uncommon and balanced between active treatment groups and the placebo group. Anemia was the most frequently observed laboratory abnormality in active and control groups and was more frequently observed in women than in men. The prevalence of anemia observed in this study was comparable to that observed in the general Puerto Rican population, and was judged independently by the medical monitor not related to the study vaccine. No SAEs related to vaccination were reported in any group through the M13 visit.

This new investigational DPIV vaccine had an acceptable safety profile in a small number of flavivirus-primed healthy adult subjects and all formulations boosted Nab responses, with complex adjuvants increasing immunogenicity versus alum adjuvantation. Neutralizing antibody titers remained high (and above baseline titers) through M13. These results encourage continuation of DPIV clinical development.

 

Source:

http://doi.org/10.4269/ajtmh.17-0627

 

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