Dengue Virus Exposures Among Deployed U.S. Military Personnel.

AbstractDengue virus infections have adversely impacted U.S. military operations since the Spanish-American War. The erosion of mission capabilities and lost duty days are underestimated. Appreciating the incidence and prevalence of dengue infections in U.S. military personnel is important to inform disease prevention strategies. Banked pre- and post-deployment serum samples from 1,000 U.S. military personnel with a single deployment to a dengue-endemic region were tested using a screening microneutralization assay to detect anti-dengue-virus-neutralizing antibodies. A total of 76 (7.6%) post-deployment samples were positive and 15 of the pre-deployment samples were negative. These figures represent an infection incidence of 1.5% and total of 17.6 seroconversions per 10,000 deployment months. These data represent a deploying military population with a relatively high background rate of dengue seropositivity, a low level of infection during deployment compared with background infection rates in the local populations, and the potential for worsening clinical attack rates with increased frequency of deployment. Additional studies are required to more clearly elucidate the dengue infection and disease risk in U.S. military personnel.

Safety and Immunogenicity of a Dengue Virus Serotype-1 Purified-Inactivated Vaccine: Results of a Phase 1 Clinical Trial.

We describe the results from a human clinical trial of a dengue virus serotype-1, purified-inactivated vaccine (DENV-1 PIV) adjuvanted with aluminum hydroxide. This first-in-man, Phase 1, open-label clinical trial consisted of two groups of flavivirus-naïve healthy adult volunteers that received two intramuscular vaccine doses of either 2.5 µg or 5 µg of DENV-1 PIV administered on days 0 and 28. Following vaccination, both vaccine doses exhibited an acceptable safety profile with minimal injection site and systemic reactions. By study day 42, 2 weeks following the second vaccine dose, all volunteers in both vaccine groups developed serum-neutralizing antibodies against DENV-1. Additional testing using an enzyme-linked immunosorbent assay demonstrated induction of a humoral immune response following both vaccine doses. The DENV-1 PIV was safe and immunogenic in a small number of volunteers supporting development and further testing of a tetravalent DENV PIV formulation.

Seroprevalence of Dengue Fever in US Army Special Operations Forces: Initial Results and the Way Ahead.

The endemicity of dengue fever (DF) and, consequently, sequelae of DF are increasing worldwide. The increases are largely a result of widespread international travel and the increased range of the mosquito vectors. US Army Special Operations Command (USASOC) personnel are at an increased risk of exposure to dengue based on their frequent deployments to and presence in dengue endemic areas worldwide. Repeated deployments to different endemic areas can increase the risk for developing the more serious sequelae of dengue: dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Information about the seroprevalence rate of dengue in USASOC personnel, in particular, is lacking and is critical to assessing the risk, tailoring preventive medicine countermeasures, leveraging field diagnostics, and maintaining mission capability. In the first part of a two-part project to assess baseline seroprevalence in USASOC units, a random, unit-stratified sample of 500 anonymous serum specimens from personnel assigned to the highest-risk units in USASOC were screened for dengue using a microneutralization assay. Of the 500 specimens screened, 56 (11.2%) of 500 had neutralizing titers (NT) (MN50≥10) against at least one DENV serotype. Subsequent sample titration resulted in 48 (85.7%) of 56 of the samples with NT (MN50≥10) against at least one dengue serotype for an overall dengue exposure rate of 9.6% (48 of 500). The second part of the ongoing project, started in 2012, was a multicenter, serosurveillance project using predeployment and postdeployment sera collected from USASOC personnel deployed to South and Central America, Africa, and Southeast Asia. Preliminary results show a 13.2% (55 of 414) seropositivity rate. The significance of these findings as they relate to personal risk and operational impact is discussed.

The human dengue challenge experience at the Walter Reed Army Institute of Research.

Recent discordance between measured levels of serotypes of dengue virus neutralizing antibody and clinical outcomes suggests a need to reevaluate the process of prescreening dengue vaccine candidates to better predict their clinical benefit before initiation of large-scale human vaccine trials. In the absence of a reliable animal model for dengue, a human dengue virus challenge model (ie, a controlled live dengue virus infectious challenge study) may prove useful and timely to elucidate mechanisms that underlie protection (as well as virulence), thus facilitating down-selection of vaccine candidates before beginning advanced field trials. Dengue challenge studies were safely used in prior decades to study the vector biology, clinical spectrum of illness, and reactogenicity of candidate live dengue virus vaccines of uncertain attenuation. Redeveloping the human dengue challenge model following current regulatory guidance, good manufacturing practice, and good clinical practice could streamline and accelerate vaccine development by offering a time- and resource-efficient method to evaluate the safety and potential efficacy of dengue vaccine and therapeutic candidates. In this article, the development of such a challenge model and its subsequent application is summarized from 2 recent reports.

A phase 3, randomized, double-blind, placebo-controlled study of the safety and efficacy of the live, oral adenovirus type 4 and type 7 vaccine, in U.S. military recruits.

Adenovirus (ADV) types 4 (ADV-4) and 7 (ADV-7) are presently the major cause of febrile acute respiratory disease (ARD) in U.S. military recruits. We conducted a multi-center, randomized, double-blind, placebo-controlled phase 3 study of the new vaccine to assess its safety and efficacy. Healthy adults at two basic training sites were randomly assigned to receive either vaccine (two enteric-coated tablets consisting of no less than 4.5 log10 TCID50 of live ADV-4 or ADV-7) or placebo in a 3:1 ratio. Volunteers were observed throughout the approximate eight weeks of their basic training and also returned for four scheduled visits. The primary endpoints were prevention of febrile ARD due to ADV-4 and seroconversion of neutralizing serum antibodies to ADV-7, which was not expected to circulate in the study population during the course of the trial. A total of 4151 volunteers were enrolled and 4040 (97%) were randomized and included in the primary analysis (110 were removed prior to randomization and one was removed after randomization due to inability to swallow tablets). A total of 49 ADV-4 febrile ARD cases were identified with 48 in the placebo group and 1 in the vaccine group (attack rates of 4.76% and 0.03%, respectively). Vaccine efficacy was 99.3% (95% CI, 96.0-99.9; P<0.001). Seroconversion rates for vaccine recipients for ADV-4 and ADV-7 were 94.5% (95% CI, 93.4-95.5%) and 93.8% (95% CI: 93.4-95.2%), respectively. The vaccine was well tolerated as compared to placebo. We conclude that the new live, oral ADV-4 and ADV-7 vaccine is safe and effective for use in groups represented by the study population.

Experimental dengue virus challenge of human subjects previously vaccinated with live attenuated tetravalent dengue vaccines.

BACKGROUND: Protection against dengue requires immunity against all 4 serotypes of dengue virus (DENV). Experimental challenge may be useful in evaluating vaccine-induced immunity. METHODS: Ten subjects previously vaccinated with a live attenuated tetravalent dengue vaccine (TDV) and 4 DENV-naive control subjects were challenged by subcutaneous inoculation of either 10(3) plaque-forming units (PFU) of DENV-1 or 10(5) PFU of DENV-3. Two additional subjects who did not develop DENV-3 neutralizing antibody (NAb) from TDV were revaccinated with 10(4) PFU of live attenuated DENV-3 vaccine to evaluate memory response. RESULTS: All 5 TDV recipients were protected against DENV-1 challenge. Of the 5 TDV recipients challenged with DENV-3, 2 were protected. All DENV-3-challenge subjects who developed viremia also developed elevated liver enzyme levels, and 2 had values that were >10 times greater than normal. Of the 2 subjects revaccinated with DENV-3 vaccine, 1 showed a secondary response to DENV-2, while neither showed such response to DENV-3. All 4 control subjects developed dengue fever from challenge. Protection was associated with presence of NAb, although 1 subject was protected despite a lack of measurable NAb at the time of DENV-1 challenge. CONCLUSIONS: Vaccination with TDV induced variable protection against subcutaneous challenge. DENV-3 experimental challenge was associated with transient but marked elevations of transaminases.