Featured Subject Matter Expert Research Corner
Dengue is the most important arboviral disease afflicting the world today. Hundreds of millions of infections occur each year, of which more than 90 million are clinically apparent . Mortality is reportedly low compared to other vector borne diseases, but the brunt of severe dengue disease and death in many regions occurs disproportionately in children . Dengue has a considerable impact at the personal, community, and regional level and is a leading cause of febrile, systemic illness in travelers [44, 45]. Dengue has placed deploying military personnel at risk for over a century [46-51].
Conditions favoring the close juxtaposition of virus, vector, and susceptible host, a requirement for sustained transmission, are numerous. Ecological conditions favoring vector expansion, population growth and increasing urbanization, and the ease of air travel have all contributed to the concentration, in time and space, of susceptible hosts, competent vectors, and dengue viruses (DENVs) .
Dengue is a significant infectious disease threat among travelers to endemic areas (Figure 1). Between 2000-2010, dengue was the third most commonly diagnosed illness among returning travelers, behind malaria and infectious diarrhea .
A review of four prospective studies of travelers to dengue-endemic regions demonstrated an incidence of dengue that ranged from 10.2–30 infections per 1000 person-months, depending on the region of travel and duration of travel . As of January 2020, there were 1,203 dengue cases reported in the U.S., 56 in U.S. Territories with local transmission reported in Florida and Puerto Rico (Figure 2). The majority of cases were traveler associated infections (98%).
Clinical Manifestations of Dengue
Dengue is a febrile illness caused by infection with one of four DENV. As discussed briefly in Section 2, transmission to humans occurs when Aedes aegypti or Aedes albopictus mosquitoes take a blood meal from a susceptible host (Figure 3) [55, 56].
Infection may be asymptomatic or present with a broad range of clinical manifestations including a mild febrile illness to a life-threatening shock syndrome. Numerous viral, host, and vector factors are thought to impact risk of infection, disease, and disease severity.
There are four closely related but serologically distinct DENV types, called DENV-1, DENV-2, DENV-3, and DENV-4. Once infected with one DENV type, there is transient cross-protection against the other types, which weakens and disappears over the months following infection. A primary DENV infection is the first wild type infection an individual sustains while a secondary infection is the second wild type infection caused by a different DENV type.
The incubation period for infection and dengue disease ranges from three to 14 days . Dengue disease may follow three phases; a febrile phase, a critical phase, and a recovery phase. The critical phase occurs in the minority of infections . The febrile phase includes sudden, high-grade fever of 38.5°C (101.3°F) or higher, accompanied by headache, vomiting, myalgia, arthralgia, and a transient macular rash in some cases. Additional manifestations may include gastrointestinal symptoms (including anorexia, nausea, vomiting, abdominal pain, and diarrhea) and respiratory tract symptoms (cough, sore throat, and nasal congestion). The febrile phase lasts for three to seven days, after which most patients recover without complications.
Hemorrhagic manifestations may be observed in the febrile phase and/or critical phase. The range and severity of hemorrhagic manifestations are variable. Major skin and/or mucosal bleeding (gastrointestinal or vaginal) may occur in adults. In children, clinically significant bleeding occurs rarely, usually in association with profound and prolonged shock. Other less frequent manifestations include hematemesis (15 to 30 percent), menorrhagia (40 percent of women), melena (5 to 10 percent), and epistaxis (10 percent). Comorbid or pre-existing medical conditions (such as peptic ulcer disease) may increase the risk for hemorrhage. Although significant thrombocytopenia increases the risk of hemorrhage, it is not always present when hemorrhagic manifestations occur [59, 60].
Leukopenia and thrombocytopenia (=100,000 cells/mm3) are common. Serum aspartate transaminase (AST) levels are frequently elevated; the elevations are usually modest (2 to 5 times the upper limit of normal values), but marked elevations (5 to 15 times the upper limit of normal) occasionally occur. Although liver associated enzyme elevations are frequently elevated in the febrile phase, synthetic liver dysfunction (i.e. elevated activated partial-thromboplastin time) and decreases in fibrinogen are not frequently identified .
Between days three and seven of the illness, the clinician must watch for signs of vascular leakage and the clinical manifestations of the same. Significant vascular leakage reduces intravascular volume and decreases organ perfusion. Clinical and lab evidence of this occurring may include persistent vomiting, increasingly severe abdominal pain, tender hepatomegaly, a high or increasing hematocrit level (=20 percent from baseline) concurrent with a rapid decrease in the platelet count, development of pleural effusions and/or ascites, mucosal bleeding, and lethargy or restlessness .
Around the time of defervescence (typically days 3 to 7 of infection), a small proportion of patients have the potential to develop a systemic vascular leak syndrome characterized by plasma leakage, bleeding, shock, and organ impairment. The greatest risk of patients entering into this critical phase and developing severe disease occurs with a secondary infection [63, 64]. The critical phase lasts for 24 to 48 hours.
During the recovery phase, plasma leakage and hemorrhage resolve, vital signs stabilize, and accumulated fluids are resorbed. An additional rash (a confluent, erythematous eruption with small islands of unaffected skin that is often pruritic) may appear during the convalescent phase. The recovery phase typically lasts two to four days and adults may have profound fatigue for days to weeks after recovery.
A number of different risk factors have been proposed to predispose someone to severe dengue disease such as medical co-morbidities, age, sex, nutritional status, and the infecting viral serotype and genotype. The most compelling data, however, supports that immune mediated mechanisms following a secondary infection drive disease pathogenesis.
Both innate and adaptive immune responses induced by DENV infection are likely to play a role in the clearance of infection . Infection of human cells in vitro induces antiviral responses (interferons) and has been measured in children with dengue . In response, DENV proteins appear able to inhibit both the production of interferons and their antiviral function in infected cells . It also appears the expression of genes associated with type I interferon signaling is lower in patients with dengue shock syndrome (DSS) than in patients without DSS .
The antibody response to DENV infection is primarily directed at serotype-specific determinants, but there is a substantial level of serotype–cross-reactive antibodies. In vitro, Envelope (E) protein–specific antibodies can mediate neutralization of infection, direct complement-mediated lysis or antibody-dependent cellular cytotoxicity of dengue virus–infected cells, and block virus attachment to cell receptors . Non-structural protein 1 (NS1) is not found in the virion; NS1-specific antibodies are therefore incapable of neutralization of virus infection but can direct complement-mediated lysis of infected cells .
Virus neutralization clearly requires a threshold level of antibodies; when the concentration of antibodies is below this threshold, the uptake of antibody-bound virus by cells that express immunoglobulin (Ig) receptors may paradoxically increase, a process known as antibody-dependent enhancement (ADE) . In rhesus monkeys, passive transfer of low levels of dengue-immune human sera or a humanized chimpanzee DENV–specific monoclonal antibody resulted in a 2- to 100-fold increase in dengue-2 or dengue-4 viremia titers as compared with controls . Dengue virus entry via ADE has also been found to suppress innate immune responses in infected monocytes in vitro .
The T lymphocyte response to DENV infection also includes both serotype-specific and serotype–cross-reactive responses . Dengue virus–specific CD4+ and CD8+ T cells can lyse DENV–infected cells in vitro and produce cytokines such as IFN-gamma, tumor necrosis factor (TNF)-alpha, and lymphotoxin. In vitro, IFN-gamma can inhibit DENV infection of monocytes. However, IFN-gamma can also increase the expression of Ig receptors potentially augmenting ADE .
Primary infection provides long-lasting immunity to infection with a virus of the same serotype but immunity to the other dengue serotypes is transient, allowing for secondary infections. Studies have reported that higher peak plasma DENV titers occur in secondary dengue infections and are associated with more severe illness . Other studies have failed to demonstrate this phenomenon .
The kinetics of DENV–specific antibodies in secondary dengue infections differ from those of primary dengue infections in several ways (Figure 4).
Low concentrations of anti-DENV antibodies to the DENV causing the secondary infection are present before exposure to the virus; as a result, ADE could occur [78, 79]. DENV–specific antibody titers increase earlier in secondary infection, reach higher peak titers, and have a lower IgM:IgG ratio, suggestive of an anamnestic response. As such, DENV–specific antibody titers are much higher during the late stage of viremia in secondary infections, with greater potential for forming immune complexes and activating complement.
The kinetics of the T lymphocyte response in secondary infections would include an earlier onset and higher level of DENV–specific T lymphocyte proliferation and cytokine production . Interestingly, the severity of dengue disease and its correlation with the level and quality of the DENV–specific T lymphocyte responses has been inconsistent .
Dengue Impact on the Warfighter
As with recreational travelers, dengue threatens deploying U.S. military personnel. It has been a cause of febrile illness in troops deployed in tropical areas since the Spanish-American War , including the Pacific Theater of World War II , Vietnam (1969) , Somalia (1992-1993) , and Haiti (1997) . Dengue affected French forces in New Caledonia (1989) , French Polynesia, and the West Indies (1997) ; and Australian forces and Italian troops in East Timor (1999-2000) . The modern-day burden of dengue infections among recently and currently globally deployed troops is still largely unknown. A serologic survey of troops hospitalized with acute febrile illness during Operation Restore Hope in Somalia from 1992 to 1993 revealed of 96 patients with unspecified febrile illness, 43% had positive serological evidence of dengue infection . This study did not capture the total incidence of dengue infections but analyzed sera only from febrile patients. In order to appreciate the infection, versus clinical disease risk, an anti-dengue virus antibody seroprevalence study was completed in 500 U.S. Special Forces soldiers who spent 30 days or greater in South America between 2006-2008. Testing of post-deployment serum found an 11% dengue seroprevalence rate among this population . In another study testing pre- and post-deployment serum samples from 1,000 U.S. military personnel, a total of 76 (7.6%) post-deployment samples were positive; of these, 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 .
Operational Case Study
On September 19, 1994, 20,000 U.S. soldiers were deployed to Haiti as part of Operation Uphold Democracy . The purpose of the mission was to provide security to the Haitian government, return the democratically elected President to office, and create a stable and secure environment in which democratic institutions could take hold. Living conditions for U.S. troops, especially the 10th Mountain Division, were described as spartan . Latrines and fresh water were in short supply. Tropical rains from Tropical Storm Gordon and poor drainage meant that soldiers were living and working in areas ankle-deep in water. As forces extended their operations to provide security, troop movement and operations occurred during the night, with day hours designated as the time for rest and sleeping. From an infectious disease perspective, it was known that both malaria and dengue were endemic in the Haitian population, and U.S. personnel were given malaria prophylaxis and also insect repellant. The combination of a wet environment with deployed U.S. forces and accompanying equipment and trash build-up meant a rapid increase in the breeding environment for the Aedes mosquito vector. As discussed in Section 2, the nature of the deployment, with soldiers resting during the day in the shade and at peak biting times for the Aedes mosquito, translated into a situation ideal for DENV transmission and infection of a susceptible population. Between September 27, 1994 and November 5, 1994, 112 U.S. soldiers (0.1% of the total U.S. deployed forces in Haiti), were evaluated for fever, of which 30 soldiers were confirmed as dengue infected. Common symptoms included malaise, headache, chills, backache, loss of appetite, rigors, joint and muscle pains, and nausea . Several required evacuations back to medical treatment facilities in the U.S. In a survey of the patients with dengue, 16.7% always used DEET and 13.3% had treated their uniforms with permethrin .
Challenges in Dengue Vaccine Development
There is no licensed prophylactic or therapeutic dengue drug (i.e. antiviral or anti-inflammatory). Vector control, even when successful from an entomologic perspective, does not always translate into a reduction in human infection or disease . Personal protective measures such as wearing long sleeves and pants, use of bed nets, use of insecticides (e.g. N,N-Diethyl-meta-toluamide, DEET), avoidance of vectors during prime feeding times, and reducing the number of man-made vector breeding sites (e.g. standing water) are inconsistently applied . A safe and efficacious dengue vaccine capable of protecting the recipient from disease caused by any of the DENV serotypes is considered the best option to reduce the global dengue burden.
However, numerous challenges plague the dengue vaccine development field. The existence of four DENV serotypes all capable of causing disease and death requires a dengue vaccine capable of preventing clinical disease caused by infection with any of the DENV [91-93]. Therefore, developers need to make tetravalent vaccines with components of each DENV serotype in the final formulation.
The coordination of innate and adaptive immune responses which confer protection or contribute to pathogenesis following a DENV infection is incompletely understood . As a result, there is concern an imperfect vaccine could induce ADE. Gaps in the understanding of dengue immunology are complicating the process of defining an immune correlate of protection.
Adversely impacting the exploration for a correlate of protection is the absence of an animal dengue disease model. Humanized small animal models are being aggressively studied but they do not appear to offer a comprehensive view of in vivo human dengue disease pathology at this time [94, 95]. There is also no validated dengue human infection model. Dengue human infection models expose healthy volunteers to mildly attenuated DENVs to produce an uncomplicated and mild dengue disease. These models can then be used to support drug and vaccine development allowing for early looks into clinical benefit before large field trials. There is active progress on developing a dengue human infection model, but it remains niche and not mainstream [96-99].
Another issue impacting the dengue vaccine field is the portfolio of assays used to measure vaccine immunogenicity during pre-clinical and clinical development activities. Neutralizing antibodies have the greatest likelihood of being identified as a correlate of protection . Unfortunately, the classic assay platform designed to measure neutralizing antibodies (Plaque Reduction Neutralization Test, PRNT) has significant inter-assay and inter-lab variability and is not robust [101-104]. Assay platforms measuring cellular mediated immunity (CMI) have also been applied to dengue vaccine development programs but remain experimental .
Dengue Vaccine Candidates
There are numerous dengue vaccine candidates in pre-clinical and clinical development with three in efficacy trials . Dengvaxia® is a chimeric live virus vaccine with the pre-membrane and envelope (preM and E) genes for each of the DENV serotypes replacing the analogous proteins in the yellow fever 17D virus [106, 107]. Takeda Pharmaceuticals has initiated a phase 3 clinical program using a DENV-DENV chimeric live virus vaccine where the preM and E genes from DENV-1, -3, and -4 are inserted into an attenuated DENV-2 backbone . The U.S. National Institutes of Health (NIH) and Butantan are conducting an efficacy study using a live virus vaccine attenuated through directed mutagenesis of the DENV-1, -3, and -4 types and chimerizing DENV-2 preM and E genes into the attenuated DENV-4 backbone . Merck &Co., Inc. have entered into agreements with both organizations to further develop the candidate. Dengvaxia® is the only vaccine which has been licensed and has been registered in over 20 countries. A safety signal observed in the youngest recipients and those who were dengue seronegative at baseline has shaped an indication for people 9-45 years of age who have been previously infected with dengue . Takeda vaccines has published data out to 12 months of follow-up following vaccination . The overall vaccine efficacy was 80.9%. Approximately 28% of the per-protocol population was seronegative prior to vaccination, in this group vaccine efficacy was 74.9%. Efficacy trends varied according to serotype with DENV-3 having no efficacy and there were not enough DENV-4 cases to make an efficacy determination . Butantan is developing an NIH vaccine construct and is currently executing a phase 3 trial in Brazil with intent to enroll approximately 17,000 people.
Dengvaxia® has been studied in 26 clinical trials including more than 41,000 volunteers. At least one injection of final tetravalent formulation has been administered to more than 28,500 individuals from 9 months through 60 years of age and 20,974 individuals aged 9 years through 45 years. Clinical end-point studies were performed in Thailand (phase 2b, CYD23) and Asia (CYD14) and Latin America (CYD15) [106, 107, 112].
Numerous phase 1 studies together with three phase 2 studies provided data on safety and immune responses induced by several different vaccine formulations and immunization schedules. The results of these studies supported the selection of the final vaccine formulation and schedule: ~5 log10 CCID50 of each live, attenuated, DENV type 1, 2, 3, 4 given as 3 injections 6 months apart [113-116]. Additional phase 2 trials testing Dengvaxia® were performed in multiple endemic and non-endemic countries in Asia (India, Philippines, Singapore, Vietnam), Latin America (Brazil, Colombia, Honduras, Mexico, Peru), Australia and the U.S, addressing questions related to dose, schedule, priming by other flaviviruses or flavivirus vaccines, and the safety of co-administration with other vaccines [117-125]. Safety and immunogenicity were assessed in Indian populations and a co-administration phase 2 study was also conducted together with measles/mumps/rubella (MMR) vaccine. An indication for traveler/non-endemic populations was explored (shorter schedule) in a phase 2 adult study in the U.S. A booster dose (five years after dose three of the primary series) has been evaluated in two phase 2 studies and alternate vaccination schedules and booster dose study in individuals 9 to 50 years of age was conducted in the Philippines and Colombia with results pending. A prime boost with Japanese encephalitis (JE) vaccine before or during Dengvaxia® vaccination along with a shortened schedule was also explored showing equivalent neutralizing antibody titers with a shortened inoculation schedule of 0, 2 and 6 months . Giving JE vaccine as a prime or concurrently didn’t boost or negate neutralizing antibody titers.
Four phase 3 clinical studies were performed in dengue naïve adults in Australia up to 60 years of age and provided data to support phase 2 to phase 3 bridging required due to new manufacturing processes. A phase 3 trial was conducted in Malaysian children (2-11 years of age) assessing Dengvaxia’s® safety and immunogenicity. Studies in Peru and Colombia assessed Dengvaxia® co-administration with yellow fever vaccine in infants and toddlers less than two years of age, while a study in Mexico assessed co-administration of DTacP-IPV (diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine) as a booster administered with the second injection of Dengvaxia®. Three co-administration studies with human papilloma virus (HPV) vaccine were completed in individuals 9 to 13 years of age in Australia and 9 to 14 years in Mexico. The third study (Philippines) assessed co-administration of a tetanus/diphtheria/pertussis vaccine in individuals 9 to 60 years [127-129]. Dengvaxia’s® acute safety profile was found to be similar to licensed yellow fever vaccine (YF-VAX®, Sanofi Pasteur, Swiftwater, PA) and not affected by pre-existing yellow fever immunity. Most volunteers seroconverted in the monovalent DENV-2 trial and pre-existing yellow fever immunity contributed to a more cross-reactive and enduring anti-DENV antibody response . Second and third doses of vaccine were also safe and demonstrated sequential increases in immune responses . Studies in Mexico, the Philippines, and Australia continued to confirm acute safety in children and adults with varied pre-existing flavivirus immunity. The benefit of this pre-existing immunity towards developing rapidly increasing, broad, and potent immune responses after Dengvaxia® administration was also reinforced [115-117].
Three clinical endpoint studies have been conducted with Dengvaxia®; a phase 2b trial in Thailand and two phase 3 trials in Asia Pacific and Latin America [106, 107, 112]. Vaccine or control/placebo was administered at study months 0, 6, and 12. The primary efficacy endpoint was protection against dengue disease of any severity caused by any DENV type. The active follow-up phase of the study assessing for all symptomatic dengue was completed between study months 0 and 25 while hospital-based surveillance was originally planned from month 25 thru year 6; mid-way thru year 4, the surveillance expansion phase (SEP) was instituted marking a return to active surveillance. Acute safety and reactogenicity in 9-17-year-olds revealed the frequency of grade 3 (severe) reactions was low. Most reactions were mild and resolved within a few days and the frequency of reactions lessened with each subsequent injection. For those with available baseline dengue serostatus (determined by PRNT50), there was no difference in the frequency or severity of acute adverse events as a function of serostatus. Finally, there were no safety concerns related to vaccine viremia, co-administration of other vaccines, or the inadvertent vaccination of pregnant women.
A phase 2b proof of concept study in 4 to 11-year-old children residing in Thailand included 2,452 vaccine and 1,221 placebo recipients. From 28 days following the last dose of vaccine (injections at time 0, 6 months, 12 months) to the end of the active surveillance phase (study months 0-25), 78 virologically confirmed dengue cases occurred in 77 subjects. The study did not meet the primary efficacy endpoint with an overall efficacy of 30.2% [95% CI: -13.4; 56.6]. Important observations from this study included: 1) tetravalent dengue vaccines may have variable DENV type-specific efficacy; 2) neutralizing antibody titers may not predict efficacy; and 3) powering a study to assess for DENV type-specific efficacy or efficacy against preventing severe disease would require extremely large sample sizes.
Two clinical end-point efficacy studies were conducted in five Asia Pacific countries (Philippines, Thailand, Indonesia, Malaysia, and Vietnam) and five Latin American countries (Brazil, Colombia, Honduras, Mexico, and U.S.) . Subjects 2-14 years (N = 10,275) and 9-16 years of age (N = 20,869) were enrolled and were randomized 2:1 (vaccine: placebo). Both studies met the primary efficacy endpoint (2-16 years old, after 3 injections, during active surveillance months 13-25) with an efficacy in Asia of 56.5% (43.8-66.4) and Latin America of 60.8% (52.0-68.0); the combined study efficacy endpoint was 59.2% (52.3-65.0).
Vaccine efficacy in the same population from the first injection (months 0-25) was very similar. Combining studies, DENV type-specific efficacy was greatest for DENV-4 [76.9% (69.5-82.6), followed by DENV-3 [71.6% (63.0-78.3) and DENV-1 [54.7 (45.4-62.3)], with the lowest efficacy against DENV-2 [43.0% (29.4-53.9%)]. Efficacy against hospitalized dengue due to any of the DENV types after the first injection (months 0-25) was 67.4% (50.6-78.7) for Asia and 80.3% (64.7-89.5) for Latin America, with a combined efficacy of 72.7% (62.3-80.3). Combined efficacy against severe dengue was 79.1% (60.0-89.0). The relative risk (RR) of hospitalized dengue due to any DENV type in Asia favored Dengvaxia® during the active study phase (years 1 and 2) and for the entire study period, but was inconclusive for years 3 and 4 as the upper limit of the RR confidence intervals crossed 1. The results were somewhat different in Latin America with more convincing RR’s for the active phase [0.197 (0.11-0.35)] and entire study period [0.323 (0.22-0.47)]. Years 3, 4, and 5 all had RR’s below 1, but the upper limit of the CIs crossed 1. The RRs of experiencing severe disease conclusively favored Dengvaxia® in Asia only for the active phase [0.300 (0.13-0.64)]. In year 3, the data strongly favored the control with a RR of severe disease of 5.497 (0.80-236.60). In Latin America, the data favored the vaccine during the active phase and the entire study period; while the year 3 safety signal was not observed.
In summary, in three clinical endpoint studies, Dengvaxia® maintained the positive acute safety and reactogenicity profile established in early clinical studies. DENV type-specific and mean tetravalent neutralizing antibody responses were superior to placebo/control, moderate in titer, and relatively balanced across the different DENV types, but were not directly associated with DENV type-specific efficacy (i.e., immunogenicity by PRNT for a certain type did not predict type-specific efficacy). Vaccine efficacy against any dengue, of any severity, caused by any DENV type was low to moderate, with DENV-4 and -3 efficacy superior to DENV-1 and -2. Efficacy against hospitalized and severe dengue was superior when compared to prevention of any dengue. Efficacy as a function of time from injection demonstrated a positive trend towards the vaccine in years 0-2 and overall (0-5 years), but there was a safety signal in year 3 among some vaccine recipients. There is a clear beneficial effect of DENV seropositivity on vaccine efficacy.
State of the Art
The state of the art for dengue infection is focused on improved diagnostics including point of care rapid diagnostic tests (RDTs), antiviral for prophylaxis and treatment of severe disease, and a tetravalent vaccine that produces durable protection. Several RDTs are available commercially and include tests to detect IgM and IgG dengue specific antibody as well as tests to detect the NS1 protein. All utilize a wicking fiber paper with embedded dengue specific proteins or antibody that wick a drop of blood and gives a color band indicating a positive test. These are sensitive and specific, can give results within an hour, and are deployable to the warfighter medical unit as a point of care device. Several antiviral drugs specific to DENV are in clinical development both to prevent infection and to decrease severity of dengue illness. As discussed, there are several dengue vaccines in clinical development that show promise in providing protection against all four DENV serotypes and potentially appropriate to protect the warfighter.
Countermeasures against DENV infection currently include: 1) understanding the risk of locally acquired diseases to the susceptible deployed warfighter; 2) employing effective countermeasures such as vector control, use of insect repellants like DEET, and permethrin impregnated battle uniforms; 3) quick diagnostics to diagnose infection; and 4) prompt recognition of severe dengue illness with supportive treatment.
Dengue is a growing public health problem with the global disease burden growing annually. Infection may not manifest clinically or cause severe plasma leakage and/or hemorrhage and death. Numerous risk factors for severe disease have been proposed but the most convincing data points to sequential infections with different DENV serotypes as a primary culprit. Treatment is supportive as there are no licensed anti-DENV antivirals or immuno-therapeutics. A single dengue vaccine has been licensed and there are two others in advanced clinical development. Dengvaxia® has been licensed in more than 20 countries but use has been minimal as a result of safety signals in the youngest recipients and those who were dengue naïve at the time of vaccination. The world still requires a safe and efficacious tetravalent dengue vaccine capable of protecting seropositive and seronegative recipients across a broad age range.
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All Contributions from Timothy Endy, MD
Countermeasures Against the Degradation of Warfighter Capabilities due to Infectious Disease Threats
This State of the Art Report (SOAR) explores the impact of infectious disease on military personnel, providing both an historical and ongoing risk profile of the various infectious diseases that put the warfighter at risk. It includes a look at the historical impact of infectious diseases on past conflicts before going on to detail current and future infectious disease risks, their impact on the warfighter, and challenges in prevention or treatment, and concludes with a quick-look summary of state of the art developments and recommended countermeasures to aid leaders during training and planning.
Podcasts / Webinars
HDIAC Webinars » Historical Significance of Endemic Infectious Diseases and Loss of Warfighter Combat Effectiveness
In this presentation, a historical review of infectious disease-related combat injuries and deaths will be presented with an emphasis on the 1918 Influenza Pandemic during WWI, dengue and US Marine Forces in Saipan during WWII, dengue and US Forces Haiti and Somalia, malaria outbreak in US Marines deployed to Monrovia, and leishmaniasis and multi-drug resistant bacteria in US Forces during Persian Gulf War II. Lessons learned for future deployments will also be discussed.
This two-part series and associated state of the art report discuss infectious diseases from the viewpoint of the military warfighter. Infectious diseases are disorders caused by pathogenic microorganisms such as bacteria, viruses, fungi, or parasites that can be passed by human-to-human contact, by insects or other animals, or by contaminated surfaces, food, or water. By its very nature, warfare lends itself to the spread of such disease, and contagions have had an impact on every conflict.