Experimental Dengue Virus Challenge of Human Subjects Previously Vaccinated With Live Attenuated Tetravalent Dengue Vaccines

Sun, Wellington; Eckels, Kenneth H.; Putnak, J. Robert; Lyons, Arthur; Thomas, Stephen J.; Vaughn, David W.; Gibbons, Robert V.; Fernandez, Stefan; Gunther, Vicky; Mammen, Mammen P.; Statler, John D.; Innis, Bruce L.

doi:10.1093/infdis/jis744

Cited by 75 publications

(50 citation statements)

References 32 publications

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“…[44][45][46] The work of Sabin indicates that human challenge studies can be conducted safely. None of the 243 subjects showed development of severe dengue.…”

Section: Discussionmentioning

confidence: 99%

Research on Dengue During World War II Revisited

Snow¹,

Haaland²,

Ooi³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. Much of the basic clinical information about dengue infection comes from experimental human studies conducted in the 1920s and 1940s. Albert Sabin's original laboratory records from one such study were bequeathed to Duane J. Gubler. These records were reviewed and 150 experiments were included in our analyses. Persons were inoculated with dengue virus 1 (DENV-1) and DENV-2. Median fever duration was shorter in primary DENV-2 infections compared with DENV-1, although maximum temperature and severity of illness were comparable. At 1.5-9 months after primary infection, 20 persons were inoculated with the heterologous serotype. Only one person inoculated with a heterologous serotype at 8 weeks showed development of a clinical infection with a maximum temperature of 38 C, and 7 (88%) of 8 persons inoculated with a heterologous serotype at 4-9 months post-primary infection showed development of fever. On average, persons had a shorter incubation period in secondary infection compared with primary infection.

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“…[44][45][46] The work of Sabin indicates that human challenge studies can be conducted safely. None of the 243 subjects showed development of severe dengue.…”

Section: Discussionmentioning

confidence: 99%

Research on Dengue During World War II Revisited

Snow¹,

Haaland²,

Ooi³

et al. 2014

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

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“…These studies also enabled investigators to characterize the clinical and laboratory manifestations of a primary dengue infection. In addition, early candidate dengue vaccines were developed and/or evaluated for protection against challenge or developed for use as challenge viruses [26][27][28][29][30]. Prior to the ability to culture the virus, investigators transmitted dengue from one infected person to another using the natural Aedes mosquito vector [25,26].…”

Section: History Of the Dengue Human Infection Model (Dhim)mentioning

confidence: 99%

“…The ideal DHIM would induce objective, reproducible endpoints with sufficient frequency that statistically significant protection could be determined using a smaller number of subjects. In addition, if the model could produce these endpoints without inducing significant illness, the risk to volunteers could be minimized and the studies may be performed [25] 1931 80 USA Vector identification, culture, infectious dose, pathology Sabin [4] 1952 >216 USA Immunology, Passaged LADV Wisseman [28] 1966 4 USA Passaged LADV challenge studies Fujita [47] 1969 10 Japan Effects of administration of DENV-1 and YF together Statler [44] 2008 12 USA Evaluation of DENV challenge strains, Ultrasound-based diagnostics Mammen [30] 2014 Sun [29] 2013 16 USA LATV-challenge study EIP, extrinsic incubation period; LADV, live attenuated dengue vaccine; LATV, live attenuated tetravalent vaccine.…”

Section: Dengue Infection Modelmentioning

confidence: 99%

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Dengue human infection models to advance dengue vaccine development

Larsen

Whitehead

Durbin

2015

Vaccine

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Dengue viruses (DENV) currently infect approximately 400 million people each year causing millions to seek care and overwhelming the health care infrastructure in endemic areas. Vaccines to prevent dengue and therapeutics to treat dengue are not currently available. The efficacy of the most advanced candidate vaccine against symptomatic dengue in general and DENV-2 in particular was much lower than expected, despite the ability of the vaccine to induce neutralizing antibody against all four DENV serotypes. Because seroconversion to the DENV serotypes following vaccination was thought to be indicative of induced protection, these results have made it more difficult to assess which candidate vaccines should or should not be evaluated in large studies in endemic areas. A dengue human infection model (DHIM) could be extremely valuable to down-select candidate vaccines or therapeutics prior to engaging in efficacy trials in endemic areas. Two DHIM have been developed to assess the efficacy of live attenuated tetravalent (LATV) dengue vaccines. The first model, developed by the Laboratory of Infectious Diseases at the U. S. National Institutes of Health, utilizes a modified DENV-2 strain DEN2Δ30. This virus was derived from the DENV-2 Tonga/74 that caused only very mild clinical infection during the outbreak from which it was recovered. DEN2Δ30 induced viremia in 100%, rash in 80%, and neutropenia in 27% of the 30 subjects to whom it was given. The Walter Reed Army Institute of Research (WRAIR) is developing a DHIM the goal of which is to identify DENV that cause symptomatic dengue fever. WRAIR has evaluated seven viruses and has identified two that meet dengue fever criteria. Both of these models may be very useful in the evaluation and down-selection of candidate dengue vaccines and therapeutics.

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“…As described in this study and previous work, AGMs are proving to be a useful model for dengue vaccine development (17,46). Recent studies in humans have shown other dengue vaccines unable to fully protect against challenge from all 4 DENV serotypes despite previous promising studies in rhesus macaques (6,12,45,(47)(48)(49)(50)(51)(52)(53). Additionally, investigations have shown that AGMs model certain human diseases better than macaques (46,(54)(55)(56).…”

Section: Discussionmentioning

confidence: 58%

Live Attenuated Tetravalent Dengue Virus Host Range Vaccine Is Immunogenic in African Green Monkeys following a Single Vaccination

Briggs

Smith

Piper

et al. 2014

J Virol

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The causative agent of dengue fever, dengue virus (DENV), is transmitted by mosquitoes, and as distribution of these insects has expanded, so has dengue-related disease. DENV is a member of the Flaviviridae family and has 4 distinct serotypes (DENV-1, -2, -3, and -4). No lasting cross protection is afforded to heterologous serotypes following infection by any one of the individual serotypes. The presence of nonneutralizing antibodies to one serotype can facilitate the occurrence of more-severe dengue hemorrhagic fever through immune enhancement upon infection with a second serotype. For this reason, the development of a safe, tetravalent vaccine to produce a balanced immune response to all four serotypes is critical. We have developed a novel approach to produce safe and effective live-attenuated vaccines for DENV and other insect-borne viruses. Host range (HR) mutants of each DENV serotype were created by truncating transmembrane domain 1 of the E protein and selecting for strains of DENV that replicated well in insect cells but not mammalian cells. These vaccine strains were tested for immunogenicity in African green monkeys (AGMs). No vaccine-related adverse events occurred. The vaccine strains were confirmed to be attenuated in vivo by infectious center assay (ICA). Analysis by 50% plaque reduction neutralization test (PRNT 50 ) established that by day 62 postvaccination, 100% of animals seroconverted to DENV-1, -2, -3, and -4. Additionally, the DENV HR tetravalent vaccine (HR-Tet) showed a tetravalent anamnestic immune response in 100% (16/16) of AGMs after challenge with wild-type (WT) DENV strains. IMPORTANCEWe have generated a live attenuated viral (LAV) vaccine capable of eliciting a strong immune response in African green monkeys (AGMs) in a single dose. This vaccine is delivered by injecting one of four attenuated serotypes into each limb of the animal. 100% of animals given the vaccine generated antibodies against all 4 serotypes, and this response was found to be balanced in nature. This is also one of the first studies of dengue in AGMs, and our study suggests that viremia and antibody response in AGMs may be similar to those seen in DENV infection in humans.

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Experimental Dengue Virus Challenge of Human Subjects Previously Vaccinated With Live Attenuated Tetravalent Dengue Vaccines

Abstract: Vaccination with TDV induced variable protection against subcutaneous challenge. DENV-3 experimental challenge was associated with transient but marked elevations of transaminases.

Cited by 75 publications

References 32 publications

Research on Dengue During World War II Revisited

Research on Dengue During World War II Revisited

Dengue human infection models to advance dengue vaccine development

Live Attenuated Tetravalent Dengue Virus Host Range Vaccine Is Immunogenic in African Green Monkeys following a Single Vaccination

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