Dengue serotype 1 vaccine development ? ? The live attenuated DEN1 vaccine candidate virus rDEN130 has been evaluated in preclinical animal models and found to be attenuated and immunogenic. These promising preclinical studies have identified rDEN130 as a candidate DEN1 vaccine virus for further testing in a human Phase I clinical trial. rDEN130 at a dose of 103 pfu was administered as a single inoculation to twenty healthy adult volunteers. Eight additional volunteers received placebo. Volunteers were monitored closely for adverse events, and serum was collected on study days 0, 28, 42, and 180 for determination of neutralizing antibody titer. The vaccine was well tolerated by the vaccinees. The most common adverse events observed were a transient asymptomatic rash in 40% of vaccinees and a mild neutropenia in 45% of vaccinees. No vaccinee developed a dengue-like illness. The vaccine was highly infectious and immunogenic with 95% of vaccinees developing a 4-fold rise in serum neutralizing antibody titer against DEN1 that persisted throughout the six month duration of the trial. The rDEN130 vaccine is safe and induced a potent and durable antibody response against DEN1. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation. ? ? Trials to determine the human infectious dose 50 are in progress.? ? Dengue serotype 2 vaccine development ? ? rDEN2430(ME) is an attenuated chimeric dengue virus in which the prM and E structural proteins of the DEN4 candidate vaccine rDEN430 have been replaced by those of the prototypic DEN2 NGC virus. rDEN2430(ME) was evaluated at a dose of 1,000 PFU in 20 healthy dengue-nave adult volunteers. Eight volunteers received placebo. Volunteers were monitored closely for adverse events and serum was collected for determination of the level and duration of viremia and neutralizing antibody response. The vaccine was well tolerated by all volunteers. The most common adverse events observed were a transient asymptomatic rash and mild neutropenia. All vaccinees seroconverted to DEN2 and maintained significant antibody titers throughout the six-month trial duration. Eleven vaccinees had vaccine virus recovered from the blood during the study. RNA derived from virus isolates obtained from viremic volunteers was sequenced for confirmation of retention of the 30 mutation in the 3 UTR. The 30 mutation remained unchanged in each isolate, confirming the stability of the 30 mutation. Further evaluation of this vaccine in a tetravalent formulation is warranted. ? Trials to determine the human infectious dose 50 are in progress.? ? Dengue serotype 3 vaccine development ? ? rDEN3430(ME) is an attenuated chimeric dengue virus in which the prM and E structural proteins of the DEN4 candidate vaccine rDEN430 have been replaced by those of the prototypic DEN3 wild type virus. rDEN3430(ME) or placebo was evaluated at a dose of 1,000 PFU in 28 healthy dengue-nave adult volunteers. Only 30% pf vaccinees were infect. A study with 100-fold higher dose has been initiated.? ? Other dengue virus vaccine trials? ? Trials have been initiated to determine if infection with one dengue virus vaccine serotype modifies the replication and clinical response to a second serotype given after six months. This trial has been initated.? ? Trials have been initiated to determine if boosting is observed in humans given two doses of a dengue virus at a four or six month interval. ? ? Trials have been initiated with two derivatives of DEN430 with mutations that specifically restrict replication in human live cells in vitro and in vivo. These studies are in progress.? ? ? West Nile virus vaccine development trials in humans? ? Phase I trials are ongoing with a live attenuated West Nile virus vaccine candidate, WNVDEN430. Studies at 1000 and 10000 infectious units per vaccinee indicated that the vaccine was safe with low viremia, but was immunogenic in only 80% of vaccinees. To achieve a higher take rate, studies are ongoing with two doses of 10000 infectious units given six months apart given to one group and 100000 infectious units given six months apart given to second group.? ? Tick-borne encephalitis virus vaccine development trials in humans? ? Phase I trials are ongoing with a live attenuated TBEV virus vaccine candidate, namely, LGTDEN4, that is administered subcutaneously at 1000 infectious units. These studies are currently being analyzed, but preliminary analysis indicates that they are satisfactorily attenuated and infectious, but the immunogenicity for circulating TBEV is weak, even after two doses.
| Wright, Peter F; Ankrah, Sharon; Henderson, Susan E et al. (2008) Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers. Vaccine 26:882-90 |
| Whitehead, Stephen S; Blaney, Joseph E; Durbin, Anna P et al. (2007) Prospects for a dengue virus vaccine. Nat Rev Microbiol 5:518-28 |
| Blaney Jr, Joseph E; Durbin, Anna P; Murphy, Brian R et al. (2006) Development of a live attenuated dengue virus vaccine using reverse genetics. Viral Immunol 19:10-32 |
