AbstractSixteen dose formulations of our live-attenuated tetravalent dengue virus vaccines (TDV) were previously evaluated for safety and immunogenicity. Two of the sixteen candidate TDV formulations (Formulations 13 and 14) were selected for further evaluation. A new TDV formulation, Formulation 17, using a higher primary dog kidney (PDK) cell passage Dengue-1 virus (DENV-1) and a lower PDK cell passage DENV-4, was developed to optimize the neutralizing antibody response. All three formulations consist of combinations of 10exp3-5 pfu/dose of the four dengue vaccine virus serotypes. This double-blind, randomized trial in 71 healthy adult subjects evaluated vaccine safety, reactogenicity and immunogenicity. TDV's were given subcutaneously in the deltoid on Day 0 and 180 (6 months). Subjects were seen in clinic on Study Days 0, 10, 28, 180, 190 and 208 and filled out daily symptom diaries for 21 days after each vaccination. Formulation 13 was the most reactogenic, while both Formulations 14 and 17 were similar in reported reactions. Seventy-five percent, 31% and 31% of subjects were viremic on Day 10 after primary vaccination with Formulations 13, 14 and 17 respectively. Viremia was not detected in any subject following the second dose of vaccine. The immunogenicity endpoint was neutralizing antibody titer one month after the second vaccination. Thirty-six percent, 40% and 63% of vaccinated subjects developed tetravalent neutralizing antibodies after two doses of Formulations 13, 14 and 17, respectively. Formulation 17 was selected for further clinical evaluation based on this study.
Journal Article Degranulation of mast cells in dengue patients Get access LVS Asher, LVS Asher Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar AS Norton, AS Norton Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar S Krivda, S Krivda Department of Medicine, Walter Reed Army Medical Center, Washington DC 20307 Search for other works by this author on: Oxford Academic Google Scholar HK Wong, HK Wong Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar MP Mammen, MP Mammen Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar AG Lyons, AG Lyons Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar S Thomas, S Thomas Department of Medicine, Walter Reed Army Medical Center, Washington DC 20307 Search for other works by this author on: Oxford Academic Google Scholar W Sun, W Sun Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar KH Eckels, KH Eckels Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar DW Vaughn DW Vaughn Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 Search for other works by this author on: Oxford Academic Google Scholar Microscopy and Microanalysis, Volume 8, Issue S02, 1 August 2002, Pages 920–921, https://doi.org/10.1017/S1431927602107288 Published: 01 August 2002
A Phase I/II observer-blind, randomized, controlled trial evaluated the safety and immunogenicity of a dengue virus (DENV) vaccine candidate in healthy Thai infants (aged 12–15 months) without measurable pre-vaccination neutralizing antibodies to DENV and Japanese encephalitis virus. Fifty-one subjects received two doses of either DENV ( N = 34; four received 1/10th dose) or control vaccine ( N = 17; dose 1, live varicella; dose 2, Haemophilus influenzae type b). After each vaccine dose, adverse events (AEs) were solicited for 21 days, and non-serious AEs were solicited for 30 days; serious AEs (SAEs) were recorded throughout the study. Laboratory safety assessments were performed at 10 and 30 days; neutralizing antibodies were measured at 30 days. The DENV vaccine was well-tolerated without any related SAEs. After the second dose, 85.7% of full-dose DENV vaccinees developed at least trivalent and 53.6% developed tetravalent neutralizing antibodies ≥ 1:10 to DENV (control group = 0%). This vaccine candidate, therefore, warrants continued development in this age group (NCT00322049; clinicaltrials.gov).
ABSTRACT Dengue virus (DENV) is a major cause of febrile illness and hemorrhagic fever in tropical and subtropical regions. Typically, patients presenting with acute dengue disease are viremic but may not have yet developed detectable titers of antibody. Therefore, early diagnosis depends mostly on detection of viral components, such as the RNA. To define the potential use of transcription-mediated amplification (TMA) DENV RNA as a diagnostic tool, we first compared its analytic sensitivity using a routine real-time reverse transcription (RT)-PCR and found that TMA is approximately 10 to 100 times more sensitive. In addition, we tested acute-phase serum samples (<5 days post-symptom onset) submitted as part of laboratory-based surveillance in Puerto Rico and determined that among patients with serologically confirmed dengue infection, TMA detected DENV RNA in almost 80% of serum specimens that were negative by the RT-PCR test used for diagnosis and in all specimens with positive RT-PCR results. We conclude that TMA is a highly sensitive method which can detect DENV RNA in approximately 89% of clinical, acute-phase serum specimens.
Four serotypes of monovalent live attenuated dengue virus vaccine candidates were tested for reactogenicity and immunogenicity in 49 flavivirus non-immune adult human volunteers. The four monovalent candidates were then combined into a tetravalent formulation and given to another 10 volunteers. Neutralizing antibody seroconversion rates after a single-dose monovalent vaccination ranged from 53% to 100%. Solicited reactogenicity was scored by each volunteer. A composite index, the Reactogenicity Index, was derived by these self-reported scores. Reactogenicity differed among the four serotype candidates with serotype-1 associated with the most vaccine related side effects. A second dose of monovalent vaccines at either 30 days or 90 days was much less reactogenic but did not significantly increase seroconversion rates. Seroconversion rates in the 10 volunteers who received a single dose of tetravalent vaccine ranged from 30% to 70% among the four serotypes. Similar to the monovalent vaccines, a second dose of the tetravalent vaccine at one month was less reactogenic and did not increase seroconversion. A third dose of the tetravalent vaccine at four months resulted in three of four volunteers with trivalent or tetravalent high-titer neutralizing antibody responses.
Dr. Emanuel Papper, the founding chairman of the Department of Anesthesiology at Columbia University, was passionate about research, training, and innovation. At an event held in his honor on March 20, 2021, experts came together to discuss the coronavirus disease 2019 (COVID-19) pandemic and its myriad challenges. Dr. Wellington Sun, MD, of Vaxcellerant LLC, an expert in infectious disease and vaccine research and development, presented a "Primer of COVID-19 vaccines for the perioperative physician." Operation Warp Speed was successful in producing multiple efficacious and safe vaccines for use in the United States and around the globe. Their development and authorization for emergency use occurred in an unprecedented timespan of <1 year. Technology such as V-SAFE has helped to accrue extensive postdevelopment safety data that will be utilized for licensure of these vaccines. The COVID-19 vaccine success is tempered by the knowledge that severe acute respiratory syndrome coronavirus 2 continues its natural selection of variants that threaten the efficacy of vaccines. Important questions remain regarding the future of the COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 variants, successful vaccination strategies, and preparedness for future pandemics.
We evaluated laboratory methods to confirm a clinical diagnosis of dengue. Acute sera were collected from personnel (n = 414) supporting the United Nations Mission in Haiti and presenting with febrile illness consistent with dengue fever or no apparent underlying cause. Dengue virus was recovered from 161 of 379 acute sera by inoculation into C6/36 cell culture. While 93 of 414 acute sera had detectable IgM antibodies, the IgM capture ELISA (MAC ELISA) had a sensitivity of only 13% compared with the virus isolation gold standard. If presumptive dengue fever cases were identified by both virus isolation and the presence of IgM, virus isolation and the MAC ELISA had clinical sensitivities of 69% and 40%, respectively. This study suggests that a combination of laboratory methods that target virus or subviral components as well as anti-viral IgM antibodies may be necessary for sensitive laboratory diagnosis with acute sera.
Dengue virus (DV) is a flavivirus carried by the Aedes aegypti mosquito that causes a spectrum of illnesses in the tropics, including dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Dendritic cells (DCs) are professional antigen presenting cells recently shown to be permissive for DV, and implicated as the primary targets of initial DV infection. DV is transmitted to human host by infected mosquitoes during a blood meal, but it is currently unknown whether transmission is modified by vector saliva that is also deposited in the host's skin during feeding. Previous studies evaluated only the outcome of DV infection of DCs, and did not address the influence of mosquito saliva. To more fully characterize natural transmission of DV, we evaluated the effects of Ae. aegypti saliva on DV infection of human myeloid DCs. We found that saliva inhibited DV infection in DCs. Moreover, pre-sensitization of DCs with saliva, prior to DV infection, enhanced inhibition. In addition, enhanced production of IL-12p70 and TNF-α were detected in DV-infected DC cultures exposed to mosquito saliva. The proportion of dead cells was also significantly reduced in these cultures. These data contribute to the overall understanding of the natural pathogenesis of DV infection and suggest that there is a protective role for mosquito saliva that limits viral uptake by DCs.
