Cell-mediated immune responses to different formulations of a live-attenuated tetravalent dengue vaccine candidate in subjects living in dengue endemic and non-endemic regions.

Three phase II randomized trials evaluated the safety/immunogenicity of two formulations of live-attenuated tetravalent dengue virus (TDEN) vaccine in dengue-endemic (Puerto Rico, Thailand) and non-endemic (US) regions (NCT00350337/NCT00370682/NCT00468858). We describe cell-mediated immune (CMI) responses; safety and humoral responses were reported previously. Participants received two doses of vaccine or control (placebo or the precursor live-attenuated TDEN vaccine) 6 months apart. Selected US participants received a booster 5-12 months post-dose 2. Evaluated subsets of the per-protocol cohorts included 75 primarily dengue virus (DENV)-unprimed US adults, 69 primarily flavivirus-primed Thai adults, and 100 DENV-primed or DENV-unprimed Puerto Rican adults/adolescents/children. T-cell responses were quantified using intracellular cytokine staining (ICS; DENV-infected cell-lysate or DENV-1/DENV-2 peptide-pool stimulation) or IFN-γ ELISPOT (DENV-2 peptide-pool stimulation). Memory B-cell responses were quantified using B-cell ELISPOT. Across populations and age strata, DENV serotype-specific CD4+ T-cell responses were slightly to moderately increased (medians ≤0.18% [ICS]), DENV-2-biased, and variable for both formulations. Responses in unprimed subjects were primarily detected post-dose 1. Response magnitudes in primed subjects were similar between doses. Multifunctional CD8+ T-cell responses were detected after peptide-pool stimulation. T-cell responses were mostly directed to DENV nonstructural proteins 3 and 5. Memory B-cell responses were tetravalent, of low-to-moderate magnitudes (medians ≤0.25%), and mainly observed post-dose 2 in unprimed subjects and post-dose 1 in primed subjects. A third dose did not boost CMI responses. In conclusion, both formulations of the live-attenuated TDEN vaccine candidate were poorly to moderately immunogenic with respect to B-cell and T-cell responses, irrespective of the priming status of the participants. Abbreviation ATP: according-to-protocol; ICS: Intracellular Cytokine Staining; NS3: Nonstructural protein 3; ELISPOT: Enzyme-Linked ImmunoSpot; JEV: Japanese encephalitis virus; PBMC: peripheral blood mononuclear cells.

Safety and Immunogenicity of a Tetravalent Dengue Vaccine Candidate in Healthy Children and Adults in Dengue-Endemic Regions: A Randomized, Placebo-Controlled Phase 2 Study.

BACKGROUND: A safe, effective tetravalent dengue vaccine is a global health priority. The safety and immunogenicity of a live attenuated, recombinant tetravalent dengue vaccine candidate (TDV) were evaluated in healthy volunteers from dengue-endemic countries. METHODS: This multicenter, double-blind, phase 2 study was conducted in Puerto Rico, Colombia, Singapore, and Thailand. During stage I, 148 volunteers aged 1.5-45 years were sequentially enrolled into 4 age-descending groups and randomized at a ratio of 2:1 to receive TDV or placebo. In stage II (group 5), 212 children aged 1.5-11 years were randomized at a ratio of 3:1 to receive TDV or placebo. Participants received a subcutaneous injection of TDV or placebo on days 0 and 90 and were followed for analysis of safety, seropositivity, and neutralizing antibodies to DENV-1-4. RESULTS: Injection site pain, itching, and erythema (mostly mild) were the only solicited adverse events more frequently reported with TDV than with placebo in all age groups. After 2 TDV doses, seropositivity was >95% in all 5 groups for DENV-1-3 and 72.7%-100% for DENV-4; geometric mean titers ranged from 582 to 1187 for DENV-1, from 582 to 1187 for DENV-2, from 196 to 630 for DENV-3, and from 41 to 210 for DENV-4 among the 5 groups. CONCLUSIONS: TDV was well tolerated and immunogenic in volunteers aged 1.5-45 years, irrespective of prevaccination dengue exposure.

Pediatric disease burden and vaccination recommendations: understanding local differences.

BACKGROUND: Diphtheria (D), tetanus (T), pertussis (P), hepatitis B (HepB), invasive Haemophilus influenzae type b (Hib) disease, and measles cause substantial global morbidity and mortality. METHODS: This unique review highlights geographic differences in disease burden across certain countries in the African, Americas, Mediterranean, South-East Asian, and Western Pacific World Health Organization (WHO) regions, and relates this to vaccination coverage and local vaccine recommendations using the authors' countries as illustrations. RESULTS: Substantial differences were observed in the incidence of these diseases and in vaccination coverage between the countries studied. Disease incidence often reflected inadequate surveillance, but also variable or poor vaccination coverage. Vaccination coverage against HepB was particularly low in the African and South-East Asian WHO regions; vaccination coverage against invasive Hib disease was low in these regions and in the Eastern Mediterranean and Western Pacific WHO regions. Vaccination schedules within some countries in these regions do not include, or have only recently included, vaccinations against HepB and Hib disease. The use of DTwP-HepB-Hib (diphtheria, tetanus, whole-cell pertussis, HepB, Hib) combination vaccines has now been adopted by some countries to help increase vaccination coverage. CONCLUSIONS: Vaccination coverage and vaccination schedules vary markedly between the countries studied, often according to the resources available. DTwP-HepB-Hib combination vaccines represent a cost-effective option, with the potential to substantially reduce the burden associated with these diseases by increasing coverage and compliance.