Assessment of bivalent and tetravalent dengue vaccine formulations in flavivirus-naïve adults in Mexico

Abstract

Several ChimeriVax-Dengue (CYD)-based vaccination strategies were investigated as potential alternatives to vaccination with tetravalent CYD vaccine (CYD-TDV) in this phase IIa trial conducted in 2008-9 in 150 healthy adults. Participants were randomized and vaccinated on D0 and D105 (± 15 days). One group received bivalent CYD vaccine against serotypes 1 and 3 (CYD-1;3) on day 0 and CYD-2;4 on day 105 (± 15 days). Two groups received an injection at each timepoint of a tetravalent blend of CYD-1;3;4 and a VERO cell derived, live attenuated vaccine against serotype 2 (VDV-2), or the reference CYD-TDV. A fourth group received Japanese encephalitis (JE) vaccine on days -14, -7 and 0, followed by CYD-TDV on day 105. Viraemia was infrequent in all groups. CYD-4 viraemia was most frequent after tetravalent vaccination, while CYD-3 viraemia was most frequent after the first bivalent vaccination. Immunogenicity as assessed by 50% plaque reduction neutralisation test on D28 was comparable after the first injection of either tetravalent vaccine, and increased after the second injection, particularly with the blended CYD-1;3;4/ VDV-2 vaccine. In the bivalent vaccine group, immune response against serotype 3 was highest and the second injection elicited a low immune response against CYD 2 and 4. Immune responses after the first injection of CYD-TDV in the JE-primed group were in general higher than after the first injection in the other groups. All tested regimens were well tolerated without marked differences between groups. Bivalent vaccination showed no advantage in terms of immunogenicity.

Clinical trial registration number: NCT00740155.

Keywords: ADE, antibody-dependent enhancement; AE, adverse event; ALT, aspartate aminotransferase; AST, alanine aminotransferase; CBA, cytometric bead array; CI, confidence interval; CPK, creatine phosphokinase; CYD-TDV, CYD tetravalent dengue vaccine; GMT, geometric mean titres; ICS, intracellular cytokine staining; IFN, interferon; JE, Japanese encephalitis; Japanese encephalitis; LLOQ, lower limit of quantitation; MOI, multiplicity of infection; MedDRA, medical dictionary for regulatory activities; PBMC, peripheral blood mononuclear cells; PFU, plaque forming unit; PRNT, plaque reduction neutralization test; RT-PCR, reverse transcriptase-polymerase chain reaction; TCID, tissue culture infectious dose; VDV, vero-cell adapted attenuated dengue vaccine; YF, yellow fever; dengue; flavivirus; immunogenicity; safety; vaccine.

Figure 1.

Study flowchart describing the 4 groups included in the report.

Figure 2.

Mean aspartate aminotransferase –AST- (top), alanine aminotransferase –ALT- (middle) and creatine phosphokinase –CPK- (bottom) measurements on days 0, 7, 14, and 28 after the first vaccination.

Figure 3.

Serotype-specific seropositivity rate (percentage of subjects with PRNT₅₀ titres ≥10 ) 28 d after the first (top) and second (middle) injections, and 1 y (bottom) after the first injection, assessed with PRNT assay using the dengue vaccine candidates’ parental wild-type strains as the challenge virus.

Figure 4.

Dengue serotype-specific cellular IFN-γ responses measured before and after vaccination upon stimulation by CYD-1 to 4. Median IFN-γ secretion measured by CBA in supernatants of PBMCs stimulated in vitro for 4 d with monovalent CYD1–4 collected from vaccinees before primary vaccination and before and 28-days after secondary vaccination. Vertical bars represent the median. The error bars represent Q1 and Q3. The reference line represents the lower limit of detection (LLOD) of 7.1 pg/mL. The values obtained for unstimulated condition (medium) were substracted from values obtained upon stimulation for each subject and visit.