A phase I randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and immunogenicity of a live-attenuated quadrivalent dengue vaccine in flavivirus-naïve and flavivirus-experienced healthy adults

Figures & data

Figure 1. Participant disposition.

Table 1. Participant baseline characteristics

	V181 TV003 Formulation		V181 TV005 Formulation		Placebo
	n	(%)	n	(%)	n	(%)
Participants in population	80		80		40
Male	30	(37.5)	28	(35.0)	17	(42.5)
Female	50	(62.5)	52	(65.0)	23	(57.5)
Mean Age, Years (Range)	35.0 (19 to 49)		34.9 (18 to 50)		34.7 (19-51†)
Race
American Indian or Alaska Native	2	(2.5)	2	(2.5)	0	(.0)
Asian	0	(.0)	1	(1.3)	1	(2.5)
Black or African American	14	(17.5)	13	(16.3)	7	(17.5)
Multiple	6	(7.5)	7	(8.8)	4	(10.0)
White	58	(72.5)	57	(71.3)	28	(70.0)
Ethnicity
Not Hispanic or Latino	24	(30.0)	23	(28.8)	11	(27.5)
Hispanic or Latino	56	(70.0)	57	(71.3)	29	(72.5)
Baseline Flavivirus Status
Baseline Flavivirus -naïve (BFN)	36	(45.0)	39	(48.8)	17	(42.5)
Baseline Flavivirus- experienced (BFE)	44	(55.0)	41	(51.2)	23	(57.5)

†All participants met the inclusion criterion of age 18 to 50 years old at vaccination. Actual day of birth is not collected; therefore, the standard rule for imputing the age by birth month resulted in misclassification of the one participant displayed as 51 years of age.

Figure 2. Percentage of participants with solicited adverse events after each vaccination, by severity.

Panel A displays solicited adverse events postvaccination 1 (placebo N=39, TV003 N=80, TV005 N=79) and Panel B shows data collected postvaccination 2 (placebo N=36, TV003 N=73, TV005 N=73). Injection-site adverse events were collected Days 1-5 and systemic events were collected on Days 1-28, respectively, after each vaccination. For both panels, the height of the stacked bars represents the total percentage of participants with the reported adverse event and the severity grades (mild, moderate, or severe) within the bar indicate the proportion of the total attributed to each respective category. For Injection site swelling and injection site erythema, mild events are defined as >0 to <5.1 cm, moderate events are defined as ≥5.1 to ≤10 cm and severe are defined as >10.0 cm. Rash is inclusive of maculo-papular, macular, and papular types. Each participant is counted a single time for each adverse event and only the highest reported severity is counted for each participant. PBO=placebo, TV003=V181, TV003 formulation, TV005=V181, TV005 formulation.

Figure 3. Vaccine viremia after each vaccination, stratified by baseline flavivirus serostatus.

Bars (and numbers above each bar) show the percent of participants with demonstrated vaccine viremia in at least one time point (Day 7, 12, or 28) after vaccination. Viremia was measured for each dengue serotype, and any dengue viremia (Any DENV) is defined as demonstrated viremia to at least one serotype at least one time point tested. Error bars represent the 95% confidence intervals. Full Analysis Set Population is shown. TV003=V181 TV003 formulation, TV005=V181 TV005 formulation, BFE=baseline flavivirus experienced, BFN=baseline flavivirus naïve.

Figure 4. Longitudinal viral reduction neutralization test (Vrnt₆₀) seropositivity frequency, stratified by baseline flavivirus serostatus.

The percentage of participants seropositive for each dengue serotype is shown in the baseline flavivirus experienced subgroup (BFE) in Panel A and the baseline flavivirus naïve subgroup (BFN) in Panel B by time point. Per protocol population shown. Seropositivity is defined as a titer ≥ the lower limit of assay quantitation (LLOQ) for each assay: DENV1 titer ≥ 14; DENV2 titer ≥ 16; DENV3 titer: ≥ 20 and DENV4 titer ≥ 15. Error bars represent the 95% confidence intervals. TV003=V181, TV003 formulation. TV005=V181, TV005 formulation. PD1= postvaccination 1, PD2=postvaccination 2. M=month, YR=year.

Figure 5. Valency of viral reduction neutralization test (Vrnt₆₀) seropositivity, stratified by baseline flavivirus serostatus.

The pie chart depicts the overall seropositivity by VRNT₆₀ by valency. Participants vaccinated with TV003 are shown in Panel A (BFE, N=44) and Panel B (BFN, N=36). Participants vaccinated with TV005 are shown in Panel C (BFE, N=41) and Panel D (BFN, N=39). Valency indicates the number of dengue types for which the participant is seropositive at a given time point. Tetravalent = 4 types positive, Trivalent = 3 types positive, Bivalent = 2 types positive, Monovalent = 1 type positive, None = 0 types positive. Seropositivity is defined as DENV1 titer: ≥ 14; DENV2 titer: ≥ 16; DENV3 titer: ≥ 20 and DENV4 titer: ≥ 15. Per protocol population shown, the lower limit of assay quantitation was used as the lowest value and each participant was counted only once per time point. TV003=V181, TV003 formulation. TV005=V181, TV005 formulation. D=day, PD1=postvaccination 1, PD2=postvaccination 2. M=month, Viral Reduction Neutralization Test=VRNT_60., BFE=baseline flavivirus experienced, BFN=baseline flavivirus naïve.

Figure 6. Longitudinal geometric mean titers stratified by baseline flavivirus status.

The geometric mean titer (GMT) of neutralizing antibody is shown over time (Study Days 1, 28, 56, 180, 208, 360, and 530). Data is displayed by dengue virus type stratified by the baseline flavivirus experienced subgroup (Panel A) and by flavivirus naïve subgroup (Panel B) as measured by virus neutralization reduction test (VRNT₆₀). Error bars represent the 95% confidence intervals. Per protocol population is shown. The dotted dashed gray line on each graph represents ½ LLOQ. TV003=V181, TV003 formulation. TV005=V181, TV005 formulation.

Figure 7. Geometric mean fold rise in VRNT₆₀ stratified by baseline flavivirus serostatus.

The geometric mean fold rise (GMFR) in virus reduction neutralization test (VRNT₆₀) is displayed after each vaccination by subgroup. Fold rise is calculated 28 days after each vaccination for the respective baseline (Postvaccination 1: Day 28 over Day 1, postvaccination 2: Day 208 over Day 180). Per Protocol population is shown and error bars represent the 95% confidence interval. TV003=V181, TV003 formulation. TV005=V181, TV005 formulation BFE=baseline flavivirus experienced, BFN= baseline flavivirus naïve.