An open-label, Phase 3 trial of TAK-003, a live attenuated dengue tetravalent vaccine, in healthy US adults: immunogenicity and safety when administered during the second half of a 24-month shelf-life

Figures & data

Figure 1. Genetic structure of the four TAK-003 vaccine strains. Abbreviations: C, capsid; E, envelope; NS, nonstructural protein; prM, premembrane; TDV-1/2/3/4, dengue serotype 1/2/3/4 strain. Reproduced with permission from Patel et al.⁴².

Figure 2. Trial visits schematic. Abbreviations: MAAEs, medically attended adverse events; SAEs, serious adverse events. Safety assessments were as follows: solicited local events (recorded up to 30 minutes, and up to 7 days after each TAK-003 dose), solicited systemic events (recorded up to 30 minutes, and up to 14 days after each TAK-003 dose), unsolicited events (recorded up to 28 days after each TAK-003 dose), and MAAEs and SAEs recorded for the entire duration of trial. Solicited local AEs comprised injection site pain, injection site erythema, and injection site swelling. Solicited systemic AEs comprised asthenia, headache, malaise, myalgia, and fever. MAAEs were defined as AEs leading to an unscheduled visit to, or by, a healthcare professional including visits to an emergency department, but not fulfilling seriousness criteria.

Figure 3. (a) Participant allocation to safety, full analysis and per-protocol sets. *Any participant not included in the per-protocol set if he/she experienced one or more trial protocol deviation(s) and (b) Participant disposition for the DEN-307 clinical trial. Abbreviations: AE, adverse event; LTF, lost to follow up; WOC, withdrawal of consent.

Table 1. Participant demographic and baseline characteristics.

	Safety set (N = 200)	Full analysis set (N = 174)	Per-protocol set (N = 139)
Mean age^a (SD), years	40.3 (12.0)	40.7 (12.0)	41.1 (11.7)
Female, n (%)	101 (50.5)	94 (54.0)	78 (56.1)
Hispanic or Latino, n (%)	64 (32.0)	58 (33.3)	45 (32.4)
Race, n (%)
White	148 (74.0)	133 (76.4)	102 (73.4)
Black or African American	41 (20.5)	32 (18.4)	29 (2.9)
Asian	5 (2.5)	4 (2.3)	4 (20.9)
Hawaiian or other Pacific Islander	1 (0.5)	1 (0.6)	1 (0.7)
Multiracial	3 (1.5)	2 (1.1)	1 (0.7)
Not reported	2 (1.0)	2 (1.1)	2 (1.4)
Mean BMI (SD), kg/m^2	27.5 (4.3)	27.6 (4.3)	27.5 (4.2)
Baseline dengue serostatus, n (%)
Seropositive	28 (14.1)	22 (12.6)	0
Seronegative	171 (85.9)	152 (87.4)	139 (100.0)

^aage range for all three analysis sets: 18.0 to 60.0 years.

Abbreviations: BMI, body mass index; n, number of participants; SD, standard deviation.

Figure 4. (a) Percentage (95% CI) of participants who were seropositive against each DENV serotype at days 120 and 270 and (b) Percentage (95% CI) of trivalent and tetravalent baseline seropositive participants (per-protocol set). Baseline seropositive defined as a reciprocal neutralizing antibody titer ≥ 10 to $\ge$ 1 dengue virus serotypes. Baseline seronegative defined as titer < 10 to all dengue serotypes. Abbreviations: CI, confidence interval; DENV, dengue virus.

Figure 5. Geometric mean titers (95% confidence interval) of neutralizing antibodies measured by MNT₅₀ for each dengue serotype (per-protocol set). Abbreviations: DENV, dengue virus; MNT₅₀, microneutralization test 50%.

Table 2. TAK-003 overview of adverse events.

	Any Vaccination (N = 200)		First vaccination (N = 200)		Second vaccination (N = 176)
	Events	Participants (%)	Events	Participants (%)	Events	Participants (%)
Any Solicited Adverse Events	454	89 (46.1)	279	69 (35.9)	175	54 (32.3)
30-min post TAK-003 dose	8	7 (3.5)	3	2 (1.0)	5	5 (2.8)
Local (within 7 days)	454	89/193 (46.1)	279	69/192 (35.9)	175	54/167 (32.3)
Systemic (within 14 days)	950	95/193 (49.2)	587	81/192 (42.2)	363	57/167 (34.1)
Related to TAK-003	893	94/193 (48.7)	557	79/192 (41.1)	336	55/167 (32.9)
Prolonged solicited local AEs (>7 days beyond diary recorded period)	15	10 (5.0)	12	8 (4.0)	3	2 (1.1)
Prolonged solicited systemic AEs (>14 days beyond diary recorded period)	4	3 (1.5)	1	1 (0.5)	3	2 (1.1)
Any Unsolicited AEs (within 28 days)^a	59	38 (19.0)	36	23 (11.5)	23	19 (10.8)
Related to TAK-003	16	11 (5.5)	14	9 (4.5)	2	2 (1.1)
Related to trial procedure	6	5 (2.5)	5	4 (2.0)	1	1 (0.6)
Mild	50	31 (15.5)	30	19 (9.5)	20	16 (9.1)
Moderate	9	7 (3.5)	6	4 (2.0)	3	3 (1.7)
Any Medically attended AEs^b	146	52 (26.0)	60	29 (14.5)	86	35 (19.9)
Related to TAK-003	2	1 (0.5)	2	1 (0.5)	0	0
Related to trial procedure	0	0	0	0	0	0
Mild	123	33 (16.5)	54	24 (12.0)	69	19 (10.8)
Moderate	23	19 (9.5)	6	5 (2.5)	17	16 (9.1)
Leading to vaccine withdrawal	5	5 (2.5)	5	5 (2.5)	0	0
Leading to discontinuation from trial	1	1 (0.5)	1	1 (0.5)	0	0
Any Serious Adverse Events^c	5	5 (2.5)	2	2 (1.0)	3	3 (1.7)
Moderate	4	4 (2.0)	1	1 (0.5)	3	3 (1.7)
Severe	1	1 (0.5)	1	1 (0.5)	0	0
Leading to vaccine withdrawal	1	1 (0.5)	1	1 (0.5)	0	0

^aNo reported unsolicited AE was severe, led to vaccine withdrawal or discontinuation from trial. ^bNo reported MAAE was severe. ^cNo reported serious AE was mild, related to vaccine or trial procedure, or led to discontinuation from the trial.

Any participant who experienced >1 adverse event is counted under each vaccine dose column, but is counted only once in the “Any vaccination” column.

Abbreviations: AE, adverse event; MAAE, medically attended adverse event; min, minutes; SAE, serious adverse event. Medically attended AEs were defined as AEs leading to an unscheduled visit to, or by, a healthcare professional, including visits to an emergency department, but not fulfilling seriousness criteria. Any MAAEs and SAEs were recorded throughout the trial duration.

Table 3. Summary of solicited local adverse events within 7 days post vaccination (safety set).

	Number (%) of participants
Adverse events	Any Vaccination (N = 200)	First Vaccination (N = 200)	Second Vaccination (N = 176)
Any solicited local adverse events	89 (46.1)	69 (35.9)	54 (32.3)
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Mild	74 (38.3)	59 (30.7)	48 (28.7)
Moderate	12 (6.2)	9 (4.7)	4 (2.4)
Severe	3 (1.6)	1 (0.5)	2 (1.2)
Pain
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Any event	80 (41.5)	57 (29.7)	52 (31.1)
Mild	67 (34.7)	49 (25.5)	46 (27.5)
Moderate	10 (5.2)	7 (3.6)	4 (2.4)
Severe	3 (1.6)	1 (0.5)	2 (1.2)
Erythema^a
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Any event	29 (15.0)	25 (13.0)	10 (6.0)
Mild: ≥2.5-≤5 cm	27 (14.0)	23 (12.0)	10 (6.0)
Moderate: >5-≤10 cm	2 (1.0)	2 (1.0)	0
Swelling^b
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Any event	9 (4.7)	8 (4.2)	4 (2.4)
Mild: ≥2.5-≤5 cm	9 (4.7)	8 (4.2)	4 (2.4)

^aNo reported severe erythema events. ^bNo reported moderate or severe swelling events.

Any participant who experienced >1 adverse event is counted under each vaccine dose column, but is counted only once in the “Any vaccination” column.

All AEs were considered attributable to TAK-003 by default. Severity of each event was attributable according to pre-defined trial protocol criteria (see Table S2).

Pain, erythema, and swelling events were to be diary-recorded by each participant up to 7 days after each TAK-003 dose.

Table 4. Summary of solicited systemic adverse events within 14 days post vaccination (safety set).

	Number (%) of participants
Adverse events	Any Vaccination (N = 200)	First Vaccination (N = 200)	Second Vaccination (N = 176)
Any solicited systemic adverse events	95 (49.2)	81 (42.2)	57 (34.1)
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Mild	64 (33.2)	59 (30.7)	43 (25.7)
Moderate	25 (13.0)	17 (8.9)	11 (6.6)
Severe	6 (3.1)	5 (2.6)	3 (1.8)
Related to TAK-003	94 (48.7)	79 (41.1)	55 (32.9)
Headache (any event)	70 (36.3)	58 (30.2)	38 (22.8)
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Mild	47 (24.4)	44 (22.9)	27 (16.2)
Moderate	19 (9.8)	11 (5.7)	9 (5.4)
Severe	4 (2.1)	3 (1.6)	2 (1.2)
Related to TAK-003	67 (34.7)	55 (28.6)	36 (21.6)
Myalgia (any event)	64 (33.2)	49 (25.5)	37 (22.2)
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Mild	53 (27.5)	40 (20.8)	34 (20.4)
Moderate	8 (4.1)	6 (3.1)	2 (1.2)
Severe	3 (1.6)	3 (1.6)	1 (0.6)
Related to TAK-003	64 (33.2)	48 (25)	37 (22.2)
Asthenia (any event)	39 (20.2)	32 (16.7)	20 (12.0)
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Mild	23 (11.9)	20 (10.4)	13 (7.8)
Moderate	12 (6.2)	10 (5.2)	5 (3.0)
Severe	4 (2.1)	2 (1.0)	2 (1.2)
Related to TAK-003	37 (19.2)	31 (16.1)	19 (11.4)
Malaise (any event)	48 (24.9)	38 (19.8)	22 (13.2)
N evaluated	193 (96.5)	192 (96.0)	167 (94.9)
Mild	31 (16.1)	25 (13.0)	15 (9.0)
Moderate	12 (6.2)	9 (4.7)	5 (3.0)
Severe	5 (2.6)	4 (2.1)	2 (1.2)
Related to TAK-003	48 (24.9)	37 (19.3)	22 (13.2)
Fever^a (any event)	6 (3.1)	5 (2.6)	2 (1.2)
N evaluated	191 (95.5)	189 (94.5)	166 (94.3)
38-<38.5°C	4 (2.1)	4 (2.1)	1 (0.6)
38.5-<39°C	2 (1.0)	1 (0.5)	1 (0.6)
Related to TAK-003	6 (3.1)	5 (2.6)	1 (0.6)

^aNo reported events of fever ≥39°C.

Any participant who experienced >1 adverse event is counted under each vaccine dose column, but is counted only once in the “Any vaccination” column.

Severity of AE assessed by participant, and attributability to TAK-003 assessed by the investigator.

All five solicited adverse events were to be diary-recorded by each participant up to 14 days after each TAK-003 dose.

Table 5. Summary of unsolicited adverse events up to 28 days post vaccination, by preferred term (safety set).

	Any vaccination (N = 200)		First vaccination (N = 200)		Second vaccination (N = 176)
Adverse events	Events	Participants (%)	Events	Participants (%)	Events	Participants (%)
Any unsolicited adverse event	59	38 (19.0)	36	23 (11.5)	23	19 (10.8)
Unsolicited adverse events experienced by ≥2 participants, by preferred term
Abdominal discomfort	3	3 (1.5)	2	2 (1.0)	1	1 (0.6)
Upper respiratory tract infection	3	3 (1.5)	2	2 (1.0)	1	1 (0.6)
Dyspepsia	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Injection site bruising	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Injection site induration	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Injection site pain	2	2 (1.0)	2	2 (1.0)	0	0
Injection site pruritus	2	2 (1.0)	2	2 (1.0)	0	0
Arthropod bite	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Oropharyngeal pain	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Sleep apnea syndrome	2	2 (1.0)	2	2 (1.0)	0	0

Any participant who experienced >1 adverse event is counted under each vaccine dose column, but is counted only once in the “Any vaccination” column.

All unsolicited adverse events were evaluated up to 28 days after each TAK-003 dose.

Table 6. Summary of medically attended adverse events (MAAEs) post vaccination up to the end of study (safety set).

	Any vaccination (N = 200)		First vaccination (N = 200)		Second vaccination (N = 176)
Adverse events	Events	Participants (%)	Events	Participants (%)	Events	Participants (%)
Any MAAE	146	52 (26.0)	60	29 (14.5)	86	35 (19.9)
MAAEs experienced by ≥2 participants, by preferred term
Acute sinusitis	10	9 (4.5)	2	2 (1.0)	8	8 (4.5)
Bronchitis	4	4 (2.0)	1	1 (0.5)	3	3 (1.7)
Dermatitis contact	4	4 (2.0)	2	2 (1.0)	2	2 (1.1)
Asthma	4	3 (1.5)	0	0	4	3 (1.7)
Contusion	4	2 (1.0)	0	0	4	2 (1.0)
Back pain	3	3 (1.5)	3	3 (1.5)	0	0
Sleep apnea syndrome	3	3 (1.5)	3	3 (1.5)	0	0
Oropharyngeal pain	2	2 (1.0)	2	2 (1.0)	0	0
Tachycardia	2	2 (1.0)	2	2 (1.0)	0	0
Dermatitis	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Hypertension	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Bacterial vaginosis	2	2 (1.0)	1	1 (0.5)	1	1 (0.6)
Cystitis	2	2 (1.0)	0	0	2	2 (1.1)
Influenza	2	2 (1.0)	0	0	2	2 (1.1)
Otitis media acute	2	2 (1.0)	0	0	2	2 (1.1)
Limb injury	2	2 (1.0)	0	0	2	2 (1.1)
Neck pain	2	2 (1.0)	0	0	2	2 (1.1)
Cervical dysplasia	2	2 (1.0)	0	0	2	2 (1.1)

Any participant who experienced >1 adverse event is counted under each vaccine dose column, but is counted only once in the “Any vaccination” column.

MAAEs were defined as adverse events leading to an unscheduled visit to, or by, a healthcare professional, including visits to an emergency department, but not fulfilling seriousness criteria. All MAAEs were evaluated for the entire duration of the trial.

Figure 6. Baseline dengue seronegative participant geometric mean titers (95% confidence interval) at day 120 and day 270 after TAK-003 administration in trials DEN-301,^19,20,29 DEN-304²⁵ and DEN-307. Abbreviation: DENV, dengue virus.

Figure 7. Baseline dengue seronegative participant geometric mean titers (95% confidence interval) at day 120 and day 270 following administration of TAK-003 in trial DEN-307. Abbreviation: DENV, dengue virus.

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