Dengue
Conditions
Brief summary
The purpose of this study was to demonstrate that V181 is safe and well tolerated and elicits an immune response that is non-inferior to that of Butantan - DV at Day 28 post-vaccination in adults 18 to 50 years of age in Brazil. The primary hypothesis was that V181 is non-inferior to Butantan - DV for each of the 4 dengue serotypes based on geometric mean titers (GMTs) and seroconversion rates at Day 28 post-vaccination.
Interventions
BIOLOGICALV181
0.5 mL SC dose of V181
BIOLOGICALButantan - DV
0.5 mL SC dose of Butantan - DV
Sponsors
Merck Sharp & Dohme LLC
Butantan Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Male participants were eligible to participate if they agreed to the following for at least 90 days after administration of study intervention: * Abstained from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agreed to remain abstinent; or agreed to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause). * A female participant was eligible to participate if she was not pregnant or breastfeeding, and at least one of the following conditions applies: * was NOT a woman of child-bearing potential (WOCBP); or * was a WOCBP and using a contraceptive a highly effective method (with a failure rate of \<1% per year), or * was abstinent from heterosexual intercourse as her preferred and usual lifestyle (abstinent on a long term and persistent basis), for at least 90 days after administration of study intervention. * Had a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) before administration of study intervention * Were dengue seronegative based on a pre-vaccination point of care (POC) dengue test.
Exclusion criteria
* Had a known history of dengue or Zika natural infection. * Had an acute febrile illness (axillary temperature ≥37.8°C) occurring within 72 hours prior to receipt of study vaccine. * Had a known hypersensitivity or history of severe allergic reaction (eg, swelling of the mouth and throat, difficulty breathing, hypotension or shock) to any component of the dengue vaccine, that required medical intervention. * Had a serious or progressive disease, including but not limited to cancer, uncontrolled diabetes, severe cardiac, renal or hepatic insufficiency, systemic autoimmune or neurologic disorder. * Had known or suspected impairment of immunological function, including but not limited to congenital or acquired immunodeficiency, human immunodeficiency virus (HIV) infection, hematologic malignancy, or treatment for autoimmune diseases. * Had a condition in which repeated venipuncture or injections pose more than minimal risk, such as hemophilia, thrombocytopenia, other severe coagulation disorders, or significantly impaired venous access * Had received a dose of any dengue vaccine (investigational or approved) prior to study entry or plans to receive any dengue vaccine (investigational or approved) for trial duration. * Had received a licensed non-live vaccine within 14 days before receipt of study vaccine or was scheduled to receive any licensed non-live vaccine within 28 days following receipt of study vaccine. Exception: Inactivated influenza vaccine might be administered, but given at least 7 days before receipt of study vaccine or at least 28 days after receipt of study vaccine. * Had received a licensed live vaccine within 28 days prior to receipt of study vaccine or was scheduled to receive any live vaccine within 28 days following receipt of study vaccine. * Had received systemic corticosteroids (equivalent of ≥2 mg/kg/day of prednisone or ≥20 mg/day for persons weighing \>10 kg) for ≥14 consecutive days and had not completed treatment at least 30 days before study entry or was expected to receive systemic corticosteroids at aforementioned dose and duration within 28 days following receipt of study vaccine. (Note: topical and inhaled/nebulized steroids were permitted.) * Had received systemic corticosteroids exceeding physiologic replacement doses (approximately 5 mg/day prednisone equivalent) within 14 days before vaccination. * Had received immunosuppressive therapies, including chemotherapeutic agents used to treat cancer or other conditions, treatments associated with organ or bone marrow transplantation, or autoimmune disease, within 6 months prior to receipt of study vaccine, or plans to receive immunosuppressive therapies within 28 days following receipt of study vaccine. * Had received a blood transfusion or blood products (including immunoglobulins) within 6 months prior to receipt of study vaccine or plans to receive a blood transfusion or blood products (including immunoglobulins) within 28 days following receipt of study vaccine. * Had planned donation of blood, eggs, or sperm at any time from signing the informed consent through 90 days post-vaccination.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Vaccine-related Serious Adverse Events (SAEs) | Up to 28 days post-vaccination | An SAE is an AE that results in death, is life-threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. Relatedness of an SAE to the study vaccine was determined by the investigator. |
| Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | Day 28 post-vaccination | A dengue VRNT was conducted to assess neutralizing antibody geometric mean titers (GMTs) for each of the 4 dengue serotypes (DENV1, DENV2, DENV3, and DENV4) in specimens collected from participants on Day 28 post-vaccination |
| Percentage of Participants Who Seroconverted, as Measured by VRNT | Day 28 post-vaccination | A dengue VRNT was conducted to assess the percentage of participants who seroconverted for each of the 4 dengue serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) at Day 28 post-vaccination. Seroconversion was defined as achieving a serotype-specific VRNT titer ≥lower limit of quantification (LLOQ) at Day 28 post-vaccination in the analysis population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs) | Up to 5 days post-vaccination | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Solicited injection-site AEs included erythema (redness), pain, and swelling. |
| Percentage of Participants Who Experience Solicited Systemic AEs | Up to 28 days post-vaccination | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Solicited systemic AEs include arthralgia (joint pain), fatigue (tiredness), headache, myalgia (muscle pain), pyrexia (axillary temperature ≥37.8°C or 100°F), and rash. |
Countries
Brazil
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| V181 Participants received a single 0.5 mL subcutaneous (SC) injection of V181. | 682 |
| Butantan - DV Participants received a single 0.5 mL SC injection of Butantan - DV. | 682 |
| Total | 1,364 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 16 | 7 |
| Overall Study | Participants Left The City | 0 | 2 |
| Overall Study | Randomized By Mistake Without Study Treatment | 1 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 6 |
Baseline characteristics
| Characteristic | V181 | Total | Butantan - DV |
|---|---|---|---|
| Age, Continuous | 32.8 years STANDARD_DEVIATION 8.9 | 32.5 years STANDARD_DEVIATION 9 | 32.2 years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 569 Participants | 1144 Participants | 575 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 99 Participants | 191 Participants | 92 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 29 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 70 Participants | 141 Participants | 71 Participants |
| Race (NIH/OMB) More than one race | 20 Participants | 47 Participants | 27 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 585 Participants | 1164 Participants | 579 Participants |
| Sex/Gender, Customized Female | 459 Participants | 884 Participants | 425 Participants |
| Sex/Gender, Customized Male | 222 Participants | 479 Participants | 257 Participants |
| Sex/Gender, Customized Undifferentiated | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 682 | 0 / 682 |
| other Total, other adverse events | 634 / 680 | 622 / 678 |
| serious Total, serious adverse events | 12 / 680 | 9 / 678 |
Outcome results
Primary
Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT)
A dengue VRNT was conducted to assess neutralizing antibody geometric mean titers (GMTs) for each of the 4 dengue serotypes (DENV1, DENV2, DENV3, and DENV4) in specimens collected from participants on Day 28 post-vaccination
Time frame: Day 28 post-vaccination
Population: All randomized participants without protocol deviations that could have substantially impacted the results of the immunogenicity analyses and with data available for this outcome. These deviations included seropositivity at baseline as assessed by VRNT and missing serological results.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| V181 | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-1 Serotype | 608.55 Titer |
| V181 | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-2 Serotype | 773.96 Titer |
| V181 | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-3 Serotype | 179.97 Titer |
| V181 | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-4 Serotype | 206.58 Titer |
| Butantan-DV | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-4 Serotype | 593.41 Titer |
| Butantan-DV | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-1 Serotype | 703.19 Titer |
| Butantan-DV | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-3 Serotype | 396.76 Titer |
| Butantan-DV | Dengue Virus (DENV)-Neutralizing Antibody Titers as Measured by Virus Reduction Neutralization Test (VRNT) | DENV-2 Serotype | 109.05 Titer |
Comparison: DENV-1 GMT Ratio (V181/Butantan - DV)p-value: <0.00195% CI: [0.76, 0.99]t-distribution
Comparison: DENV-2 GMT Ratio (V181 / Butantan - DV)p-value: <0.00195% CI: [6.03, 8.35]t-distribution
Comparison: DENV-3 GMT Ratio (V181 / Butantan - DV)p-value: 195% CI: [0.39, 0.53]t- distribution
Comparison: DENV-4 GMT Ratio (V181 / Butantan - DV)p-value: 195% CI: [0.29, 0.42]t-distribution
Primary
Percentage of Participants Who Seroconverted, as Measured by VRNT
A dengue VRNT was conducted to assess the percentage of participants who seroconverted for each of the 4 dengue serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) at Day 28 post-vaccination. Seroconversion was defined as achieving a serotype-specific VRNT titer ≥lower limit of quantification (LLOQ) at Day 28 post-vaccination in the analysis population.
Time frame: Day 28 post-vaccination
Population: All randomized participants without protocol deviations that could have substantially impacted the results of the immunogenicity analyses and with data available for this outcome. These deviations included seropositivity at baseline as assessed by VRNT and missing serology results.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V181 | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-1 Serotype | 98.6 percentage of participants |
| V181 | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-2 Serotype | 99.2 percentage of participants |
| V181 | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-3 Serotype | 95.3 percentage of participants |
| V181 | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-4 Serotype | 92.2 percentage of participants |
| Butantan-DV | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-4 Serotype | 95.9 percentage of participants |
| Butantan-DV | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-1 Serotype | 98.9 percentage of participants |
| Butantan-DV | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-3 Serotype | 98.9 percentage of participants |
| Butantan-DV | Percentage of Participants Who Seroconverted, as Measured by VRNT | DENV-2 Serotype | 84.2 percentage of participants |
Comparison: DENV-1 Difference in percentage (V181 - Butantan-DV)p-value: <0.00195% CI: [-1.8, 1.3]Miettinen & Nurminen method
Comparison: DENV-2 Difference in Percentage (V181 - Butantan-DV)p-value: <0.00195% CI: [12, 18.5]Miettinen & Nurminen method
Comparison: DENV-3 Difference in Percentage (V181 - Butantan-DV)p-value: <0.00195% CI: [-5.8, -1.6]Miettinen & Nurminen method
Comparison: DENV-4 Difference in Percentage (V181 - Butantan - DV)p-value: <0.00195% CI: [-6.7, -0.8]Miettinen & Nurminen method
Primary
Percentage of Participants With Vaccine-related Serious Adverse Events (SAEs)
An SAE is an AE that results in death, is life-threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. Relatedness of an SAE to the study vaccine was determined by the investigator.
Time frame: Up to 28 days post-vaccination
Population: All randomized participants who received at least one dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V181 | Percentage of Participants With Vaccine-related Serious Adverse Events (SAEs) | 0.0 percentage of participants |
| Butantan-DV | Percentage of Participants With Vaccine-related Serious Adverse Events (SAEs) | 0.0 percentage of participants |
Secondary
Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Solicited injection-site AEs included erythema (redness), pain, and swelling.
Time frame: Up to 5 days post-vaccination
Population: All randomized participants who received at least one dose of study intervention.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V181 | Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs) | Injection-site erythema | 10.3 percentage of participants |
| V181 | Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs) | Injection-site pain | 17.6 percentage of participants |
| V181 | Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs) | Injection-site swelling | 2.8 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs) | Injection-site erythema | 6.0 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs) | Injection-site pain | 17.8 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Injection-site Adverse Events (AEs) | Injection-site swelling | 2.2 percentage of participants |
Comparison: Erythema: Difference in Percentage (V181-Butantan - DV)95% CI: [1.4, 7.2]
Comparison: Pain: Difference in Percentage (V181 - Butantan - DV).95% CI: [-4.3, 3.9]
Comparison: Swelling: Difference in Percentage (V181 - Butantan - DV)95% CI: [-1.1, 2.3]
Secondary
Percentage of Participants Who Experience Solicited Systemic AEs
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Solicited systemic AEs include arthralgia (joint pain), fatigue (tiredness), headache, myalgia (muscle pain), pyrexia (axillary temperature ≥37.8°C or 100°F), and rash.
Time frame: Up to 28 days post-vaccination
Population: All randomized participants who received at least one dose of study intervention.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V181 | Percentage of Participants Who Experience Solicited Systemic AEs | Rash | 70.6 percentage of participants |
| V181 | Percentage of Participants Who Experience Solicited Systemic AEs | Headache | 64.6 percentage of participants |
| V181 | Percentage of Participants Who Experience Solicited Systemic AEs | Arthralgia | 21.0 percentage of participants |
| V181 | Percentage of Participants Who Experience Solicited Systemic AEs | Pyrexia | 5.6 percentage of participants |
| V181 | Percentage of Participants Who Experience Solicited Systemic AEs | Myalgia | 37.2 percentage of participants |
| V181 | Percentage of Participants Who Experience Solicited Systemic AEs | Fatigue | 44.6 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Systemic AEs | Rash | 63.7 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Systemic AEs | Arthralgia | 22.1 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Systemic AEs | Fatigue | 46.8 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Systemic AEs | Myalgia | 45.1 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Systemic AEs | Pyrexia | 10.8 percentage of participants |
| Butantan-DV | Percentage of Participants Who Experience Solicited Systemic AEs | Headache | 67.7 percentage of participants |
Comparison: Arthralgia: Difference in Percentage (V181 - Butantan - DV)95% CI: [-5.5, 3.3]
Comparison: Fatigue: Difference in Percentage (V181 - Butantan - DV)95% CI: [-7.5, 3.1]
Comparison: Headache: Difference in Percentage (V181 - Butantan - DV)95% CI: [-8.2, 1.9]
Comparison: Myalgia: Difference in Percentage (V181 - Butantan - DV)95% CI: [-13.1, -2.7]
Comparison: Pyrexia: Difference in Percentage (V181 - Butantan - DV)95% CI: [-8.2, -2.3]
Comparison: Rash: Difference in Percentage (V181 - Butantan - DV)95% CI: [1.9, 11.8]