Dengue
Conditions
Brief summary
The purpose of this research study is to test the protection of volunteers previously vaccinated with Tetravalent Dengue Virus (TDEN) Purified Inactivated Vaccine (PIV) with alum and boosted with TDEN live attenuated vaccine (LAV) formulation against a weakened form of an experimental dengue virus challenge. The Investigators will also include people that have not received the study vaccine. The Investigators are collecting information about how the vaccine protects against a dengue virus challenge as well as adding to knowledge about the safety of the challenge.
Detailed description
The purpose of this research study is to test the protection of volunteers previously vaccinated with Tetravalent Dengue Virus (TDEN) Purified Inactivated Vaccine (PIV) with alum and boosted with TDEN live attenuated vaccine (LAV) formulation against a weakened form of an experimental dengue virus challenge. The Investigators will also include people that have not received the study vaccine. The Investigators are collecting information about how the vaccine protects against a dengue virus challenge as well as adding to knowledge about the safety of the challenge. The information will help Investigators develop vaccines to protect people from dengue. Participation is voluntary. The duration of participation will last for 180 days (six months). After participants are exposed to the weakened dengue virus, the Investigators will follow them closely to measure their symptoms. Like the flu, participants might expect to have a headache, rash, body aches, fever and chills or they may experience no symptoms whatsoever. If a participant does develops symptoms, the Investigators will monitor him/her closely in a local hotel or a wing of our hospital to ensure safety and to treat symptoms if they occur. Participants will be compensated for their time.
Interventions
one subcutaneous injection of Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) at 0.5 mL of 6.5 x 10\^3 PFU/mL
Sponsors
United States Army Medical Materiel Development Activity
Medical Technology Enterprise Consortium (MTEC)
University of Maryland, Baltimore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* 1\. Male or non-pregnant, non-breastfeeding female between 18 and 50 years of age (inclusive) at the time of consent. * 2\. Tetravalent dengue antibody response at 28 days following final vaccination for vaccinated groups of volunteers. * 3\. Volunteers must be able and willing to provide written informed consent. * 4\. Volunteers must be healthy as established by medical history and clinical examination at study entry. * 5\. Volunteers must pass a comprehension test and be able to comply with all study requirements. * 6\. Female volunteers of non-childbearing potential (non-childbearing potential is defined as having had one of the following: a tubal ligation at least 3 months prior to enrollment, a hysterectomy, an oophorectomy, or is post-menopausal). * 7\. Female volunteers of childbearing potential may be enrolled in the study, if all of the following apply: * Practiced adequate contraception (see Definition of Terms, section 5.4.2.3.) for 30 days prior to challenge * Has a negative urine pregnancy test on the day of DHIM * Agrees to continue adequate contraception until two months after completion of the DHIM * 8\. Provide consent for release of medical history records from primary care physician, college or university medical center, urgent care, or emergency room visit
Exclusion criteria
* 1\. Planned travel during the study period (180 days) which would interfere with the ability to complete all study visits * 2\. Recent (in the past 4 weeks) travel to any dengue endemic area. These potential volunteers may be eligible for enrollment a minimum of 4 weeks later * 3\. Volunteer seropositive for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), or human immunodeficiency virus antibodies (anti-HIV) * 4\. Unvaccinated volunteers positive for antibodies to flaviviruses (FV) to include dengue virus, West Nile virus, Yellow Fever virus, Zika virus, and Japanese encephalitis virus. * 5\. Any history of FV infection or FV vaccination except for participation in the ADVP003 or ADVP004 dengue vaccination studies; during the study period (Note: Late time point serology from the trials can be tested concomitant to screening serology to clarify if incident FV infection has occurred between vaccination and challenge) * 6\. Medical history of, or current, diabetes, chronic obstructive pulmonary disease, peptic ulcer disease, coronary artery disease, cardiac arrhythmia, cardiomyopathy, pericarditis, or auto-immune disease * 7\. Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months) * 8\. History of Guillain-Barré syndrome (GBS) * 9\. History of bipolar disorder, schizophrenia, hospitalization in the past year for a mental health disorder, or any other psychiatric condition, which in the opinion of the investigator prevents the volunteer from participating in the study * 10\. Safety laboratory test results at screening that are deemed clinically significant or more than Grade 1 deviation from normal with the exception of PT/PTT, fibrinogen decrease, ALT/AST increase (\<1.1 x ULN acceptable), platelet decrease which will be exclusionary at Grade 1 or higher * 11\. Significant screening physical examination abnormalities at the discretion of the investigator, including a BMI \> 35 kg/m2 * 12\. Women who intend to become pregnant or men who intend to father a child during the study period (approximately 6 months) * 13\. Female: pregnant, lactating or history of heavy menstrual bleeding menstrual periods lasting consistently and regularly longer than 6 days, or consistently and regularly requiring 5 or more pads or tampons per day, and volunteer to the opinion and review of the investigator. * 14\. Female volunteers using an intrauterine device (IUD) or Mirena® * 15\. Female volunteers with a history of clinically significant fibroids or uterine polyps, endometriosis, dysmenorrhea, adenomyosis, and uterine scarring (e.g. after D&C), unless treated, with no active clinically significant disease * 16\. Allergy (hives, shortness of breath, swelling of the lips or throat), or hospitalization related to a previous vaccination, anaphylaxis of unknown etiology, or allergy to specific medications/animals for which antigens may be in the virus preparations to include: Shellfish allergy, Fetal Bovine Serum, L-Glutamine, Neomycin and Streptomycin * 17\. Recent blood donation within prior 56 days of inoculation or planning to donate blood in the one 1 year following inoculation with dengue virus * 18\. Receipt of blood products or antibodies within 90 days of inoculation or during the study period * 19\. Any personal beliefs that bar the administration of blood products, transfusions, or serum albumin * 20\. Participation in the 4 weeks preceding inoculation, or planned participation during the present trial period, in another clinical trial investigating a vaccine except for participation in the ADVP003 or ADVP004 study, drug, medical device, or medical procedure * 21\. Planned administration of a licensed or study vaccine not planned in the study protocol during the period starting 30 days prior to the DHIM for a live vaccine or 14 days prior to DHIM for inactivated vaccines and extending until 56 days after study completion * 22\. Planned or current administration of an HMG-CoA reductase inhibitor (i.e., lovastatin, simvastatin, atorvastatin, etc.) * 23\. Currently taking methadone or suboxone * 24\. Currently regularly taking anti-coagulant medication, aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) * 25\. Chronic migraine headaches, defined as more than 15 headache days per month over a 3-month period of which more than 8 are migraines, in the absence of medication over use * 26\. Chronic or recent acute medical condition that, in the opinion of the investigator, impacts volunteer safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Solicited Injection Site Adverse Events | Days 2, 4, 5, 6, and 7 | Number of Participants with Solicited Injection Site Erythema - solicited injection site adverse event until 7 days post virus inoculation |
| Number of Participants With Unsolicited Injection Site Adverse Events | Days 2, 4, 5-16, 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days) | Number of Participants with Injection site pain - unsolicited injection site adverse events until 28 days post virus inoculation or 7 days post hospitalization, whichever is later |
| Number of Participants With Solicited Systemic Adverse Events | Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days) | Number of participants with solicited systemic adverse events until 28 days post virus inoculation or 7 days post hospitalization, whichever is later |
| Number of Participants With Incidence of Abnormal Laboratory Measurements | Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days) | Number of participants with incidence of abnormal laboratory measurements until 28 days post virus inoculation or 7 days post hospitalization, whichever is later |
| Dengue-Related Illness Index | Days 1-16 | Scales: Clinical Symptoms: None=0, Mild=1, Moderate=2, Severe=3 (Min Score=0, Max=3) Laboratory Abnormalities: None=0, Mild=1, Moderate=2, Severe=3 based on modified FDA CBER laboratory scale (per protocol) (Min=0, Max=3) Symptoms (Clinical symptoms or Laboratory Abnormalities) duration: 1 point/day (Day 1-16) (Min=0, Max=16) Subscale A (Symptom Duration): 1 point/day (Day 1-16) across 10 Clinical/Laboratory findings (Min = 0, Max = 160) Subscale B (Symptom # per day): 1 point/ Clinical/Laboratory finding (n=10) per day across 16 days Min=0, Max=160 Subscale C (Max Severity Score/day): None=0, Mild=1, Moderate=2, Severe=3 across 16 days: Min=0, Max=48 Total Range in DII score (total scale) which equates to subscale (A + B + C)/3: Min=0, Max=122.7 https://doi.org/10.1016/s1473-3099(24)00100-2. |
| Number of Participants With Unsolicited Systemic Adverse Events | Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days) | Number of participants with unsolicited systemic adverse events until 28 days post virus inoculation or 7 days post hospitalization, whichever is later |
| Number of Participants With Short-Term SAEs | Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days) | Number of participants with SAEs until 28 days post virus inoculation or 7 days post hospitalization, whichever is later |
| Number of Participants With Long-Term SAEs | Days 2-180 | Number of participants with SAEs until 6 months post virus inoculation |
| Number of Participants With Persistent Fever | Days 2-28 | Number of participants with persistent fever defined as greater than or equal to 38°C (100.4° F) measured at least 2 times at least 4 hours apart |
Countries
United States
Participant flow
Recruitment details
18 volunteers assessed - 6 ineligible (lab results n = 4, abnormal physical findings n = 1, Other n = 1), Decline participation n = 2
Participants by arm
| Arm | Count |
|---|---|
| Vaccinee Recipient of tetravalent dengue prime boost vaccine | 6 |
| Control Dengue and flavivirus naive | 4 |
| Total | 10 |
Baseline characteristics
| Characteristic | Vaccinee | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 4 Participants | 10 Participants |
| Age, Continuous | 32.5 Years | 40.7 Years | 36.6 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 |
| other Total, other adverse events | 5 / 6 | 4 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 4 |
Outcome results
Primary
Dengue-Related Illness Index
Scales: Clinical Symptoms: None=0, Mild=1, Moderate=2, Severe=3 (Min Score=0, Max=3) Laboratory Abnormalities: None=0, Mild=1, Moderate=2, Severe=3 based on modified FDA CBER laboratory scale (per protocol) (Min=0, Max=3) Symptoms (Clinical symptoms or Laboratory Abnormalities) duration: 1 point/day (Day 1-16) (Min=0, Max=16) Subscale A (Symptom Duration): 1 point/day (Day 1-16) across 10 Clinical/Laboratory findings (Min = 0, Max = 160) Subscale B (Symptom # per day): 1 point/ Clinical/Laboratory finding (n=10) per day across 16 days Min=0, Max=160 Subscale C (Max Severity Score/day): None=0, Mild=1, Moderate=2, Severe=3 across 16 days: Min=0, Max=48 Total Range in DII score (total scale) which equates to subscale (A + B + C)/3: Min=0, Max=122.7 https://doi.org/10.1016/s1473-3099(24)00100-2.
Time frame: Days 1-16
Population: only people with dengue were assessed (n=9).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vaccinees | Dengue-Related Illness Index | 19.4 Dengue-Related Illness Index Score |
| Controls | Dengue-Related Illness Index | 23.1 Dengue-Related Illness Index Score |
Primary
Number of Participants With Incidence of Abnormal Laboratory Measurements
Number of participants with incidence of abnormal laboratory measurements until 28 days post virus inoculation or 7 days post hospitalization, whichever is later
Time frame: Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccinees | Number of Participants With Incidence of Abnormal Laboratory Measurements | ALT | 4 participants |
| Vaccinees | Number of Participants With Incidence of Abnormal Laboratory Measurements | Thrombocytopenia | 0 participants |
| Vaccinees | Number of Participants With Incidence of Abnormal Laboratory Measurements | Fibrinogen | 1 participants |
| Vaccinees | Number of Participants With Incidence of Abnormal Laboratory Measurements | AST | 4 participants |
| Vaccinees | Number of Participants With Incidence of Abnormal Laboratory Measurements | Leukopenia | 4 participants |
| Controls | Number of Participants With Incidence of Abnormal Laboratory Measurements | AST | 3 participants |
| Controls | Number of Participants With Incidence of Abnormal Laboratory Measurements | Leukopenia | 4 participants |
| Controls | Number of Participants With Incidence of Abnormal Laboratory Measurements | ALT | 3 participants |
| Controls | Number of Participants With Incidence of Abnormal Laboratory Measurements | Fibrinogen | 0 participants |
| Controls | Number of Participants With Incidence of Abnormal Laboratory Measurements | Thrombocytopenia | 1 participants |
Primary
Number of Participants With Long-Term SAEs
Number of participants with SAEs until 6 months post virus inoculation
Time frame: Days 2-180
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vaccinees | Number of Participants With Long-Term SAEs | 0 Participants |
| Controls | Number of Participants With Long-Term SAEs | 0 Participants |
Primary
Number of Participants With Persistent Fever
Number of participants with persistent fever defined as greater than or equal to 38°C (100.4° F) measured at least 2 times at least 4 hours apart
Time frame: Days 2-28
Population: Per protocol analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vaccinees | Number of Participants With Persistent Fever | 4 Participants |
| Controls | Number of Participants With Persistent Fever | 1 Participants |
Primary
Number of Participants With Short-Term SAEs
Number of participants with SAEs until 28 days post virus inoculation or 7 days post hospitalization, whichever is later
Time frame: Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vaccinees | Number of Participants With Short-Term SAEs | 0 Participants |
| Controls | Number of Participants With Short-Term SAEs | 0 Participants |
Primary
Number of Participants With Solicited Injection Site Adverse Events
Number of Participants with Solicited Injection Site Erythema - solicited injection site adverse event until 7 days post virus inoculation
Time frame: Days 2, 4, 5, 6, and 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vaccinees | Number of Participants With Solicited Injection Site Adverse Events | 0 Participants |
| Controls | Number of Participants With Solicited Injection Site Adverse Events | 1 Participants |
Primary
Number of Participants With Solicited Systemic Adverse Events
Number of participants with solicited systemic adverse events until 28 days post virus inoculation or 7 days post hospitalization, whichever is later
Time frame: Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Fever | 4 participants |
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Joint or Bone Pain | 3 participants |
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Eye pain / Headache | 5 participants |
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Fatigue | 4 participants |
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Abdominal Pain | 2 participants |
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Nausea or Vomiting | 3 participants |
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Muscle Pain | 4 participants |
| Vaccinees | Number of Participants With Solicited Systemic Adverse Events | Rash | 3 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Muscle Pain | 4 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Fever | 2 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Abdominal Pain | 2 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Eye pain / Headache | 4 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Rash | 4 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Joint or Bone Pain | 2 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Fatigue | 4 participants |
| Controls | Number of Participants With Solicited Systemic Adverse Events | Nausea or Vomiting | 1 participants |
Primary
Number of Participants With Unsolicited Injection Site Adverse Events
Number of Participants with Injection site pain - unsolicited injection site adverse events until 28 days post virus inoculation or 7 days post hospitalization, whichever is later
Time frame: Days 2, 4, 5-16, 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vaccinees | Number of Participants With Unsolicited Injection Site Adverse Events | 0 Participants |
| Controls | Number of Participants With Unsolicited Injection Site Adverse Events | 1 Participants |
Primary
Number of Participants With Unsolicited Systemic Adverse Events
Number of participants with unsolicited systemic adverse events until 28 days post virus inoculation or 7 days post hospitalization, whichever is later
Time frame: Days 2, 4-16, 19, 22, 25, and 28 (until 28 days post virus inoculation or 7 days post hospitalization, whichever is later, up to a maximum of 28 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccinees | Number of Participants With Unsolicited Systemic Adverse Events | Generalized Muscle Pain | 0 participants |
| Vaccinees | Number of Participants With Unsolicited Systemic Adverse Events | Shoulder Pain - Left | 1 participants |
| Vaccinees | Number of Participants With Unsolicited Systemic Adverse Events | Headache | 0 participants |
| Vaccinees | Number of Participants With Unsolicited Systemic Adverse Events | Lower Back Pain | 0 participants |
| Vaccinees | Number of Participants With Unsolicited Systemic Adverse Events | Gastrointestinal Upset | 0 participants |
| Controls | Number of Participants With Unsolicited Systemic Adverse Events | Lower Back Pain | 1 participants |
| Controls | Number of Participants With Unsolicited Systemic Adverse Events | Gastrointestinal Upset | 1 participants |
| Controls | Number of Participants With Unsolicited Systemic Adverse Events | Generalized Muscle Pain | 1 participants |
| Controls | Number of Participants With Unsolicited Systemic Adverse Events | Headache | 1 participants |
| Controls | Number of Participants With Unsolicited Systemic Adverse Events | Shoulder Pain - Left | 0 participants |