Safety and Immunogenicity of a Tetravalent Dengue Vaccine in HIV-Positive Adults

Phase 2

Completed

Conditions: Dengue Fever
Dengue Hemorrhagic Fever
Human Immunodeficiency Virus

Interventions: Biological: Placebo (NaCl 0.9%) vaccine group
Biological: CYD Dengue Vaccine

Registration Number: NCT02741128

Lead Sponsor: Sanofi Pasteur, a Sanofi Company

Brief Summary: The aim of the study was to evaluate the safety and immunogenicity of the Dengue vaccine in a population of special interest, such as HIV-positive adults previously exposed to dengue.

Primary Objective:

* To describe the safety of each injection of CYD dengue vaccine in HIV-positive adults previously exposed to dengue.

Secondary Objectives:

* To describe the humoral immune response to each dengue serotype at baseline and after each injection of CYD dengue vaccine in HIV-positive adults previously exposed to dengue.

* To detect the CYD dengue vaccinal viremia post-Inj 1 in HIV-positive adults previously exposed to dengue.

* To describe changes in CD4 count and HIV RNA viral load after each injection of CYD dengue vaccine in HIV-positive adults previously exposed to dengue.

Observational Objective:

* To describe the FV (YF, Dengue, Zika) serological status in the study population at baseline.

Detailed Description: Eligible subjects were randomized in a 2:1 ratio into 1 of 2 groups to receive 3 injections of either CYD dengue vaccine or placebo at 0, 6, and 12 months. The enrollment of subjects was carried out in two steps, including an early safety data review before the second step. The duration of each subject's participation in the study was approximately 18 months.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 133

Inclusion Criteria

Aged 18 to 50 years on the day of first study vaccination (study product administration) ("18 to 50" means from the day of the 18th birthday to the day before the 51th birthday)
Inform concent form has been signed and dated
Able to attend all scheduled visits and to comply with all trial procedures
Documented seropositivity for HIV-1 infection based on the Brazilian HIV Guidelines' laboratory criteria (i.e., two positive results obtained from different and independent determination methods) or detectable HIV-1 viral load results in the past
Stable HIV condition according to Brazilian HIV Guidelines (i.e., with both CD4 count > 350 cells/mm3 and sustainable and undetectable HIV viral load [< 50 copies/mL]) for at least 1 year before consent
Stable antiretroviral (ART) regimen based on local HIV protocol for at least 1 year before consent.
Previous exposure to dengue confirmed by rapid diagnostic test (RDT) or dengue IgG ELISA

Exclusion Criteria

Subject is pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be pre-menarche or post-menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination until at least 4 weeks after the last vaccination)
Participation at the time of study enrollment (or in the 4 weeks preceding the first trial vaccination) or planned participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure
Receipt of any vaccine in the 4 weeks preceding the first trial vaccination or planned receipt of any vaccine in the 4 weeks following any trial vaccination
Previous vaccination against dengue disease with either the trial vaccine or another vaccine
Receipt of immune globulins, blood or blood-derived products in the past 3 months
Self-reported or suspected congenital or acquired immunodeficiency, except HIV; 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)
Previous acquired immunodeficiency syndrome (AIDS), defined as the occurrence of opportunistic infection in the last 2 years before consent
Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances
Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily
Current alcohol abuse or drug addiction
Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion
Moderate or severe acute illness/infection (according to investigator judgment) or febrile illness (temperature ≥ 38.0°C) on the day of vaccination. A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided
Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study
Previous CD4 count < 200 cells/mm3 (nadir) since diagnosis of HIV
History of chronic and active hepatitis B infection or HBsAg-positive
History of chronic and active hepatitis C infection or HCV Ab-positive
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine > 3 times the upper limit of normal range (ULN)
Hemoglobin (Hb) < 10 g/dL
White blood cell count (WBC) < 1500 cells/mm3
Platelets < 100,000 cells/mm3.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo vaccine group	Placebo (NaCl 0.9%) vaccine group	Subjects will receive 3 doses of placebo (NaCl, 0.9%) vaccine at 0, 6, and 12 months
CYD Dengue vaccine group	CYD Dengue Vaccine	Subjects will receive 3 doses of CYD dengue vaccine at 0, 6, and 12 months

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Solicited Injection-Site Reactions	Up to 7 days after each injection	An AE was any untoward medical occurrence in a participant administered study vaccine and which did not necessarily have a causal relationship. A solicited reaction was an expected adverse reaction (AR) observed and reported under the conditions pre-listed in the protocol and CRF and included pain, erythema, and swelling. Injection site reaction was an AR at and around the injection site. Injection site reactions were commonly inflammatory reactions.
Percentage of Participants With Solicited Systemic Reactions	Up to 14 days after each injection	A solicited reaction was an "expected" adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) pre-listed in the protocol and CRF. Solicited systemic reactions included headache, fever, localized or topical manifestations that were not associated with the vaccination or administration site.
Percentage of Participants With Unsolicited AE, Serious and Non-Serious AEs of Special Interest (AESIs)	Up to 28 days after each injection	An unsolicited AE was an observed AE that did not fulfill the conditions pre-listed in the protocol and CRF in terms of diagnosis and/or onset window post-vaccination. An AESI was one of scientific and medical concern specific to the study vaccine, for which ongoing monitoring, and rapid communication by the Investigator to the Sponsor was appropriate. The following were considered as serious AESI: serious hypersensitivity/allergic reactions occurring in all participants within 7 days after vaccination; serious viscerotropic disease occurring in all participants within 30 days after vaccination; serious neurotropic disease occurring in all participants within 30 days after vaccination; serious dengue disease requiring hospitalization occurring in all participants at any time during the study. The following were considered as non-serious AESIs, hypersensitivity/allergic reactions occurring in all participants within 7 days after vaccination.
Percentage of Participants With Serious AEs (SAEs) and Hospitalized Virologically-Confirmed Dengue (VCD) Cases	From the date of randomization until 6-month safety follow-up (approximately 38 months)	An AE was any untoward medical occurrence in a participant administered study vaccine and which does not necessarily have a causal relationship. SAEs were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Hospitalized VCD cases were defined as an acute febrile illness with diagnosis of dengue requiring hospitalization. The confirmatory dengue diagnosis was performed through virological detection.
Percentage of Participants With Unsolicited Systemic Adverse Event (AE)	Within 30 minutes after each injection	An AE was any untoward medical occurrence in a participant administered study vaccine and which did not necessarily have a causal relationship. An unsolicited AE was an observed AE that did not fulfill the conditions pre-listed in the protocol and case report form (CRF) in terms of diagnosis and/or onset window post-vaccination.

Secondary Outcome Measures

Name	Time	Method
Geometric Mean Titers of Neutralizing Antibody Levels Against Each of the 4 Parental Dengue Virus Strains	Baseline (Day 0) and 28 days after each injection	Dengue neutralizing antibody levels were measured by PRNT50. Serial, 2-fold dilutions of serum to be tested (previously heat-inactivated) were mixed with a constant challenge-dose of each dengue virus serotype 1, 2, 3 or 4. The presence of dengue virus infected cells was indicated by formation of plaques. A reduction in virus infectivity due to neutralization by antibody present in serum samples was detected. The reported value represented the highest dilution of serum at which \>= 50% of dengue challenge virus (in plaque counts) was neutralized when compared to the mean viral plaque count in the negative control wells which represented the 100% virus load.
Percentage of Participants With a Detected and Quantified CYD Dengue Vaccinal Viremia	At 7 and 14 days post-injection 1	The percentage of participants with detected and quantified CYD dengue vaccinal viremia, i.e above the detection level as assessed by reverse transcription-polymerase chain reaction (RT-PCR) and for each of the 4 dengue serotypes after the first CYD dengue vaccine injection has been reported. Four RT-PCRs were used to perform quantitation and serotype identification of post-vaccinal serotype-specific dengue vaccine viremia from serum samples displaying a positive yellow fever (YF) RT-PCR result. The assay was performed only for YT RT-PCR-positive samples.
Percentage of Participants With Confirmed Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) Viral Load Increase	From Day 28 to Day 393 (28 days after each injection)	A confirmed HIV viral load increase was defined as plasma HIV-1 RNA \>1000 copies/milliliter (mL) 28 days post-injection after having been undetectable (\< 50 copies/mL) pre-injection, not explained by non-adherence to ART and not explained by any other possible etiology and confirmed by a second test taken 4 weeks after the first (i.e, approximately 2 months post-injection) showing the same value/trend.
Percentage of Participants With Clusters of Differentiation 4 (CD4) Count Decrease	From Day 28 to Day 393 (28 days after each injection)	A decrease in CD4 count greater than 30 % assessed 28 days post-injection compared to the pre-injection value, not explained by non-adherence to antiretroviral therapy (ART) and not explained by any other possible etiology, and confirmed by a second test taken 4 weeks after the first (ie, approximately 2 months post-injection) showing the same value/trend.

Trial Locations

Locations (4): Investigational Site Number :0760004
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Natal, Rio Grande Do Norte, Brazil
Investigational Site Number :0760002
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Nova Iguaçu, Rio De Janeiro, Brazil
Investigational Site Number :0760003
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Sao Paulo, Brazil
Investigational Site Number :0760001
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São Paulo, Brazil