A Combination Efficacy Study in Africa of Two DNA-MVA-Env Protein or DNA-Env Protein HIV-1 Vaccine Regimens With PrEP
- Conditions
- HIV Infections
- Registration Number
- NCT04066881
- Lead Sponsor
- MRC/UVRI and LSHTM Uganda Research Unit
- Brief Summary
This international, multi-centre, double-blind vaccine study is a three-arm prospective 1:1:1 randomisation comparing each of two experimental combination vaccine regimens i.e. DNA/AIDSVAX (weeks 0,4,24,48) and DNA/CN54gp140 (weeks 0,4) + MVA/CN54gp140 (weeks 24,48) with placebo control. There will be a concurrent open-label 1:1 randomisation to compare daily TAF/FTC (week 0-26) to daily TDF/FTC (weeks 0-26) as pre-exposure prophylaxis.
The study aims to randomise up to 1668 eligible adults (18-40 years) through collaborating clinical research centres in 4 countries (Mozambique; South Africa; Tanzania; and Uganda). Each participant will be followed for a minimum of 74 weeks after enrolment.
The trial is designed to detect a reduction in HIV incidence that has public health relevance sufficient to justify implementation of the combination vaccine regimen. In light of the high level of effectiveness demonstrated in the PrEP trials (up to 86% reduction in HIV), this trial is powered to detect a protective vaccine efficacy of 70% at the final analysis.
The PrEP component will determine whether the effectiveness of TAF/FTC is unacceptably lower than the effectiveness of TDF/FTC.
- Detailed Description
This international, multi-centre, double-blind vaccine study will be a three-arm prospective 1:1:1 randomisation comparing each of two experimental combination vaccine regimens with placebo control.
Pre-screening for risk and HIV status will take place as part of a Registration Cohort which will precede and continue in parallel to the PrEPVacc trial enrolments. This will give HIV negative volunteers time to learn about the PrEPVacc trial and facilitate timely enrolment.
Clinical screening for the vaccine trial will take place during the 8 weeks prior to randomisation from local communities in Mozambique, South Africa, Tanzania and Uganda where the clinical research centres are located. Eligible participants who are HIV-uninfected adults aged 18-40 years at high risk of HIV infection will be enrolled at week 0 and randomised to one of three vaccine arms:
1. Vaccine group A: DNA-HIV-PT123 and AIDSVAX® B/E (weeks 0,4,24,48)
2. Vaccine group B: DNA-HIV-PT123 and CN54gp140 in MPLA-L (wks 0,4), then MVA-CMDR and CN54gp140 in MPLA-L (wks 24,48)
3. Vaccine group C: Saline Placebo (wks 0,4,24,48)
There will be a concurrent open-label 1:1 randomisation to one of two PrEP regimens:
1. Control PrEP: Daily TDF/FTC (week 0-26)
2. Experimental PrEP: Daily TAF/FTC (week 0-26)
Participants will be randomised at each clinical centre through web randomisation after entering the quantifiable eligibility criteria. Randomisation will be stratified by centre and by gender for vaccines and for PrEP. Clinic staff and participants will be blind to allocation of active or placebo vaccines, but the pharmacist preparing the vaccines will know. As the volume of gp140 in MPLA-L is 0.4ml and given at the same timepoints as products with a volume of 1ml, clinic staff will be able to identify participants allocated to the CN54gp140 in MPLA-L or matched placebo.
Clinic staff and participants will know which PrEP agent each participant is allocated to. Participants will continue to receive study PrEP through to week 26 after which access to PrEP will revert to local supply of generic drug.
The target accrual is around 1668 HIV uninfected adults, but this is an endpoint driven multi-arm, multi-stage (MAMS) trial design, and therefore the target may be adjusted following a recommendation from the IDMC. In addition, participants who do not complete the third immunisation will be replaced whilst this is feasible. Participants will be followed up for a minimum of 74 weeks after enrolment.
The primary efficacy outcome measure for the vaccine analysis is HIV acquisition by a participant who completed three immunisations and was HIV negative at week 26.
The primary efficacy outcome for the PrEP analysis is HIV acquisition at or before week 26 by a participant who was HIV negative at enrolment.
The primary safety outcome for both analyses is a clinical decision to discontinue the vaccine or PrEP regimen for an adverse event that is considered related to product.
This trial is designed to detect a reduction in HIV incidence that has public health relevance sufficient to justify implementation of the combination vaccine regimen. In light of the high level of effectiveness demonstrated in the PrEP trials (up to 86% reduction in HIV), this trial is powered to detect a protective vaccine efficacy of 70% at the final analysis.
The PrEP component of the trial aims to show the effectiveness of TAF/FTC is not unacceptably lower than the effectiveness of TDF/FTC, assessed from the observed lower confidence limit for the Averted Infections Ratio (AIR).
The Independent Data Monitoring Committee will review an interim analysis of vaccine efficacy in order to determine whether each active vaccine arm has demonstrated sufficient efficacy to warrant further investigation. This analysis will only consider new infections arising after the week 26 visit and only those in individuals who have completed the first three immunisations. The analysis will take place after approximately 7 of these infections have occurred in the placebo group. The investigators will not be informed of the timing of the interim analysis, unless there is a recommendation to modify the protocol.
The PrEP analysis will consider new infections up to the week 26 visit in individuals who were HIV negative at enrolment.
To enhance understanding of the trial results within their broader context, indepth interviews and group discussions with trial participants, as well as structured debriefs with study staff, will be conducted throughout the trial (week 0-74). These activities will examine risk and adherenvce behaviours, along with knowledge, attitudes and perceptions of participants, study staff and wider community.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1512
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Incident HIV infection week 0-26 HIV acquisition at or before week 26 by a participant who was HIV negative at enrolment
A clinical decision to discontinue the vaccine regimen for an adverse event that is considered related to product week 0-48 A clinical decision to discontinue the vaccine regimen for an adverse event that is considered related to product
A clinical decision to discontinue PrEP regimen for an adverse event that is considered related to product week 0-26 A clinical decision to discontinue PrEP regimen for an adverse event that is considered related to product
- Secondary Outcome Measures
Name Time Method Discontinuation or interruption of PrEP week 0-26 A clinical decision to discontinue or interrupt the PrEP regimen for an adverse event that is considered related to product
Serious adverse events week 0-74 Serious adverse events
Other clinical and laboratory adverse events week 0-74 Other clinical and laboratory adverse events
Binding antibodies week 0-74 Binding antibodies to Cn54gp140 and AIDSVAX® B/E gp120
Resistance mutations to tenofovir and emtricitabine week 0-74 Genotypic resistance at HIV seroconversion, focussing on the mutations selected by tenofovir and emtricitabine (codons 65, 70, 184 in reverse transcriptase)
Number of PrEP pills missed week 0-26 Adherence to PrEP assessed by self-report
Tenofovir level in urine week 0-26 Adherence to PrEP assessed by results of point of care urine tests
Tenofovir level in red blood cells week 0-26 Adherence assessed by TFV DP levels measured on DBS in red blood cells
Number of PrEP Pills dispensed week 0-26 Adherence assessed by total number of PrEP pills dispensed
Grade 3 and worse solicited clinical and laboratory adverse events within 7 days of receiving vaccine injection Grade 3 and worse solicited clinical and laboratory adverse events
Discontinuation or interruption of vaccine regimen week 0-74 A clinical decision to discontinue or interrupt the vaccine regimen for an adverse event that is considered related to product
Trial Locations
- Locations (1)
MRC/UVRI and LSHTM Uganda Research Unit
🇺🇬Entebbe, Uganda