A Combination Efficacy Study in Africa of Two DNA-MVA-Env Protein or DNA-Env Protein HIV-1 Vaccine Regimens With PrEP

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:

• Vaccine group A: DNA-HIV-PT123 and AIDSVAX® B/E (weeks 0,4,24,48)
• 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)
• 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:

• Control PrEP: Daily TDF/FTC (week 0-26)
• 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.

Inclusion criteria

• HIV uninfected adults aged between 18 and 40 years old on the day of screening
• Willing and able to provide informed consent prior to participation
• Willing and able to comply with the visit schedule and provide blood, urine and other samples at the required time points
• Home address accessible for visiting and intending to remain within the recruitment area for at least 82 weeks from screening
• Likely to be at risk from exposure to HIV during follow up
• Willing to undergo HIV testing, receive HIV test results and risk reduction counselling which includes promotion of PrEP and condoms
• If female, of child-bearing age and not sterilised, willing to use a highly effective method of contraception from screening until 18 weeks after the last injection
• If male and not sterilised, willing to avoid impregnating female partners from screening until 18 weeks after the last injection

Exclusion criteria

• HIV infection or indeterminate HIV result at screening or enrolment
• Hepatitis B surface antigen positive
• If female, currently pregnant (evidence from positive serum or urine pregnancy test), or lactating
• Participating in another biomedical research study or in receipt of a live vaccine within 30 days prior to randomisation
• Participation in a previous HIV vaccine or HIV immunotherapy trial
• Receiving blood products or immunoglobulins within 12 weeks of screening
• Known hypersensitivity to any component of the vaccine formulations used in this trial or history of severe or multiple allergies to vaccines, drugs or pharmaceutical agents
• Presence of a systemic disease at the time of randomisation or history of chronic illness that in the opinion of the investigator may compromise the participant's safety, preclude vaccination or compromise an immune response to vaccine
• Abnormalities in routine laboratory parameters (Hb, creatinine, AST/ALT, alkaline phosphatase, total Bilirubin and glucose) of Grade 2 and above using the DAIDS toxicity table, version 2.1 July 2017 or estimated glomerular filtration rate less than 50ml/min