NIAID/HVTN 702 – Uhambo
[Why is this study taking place?]
The HVTN 702 study follows in the steps of a vaccine study called RV144 conducted in Thailand from 2003 to 2009. RV144 is the only vaccine trial to show protection from HIV in a clinical trial. For the HVTN 702 study, the vaccine candidate was adapted to the type of virus prevalent in southern Africa (Clade C), and a different adjuvant was used to boost immune responses and make them more robust and durable.
Study sponsors and participants
Study sponsors and collaborators
The National Institute of Allergy and Infectious Diseases (NIAID) sponsored the study, and the HIV Vaccine Trials Network (HVTN) conducted it. Sanofi Pasteur and GSK supplied the study vaccines. The South African Medical Research Council (SAMRC) and the Bill & Melinda Gates Foundation also provided support for this study. All partners developed the study protocol, with support from the Military HIV Research Program (MHRP).
Study participants
5,407 HIV-negative males and females vulnerable to HIV infection, aged 18-35 years.
Study phase
Phase I > Phase IIa > Phase 2b > Phase III
Map of trial locations

- The Aurum Institute, Klerksdorp, North West
- Soweto HVTN CRS, Johannesburg, Gauteng
- Rustenburg CRS, Rustenburg, North West
- Setshaba Research Centre, Shoshanguve, Gauteng
- Kliptown, Soweto, Gauteng
- The Aurum Institute, Tembisa Hospital, Tembisa, Gauteng
- MeCRU CRS, Pretoria, Gauteng
- Madibeng Centre for Research, Brits, North West
- Emavundleni CRS, Cape Town, Western Cape
Khayelitsha CRS, Cape Town, Western Cape - eThekwini CRS, Durban, KwaZulu-Natal
- Isipingo CRS, Westville, KwaZulu-Natal
- Verulam CRS, Verulam, KwaZulu-Natal
- Qhakaza Mbokodo Research Clinic, Ladysmith, KwaZulu-Natal
Trial design
HVTN 702 was a randomized, double-blind, placebo-controlled trial.
Vaccine tested
The vaccine consisted of three non-infectious components injected intramuscularly at pre-defined times to stimulate an immune response against the Clade C virus.
ALVAC-HIV: A weakened non-infectious, non-replicable canarypox virus modified to include part of HIV.
Bivalent subtype C gp120: Proteins found at the surface of two different HIV viruses.
MF-59: An adjuvant added to the gp120 protein to stimulate a stronger immune response against this component.
Vaccine administration
The vaccine regimen was based on a “prime boost” approach consisting of a series of six intramuscular injections over 18 months. The ALVAC-HIV component was intended to prime the immune system; the following immunizations combining ALVAC-HIV and bivalent subtype C gp120 in MF59 were intended to boost immune responses.
Timeline
Week 0
Week 4
ALVAC-HIV
Week 12
ALVAC-HIV + Bivalent Subtype C gp120/MF59
Week 24
ALVAC-HIV + Bivalent Subtype C gp120/MF59
Week 52
ALVAC-HIV + Bivalent Subtype C gp120/MF59
(booster, 12m)
Week 78
ALVAC-HIV + Bivalent Subtype C gp120/MF59
(booster, 18m
Study details
Planning – Ongoing – Discontinued – Completed
Recruiting> Closed to recruitment> Follow up
5,407 participants, 70% of whom were female, were recruited in the study. Immunizations were discontinued on 27 February 2020 when the study’s independent Data and Safety Monitoring Board recommended that it be stopped for futility.
The board concluded that the regimen was safe, but would not be shown to offer protection against HIV infection if the trial continued.
Conclusions
What were the conclusions?
- There was no efficacy; that is, the vaccine was not preventing HIV infections.
- There were no safety concerns. The vaccine did not increase the risk of HIV infection or cause any serious adverse events.
What happens next?
Immunizations have been discontinued. Study participants have entered a follow-up period during which they will continue to receive HIV counselling and testing and will be monitored for safety.
The Uhambo Story
The Uhambo series of clinical studies was conceived to develop a safe, effective vaccine against HIV for use in southern Africa.
Many studies contributed to the research effort, but the journey started in 2003 with the RV144 study in Thailand, which showed that an HIV vaccine regimen could reduce the risk of infection. The reduction was not sufficient to license the vaccine, but gave the basis to develop a better one. Following RV144, the small HVTN 097 study assessed the safety and immunogenicity of the vaccines tested in Thailand in African populations.
Then came the HVTN 100 study, testing the safety of the RV144 vaccines (ALVAC and gp120) modified to fit the type of virus found in South Africa. Results showed that the modified candidate vaccines were safe and triggered immune responses similar to those observed in Thailand. This allowed progression to the HVTN 702 study in 2016 to assess safety and efficacy in a much larger population.
The trials recruited 18-35 year olds (70% female) in South Africa, which has one of the highest HIV prevalence and risk of infection, with 20% of new infections among young women. A safe, efficacious vaccine would be an essential addition to intervention tools already available in this setting.
More information on HVTN 702
South Africa has one of the highest HIV prevalence rates worldwide, with 20.4% of the population living with HIV in 2018. Most affected are women and those aged 18-35 years: 4.7 million women were living with HIV in South Africa as of 2018. As the RV144 study regimen did not target the virus subtype found in South Africa, there was a need to conduct a new study with a modified vaccine. This was possible through strong community support for HIV prevention research in South Africa, which has made tremendous contributions to the search for a safe and effective vaccine.
HVTN 702, a randomized, double-blind, placebo-controlled Phase 2b/Phase 3 clinical trial
The vaccine regimen completed Phase 1 and Phase 2 before entering the efficacy stage. There are typically four phases in human clinical trials:
Phase I and II studies assess the safety of a drug, vaccine or device on a small to medium number of healthy volunteers (20 to 100 and up to a few thousand). Most Phase II trials are randomized and typically double blinded: this means that neither the staff nor the participant knows if a participant receives the vaccine or a placebo. Phase III studies assess the efficacy of a drug or device and involve randomized and double-blind testing in several hundred to several thousand volunteers. If found to be safe and effective, the product can be marketed. Phase IV studies are conducted as post-marketing efforts to further evaluate the characteristics of the new drug with regard to safety, efficacy, new indications for additional patient populations and new formulations.
Study participants in HVTN 702 were randomly assigned to a group receiving the vaccine or a group receiving a placebo. This design is considered the gold standard because people are assigned by chance alone, minimizing the risk of bias in the study.
Globally, different virus clades are found in different geographic locations. The original RV144 was designed as a vaccine to target Clade B/E subtypes. The HVTN702 vaccine regimen was adapted to the Clade C subtype of HIV that is predominant in southern Africa.
The HVTN 702 vaccine regimen consisted of the following components:
- ALVAC-HIV, a canarypox vector-based vaccine, which is non-infectious, non-replicable in human cells and modified to express several HIV components, for example, the gp120 envelop protein (subtype C ZM96), the transmembrane region of the gp41 protein, and the main structural virus protein (gag) and virus protease (all Clade B).
- The gp120protein bivalent subtype C subunit, a combination of two non-infectious subtype C recombinant envelop gp120 proteins (TV1.C and 1086.C) found at the surface of HIV. The proteins were further combined with an adjuvant, MF59, to stimulate a stronger immune response against this component. MF-59 is also commonly used in influenza vaccines and is safe.
Assessing efficacy and immune response
The primary outcome measurements were the efficacy and safety of the vaccine regimen. The planned secondary outcomes included measuring the durability of the immune response, the type of responses generated, vaccine efficacy by various demographic characteristics, and whether there was a difference in the type of infecting virus between the vaccine and placebo groups that could have been caused by the vaccine stopping infection by only a subset of viruses.
What is happening next?
Participants will be followed until the study is closed as per protocol. They will continue to receive HIV counselling and HIV testing and be monitored for side effects during the follow-up period. Further studies may be performed to better understand why the vaccine was not effective, which could contribute to improving future vaccine designs and studies.
Other ongoing HIV prevention trials
Several early- and late-phase vaccine trials currently underway are testing different vaccine regimens in different populations alone or in combination with other interventions, such as pre-exposure prophylaxis (a prevention strategy in which healthy people routinely take one or more antiretroviral drugs to reduce their chance of getting HIV). In addition, trials are taking place to assess the effectiveness of passive immunization with monoclonal antibodies.
References
UNAIDS data 2019 https://www.unaids.org/en/resources/documents/2019/2019-UNAIDS-data
HVTN702 website: http://uhambo.org.za/about
ClinicalTrials.gov database trial reference CT02968849
Glossary
A
Adjuvant: This is an ingredient included with the vaccine to boost the immune response.
C
Clade: A clade describes a family or strains or sub-types of HIV descended from the same origin.
E
Efficacy: This is a measure of how effective a drug or vaccine is in the context of a clinical trial. Drugs and vaccines can show high efficacy within research studies, but not be very effective in the real world due to issues such as compliance with the vaccine regimen. A vaccine that requires multiple injections to prevent HIV infection may not be as effective if all injections are not received.
Effectiveness: Refers to the performance of an intervention, such as a vaccine, under “real-world” conditions.
F
Follow-up: This describes the monitoring of a person’s health over time after the intervention has been administered. It includes keeping track of the health of people who participate in a clinical study or clinical trial for a period of time, both during the study and after the interventions are completed.Formulation: This is the way different components are combined to make a vaccine or medicine.
P
Passive immunization: This refers to pre-formed antibodies administered passively to protect against infection. Current formulations are likely to give immediate, but short-lived protection – several weeks to three to four months at most – so needs to be repeated. See also Active immunization.
Phase 1 clinical trial: This is a safety study that involves giving the vaccine to a small group of people (up to 100) to ensure there is no harm and to see if it provokes an immune response.
Phase 2 clinical trial: This is a larger safety study with hundreds of people to learn more about safety in diverse populations, the most appropriate dosage and to expand knowledge of the vaccine’s immunogenicity.
Phase 2b clinical trial: This is a “proof-of-concept” study to see if there is value in taking a candidate further before committing to a much larger and more costly Phase 3 study to establish efficacy. The number of volunteers required is smaller, around 2,000 to 5,000, while more than 10,000 volunteers are required for Phase 3 trials.
Phase 3 clinical trial: This is a final study where the vaccine is compared against a placebo to measure how effective it is at preventing infection (known as efficacy). These studies enrol thousands of people and can detect rarer side-effects, as well as identify the best dosage levels. Phase 3 trials are required before new vaccines can be licensed for use.
Prime boost: This is a combination strategy whereby the immune system is “primed” or triggered by one vaccine component and then a different element targeting another part of the immune system provides a “boost”.
V
Vaccine candidates: These are potential vaccines being tested in clinical trials.
A
Adenovirus: This is a common virus that causes colds and sore throats. A defective adenovirus (one that cannot grow or cause adenovirus infections in humans), such as Ad26, is sometimes used as a viral vector in HIV vaccines.
Active immunization: This is what takes place when a vaccine stimulates the body to produce an immune response, such as the production of antibodies. Active immune response takes days or weeks to develop but may be long lasting – even lifelong. See also Passive immunization.
Adjuvant: This is an ingredient included with the vaccine to boost the immune response.
Amino acids: These are molecules that link together in combinations to form proteins.
Animal models: Research workers often use laboratory animals as models of humans to test medicinal products they want to develop. The safety of drugs and vaccine candidates are studied in animals at the pre-clinical stage of research. Such testing is a legal requirement before tests on human volunteers can take place in clinical trials.
Antibodies: These are protein molecules produced by the immune system to disable or destroy harmful pathogens (for example, bacteria and viruses).
Antigen: Any substance that causes the body to make an immune response against it is an antigen. Antigens include viruses, bacteria, toxins, chemicals or other substances that usually come from outside the body.
B
Broadly neutralizing antibodies (bNAbs): These antibodies can protect the body from a wide range of different types of HIV. bNAbs are passively administered candidates in HIV prevention studies; researchers are also exploring how to induce bNAbs with a vaccine.
C
Clade: A clade describes a family or strains or sub-types of HIV descended from the same origin.
D
DNA vaccine (nucleic acid vaccine): This is a direct injection of genetic material that contains the instructions for making specific antigenic protein(s), resulting in direct production of such antigen(s) within the vaccine recipient in order to trigger an active immune response against the antigen (see active immunization).
E
Efficacy: This is a measure of how effective a drug or vaccine is in the context of a clinical trial. Drugs and vaccines can show high efficacy within research studies, but not be very effective in the real world due to issues such as compliance with the vaccine regimen. A vaccine that requires multiple injections to prevent HIV infection may not be as effective if all injections are not received.
Envelope protein trimer (gp140): This protein on the surface of HIV binds to immune system cells to gain entry into them, allowing HIV to multiply and spread. The envelope is made up of identical units linked together in groups of three; hence the name, trimer. HIV’s high rate of mutation allows it to change the structure of the trimer and enables evasion by the immune system. Antibodies that target HIV recognize structures (epitopes) on the HIV trimer, while trimer-binding neutralizing antibodies block HIV from infecting cells. Trimers have been engineered synthetically and are now being tested as vaccine candidates that induce active immunity.
Epitope: An epitope is the part of an antigen that is recognized by and binds to components of the immune system, such as antibodies or immune system cells.
F
First in human: This term is used to describe the first time a vaccine or drug has been given to humans.
Follow-up: This describes the monitoring of a person’s health over time after the intervention has been administered. It includes keeping track of the health of people who participate in a clinical study or clinical trial for a period of time, both during the study and after the interventions are completed.
Formulation: This is the way different components are combined to make a vaccine or medicine.
H
HIV proteins: The mature, infectious HIV has five structural proteins. Harmless synthetic versions of these are used in many vaccine approaches and tests for infection.
M
Monoclonal antibodies (mAbs): These antibodies are produced by identical immune cells that are all clones of a unique parent cell. Broadly neutralizing antibodies (bnAbs) are mAbs that bind diverse and neutralize multiple HIV strains, despite their differences.
P
Passive immunization: This refers to pre-formed antibodies administered passively to protect against infection. Current formulations are likely to give immediate, but short-lived protection – several weeks to three to four months at most – so needs to be repeated. See also Active immunization.
Pathogen: A pathogen is an organism (for example, a bacteria or virus) that has the potential to cause disease.
Phase 1 clinical trial: This is a safety study that involves giving the vaccine to a small group of people (up to 100) to ensure there is no harm and to see if it provokes an immune response.
Phase 2 clinical trial: This is a larger safety study with hundreds of people to learn more about safety in diverse populations, the most appropriate dosage and to expand knowledge of the vaccine’s immunogenicity.
Phase 2b clinical trial: This is a “proof-of-concept” study to see if there is value in taking a candidate further before committing to a much larger and more costly Phase 3 study to establish efficacy. The number of volunteers required is smaller, around 2,000 to 5,000, while more than 10,000 volunteers are required for Phase 3 trials.
Phase 3 clinical trial: This is a final study where the vaccine is compared against a placebo to measure how effective it is at preventing infection (known as efficacy). These studies enrol thousands of people and can detect rarer side-effects, as well as identify the best dosage levels. Phase 3 trials are required before new vaccines can be licensed for use.
Pre-clinical study: This term refers to research undertaken before vaccines can be tested in humans.
PrEP: This acronym stands for pre-exposure prophylaxis. It is a pill or tablet taken daily or peri-coitally (before and after sex) by HIV-negative people that reduces the risk of getting HIV.
Prime boost: This is a combination strategy whereby the immune system is “primed” or triggered by one vaccine component and then a different element targeting another part of the immune system provides a “boost”.
Protein-based vaccine: This vaccine is made up of a protein antigen designed to trigger an active immune response.
T
Trimer: See Envelope protein trimer (gp140)
V
Vaccine candidates: These are potential vaccines being tested in clinical trials.
Viral vector: This virus does not cause disease in humans and is used as a vehicle to transport vaccine ingredients into the body.
About
Established in 2003, the Global HIV Vaccine Enterprise (the Enterprise) became a programme of IAS – the International AIDS Society – in 2018. The Enterprise unites stakeholders to share knowledge, foster collaboration, enable solutions and expand support critical to the development of – and future access to – an HIV vaccine.
Global HIV Vaccine Enterprise
IAS – the International AIDS Society
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