RV 144, or the Thai trial, was an
HIV vaccine
An HIV vaccine is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine, which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals.
It is thought that an HIV ...
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
that was conducted in
Thailand
Thailand ( ), historically known as Siam () and officially the Kingdom of Thailand, is a country in Southeast Asia, located at the centre of the Indochinese Peninsula, spanning , with a population of almost 70 million. The country is b ...
between 2003 and 2006. It used a combination of two HIV vaccines that had each failed in earlier trials. Participants were vaccinated over the course of 24 weeks beginning in October 2003 and were then tested for HIV until July 2006.
The results of the study were publicized in September 2009. The initial report showed that the rate of HIV infection among volunteers who received the experimental vaccine was 31% lower than the rate of HIV infection in volunteers who received the
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
.
This reduction was not large enough for the Ministry of Public Health in Thailand to support approving the vaccine; it would have licensed it if the reduction had been 50% or more.
The trial collaborators have stated that results of this trial give the first supporting evidence of any vaccine being effective in lowering the risk of contracting HIV. On October 20, 2009, the organizers released full results of the study through publishing in the ''
New England Journal of Medicine
''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one.
His ...
'' and presented them at the AIDS Vaccine Conference in Paris.
[
]
Protocol
A total of 16,402 Thai volunteers aged 18–30 were recruited to participate in Chon Buri
Chonburi ( th, ชลบุรี, , IAST: , ) is the capital of Chonburi Province and Mueang Chonburi District in Thailand. It is about 100 km southeast of Bangkok, on the coast of the Gulf of Thailand. Its name means 'city of water'. Cho ...
and Rayong Provinces in Thailand. These volunteers were randomized into double-blind
In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...
study groups, with those in the experimental group receiving a phase III prime-boost HIV vaccine
An HIV vaccine is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine, which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals.
It is thought that an HIV ...
. Eligibility criteria for participation in the study required that all volunteers be HIV negative prior to enrollment in the study and be willing to participate in educational counseling intended to teach ways to reduce risk behavior associated with contracting HIV. After being vaccinated, volunteers were asked to receive HIV testing every six months for three years, as well as receive additional risk-behavior counseling at every testing visit.[
Before this vaccine trial was initiated, an opinion letter from 22 established HIV researchers had been published in the journal ''Science'' calling into question the rationale for this study of combining two vaccines that each failed in prior human trials to generate immune responses that they were designed to elicit. This letter stated that spending $119 million when "the overall approval process lacked input from independent immunologists and virologists who could have judged whether the trial was scientifically meritorious" was an ill-advised use of precious resources.
]
Vaccine composition
Over six months, volunteers received a prime-boost vaccination including six injections, four injections of a vaccine called ALVAC HIV (vCP1521) with the last two being at the same time as two injections of another vaccine called AIDSVAX B/E (gp120).
ALVAC‐HIV consists of a viral vector containing genetically engineered versions of three HIV genes (env, gag and pol). The ALVAC vector is an inert form of canarypox
Canarypox virus (CNPV) is an ''Avipoxvirus'' and etiologic agent of canarypox, a disease of wild and captive birds that can cause significant losses. Canarypox can enter human cells, but it cannot survive and multiply in human cells. There is a ...
, a bird virus which cannot cause disease or replicate in humans. AIDSVAX B/E is composed of genetically engineered gp120, a protein on the surface of HIV, together with the adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to:
* Adjuvant therapy in cancer management
* Analgesi ...
alum.
Results
During the study, 125 of the 16,402 participants contracted HIV through behavior unrelated to their study participation. Of those 125, 74 infected persons had received placebo and 51 had received the vaccine, or 31.2% reduction. By one of the three pre-decided statistical tests for analysis of the trial there was a statistically significant lower rate of infection in the vaccine group compared to the placebo group, with p=0.04 for the "modified intent to treat" analysis that excluded persons who were found to have HIV infection after enrollment but before the first vaccination. However, by the other two methods of analysis, there was no statistical significance in infection rates between the vaccine and placebo groups, with p=0.08 for the "intent to treat analysis" including all persons originally enrolled in the trial, and p=0.16 for the "per protocol analysis" including only persons from the modified intent to treat group who completed all three vaccinations and subsequent screening.[ Additionally, the vaccine regimen had no effect on the amount of virus in the blood of volunteers who became HIV-infected during the study.][
Immediately after release of the results, there was controversy and dispute over the significance of these results raised by several researchers, who also questioned the unusual strategy of pre-releasing the conclusion of vaccine efficacy to the press before publication of the actual data in a peer-reviewed scientific journal and lack of explanation regarding the three different statistical evaluations of which two did not yield significant results; Dr. Anthony Fauci defended this by stating that explaining these nuances in the press release "would have confused everybody".
In May 2011, a new analysis initiated at Duke University showed that there is a 29% chance that the vaccine is not effective (although this ]posterior probability
The posterior probability is a type of conditional probability that results from updating the prior probability with information summarized by the likelihood via an application of Bayes' rule. From an epistemological perspective, the posterior ...
is very different conceptually from a p-value, and cannot be directly compared to the p=.04 from the original analysis).
Cautious optimism
In a study in September 2011, researchers involved with the trial at Mahidol University in Bangkok and the United States Military HIV Research Program in Washington DC tested the blood of trial subjects for different immune indicators between those who received the vaccine and contracted HIV (41 subjects) and those who did not become infected (205 subjects).
Their work is not complete, but those in the study who produced IgG
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
antibodies that recognise the V2 loop in the HIV envelope protein gp120
Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1988. The 120 in its name comes from ...
were 43% less likely to become infected. Those who produced envelope specific IgA were 54% more likely to become infected, but no more susceptible than trial subjects receiving the placebo. However, these studies all emphasize that such post-hoc analyses are subject to inherent bias and must be interpreted with caution.
The immune responses of uninfected patients could point the way to more fruitful research. Nelson Michael, director of the U.S. Military HIV Research Program who ran the trial, says that results lend "biological credence to the initial clinical study results".
Conclusion
The vaccine was found to be safe, well tolerated, and suitable for large-scale further research.
Sponsors
The RV 144 trial was sponsored by the Surgeon General of the United States Army and conducted by the Thailand Ministry of Public Health with support from the United States Army Medical Research and Materiel Command
United may refer to:
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and the National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's ...
, which is part of the National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
. The cost of the trial was $119 million.
Supported in part by an Interagency Agreement (Y1-AI-2642-12) between the U.S. Army Medical Research and Materiel Command and the National Institute of Allergy and Infectious Diseases and by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Department of Defense. Sanofi Pasteur provided the ALVAC-HIV vaccine, and Global Solutions for Infectious Diseases (VaxGen) provided the reagents for the immunogenicity assays.
ALVAC‐HIV (vCP1521) was manufactured by Sanofi Pasteur
Sanofi Pasteur is the vaccines division of the French multinational pharmaceutical company Sanofi. Sanofi Pasteur is the largest company in the world devoted entirely to vaccines. It is one of four global producers of the yellow fever vaccine. ...
. AIDSVAX B/E was manufactured by Genentech under a license and supply agreement with VaxGen, which itself is a spin-off company of Genentech founded for the purpose of developing AIDSVAX. Global Solutions for Infectious Diseases, a nonprofit organization co‐founded by former VaxGen executives, has ownership of certain intellectual and manufacturing rights of AIDSVAX.
Subsequent trials
In 2016 the HIV vaccine trial HVTN 702 was started in South Africa. It tested a combination of two HIV-vaccines which were slight modifications of those used in the RV 144 trial. The trial was stopped early in 2020 because no evidence of efficacy was seen.
A somewhat similar combination of two HIV-vaccines, a vector-based vaccine and a recombinant protein vaccine, was tested in the Imbokodo study in Africa between 2017 and 2021. The efficacy was found to be small and not statistically significant. A slightly modified vaccine combination is being tested in the ongoing Mosaico trial in Europe and the Americas.
References
External links
ClinicalTrials.gov record of the study
{{DEFAULTSORT:Rv 144
HIV vaccine research
Clinical trials related to HIV