Vaccine trial “is the beginning” of a new path of research, says US health chief

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General Eric Schumaker, Surgeon-General of the US Army, said today that the result of the RV144 HIV vaccine trial - see this report - “opened new doors and switched on lights” in the field of HIV vaccine research but emphasised that the “modest” efficacy seen in the trial posed more new questions than it provided answers.

Dr Anthony Fauci, the Director of the US National Institute of Allergies and Infectious Diseases (NIAID), said: “This is the beginning of a new HIV vaccine research effort, not the end.”

But he added: “This is a welcome and exciting result in a field characterised by disappointment in the last two decades.”

Glossary

CD8

A molecule on the surface of some white blood cells. Some of these cells can kill other cells that are infected with foreign organisms.

protocol

A detailed research plan that describes the aims and objectives of a clinical trial and how it will be conducted.

broadly neutralising antibodies (bNAbs)

A neutralising antibody (NAb) is an antibody that fully defends its target cell from an antigen. A broadly neutralising antibody (bNAb) is a neutralising antibody that has this effect against a wide range of antigens. A number of broadly neutralising antibodies have been isolated from persons living with HIV. Some of them are being studied and, in some cases, used in clinical trials, to defend humans against HIV infection, treat HIV infection, and kill HIV-infected CD4+ T cells in latent reservoirs.

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

neutralising antibody

An antibody that neutralises (renders harmless) an infectious microorganism.

The trial today produced an unexpectedly positive result when 31% fewer infections were seen in recipients of the combined ALVAC/AIDSVAX prime-boost vaccine than in placebo recipients, despite previous trials of both individual vaccine concepts producing negative results.

“This trial poses fundamental ‘black box’ questions,” Fauci continued. “What are the correlates of HIV immunity? Has this trial overturned our understanding of what might constitute a protective response to HIV? Can we improve on this efficacy? And does this result mean we should refocus more on clinical research than basic science?”

He answered his own last question by saying “Not at all. NIAID’s commitment to keeping an appropriate balance between basic science and vaccinology versus empirical clinical trials has not changed.”

Fauci was referring to the controversy which has dogged the RV144 trial - see this report - which included a group of scientists condemning the trial as a waste of money (NIAID funded three-quarters of the trial’s $105 million cost). But those who said the trial should go ahead, and that the discovery of vaccines has relied as much on serendipity as scientific rationale, appeared today to be vindicated.

The Principal Investigator of the Thai trial, Dr Supachai Rerks-Ngam, said: “We did hesitate to continue the trial because of the criticism from the scientific point of view. But in view of the need for an HIV vaccine, and in consultation with many international experts, we decided to move forward. That determination turned out to be very significant.”

Colonel Nelson Michael, Director of the US Military HIV Research Programme (MHRP), which funded the other 25% of the trial, said that the most surprising and probably significant aspect of the result was that the vaccine appeared to produce a mild protective effect while producing no effect on the viral load in those who were infected.

“We are humbled by this finding,” he said. “This may have turned several key assumptions in HIV vaccine research on their heads.” He added that the trial showed that “human experimentation trumps everything we do in animals and test tubes.”

What Michael was referring to is that the RV144 trial consisted of two vaccines with two modes of action. The ‘prime’ vaccine, ALVAC, consisted of HIV genes contained in a canarypox virus vector. This model of vaccine delivery was designed to stimulate a cellular immune response. This does not prevent initial infection, but the scientific model – supported by data from some monkey studies - was that the cytotoxic T-lymphocytes (CTLs or CD8 cells) thereby generated would subsequently reduce HIV proliferation, contain viral load, and slow or stop progression to AIDS.

ALVAC appears to have made no difference to viral load at all, a finding at least in harmony with the failure of the STEP Trial of a CD8 vaccine in 2007; but at the start of RV144 study, CTL vaccines appeared promising.

AIDSVAX, on the other hand, was designed to produce an antibody response against the gp120 protein on HIV’s surface, a concept thought to have been discredited in 2003, just after RV144 started, when it failed an earlier trial. The assumption was that HIV’s genetic hypervariability would mean that any antibody response would be hopelessly specific; at the time HIV research pioneer Dr Robert Gallo said: “This is not a vaccine approach that was based on science.”

Nonetheless what RV144 appears to have done is block infection without containing viral load in those infected, which looks like an antibody response, though Nelson Michael added that a longer-term study, RV152, was following up a proportion of trial participants to see if there were longer-term effects on viral load.

When asked what was causing the vaccine’s efficacy, Anthony Fauci commented: “Simply, we don’t know. We did not see broadly neutralising antibody responses, though there is an indication of a small antibody response. We also saw a lympho-proliferative response but didn’t see an increase in CTLs.

"We may not even have started to measure the correct immune parameters in the body that in fact indicate protection against HIV.”

Fauci said there were a number of further questions left unanswered by the trial. These included:

  • Was the vaccine’s effect durable or would further boosters be needed?
  • Are there ways of improving this model’s efficacy?
  • Would we see similar results in high-risk populations such as men who have sex with men, injecting drug users, and high-risk heterosexuals?

Regarding the last question, MHRP Deputy Director Jerome Kim said that contrary to some reports RV144 did not exclude high-risk people. At baseline a small number of participants did turn out to be MSM and sex workers. The trial was designed to vaccinate a “community sample,” in other words a truly representative cross-section of the Thai population, “ranging from people at high risk to people at no risk”.

However, Kim also speculated, one reason for the positive result may have been that “the average intensity of exposure to HIV may have been lower than in high-risk populations…we know a sufficiently large innoculum of virus can overcome any vaccine-generated response.”

When asked what scientific studies of the RV144 protocol would come next, given this positive result, Don Francis, Director of Global Solutions for Infectious Diseases and the man who developed AIDSVAX, indicated that there were only enough stocks of remaining vaccine to conduct very small trials – possibly an indication of the unexpectedness of the result. Anthony Fauci said that the first step was to convene a collaborative meeting with outside experts to understand how the vaccine works.

In response to a press question about whether the trial would lead to licensing the current vaccine protocol, Francis and Sanjay Gurunathan of Sanofi Pasteur, who developed ALVAC, emphasised that the study was not powered for approval by the US Food and Drug Administration and that although the threshold of efficacy above which a vaccine might be deemed to be worth using was up to individual countries, the efficacy seen was only modest. “What is on the cards is a series of investigations over the next few years to extend the findings,” commented Gurunathan.

Nelson Michael added that the power of the trial to detect efficacy was greater while it was being designed than turned out to be the case, because of Thailand’s successful attempts to reduce HIV incidence in the trial population.

Nonetheless, the researchers concluded, the trial results mark a turning point in the history of HIV vaccine development. General Schumaker summed up by saying that this is a “great moment for the world of medicine and for the global human family.”

More information and analysis

See also An unpopular vaccine study produces surprising result.

See also Vaccine reduces risk of HIV infection by one-third in large trial.

Further information

See aidsmap.com's guide to The search for an HIV vaccine for further background information.

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