HIVe Home
HIV VACCINE ELECTRONIC (E) RESOURCE
Posted: 17 Nov 2011
30 years in 30 weeks, 2009

It took a quarter of the century from the discovery of HIV to show that HIV infection can be prevented by vaccination. While protection shown in the RV144 trial in Thailand was modest and short-lived, this trial provided the first proof of concept that a vaccine to protect against acquisition is possible and has enabled the search for correlates of protection. In his commentary, Dr. Jerome Kim recalls the multiple scientific and logistical challenges that the team overcame in designing and conducting the trial.

Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.
N Engl J Med. 2009 Dec 3;361(23):2209-20.
Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH; MOPH-TAVEG Investigators.

Article PDF

View the rest of the series:
2008 < All years > 2010

Commentary by Dr. Jerome Kim

212
Dr. Jerome Kim
The German strategist Helmut von Moltke said famously, "No battle plan survives contact with the enemy."  He did not have viruses in mind, but no virus captures the sense of that aphorism better than HIV-1.  Prevention efforts, the plans designed to combat the HIV pandemic, are similarly challenged.  The Thai Phase III HIV vaccine trial (RV144) is an example of successful adaptation of a clinical development plan to the changing epidemiology of HIV-1 in Thailand, the nuances of industrial strategy, the frustrations of vaccine science, and the difficulty of funding. 

In the early 1990s, US Army researchers working with Thai colleagues at the Armed Forces Research Institute of Medical Sciences, a 50-year old joint medical research laboratory in Bangkok, noted a rapid increase in HIV prevalence among young Thai conscripts.  Using samples obtained from these military recruits, investigators at the Walter Reed Army Institute of Research identified the first recombinant virus, now referred to as CRF01_AE. The Thai epidemic was explosive. At its peak in 1993, prevalence in the Thai military recruit population hit 4.6%, with the most heavily burdened provinces posting rates of >12% in young, sexually active men.  Underlying this epidemic was a very high prevalence of HIV infection in Thai commercial sex workers.

Building on previous successful vaccine development collaborations in Thailand (Japanese encephalitis vaccine and hepatitis A vaccine were both tested in Thailand by the US Army), scientists provided CRF01 viruses to companies for the manufacture of vaccines and discussed plans for HIV-1 vaccine trials in high-prevalence populations in Thailand.
Then the Thai government did an amazing thing: it acknowledged the importance of HIV, identified the source and instituted a prevention program, enforcing condom use in brothels.  The impact was dramatic. Rates of infection declined precipitously and prevalence in sentinel populations fell. The epidemic was changing before a vaccine could be brought to the field.  As incidence dropped, the trial had to become larger and compromises had to be introduced.

Initial plans called for optimizing both cellular and humoral HIV-specific responses using a "prime-boost" approach: a single prime (ALVAC-HIV, a CRF01-specific canarypox vaccine) was to be tested with three different boosts (subunit vaccines) in phase II trials from which the best regimen would be chosen for the Phase III trial. Shortly before the Phase II trials were complete, two of the manufacturers withdrew their products.  The ALVAC-HIV + AIDSVAX B/E combination, the only regimen remaining, "passed" immunogenicity criteria for advancement to a Phase III trial. 

Then, the ALVAC-HIV lots for the trial failed quality controls, resulting in a year’s delay as new ALVAC was manufactured. The NIH and the HIV Vaccine Trials Network (HVTN) decided against doing a parallel trial in North America, deeming that a similar combination of prime and boost was insufficiently immunogenic for determining correlates of protection. At the same time, a trial of AIDSVAX B/E, a vaccine to be used as a boost in RV144, showed no evidence of protection in Thai intravenous drug users. Finally, the NIH decision to support the trial was called into question in the journal Science.

Despite skepticism in the field about the ability of the vaccine regimen to have an effect on either of the co-primary endpoints, acquisition and viral load, due to the apparently "weak" cellular and humoral resonses induced by the prime-boost combination, the RV144 trial moved forward ̶ notably, in the absence of efficacy, a known correlate or a validated animal model, "weak" and "strong" immune responses are notional rather than evidence based.

Initially, the trial had difficulty recruiting the 16,000 "community risk" (neither high nor low risk behavior) men and women, extending the trial enrolment period by 12 months.  In parallel, retention also began to fall dramatically. A series of hastily assembled meetings resulted in a remediation plan that gradually turned retention around—and, by the end of the trial, had resulted in an extraordinary level of retention for a trial of this size.

The adaptive design of this trial mandated periodic analysis for futility (ie, the statistical situation where the trial is highly unlikely to yield a positive result and stopping is recommended), and each time the DSMB allowed the trial to continue.  An interim analysis in 2007, the only opportunity to stop early for success, also passed without trial termination (for success or futility). In 2007, the disappointing early termination of the STEP and Phambili vaccine trials led some to question whether any HIV vaccine would protect against infection—and raised the spectre, seen primarily in the HIV microbicide field, of a biomedical intervention enhancing the rate of infection. The Independent (UK) newspaper conducted an informal survey of AIDS experts and reported (24 April 2008) that a "substantial minority (undefined) … admitted an HIV vaccine might never be developed."

In September 2009, a small group of Thai Phase III collaborators met at the Presidio of Monterey, an Army base that is home to the Defense Language Institute, to review the analyzed data and conclusions. The vaccine regimen was found to have had a modest effect on acquisition of HIV and no effect on post-infection viral load or CD4 T cell counts—an effect that appeared concentrated in the 12 months post vaccination.

As we move forward, Drs. Bart Haynes and Julie McElrath are leading a tremendous effort to identify correlates of protection. A new collaboration of the Division of AIDS/NIAID, the Bill and Melinda Gates Foundation, sanofi pasteur, Novartis, MHRP and the HVTN is planning the next set of Phase IIb trials. Though the compromises made a decade ago are, in hindsight, frustrating—foregoing the 12-month AIDSVAX boost, limiting the peak immunogenicity blood draws and limiting enrollment to 16,000—the results of the RV144 trial now represent new and testable hypotheses for the next set of trials. The willingness of 16,402 Thai men and women to participate in a 42-month, 20-visit study has given us much to ponder and plan for.

About the Author: Dr. Jerome H. Kim, M.D. is the Deputy Director for Science and the Chief, Department of Molecular Virology and Pathogenesis, U.S. Military HIV Research Program (MHRP), Walter Reed Army Institute of Research (WRAIR) in Rockville, MD. He also serves as the HIV Vaccines Product Manager for the U.S. Army.

The Image of HIV used in the logo was created exclusively for the Global HIV Vaccine Enterprise by Visual Science.