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AIDS Vaccine Update: Questions After Candidate Fails in the STEP Study

By Cindra Feuer and Emily Bass

April 2008

The HIV vaccine research field suffered a blow last fall with the announcement that Merck's promising HIV vaccine candidate was not effective and may have even increased susceptibility to acquiring HIV. The candidate, known as MRK-Ad5, used a disabled version of a common cold virus, known as adenovirus-5, to carry synthetic fragments of HIV genetic material. The vaccine was designed to induce immune responses that developers hoped would either prevent infection and/or reduce viral load in HIV negative people who received the vaccine and went on to become infected with HIV through high risk exposure.

The vaccine failed to show efficacy in two large trials, known as STEP and Phambili. In the STEP study, volunteers who received the vaccine were more likely to acquire HIV as compared to volunteers who received the placebo. This effect was strongest in volunteers who had been exposed to cold-causing adenovirus prior to receiving the vaccine.

The lack of efficacy and the possibility of vaccine-related enhancement of susceptibility to HIV infection have raised serious questions for AIDS vaccine researchers and prevention advocates: Why did the vaccine fail to reduce viral load setpoint or the risk of infection? What is the explanation for the apparent increase in susceptibility to HIV infection? Were the unexpected results a fatal knockout to all Ad5-vector vaccines, or a knockdown punch to a single candidate? And finally, how do prevention advocates respond to the crisis?

What Happened

After extensive preclinical testing and several prior studies in humans, MRK-Ad5 was being tested in STEP (which enrolled MSM and heterosexual women in the US, Latin America and the Caribbean and Australia) and Phambili (which enrolled heterosexual men and women in South Africa). Both studies were jointly conducted by Merck & Co., and the HIV Vaccine Trials Network (HVTN) which is funded by the National Institutes of Health (NIH).

The vaccine candidate was designed to elicit T-cell based immunity. There is strong evidence that this type of "cell-mediated" immunity can play a role in control of HIV.

The STEP and Phambili trials involved participants who were HIV negative but at high risk for infection. All of the volunteers received ongoing risk reduction counseling, condoms, and STD treatment. During the informed consent process and the follow-up study visits, volunteers were counseled not to assume that they had received the vaccine, and not to assume that the vaccine provided any protection. All volunteers were urged to practice safe sex and other risk reduction strategies.

In September 2007, the Data and Safety Monitoring Board (DSMB) for the STEP study recommended that the trial halt immunizations after a scheduled data analysis showed "futility," meaning that there was no possibility that the vaccine would prove efficacious for either preventing infection or reducing viral load. Out of 1,850 men in the trial, there were 49 seroconversions in those who received the vaccine, compared with 33 in those who received the placebo. There was only one HIV infection in STEP's cohort of 1,150 women. This was not evidence that the vaccine worked better in women, since there were almost no infections among women in either the vaccine or the placebo arm. All subsequent analysis of STEP data related to vaccine effects focused on the male volunteers.

Immediately after the STEP DSMB recommendation that immunizations be halted, the Phambili trial also halted immunizations. Within three weeks, the DSMB for that study recommended that volunteers be unblinded, meaning that they were informed about whether they had received the vaccine or the placebo. The DSMB also recommended that they be counseled that receiving the vaccine might have increased their risk of HIV infection.

Understanding the Data

The primary finding from the STEP study is of great concern; it is also quite confusing. While there were more infections among male volunteers who received the vaccine, as compared to male volunteers who received the placebo, scientists have yet to come up with an explanation for this apparent effect, which was most pronounced in volunteers who had levels of pre-existing immunity to adenovirus.

As part of ongoing research to try to understand the mechanism which might explain the finding, researchers are looking at samples stored from STEP participants. They are asking all volunteers from both STEP and Phambili to continue coming for study visits, where additional, intensified risk-reduction counseling is being made available.

Among other things, scientists are trying to understand whether and how pre-existing immunity to adenovirus might have affected vaccine-induced immune responses and subsequent susceptibility to HIV infection. They are also looking at other variables like circumcision status, HSV-2 status (whether or not volunteers had herpes simplex virus type 2) and other issues, which might explain the difference.

One reason for this is that there were noteworthy differences in some of the demographic characteristics of men in the high and low Ad5 titer groups. For example, there were considerably more nonwhite, non-US men in the high Ad5 titer group. This group also had significantly more uncircumcised men and more men under the age of 30. However, in the analyses that have been conducted to date, none of these demographic differences explain the observed trend towards increased rates of infection in vaccine recipients.

In discussions of this data analysis, scientists have emphasized repeatedly that it is quite possible that there may never be a clear answer about what happened in the STEP study.

Where to From Here?

What is the best way to move forward in the context of such great disappointment and uncertainty? The reality is that for any drug or vaccine which reaches the market, there are many, many candidates which fail. The fact that MRK-Ad5 failed to provide any protection is hugely disappointing, but its failure is part of the product development pathway.

While there are many questions, there are also some clear lessons from the STEP data, particularly about the animal models that are used to evaluate future candidates. MRK-Ad5, like all candidate vaccines, was advanced into human trials after extensive pre-clinical testing and studies in nonhuman primates. In the primary non-human primate study that showed vaccine-related benefit, monkeys were given a candidate vaccine closely resembling MRK-Ad5 and challenged with a viral strain called SHIV 89.6p. Monkeys that received the vaccine had lower viral loads than those that did not get the vaccine. Based on the subsequent failure of the candidate in human clinical trials, there is a strong sense that animal model challenge experiments using SHIV 89.6p should not be used as the basis for advancing candidates.

The extremely low rate of HIV infections in women enrolled in the STEP study is also prompting some hard thinking. The fact that women in the STEP study got infected at much lower rates than men could have something to do with the prevention package provided at the trial sites; it could be that the criteria used to classify women as "high risk" for HIV infection did not identify women who fit into this category. Going forward, it is critical to understand how to reach and engage with high risk women, both for prevention research and for prevention services in general.

In terms of next steps for HIV vaccine development, one of the major questions facing the field is whether or not to proceed with an efficacy trial of a vaccine strategy developed by the US NIH's Vaccine Research Center. This strategy combines two types of vaccines in a prime-boost strategy -- the priming vaccine is a DNA-based vaccine candidate and the boosting vaccine uses an adenovirus-5 vector which is similar, though not identical, to the MRK-Ad5 candidate.

An efficacy trial known as PAVE 100 of this vaccine combination strategy was scheduled to start in late 2007, and was put on hold after the STEP results were announced. Subsequent discussion has led to consensus in the scientific community that this strategy could only be tested in people who have no pre-existing immunity to adenovirus. This is a critical safety precaution, given the apparent trend towards increased susceptibility in people with pre-existing Ad5 immunity in the STEP trial.

Conducting a trial of the VRC strategy in "Ad5 seronegatives" could provide an answer about whether a different strategy (combining two vaccines, aiming at different qualities of immune responses) could have better results that the MRKAd5 product. However, at this time, it is difficult to imagine that an Ad5-vectored candidate could be taken through the full series of efficacy evaluations and licensed for use, given the safety concerns raised by the STEP data.

While this could change, we must acknowledge the many unknowns that surround the STEP data and all Ad5-vectored candidates at this time. The AIDS Vaccine Advocacy Coalition (AVAC) has argued that the PAVE collaborators moving ahead with a redesigned PAVE 100 should have a clear agenda for next steps should the study show any benefit.

Discussions about whether and how to proceed with a redesigned PAVE 100 study are ongoing. AVAC and other advocates have emphasized that input from communities that will be asked to participate in the studies is absolutely essential before any decision to proceed with the study is made.

The STEP and Phambili trials have led to a moment of disappointment and confusion in the AIDS vaccine field and in the broader field of prevention research, where trials of candidate microbicides and the diaphragm have also failed to show efficacy in the last 12 months. In this context, it is as important as it has ever been that communities convey clear, accurate messages about what is known and what is not known, both about specific products and about the overall effort to find additional, new interventions to prevent HIV infections.

Results are due from a trial which looks at herpes treatment as a strategy for reducing susceptibility to HIV infection. Some data on pre-exposure prophylaxis (PrEP) is expected beginning in the next 12-18 months. These trials could bring positive news, or additional setbacks. Whatever happens, prevention research must continue to be a priority as part of a comprehensive response to the epidemic. This means providing full access to what prevention and treatment options are available today, and continuing to search for additional strategies that can help save lives tomorrow.

For more information visit www.avac.org and www.aidsvaccineclearinghouse.org.

Cindra Feuer and Emily Bass are with the AIDS Vaccine Advocacy Coalition (AVAC).

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