IAVI Report - January / February 2002
Patricia Kahn

In a major decision for the AIDS vaccine field, the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), announced on 25 February that it will not proceed with a Phase III trial which was tentatively planned for early next year.

The Phase III study would have tested an HIV vaccine (called ALVAC 1452) based on a canarypox viral vector, both as a stand-alone vaccine and in a prime-boost combination with VaxGen's gp120 product, AIDSVAX. Several different ALVAC vaccines, each with different HIV genes, have been developed by the French-German pharmaceutical company Aventis Pasteur and tested in over 40 Phase I and II trials since the late 1980s; AIDSVAX is now in efficacy trials as a single-component vaccine. The new Phase III study was to be carried out by the NIAID-sponsored HIV Vaccine Trials Network (HVTN) at its clinical research sites in the US and Latin America, and to enroll about 11,000 high-risk heterosexuals and gay men.

The decision revolved around a specific goal of the trial other than testing efficacy: to determine if a particular cellular immune response to HIV (measured from blood cells by the Elispot assay) correlates with protection against HIV. Identifying such a correlate would greatly ease the testing of future vaccines, even if ALVAC/gp120 proved to be only weakly effective. But results emerging from an ongoing Phase II study of the two vaccines (HVTN 203) indicated that the proportion of volunteers showing this response was too low to answer the question definitively, leading NIH to shelve the trial.

In announcing the decision, NIH reaffirmed its support for a planned efficacy trial of a different ALVAC vaccine (ALVAC 1521) with a gp120 boost. That study will be done through a long-standing collaboration between the US Army's AIDS vaccine program and the Thai government. It is designed solely to determine whether the two vaccines protect 50% or more of the volunteers from HIV, and is not powered to establish a correlate of protection. Pending approvals by the requisite Thai committees and the US FDA, the trial is expected to begin in mid-2002. NIH will be a major funder of the trial, since oversight of the Army's program will soon move from the Department of Defense to NIH (see article, US Army AIDS Vaccine Program Transferred to NIH).

NIAID officials also emphasize that the decision is not a vote of no-confidence in the vaccine strategy, but is based solely on the correlates-of-protection issue. "NIAID and the HVTN are eager to see the Thai trial go forward," says Peggy Johnston, NIAID's associate director of vaccines and prevention research. Ed Tramont, who heads NIH's Division of AIDS, went further, saying that "if for any reason the Thai trial would not go ahead, we would probably redesign our trial as an efficacy study and move it forward."

Behind the Decision
To all but those who follow the AIDS vaccine field closely, it may seem surprising that, after so many years of clinical testing, the level of immune responses induced by the ALVAC vaccines was not already well-known.

The explanation lies in the methods used to measure cellular immunity, an arm of the immune system thought to be key for protection against HIV. Until recently, vaccine developers relied on an old assay that detects the presence of "killer" cells (cytotoxic T-lymphocytes, or CTLs) by measuring whether CD8+ T-cells in blood samples from vaccinated people can specifically kill HIV-infected target cells. In the ALVAC trials to date, 20-40% of vaccinees show CTL responses; the decision to proceed with the Thai trial was based on finding CTLs in about 30% of the Phase II volunteers.

But vaccine developers have long known that the CTL assay's many disadvantages—it is highly labor-intensive, non-quantitative and difficult to do with frozen cells—make it unusable in large-scale trials. So they turned to a new generation of simpler, more reproducible assays, including Elispot—which measures the presence of HIV-specific, "activated" T-cells based on their production of an immune-stimulating molecule such as gamma-interferon.

"Elispot can be transferred to every country where vaccines are tested," says Tramont. "We gambled on Elispot and made it the cornerstone of our Phase III trial." For the trial to resolve whether it correlates with protection, at least 36% of vaccinees would have to show Elispot responses on day 182, or alternatively, 47% on either day 98 or 182, according to protocol co-chair Susan Buchbinder (San Francisco Department of Public Health)—a higher response rate than that seen with CTLs but attainable, the researchers hoped, through Elispot's presumed greater sensitivity.

But HVTN 203, the first ALVAC trial to gather Elispot data on a larger number of volunteers (330), found otherwise. By early 2002, with about 80% of the data analyzed, it became clear that they were below the threshold, said Johnston—so the no-go decision was made.

What About Efficacy?
This leaves the more important question of efficacy riding on the trial in Thailand, where preparations are in full swing: Community and media activities are underway, a high-throughput HIV diagnostic lab is being readied, the vaccines are made and procedures to freeze plasma and blood cells from all volunteers at selected timepoints are in place. (See IAVI Report, Oct/Dec 2001: Thailand Prepares for a New Phase III Trial, and Thailand, AIDS and Vaccines: An Interview with Supachai Rerks Ngarm.)

But the current trial plan potentially leaves a key gap in assessing efficacy, since it tests ALVAC only in combination with gp120, but not alone. So if the combination shows some efficacy, it will be unclear whether ALVAC protects by itself or if the gp120 boost is needed. This was left out because the low incidence of new HIV infections in the

Thai study population makes even a two-arm trial (ALVAC/gp120 and placebo) very large (16,000 people); the HVTN study, with an ALVAC-only arm, would have filled the gap, albeit with a different vaccine and different populations. As things now stand, if the prime-boost shows any protection it could mean licensing this more expensive, complex regimen and then taking several more years for another trial to resolve the issue. Although NIH and HVTN scientists are talking with the Thai team about possible enhancements to the trial, says Tramont, especially to boost its statistical power, an ALVAC-only group is not on the table.

Another issue that will arise if the trial shows any efficacy is whether regulatory authorities would license these subtype E-based vaccines for use in countries where other subtypes predominate. So far, there's been no official reaction to the NIH decision from Thailand. Privately, however, some investigators are worried—less about getting approval from the requisite Thai committees than about the possible impact on public perceptions and willingness to volunteer. "It's very hard to convey the distinction between an efficacy trial and a correlates-of-protection study to the press and public," says one. "Even trying to do this generates some suspicion."

Moving On
Despite the decision not to conduct the large-scale trial, HVTN will continue studies on ALVAC vaccines, says the network's director, Judith Wasserheit. Besides HVTN 203, an ongoing study in Brazil, Haiti and Trinidad and Tobago (HVTN 026) will provide comparative data on safety and immune responses to ALVAC 1452 in populations with different ethnicity and nutritional and immune status. Plans for further ALVAC trials include a study of higher vaccine doses and another to evaluate immunogenicity with a different boost: a mixture of lipopeptides, developed and tested in France, and which (like ALVAC 1452) contain epitopes from nef and pol—and might therefore broaden the vaccine-induced responses.

In a broader sense, it still remains to be seen if and how the no-go decision will influence the larger discussion of how to decide which vaccines should move into large-scale efficacy studies—a debate that was largely bypassed this time, given the focus on the correlates of protection aspect of the trial.

Some researchers in the field see the ALVAC vaccines as relatively unpromising, since they fail to protect rhesus monkeys against high-dose intravenous challenges with pathogenic SIV, and because of the low (20-40%) CTL response rate in vaccinees.

Others are less confident of our ability to predict which vaccines are likely to work. "People sometimes decide these things based on what they think, not what they know," says NIH's Tramont. For example, data from Marta Marthas' group (University of California at Davis) showed good protection of infant macaques immunized with an SIV-canarypox vaccine and then challenged orally with a low dose of the highly pathogenic SIVmac251 (see IAVI Report, Oct/Dec 2001, Helping Pediatric HIV Vaccines Grow Up). Interestingly, these animals show no detectable Elispot responses in their blood, says Marthas.

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