HIV/AIDS

HVTN: Reshaped scientific agenda involves understanding the clinical and immunological aspects of the Step trial

One of the profound changes stemming from the halt of vaccinations in the Phase IIB Step trial of Merck’s HIV vaccine candidate is a redirection and reinvigoration of the research agenda of the various organizations involved in HIV vaccine research. Key among these organizations, the HIV Vaccine Trials Network (HVTN) has revamped its scientific agenda in response to the Step results.

Between 1999 and 2008, the HVTN conducted twenty-two Phase IA trials, three Phase IIA trials, and initiated two Phase IIB trials of Merck’s HIV vaccine candidate (Step and Phambili). During this period, the focus of the HVTN had shifted from efficiently streamlining the process of systematically testing HIV vaccine candidates in Phase I/II trials to initiating efficacy testing of products that emerge through that process as promising. The results of the studies of the Merck HIV vaccine candidate have inspired a reassessment by the HVTN, with refinement and expansion of the key basic questions being addressed. Among the current areas of focus:

• Learn from the Step trial data to design improvements in T cell-based vaccine concepts that:
• Increase breadth, quality and magnitude of the immune response
• Induce both memory and mucosal effector immune responses that would control the early events of viral replication
• Understand the biological reasons behind the unexpected results from the Step trial through collaborative studies with investigators outside of HVTN
• Explore in nonhuman primates the immune readouts that may predict protection, to guide improvements in HIV vaccine candidates for human clinical trials
• Expand the scientific breadth and analytical capability to support trials in the field
• Investigate how pre-existing humoral and cellular immunity to the vector alters host responses to HIV gene inserts
• Refine and validate methodologies to acquire mucosal/ biopsy samples from trial volunteers and process the samples
• Evaluate methods to identify and recruit women at high risk of HIV infection for HIV vaccine trials in the Americas

A Step Scientific Review Committee including outside scientists and the Step trial partners (Merck/HVTN/DAIDS) chaired by Dr. Bruce Walker has begun to consider proposals for studies using the stored samples and reagents used in the Step and Phambili trials. To date the committee has reviewed 20 proposals of which 13 have been approved to receive specimens. Some examples of such research include:

• To evaluate the “mechanisms” of increased HIV-1 acquisition in Ad5 seropositive persons, collaborations have been initiated with Dr. David Goldstein and Dr. Mary Carrington.
• Dr. Goldstein will explore through genome-wide association study whether host genetic determinants may have played a role in HIV acquisition and pre-existing Ad5 immunity
• Drs. Carrington and Geraghty will examine the relationship between HLA and KIR genotypes and HIV acquisition among vaccine and placebo recipients
• To assess whether Ad5 Gag/Pol/Nef elicits either a T cell or antibody responses that enhance HIV infection, several studies have begun.
• Dr. John Moore is evaluating IgG subtype levels as a surrogate marker to assess whether Th1 to Th2 “switch” may account for HIV acquisition in vaccine recipients.
• Dr. Donald Forthal is examining whether vaccination generates antibodies that increase chances of HIV infection.
• Dr. Otto Yang will study whether T cells after vaccination have the capability to recognize HIV-1-infected cells expressing the same epitope sequences contained in the vaccine.
• Dr. Michael Katze will compare transcriptional profiling of immune response between Ad5 seropositive and seronegative volunteers.

These ancillary studies and the ongoing analysis of Step and Phambili data provide a rich opportunity to advance our knowledge of the immunology of HIV. It may be that through the lack of efficacy of an experimental vaccine the field of HIV vaccine research will take its greatest step forward.

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