On April 7, 2009, TAG sent the following letter to NIAID Director Anthony S. Fauci expressing our opposition to moving forward with the proposed HVTN 505 vaccine trial.
Anthony S. Fauci MD
Director, National Institute of Allergy & Infectious Diseases
Building 31 – Claude D Pepper Building, 7A03
Mail Stop: 2520
31 Center Drive
Bethesda, MD 20892
Dear Dr. Fauci:
TAG has previously expressed opposition to the PAVE100A vaccine trial involving the Vaccine Research Center’s DNA and Ad5 candidate(i). With the recent presentation by Dan Barouch of new macaque challenge data involving a DNA/adenovirus prime-boost regimen at the 2009 Keystone meeting(ii), we now must vociferously oppose the proposed descendant of PAVE100A, the HVTN 505 trial.
Our reasons are as follows:
- There appear to be no data supporting a significant advantage of the VRC’s DNA/Ad5 prime-boost over Ad5 alone in the SIV challenge model. The macaque study most frequently cited in support of HVTN 505 (which was also presented at the AVRS meetings on PAVE100) reports no difference between any of the vaccine arms and, for the published analyses, considers all arms together compared to placebo(iii). Ad5 alone has already failed to show efficacy in a human trial. Now there is a macaque study indicating that addition of a DNA prime to an adenovirus vector leads to worse outcomes than the Ad vector alone, outcomes that are comparable to placebo immunization.
- One of the major shortcomings of the Ad5 vaccine used in the STEP trial was the poor breadth of the induced T-cell response. A large body of evidence indicates that broad responses to the Gag protein are a particularly important goal for HIV vaccines. The Merck Ad5 vaccine used in the STEP trial induced a response to an average of one epitope from Gag (zero epitopes among individuals with pre-existing immunity to the vector). We are aware of no evidence that the VRC vaccine induces broader responses to Gag than the Merck vaccine.
- The safety issue relating to Ad5’s adverse impact on susceptibility to HIV infection necessitates excluding Ad5 seropositive, uncircumcised men from HVTN 505. This adds an extraordinary burden in terms of explaining the trial to potential participants, and also raises questions regarding the generalizabilty of any findings from the trial. It is possible that there are as yet unknown confounding factors associated with a lack of seroconversion after exposure to Ad5.
Overall, the risk/benefit of proceeding with HVTN 505 appears entirely skewed toward risk, with no clear evidence of any potential benefit. Even though the majority of AVRS members voted in favor of proceeding with PAVE100A, the reasons offered diverged into two mutually incompatible rationales: 1) that the VRC vaccine is similar enough to Merck’s that the trial may confirm some of the hints of immune correlates of viral load control that have emerged from STEP. 2) That the VRC vaccine is different enough from Merck’s (due to the DNA prime and inclusion of Env) that the vaccine might offer benefit in terms of reducing viral load. The AVRS members split roughly 50/50 into these two incompatible camps. As far as TAG can discern, the extant macaque data offers no support for either rationale.
Furthermore, an adverse outcome of HVTN 505 — when evidence warning of several worst-case scenarios already exists — would seriously undermine future HIV vaccine research and also harm the wider HIV research effort. To date, TAG has not heard any consistent or plausible explanation of what benefit might accrue from HVTN 505 to justify such a risk.
TAG urges NIAID to cancel HVTN 505 and focus on developing improved T cell immunogens with enhanced breadth, demonstrated induction of CD8 T cells capable of killing HIV-infected cells, and the potential for further development if shown to be successful. The consensus appears to be that Ad5 cannot be rehabilitated as an HIV vaccine vector after the Merck results, and this has been the consistent message around HVTN 505.
Coordinator, Michael Palm Basic Science, Vaccines & Prevention Project
Treatment Action Group
cc. Carl Dieffenbach, MD, Ph.D
Director, Division of AIDS
ii Barouch D. Novel Adenovirus Vector-Based Vaccines for HIV-1. Abstract #017, Keystone Symposia: Prevention of HIV/AIDS (X3), Keystone, Colorado, March 22 – 27, 2009.
iii Letvin NL, Mascola JR, Sun Y, et al. Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys. Science 312;5779:1530-3, 2006.