A surreal, deeply troubling week for AIDS vaccine research

Richard Jefferys, TAG

At the prompting of several basic scientists, NIAID held a vaccine summit on 25th March 2008. The event, which from my perspective had all the rationality and conviviality of a hastily-convened Soviet era show trial, was webcast for posterity and the archived version can be seen online. [1]

Essentially, frustration with the dismal, unacceptably low NIAID payline for investigator-initiated grants appears to have caused a number of basic researchers to see the failure of Mercks HIV vaccine candidate as an appropriate latch on which to hang their argument that money should be directed away from human trials of other experimental HIV vaccine candidates and into basic research and discovery.

There is certainly logic to the argument, despite the clumsy and alienating manner in which it has been advanced. The STEP trial has at the least shown that T cell-mediated control of HIV replication will not easily be achieved, and there is a strong case for rigorously reviewing the current vaccine pipeline and trimming it down to only candidates that might be able to address the potential shortcomings of the Merck construct (particularly in terms of HIV-specific T cell breadth, proliferative capacity, functionality, CD4 help and – of course – vector safety). In the longer term, discovery will also be vitally important to develop neutralizing antibody-based candidates (or other novel approaches) with the potential to completely protect against HIV acquisition.

However, this type of discussion is not what primarily emerged from the summit. Instead, panelists such as virologist and summit co-chair Warner Greene used the opportunity as a bully pulpit to make outrageous and offensive claims about the state of the HIV vaccine field and the work of their colleagues. Even cellular immunologist Rafi Ahmed offered a bizarre revisionist history of his thinking on T cell-based candidates: he claimed he had cringed when hearing of Mercks candidate – an odd assertion given that he is on the immunology advisory committee of the HVTN, which conducted the STEP study and that vaccines that focus on one arm of the immune system are doomed to failure.

When I interviewed him a little over a year ago he said he was optimistic about the potential for T cell-based approaches to reduce post-infection viral load: Im a big believer in memory T cells bringing viral load down because thats what we keep seeing. That doesnt mean it will hold up in HIV but at least in all the models we study if you have memory T cells – even without any antibody – the initial burst is less and its pulled down much faster. And then the HIV data suggests that if that happens the prognosis is better, so thats where my optimism comes from. Ahmed also stated at the summit that immunology 101 says antibodies are required for control of HIV replication, yet studies of elite controllers offer little evidence for this claim. [2]

Predictably, the media coverage surrounding the event amplified these soundbites across the world. Researchers in places such as South Africa, where skepticism about AIDS research runs high and AIDS denial has been politically embraced, will be dealing with the fall-out for years to come. Even elsewhere and here in the US, there has been a growth of anti-research and anti-science movements which will feed off these false, widely-publicized statements that no progress has occurred in AIDS vaccine research.

The misinformation actually started on Friday March 21, when a David Brown article in the Washington Post offered a series of misrepresentations about the Merck vaccine in the guise of facts. [3]

The deck quote was from Bob Gallo who, in a truly woeful bout of self-serving hyperbole, compared the STEP trial results to the Space Shuttle Challenger Disaster. Brown went on to misleadingly suggest that the strong trend toward enhancement seen in a subset of the STEP study participants was somehow connected to the T cell-based vaccine strategy; he does so by saying that the vaccine primed people to be more susceptible, and then stating that immune activation one of the factors that has been suggested as a potential explanation for the adverse events has never been associated with increased susceptibility to HIV infection. This is simply false; studies have shown that several immuneactivating infections (to use Browns words) such as CMV and HSV-2 are associated with an increased susceptibility to HIV acquisition. [4]

Peripheral blood cells from highly immune-activated individuals also show increased susceptibility to HIV infection. [5]

In addition, if the enhancement effect had been related to the HIV-specific T cell responses induced by the vaccine, the effect would have been worst for the participants with no pre-existing immunity to the Ad5 vector (who developed the highest magnitude HIV-specific responses), but the opposite was the case (at the vaccine summit, a CDC researcher noted that the multivariate analyses showed that these vaccinated individuals were actually at a slightly but non-significantly reduced risk of HIV infection compared to the other study participants, with a point estimate of 0.6-0.8). In the same piece, Brown also attempts to indict researchers for not testing the Merck vector in a low-dose SIV challenge model as if this was some kind of oversight, completely glossing over the many complexities and controversies that attend these models and not mentioning that David Watkins did in fact use the Merck vector in one of his repeated low dose SIV challenge experiments. [6]

Browns follow-up article from the March 25 summit compounded and expanded upon the misinformation offered in the first, claiming that the event was tantamount to an admission that almost no progress has been made in the search for an AIDS vaccine in the past 25 years. [7]

This must have come as an unwelcome surprise to the researchers and study participants who have been slogging away for years, slowly improving the scientific understanding of both the immunological and immunogenetic underpinnings of long-term non-progression and resistance to HIV infection in highly exposed seronegative individuals, not to mention those involved in trying to iteratively improve the immunogenicity of experimental vaccine constructs. There has certainly been waste, duplication, and a sunny over-simplification of the complexities and unknowns that still face the HIV vaccine field from some quarters but these problems are not best addressed by trashing the entire endeavor and everyone involved in it. The statements quoted in Browns piece from Warner Greene and James Hoxie are de facto accusations that researchers who followed the strong scientific evidence that T cells play a key role in controlling HIV replication and used that evidence to inform vaccine design have led the field in the wrong direction and brought us no closer to an AIDS vaccine; in addition to being horrifically hostile and unfair, these claims are simply untrue.

Amidst all the sturm and drang at the summit, few people seemed to pick up on the comments of immunologist Mark Connors. Over the years, Connors has studied HIV-specific immune responses and authored many skeptical articles questioning some of the correlations with control of HIV replication that have been reported in the literature. In 2002, however, he identified HIV-specific CD8 T cell proliferation as a potentially important correlate, a finding several other research groups have now confirmed. [8]

At the summit, he cited additional assays his lab is working on, and expressed confidence that robust and broadly applicable correlates of immunological control are within striking distance. Furthermore, he also cited the fact that several Merck vaccine recipients who became infected in the STEP trial and carry the favorable immune response gene HLA B*57 are controlling their viral loads to undetectable levels. Initially, this was assumed to be an HLA B*57 effect but Connors argued that the frequency of the occurrence is far higher than would be anticipated in the absence of immunization, suggesting that it reflects an interaction between the vaccine and the favorable HLA allele akin to that seen in Mercks now notorious SIV challenge studies, in which only immunized macaques bearing the Mamu A*01 allele (the B*57 equivalent) showed significant viral load reductions. The implication is that while the Merck vaccine was far from optimal, it may have been able to enhance the HLA B*57 effect. If this finding actually holds up, it may offer additional validation of the SIV/macaque model and it would also strengthen the argument for developing improved immunogens with the potential to achieve this outcome in people lacking HLA B*57.

The AIDS Vaccine Advocacy Coalition and the National Association of People with AIDS both issued concerned statements about the summit and the media coverage it engendered. Exactly where things go from here remains to be seen. [9[

Source:
Michael Palm Basic Science, Vaccines & Prevention Project Weblog(28 Mar 2008)

References:

Summit on HIV vaccine research and development, 25 March 2008, Bethesda.
http://hivsummit.dgimeetingsupport.com/
Pereyra et al. Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy. Journal of Infectious Diseases 2008;197:563571.
http://www.journals.uchicago.edu/doi/abs/10.1086/526786
David Brown. Vaccine Failure Is Setback in AIDS Fight. Washington Post, 21 March 2008.
http://www.washingtonpost.com/wp-dyn/content/article/2008/03/20/AR2008032003398.html
Kaul R et al. The genital tract immune milieu: an important determinant of HIV susceptibility and secondary transmission. J Reprod Immunol 2008 Jan;77(1):32-40.
http://www.ncbi.nlm.nih.gov/pubmed/17395270
Sahpira-Nahor et al. Increased susceptibility to HIV-1 infection of peripheral blood mononuclear cells from chronically immune-activated individuals. AIDS 1998 Sep 10;12(13):1731-3.
http://www.ncbi.nlm.nih.gov/pubmed/9764802
Watkins D et al. Vaccine-Induced Cellular Immune Responses Reduce Plasma Viral Concentrations after Repeated Low-Dose Challenge with Pathogenic Simian Immunodeficiency Virus SIVmac239. J Virology, June 2006, p. 5875-5885, Vol. 80, No. 12.
http://jvi.asm.org/cgi/content/full/80/12/5875
Brown D. AIDS vaccine testing at crossroads. Washington Post, 26 March 2008.
http://www.washingtonpost.com/wp-dyn/content/article/2008/03/25/AR2008032503153.html
Migueles SA et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002 Nov;3(11):1061-8.
http://www.ncbi.nlm.nih.gov/pubmed/12368910
AVAC. A call for accuracy, a call for respect. 26 March 2008.
http://www.avac.org/pdf/summit_commentary_mar2008.pdf