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precedence

precedence. 1. the condition of preceding others in importance, order or rank 2. an acknowledged or legally determined right to such precedence. Clinical trials take precedence for vaccine development at the current time: yes or no?.

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precedence

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  1. precedence 1. the condition of preceding others in importance, order or rank 2. an acknowledged or legally determined right to such precedence

  2. Clinical trials take precedence for vaccine development at the current time: yes or no? = clinical trials should go ahead of, be prioritized relative to, basic research at the current time: yes or no?

  3. Yes/No? No!! Why not? Because there are too few quality vaccine candidates in the pipeline at the current time. We need more quality candidates if we are to succeed. We need basic research to find those quality candidates.

  4. NOT saying That clinical trials are not very important That empiricism is not very important and make a clear distinction between phase I, II and III clinical trials

  5. The HIV vaccine candidate pipeline is trickling rather than gushing with quality immunogens at this time. Why? We don’t have immunogens that elicit (broadly) neutralizing antibodies. There are many uncertainties about what kind of vaccine-induced cellular immune responses are going to provide benefit against exposure to HIV.

  6. Why is the vaccine candidate pipeline trickling with quality immunogens rather than gushing? We don’t have immunogens that elicit (broadly) neutralizing antibodies There are many uncertainties about what kind of vaccine-induced cellular immune responses are going to provide benefit against exposure to HIV.

  7. We don’t have immunogens that elicit neutralizing antibodies 1. Virtually all current effective vaccines elicit neutralizing antibodies. 2. For HIV, because of viral variation, we require broadly neutralizing antibodies. 3. The VaxGen efficacy trials showed no protection by monomeric gp120 subunit vaccine.

  8. We don’t have immunogens that elicit neutralizing antibodies 1. Virtually all current effective vaccines elicit neutralizing antibodies. 2. For HIV, there is the added problem of viral variation, requiring broadly neutralizing antibodies 3. The VaxGen efficacy trials showed no protection by monomeric gp120 subunit vaccine.

  9. Pantaleo and Koup (2004) Nature Med 10, 806.

  10. We don’t have immunogens that elicit broadly neutralizing antibodies 1. Virtually all current effective vaccines elicit neutralizing antibodies. 2. For HIV, because of viral variation, we require broadly neutralizing antibodies 3. The VaxGen efficacy trials showed no protection by monomeric gp120 subunit vaccine.

  11. The enormous variability of HIV means that the NAbs we elicit by vaccination must recognize a multitude of viruses of differing sequences Sequence divergence of HIV gp120 (V2-C5) as compared to influenza A

  12. All neutralizing antibodies are directed to Env spikes on the virion surface gp120 CD4bs gp41 Viral envelope

  13. The Env spike has evolved to avoid broadly neutralizing antibodies (low accessibility of conserved regions of Env) Functional oligomeric gp120/gp41 (virion surface)

  14. Broadly neutralizing antibody epitopes on the HIV-1 Env spike; chinks in the armor Virus Membrane 4E10 2F5 2G12 b12 CD4i Fabs V3 loop Abs

  15. CROSS-CLADE NEUTRALIZATION OF HIV-1 none1-30% 31-60% 61-90% >90% IC5050 g/ml Binley et al, J Virol, 78, 13232-13252, 2004.

  16. Basic research to exploit these chinks and design immunogens to elicit broadly neutralizing antibodies should not receive a lowered priority

  17. We don’t have immunogens that elicit neutralizing antibodies 1. Virtually all current effective vaccines elicit neutralizing antibodies. 2. For HIV, because of viral variation, we require broadly neutralizing antibodies 3.The VaxGen efficacy trials showed no protection by monomeric gp120 subunit vaccine.

  18. The Env spike has evolved to avoid broadly neutralizing antibodies (low accessibility of conserved regions of Env) host cell-derived carbohydrates (‘silent face’) non-neutralizing face CD4bs (neutralizing face) Monomeric gp120 Functional oligomeric gp120/gp41 (virion surface)

  19. The AIDSVAX trials Monomeric gp120 subunit vaccine (VaxGen Inc), designed to induce neutralizing antibodies. Monomeric gp120s protected chimps against homologous challenge with a neutralization sensitive lab strain (IIIB), and heterologous challenge with a minimally replicating, neutralization sensitive virus (SF-2). Monomeric gp120s fail to induce neutralizing antibodies against representative primary isolates. Monomeric gp120s failed to protect humans against HIV-1 infection in two Phase III trials (N. America/Europe and Thailand).

  20. Why is the vaccine candidate pipeline trickling with quality immunogens rather than gushing? We don’t have immunogens that elicit broadly neutralizing antibodies There are many uncertainties about what kind of vaccine-induced cellular immune responses are going to provide benefit against exposure to HIV.

  21. There are many uncertainties about what kind of vaccine-induced cellular immune responses are going to provide benefit against exposure to HIV. 1. Superinfection by HIV in the face of cellular immune responses is well documented. 2. Many promising vaccine approaches have failed to protect even against homologous challenge by SIVmac239 in macaques. 3. Live attenuated vaccination does protect against SIVmac239 challenge but we don’t know why.

  22. There are many uncertainties about what kind of vaccine-induced cellular immune responses are going to provide benefit against exposure to HIV. Superinfection by HIV in the face of cellular immune responses is well documented. 2. Many promising vaccine approaches have failed to protect even against homologous challenge by SIVmac239 in macaques. 3. Live attenuated vaccination does protect against SIVmac239 challenge but we don’t know why.

  23. Superinfection Superinfection rates in newly infected individuals reported to approach those in VaxGen trial i.e. ~5% Rates reportedly lower in chronic infection. Nevertheless suggestion that infection is occurring in face of quite vigorous immune (particularly T cell) responses Smith, Richman & Little (2005) JID 192, 438.

  24. There are many uncertainties about what kind of vaccine-induced cellular immune responses are going to provide benefit against exposure to HIV. 1. Superinfection by HIV in the face of cellular immune responses is well documented. 2. Many promising vaccine approaches have failed to protect even against homologous challenge by SIVmac239 in macaques. 3. Live attenuated vaccination does protect against SIVmac239 challenge but we don’t know why.

  25. Vaccine Protection Against Pathogenic SIV in Indian Rhesus Macaques Koff et al, Nature Immunology, submitted.

  26. Basic research to understand protection against SIV by live attenuated vaccines should not receive a lowered priority

  27. So what’s all the fuss about? Where is the tension between advocates of clinical trials and basic research in HIV vaccine development?

  28. The ALVAC + gp120 Thai trial Science 303, 316 (16 January 2004) Science 303, 961 (13 February 2004) A difference of opinion exists over the merits of this trial

  29. The ALVAC + gp120 Thai trial A large (n = 16,000), simple trial with the sole goal of determining efficacy, cost ~$120m. Primary end-point: protection from infection Secondary endpoint: protection from disease (IF enough VL data collected) Initial assumption was ~5% infection rate, this may be much less

  30. The ALVAC + gp120 Thai trial ALVAC induces CTL activity with a cumulative freq of only 24% and a sustained freq of only 10% Monomeric gp120 does not induce NAbs Vaccine induces moderate CD4+ T cell responses Such a clinical trial should not take precedence over basic research

  31. Clinical trials take precedence for vaccine development at the current time: yes or no? No. Not enough good candidates to put into clinical trials costing $100m’s. Much basic research needs to be done to find better candidates.

  32. Contrasting ways to do efficacy trials Vaccine ALVAC + gp120 MRKAd5 adenovirus/HIV Sponsor Aventis + DoD (NIH) Merck + NIH (HVTN) Trial location Thailand N.America/Caribbean Immunogenicity (CTL) < 30% ~ 80% Trial size 16,000 1,500 Trial cost $119m ?? $25m ?? Corporate funds used No Yes Road to FDA licensure No Yes Primary endpoint Infection rate Infection rate and VL Immunological analyses Some, n = 300 Samples saved from all Which trial design gives more bangs per buck and per volunteer? Corporate funding (answering to stock-holders) creates fiscal discipline. This appears not to apply when Uncle Sam picks up the tab. Who will be held accountable when the results come in from Thailand?

  33. The ALVAC + gp120 Thai trial Pal R, et al. 2002. ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency. J Virol 76, 292-302. Cited by McNeil et al. (Science) as supporting the use of ALVAC + gp120 BUT, IN FACT…….. None of the animals was protected; all would have failed the primary end-point for the Thai trial. The inclusion of gp120 had no effect, to the extent that animals that did or not receive gp120 were pooled to make a common control group for subsequent immunological and virological analyses, showing that: ".... the gp120 subunit immunization (did not influence) the virological outcome”. i.e., ALVAC alone was as good (or bad) as ALVAC + gp120.

  34. The ALVAC + gp120 Thai trial Buge SL et al. 2003. Gp120-alum boosting of a Gag-Pol-Env DNA/MVA AIDS vaccine: poorer control of a pathogenic viral challenge. AIDS Res Hum Retroviruses 19, 891-900. “…..... the plus-gp120 group had less consistent control of viremia and higher levels of plasma viral RNA for the first year post challenge.” “We conclude that gp120 inoculations that fail to raise neutralizing antibody do not improve the efficacy of Gag-Pol-Env DNA/MVA vaccines.” An ineffective gp120 vaccine may actually detract from the protective potential of the CMI-inducing vaccines!

  35. Human clinical trials have an important role to play in vaccine development New immunogens need to carefully evaluated in humans. BUT Product availability should not be the main driving force behind a trial. The design of small trials needs to be aimed as much as gathering information as at product development, per se. There must be a compelling reason to move from small trials to larger trials, then to Phase III trials. Comparability among immunogens of “similar” design is critical. A non-controversial way to end trials of poorly performing immunogens needs to be devised and adhered to.

  36. Combine different vaccine technologies Rather than try to devise one immunogen to do everything (a probably impossible task): Make the best possible NAb-inducing antigen Make the best possible CTL-inducing vector Find the best available adjuvant or delivery system Find a way to combine these different technologies into one vaccine MAKE THE OMELETTE FROM MANY SMALL EGGS, NOT ONE LARGE ONE!

  37. Not every vaccine hypothesis is worth testing If I argued that the moon were made of green cheese, would NASA fly me there to check it out?

  38. Empiricism vs Understanding? All the “old-time” vaccines were made without much knowledge of the immune correlates or how the vaccines actually worked. This is a perfectly fine approach, IF IT WORKS! HIV-1 is so much more formidable an enemy that we MUST structure are approaches differently. We need to use a knowledge-based approach, and we must increase our knowledge, particularly of the underlying immunology.

  39. Cell Mediated Immunity Based Vaccines in Monkeys: Which Model Mimics Human-HIV? Virtually all vaccine candidates effective SHIV 89.6P Very easy to protect* Monkey Challenge Study Some viral vectors effective More rigorous challenge than SHIV 89.6P SIVE660 SIVmac239 Live-attenuated Most difficult to protect *Protection is defined as greater than 1 log of suppression of viral load compared to control animals; slower progression to AIDS

  40. “T cell vaccine” trials based on Adenovirus vectors Merck trial, rAd5, n=1,500 NIH VRC, DNA/rAd5, Trials will test the concept of protection against HIV challenge by a vaccine eliciting “robust” T cell responses

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