Animal Rights

Pharma Needs Predictive Technologies

| by Dr Ray Greek

In the inaugural issue of Disruptive Science And Technology, a publication by Mary Ann Liebert, Inc. Drake et al describe a new in vitro-based testing system for vaccines and the immunotherapeutics. Drake et al (of Sanofi Pasteur):

While it can be fairly argued that animal models have prompted significant gains in our understanding of the mammalian immune system, it has also been shown in numerous examples that laboratory species do not always mimic human diseases or recapitulate/predict human immunity.(Lewis and Johnson 1995; Watkins et al. 2008) Likewise, current-day culture techniques generally fail to provide predictive data on human immunity. For example, few, if any, existing assay protocols are available to researchers to investigate human antibody responses against primary/naïve antigens.(Drake et al. 2012)

Drake et al and Americans For Medical Advancement (AFMA) are in agreement that if one wishes to learn about the mammalian immune system then studying mammals will accomplish this purpose. It is another thing entirely however to design and test drugs that affect the human immune systems and to study diseases that affect the human immune system. Animal models have clearly not been predictive modalities for this purpose. Those two activities need to be human-based and this is what Drake et al are attempting to accomplish with their system called Modular Immune In vitro Construct (MIMIC®). The system will need to be tested thoroughly, and it is in the process of such testing, but the initial results look good. Regardless of the final outcome, Sanofi Pasteur is on the right track.

This new article illustrates two points I try to emphasize as one point is at odds with what vivisection activists claim and the other is at odds with what animal activists believe. Point number 1: animal models are not predictive modalities for human response to drugs and disease. Period. MIMIC® is an example of industry trying to come up with something that will predict human response while acknowledging that animal models fail in this effort. One need go no further back in history than the current vaccine attempts for HIV to illustrate this point further. An editorial in Nature Biotechnology stated: “The best large animal model for HIV, for example, is simian immunodeficiency virus infection of macaques (chimpanzees injected with HIV fail to develop a human-like disease). To recognize the limitations of such models, look no further than the recent high-profile failure of Merck's HIV trivalent V520 vaccine—which monkey studies had predicted would be protective.” (Editorial 2007) (Emphasis added.)

Connor and Green writing in The Independent in 2008 state: “One of the major conclusions to emerge from the failed clinical trial of the most promising prototype vaccine, manufactured by the drug company Merck, was that an important animal model used for more than a decade, testing HIV vaccines on monkeys before they are used on humans, does not in fact work.” (Connor and Green Thursday, 24 April 2008)

Connor and Green quote Anthony Fauci, then-director of the US National Institute of Allergy and Infectious Diseases (NIAID) as saying: “We've learnt a few important things [from the clinical trial]. We've learnt that one of the animal models, the SHIV model, really doesn't predict very well at all.” The failure of the NHP model to predict human response has been acknowledged by others. (Corey et al. 2011; Letvin 2009; Thomas 2009; Watkins et al. 2008; Check 2004)

Compare the above with the following from Bertha Madras of the New England Regional Primate Center in testimony before The House of Representatives Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies (US Government Printing Office, Washington DC. 1990, p1481-1489): “The course of AIDS in primates is virtually identical to that of humans.” The perfidy here is unbelievable. (I have a review article on animal models of HIV vaccine development in an upcoming issue of the Journal of AIDS & Clinical Research and will post when it is available.)

Furthermore, there is ample evidence that the immune systems of animals and humans differ in clinically relevant ways. Analyzing past vaccine successes and failures can help us make intelligent decisions moving forward. The pursuit for a vaccine against HIV has been compared to the search for the polio vaccine. NHPs were successfully used in polio vaccine research as reservoirs for the virus, but they were not successful as models of the human disease. (Paul 1971; Oshinsky 2005) Shedlock et al state:

However, at the time it was unknown that the rhesus macaque, unlike the cynomolgus macaque (Macaca fascicularis), is one of the rare monkeys in which poliovirus does not replicate in the digestive tract and subsequently does not cause an orally acquired infection. Unfortunately, Flexner’s conclusions that vaccines maybe impossible to develop owing to the absence of a blood replication stage for poliovirus and that vaccine candidates should be grown only in neural cell lines, ideas that were widely embraced by the poliovirus research field, delayed the development of an effective poliovirus vaccine by as many as 40 years. Thus, this interpretation from the rhesus macaque model system shows that scientific assumptions of the importance of a particular primate infection model, based on the manifestation of similar disease symptoms and in the absence of known human correlates, may be ultimately misleading. (Shedlock, Silvestri, and Weiner 2009)

Leslie discusses the immune system of mice used to model the human immune system:

Researchers’ reliance on mice deserves some of the blame for this ignorance, says Davis [Mark Davis, an immunologist at Stanford]. No mouse-phobe, he keeps 400 cages of the rodents for studies of how T cells recognize pathogen molecules. But mice, says Davis, make a “lousy model” for the human immune system. The human and mouse lineages diverged some 65 million years ago, and the rodent’s immune system has adapted to safeguard a small, short-lived animal that scurries around with its nose in the dirt. However, nobody has cataloged the differences, and as a result, inconsistencies between human and mouse immunity often leave patients in the lurch, Davis says: “Hundreds of clinical trials have been based on curing mice, but almost none led to clinical treatments” . . . Davis is far from the first to point out the "mouse" problem in immunology. “Studies on mice are very elegant and beautiful, but they aren't reflecting the needs of the [human] population,” says Jacques Banchereau, head of the Baylor Institute for Immunological Research in Dallas, Texas . . . Ralph Steinman of Rockefeller University in New York City . . . “The truth is that to push vaccine science—say, for HIV or cancer—will require a major effort in human immunology.” (Leslie 2010)

Wenner, writing in Scientific American 2009, discusses the failure of gene therapy for patient Jesse Gelsinger:

Seventeen patients had undergone treatment before Gelsinger, who was in the final cohort—the one receiving the highest dose of the therapy. Many scientists, as well as the FDA, have raised questions as to why Gelsinger was being treated, given that several patients in earlier cohorts suffered severe liver reactions. Wilson says that they moved forward because it was “the kind of toxicity we would have expected,” based on their work in animals, and they thought it would be manageable. According to Mark Batshaw, director of the Children’s Research Institute at the Children’s National Medical Center in Washington, D.C., Wilson and the rest of the scientific community had to learn the hard way “that what you’ve learned from animals will not necessarily predict what’s going to happen in humans.” Batshaw was also involved in the 1999 trial. (Wenner 2009)

Forbes magazine published an article in their December 27, 1999 (p190) issue about why new inventions and discoveries don’t pan out. They singled out the failure of drug companies to find a drug to treat sepsis and cancer in humans in part on believing animal experiments.

Each [drug company] had a drug that targeted one or another link in the supposed chain – endotoxin, the irritant spewed out by invading bacteria: tumor necrosis factor, which the body deploys against bacteria; interleukin-1, a chemical signal by which the body marshals all its weapons. All seemed to help in animal models of sepsis and Wall Street entertained high hopes. Indeed, the main question for investors was not whether the drugs would work, but which would work first. None did. In several cases the drugs were so much worse than the sugar pill given as an experimental control that the trials had to be cut short… “We don’t know what went wrong,” says R Phillip Dellinger, a specialist in critical care medicine at Rush-Presbyterian-St. Luke’s Medical Center in Chicago, who headed a panel that investigated the problem. “The animal models may have been inappropriate; we may have been treating the wrong patients.”

Chapman 2011:

A major factor complicating risk analysis in FIH trials is the difficulty of making accurate predictions from preclinical laboratory research on human tissues and animal studies of the likely effect of the investigational agent on humans. According to Rebecca Dresser, risk analysis based on preclinical research can fall short in three ways. It may fail to predict human risks, leading to adverse effects in human trials – one example being the TGN1412 trial. It may predict clinical benefits that then fail to materialize for human subjects. And it may predict nonexistent risks in humans with the result that a potentially useful agent is discarded(Dresser 2009). (Chapman 2011)

The second point the Drake et al article illustrates is that Pharma, the view of some animal rightists notwithstanding, is not sitting on nonanimal tests that predict human response to drugs and disease just because they are mean people that hate bunnies. If Pharma had predictive tests they would use them because Pharma is concerned primarily, if not solely, about the bottom line. If Pharma already had a MIMIC® system there would be no need to invent one and they would be using it to make money by developing drugs that are efficacious and safe.

Vivisection activists maintain their position on prediction either because they have a vested interest or because they have naively bought into something they do not understand. Animal activists are suspicious of science in general and Pharma in particular because of practices they deem as cruel. Both camps need to learn more about the actual science of the issue and or be honest about the science they already know.

References

Chapman, Audrey R. 2011. Addressing the Ethical Challenges of First-in-Human Trials. J Clinic Res Bioeth 2 (4):113.

Check, E. 2004. HIV vaccine research a shot in the arm for immunologists. Nat Med 10 (12):1268.

Connor, Steve, and Chris Green. 2011. Is it time to give up the search for an AIDS vaccine? The Independent Thursday, 24 April 2008 [cited November 7 2011]. Available from http://www.independent.co.uk/news/science/is-it-time-to-give-up-the-search-for-an-aids-vaccine-814737.html.

Corey, L., G. J. Nabel, C. Dieffenbach, P. Gilbert, B. F. Haynes, M. Johnston, J. Kublin, H. C. Lane, G. Pantaleo, L. J. Picker, and A. S. Fauci. 2011. HIV-1 vaccines and adaptive trial designs. Science Translational Medicine 3 (79):79ps13.

Drake III, Donald R., Inderpal Singh, Michael N. Nguyen, Anatoly Kachurin, Vaughan Wittman, Robert Parkhill, Olga Kachurina, Janice M. Moser, Nicolas Burdin, Monique Moreau, Noelle Mistretta, Anthony M. Byers, Vipra Dhir, Tenekua M. Tapia, Charlotte Vernhes, Jyoti Gangur, T. Kamala, Nithya Swaminathan, and William L. Warren. 2012. Disruptive Science and Technology 1 (1):28-40.

Dresser, R. 2009. First-in-human trial participants: not a vulnerable population, but vulnerable nonetheless. The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics 37 (1):38-50.

Editorial. 2007. Beyond interferon. Nat Biotech 25 (12):1375-1375.

Leslie, M. 2010. Biomedical research. Immunology uncaged. Science 327 (5973):1573.

Letvin, N. L. 2009. Virology. Moving forward in HIV vaccine development. Science 326 (5957):1196-8.

Lewis, A. D., and P. R. Johnson. 1995. Developing animal models for AIDS research--progress and problems. Trends in Biotechnology 13 (4):142-50.

Oshinsky, David M. . 2005. Polio: An American Story: Oxford University Press.

Paul, J R. 1971. A History of Poliomyelitis. New Haven: Yale University Press.

Shedlock, D. J., G. Silvestri, and D. B. Weiner. 2009. Monkeying around with HIV vaccines: using rhesus macaques to define 'gatekeepers' for clinical trials. Nature reviews. Immunology 9 (10):717-28.

Thomas, C. 2009. Roadblocks in HIV research: five questions. Nat Med 15 (8):855-9.

Watkins, D. I., D. R. Burton, E. G. Kallas, J. P. Moore, and W. C. Koff. 2008. Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans. Nat Med 14 (6):617-21.

Wenner, Melinda. 2009. Gene therapy: An Interview with an Unfortunate Pioneer. Lessons learned by James M. Wilson, the scientist behind the first gene therapy death. Scientific American Magazine (September):14.