From the Nobel Prize to the clinic through animal research

The winners of the Nobel Prize in Physiology or Medicine for 2008 have been announced today, and this year the prize has been split between three scientists whose epidemiological work lead to the identification of viruses responsible for two deadly diseases.  Luc Montagnier and Françoise Barré-Sinoussi were given the award for their discovery of the human immunodeficiency virus (HIV) while Harald zur Hausen was recognized for his discovery that the human papillomavirus (HPV) causes nearly all cases of cervical cancer.  This years awards will get a lot of people talking, the decision not to award a share in the Nobel Prize to Robert Gallo cannot fail to be controversial, since he played an important role in the discovery of HIV and provided the bulk of the early evidence showing that it caused AIDS. Aside from that I think we can look forward to some interesting debates as every HIV/AIDS denialist and and anti-vaccine crank out there jumps on the Nobel Prize committee’s decision.  Amusing as such debates can be  is it would be a shame if they distracted from the achievements of Montagnier, Barré-Sinoussi and zur Hausen, because make no mistake about it their discoveries were of great importance to modern medicine, leading to effective tests and treatments for HIV and more recently vaccines against HPV.  We offer our heartfelt congratulations to each of them!

At this point you’re probably wondering what any of this has to do with animal research?  This is one of those years when the discoveries for which the Nobel Prize was awarded did not depend directly on animal research, but we do not have to look far to see where animal research played its part. Identifying the cause of a disease is just the start, you next have to work out how to prevent or cure it. Where HIV is concerned much has been written about the role of animal research in developing antiviral drugs and vaccines, and rather than going into that now I’ll direct you to which is an excellent introduction to the topic. The role of animal research in the development of HPV vaccines is less well known, so that’s what I’d like to discuss here.

Once it had been established that HPV was the cause of most cases of cervical cancer work began on developing vaccines to protect against the virus.  As with any vaccine there was a need to ensure that the vaccine was both safe and capable of stimulation the immune system to protect against the virus, and animal models of HPV infection were sought.  While HPV is specific to humans other papillomaviruses infect species such as cattle, rabbits and dogs, and these provided a good model for the study of papillomavirus vaccines.  Early work on the vaccines proved discouraging. Immunization with whole papillomavirus protected against infection but was simply too dangerous to try in humans since there was a risk that the virus used to immunize could itself cause cancer, it was after all the same virus. This study did however show that a vaccine was possible. The next approach tried was to immunize animals using fragments of virus protein, a common method in vaccine design, but this failed to provide any significant protection (1).  It seemed that the whole virus was required to elicit a strong immune response. The breakthrough came from scientists who were studying the bovine papillomavirus capsid protein L1, a protein that forms the outer shell of the virus.  They found that when the L1 protein was expressed in vitro it could self-assemble to form a virus-like particle (VLP), which when injected into rabbits stimulated the immune system to produce antibodies antibodies that bound strongly to bovine papillomavirus (2).
The discovery that the bovine papillomavirus VLP could stimulate antibody production was good news, but the presence of such antibodies does not necessarily confer protection against the virus, so they next examined if bovine papillomavirus VLPs could protect cattle against bovine papillomavirus, and if VLPs made from the papillomavirus specific to their species could  protect dogs and rabbits against the canine and rabbit papillomavirus’s.  The animals were protected, and no adverse effects were noted (1), a success that lead directly to the development of VLP vaccines against HPV.  So far two HPV vaccines have been approved for clinical use, Merck’s Gardasil and GlaxoSmithKline’s Cervarix, and many states are now considering if they should make immunization against HPV part of their vaccination schedule.  Hopefully, if their price tag does not prove too high, these vaccines will go on to prevent many cervical cancer deaths.

So as usual medical progress is made by scientists working in a variety of disciplines, each playing their part to make breakthroughs possible.

1) Schiller J.T. and Lowy D.R. “Papillomavirus-like particles and HPV vaccine development.” Seminars in Cancer Biology, Volume 7, pages 373-382 (1996) PubMed: 9284529.
2) Kirnbauer R. et al. “Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic.” Proc Natl Acad Sci U S A., Volume 89(24), pages12180-4 (1992) PubMed: 1334560.