Tag Archives: cynomologous macaque

The new face of transplant surgery, thanks to animal research

Yesterday the University of Maryland Medical Center (UMM) announced most extensive full face transplant completed to date, including both jaws, teeth, and tongue. In a marathon 36-hour operation the surgical team led by Professor Eduardo Rodriguez were able to transplant a face of an anonymous donor onto their patient Richard Lee Norris, who had been injured in a gun accident 15 years ago.  The operation was the culmination of years of clinical and animal research undertaken at UMM under the leadership of Professor Stephen Bartlett, and funded by the Department of Defense and  Office of Naval Research due to its potential to help war veterans who have received serious facial injuries.

This successful operation, termed a vascularized composite allograft, was made possible not only by the selflessness of the family of the anonymous donor, but also by the years of animal research undertaken by Professors Rodriguez and Bartlett and colleagues. For example, a key factor in the success of this operation was that they transplanted high amounts of vascularized bone marrow (VBM), which came inside the transplanted jaw, a technique that was developed by the team after observing that tissue rejection following composite tissue allotransplantation in a cynomolgus monkeys was greatly reduced when VBM was included in the transplant. This discovery will also help to reduce the amount of immunosuppression that Mr. Norris and future patients require following facial transplants.

Of course this is far from the first contribution that animal research has made to transplant surgery, from the development of the techniques of kidney transplant through research in dogs by Joseph Murray and colleagues, to the careful experiments in dogs conducted by Norman Schumway and Richard Lower that led to the first successful heart transplants, to the studies in mice and rats that identified the immunosuppressive properties of the drug cyclosporin that transformed the transplantation field in the 1980’s, animal research has made a crucial contribution to this field. Indeed, in his 1990 Nobel Lecture Edward Donnall Thomas stressed the importance of animal research to his Nobel prize winning discoveries concerning bone marrow transplantation.

Finally, it should be noted that marrow grafting could not have reached clinical application without animal research, first in inbred rodents and then in outbred species, particularly the dog.”

Animal research continues to make key contributions to transplant science, and we have had several opportunities to discuss its role in the development of lab-engineered tissues for transplant, such as the artificial bladder, on this blog.

Yesterday’s news from the University of Maryland is another reminder that animal research is still crucial to advances in transplant surgery. It is also worth remembering that when animal rights groups attack animal research conducted by the Department of Defense, it is work such as that which led to yesterday’s breakthrough that they are attacking.

Paul Browne

A shield against the nightmare: Ebola virus vaccine success

There must be few diseases that can conjure up images of horror the way Ebola virus can. Since it was first identified in Zaire (now the Democratic Republic of the Congo) in the mid-1970’s there have been several outbreaks that have left hundreds of people dead, but it is the potential for far worse outbreaks that has epidemiologists worried. Ebola infection causes a viral hemorrhagic fever characterised by rapid onset of fever, followed within days by vomiting and diarrhea, and eventually bleeding from bodily orifices and injection sites; mortality varies between 50 and 90% depending on the strain of Ebola. There is no specific treatment or cure available for Ebola virus, although through research on mice and guinea pigs scientists at the U.S. Army Medical Research Institute of Infectious Diseases developed a morpholino based treatment that protected 75% of rhesus monkeys exposed to Ebola virus. Subsequent studies showed that these morpholino based therapies – AVI-6002 and AVI-6003 – could confer protection against Ebola and Marburg viruses respectively when administered within an hour of infection, and further studies are under way to determine if they can offer protection when administered later.

Transmission electron micrograph of Ebola virus. Courtesy of the Centers for Disease Control and Prevention

While efforts to improve the efficiency of this treatment are ongoing other scientists have turned to developing a vaccine against Ebola virus.  So far we have been quite lucky with Ebola, most outbreaks have occurred in remote areas and due to the rapid progression of the disease – and the fact that no strains have been capable of airborne infection – the outbreaks have tended to burn themselves out quite quickly once travel restrictions and containment protocols were implemented, but we can’t rely on being lucky forever.

A difficulty with designing vaccines against Ebola is that the antibody-producing B-cells of the immune system that many vaccines stimulate can only recognize one strain at a time, so for each new strain of Ebola that emerges you would need a new vaccine.  This would obviously result in a significant delay between reporting of an outbreak and getting the vaccine into the areas where it’s needed, so scientists have been studying another vaccination strategy that stimulates the cellular arm of the immune system that is capable of recognizing a wider range of virus strains. The two part “Prime-Boost” strategy they developed involves first administering a “prime”, a DNA vaccine that codes for part of the surface proteins of the “Zaire” and “Sudan” strains of Ebola, followed several months later by administration of a “boost” vaccine based on a weakened adenovirus (cold virus) that also produces fragments of the Ebola surface proteins that are then recognized as foreign by the immune system. This strategy successfully protected cynomolgus macaques from the Zaire strain of Ebola virus (1) and has since been shown to be safe to stimulate an immune response in small scale human trials (2).

The question remained as to whether this vaccine strategy would be able to protect against Ebola strains other than “Zaire” and “Sudan”, and the opportunity to test this came in 2007 when a new strain of Ebola was identified in the Bundibugyo region of Uganda. The outbreak burnt itself out before any program of vaccination could be implemented, but the new strain did offer the opportunity to re-evaluate the prime-boost vaccination strategy.  In a report, published yesterday in the open access journal PloS Pathogens, Dr Nancy J. Sullivan and colleagues at the National Institute of Allergy and Infectious Diseases report that the prime-boost strategy can protect cynomolgus macaques from the otherwise fatal Bundibugyo Ebola virus, demonstrating that it can protect against several different strains of the disease.

This is great news and brings us a lot closer to the goal of a vaccine that can protect us against Ebola virus, in particular it is possible that this vaccine could be used to immunize people living in areas where Ebola is a threat even before an outbreak is detected.  It is not just humans who may benefit from this vaccine research, in the past decade tens of thousands of chimpanzees and gorillas have died from Ebola, and the disease now poses a significant threat to the their very survival.  A vaccine against Ebola would help reduce death toll among these endangered apes, though even with an effective vaccine developing and implementing a successful immunization program will be neither cheap nor easy.

Paul Browne

1)      Sullivan N. J. et al. (2000) Development of a preventive vaccine for Ebola virus infection in primates. Nature 408: 605–609. DOI:10.1038/35046108

2)      Martin J.E., et al. (2006) A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol 13: 1267–1277. DOI:10.1128/CVI.00162-06

3)      LE Hensley et al. Demonstration of cross-protective vaccine immunity against an emerging pathogenic Ebolavirus species. PLoS Pathogens Online open-access publication (2010) DOI: 10.1371/journal.ppat.1000904

Defeating diseases of the developing world: tuberculosis and Chikungunya fever

Helicobacter pylori, the bacterium that causes stomach ulcers and stomach cancer, may also play a protective role against tuberculosis, according to studies in both humans and monkeys by a team from Stanford University, UC Davis, the University of Pittsburgh and Aga Khan University in Pakistan (1).

Scanning electron micrograph of Mycobacterium tuberculosis, courtesy of the CDC Public Health Image Library

One-third of the world’s population is infected with TB, although most infections are latent and only one in ten progress to active disease.

The presence of H. pylori in the stomach may boost immunity to the TB bacterium, Mycobacterium tuberculosis. H. pylori infection is still almost universal in developing countries.

The researchers studied people with latent tuberculosis in California, Pakistan and the Gambia over a two-year period. They found that people who were also infected with H. pylori mounted a stronger immune response against TB and were less likely to advance to clinical tuberculosis than those who were not infected with the stomach bug.

They also carried out complementary studies with cynomolgous macaques at the California National Primate Research Center at UC Davis. Like humans, many monkeys naturally carry H. pylori in their stomachs. This study used tissues and samples from monkeys that had already been infected with tuberculosis for other experiments.

Of 41 monkeys, 30 carried H. pylori and only five of these developed active tuberculosis. Six of 11 monkeys that were negative for H. pylori developed tuberculosis. This finding supports the observations made in the human studies and indicates these monkeys are a good experimental model in which further studies can be performed. Already they plan to test whether experimental infection of H. pylori can protect monkeys from TB, and whether it can enhance the protective effect of immunization with current TB vaccines, which are only partially effective.   If these experiments are successful, they will test a genetically modified H. pylori strain developed by Ondek Biologic Delivery Systems that expresses TB antigens as a possible new and more effective vaccine against TB.

A paper describing the results was published Jan. 20 in the open access journal PloS (Public Library of Science) One. The work was funded by grants from the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation.

Of course TB is only one of many infectious diseases that scientists wish to prevent, and another report this week shows what can be achieved when you have a good animal model for a disease. You may not have heard of Chikungunya fever, but outbreaks of this mosquito transmitted illness have blighted the lives of hundreds of thousands of people in Africa and Asia in recent years.

As yet there is no vaccine available, but this week the National Institute of Allergy and Infectious Diseases (NIAID) announced an important step towards a vaccine for Chikungunya fever (2).  Scientists at the NIAID Vaccine Research Center developed an experimental vaccine that employs non-infectious virus-like particles and found it to confer complete protection against Chikungunya fever in rhesus macaques. Antibody-containing serum from these monkeys also protected immunodeficient mice against otherwise lethal doses of Chikungunya virus.  Clinical trials to evaluate the safety of this vaccine and its ability to prevent Chikungunya fever in humans are now being planned.

Regards

Andy Fell, UC Davis

1) Perry S, de Jong BC, Solnick JV, Sanchez MdlL, Yang S, et al. (2010) Infection with Helicobacter pylori is associated with protection against tuberculosis. PLoS ONE 5(1): e8804. doi:10.1371/journal.pone.0008804

2) Akahata W., Yang Z.-Y, Andersen H., Sun S. et al. “A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection” Nature Medicine Published online: 28 January 2010 doi:10.1038/nm.2105