Long-time readers of this blog will not be surprised to hear that animal research has featured prominently in the work for which this year’s winners of the Nobel Prize in Physiology or Medicine are being honoured- Bruce A. Beutler and Jules A. Hoffmann for their for their discoveries concerning the activation of innate immunity, and Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity. After all animal research played a key role in Nobel winning scientific discoveries and medical advances every year since Speaking of Research was founded, in 2008, 2009 and 2010.
As the Nobel Prize Press release notes Jules A. Hoffmann made his discoveries on the importance of the Toll gene in the innate immune response in 1996 while studying how different gene mutations in the fly Drosophila melanogaster affected its ability to combat fungal infections. The innate immune system includes the processes that enable an organism to respond quickly and non-specifically to infections, and differs from the more familiar adaptive-immune system – typified by the involvement of B- and T-cells – which provides more long-lasting protection that is directed against specific threats. Drosophila melanogaster lacks the adaptive immune system that is found in vertebrates, and is therefore an ideal species in which to study the innate immune system.
Jules Hoffman. Image courtesy of Mosimann for Balzan
Bruce A. Beutler’s breakthrough was to show two years later, through research in mice, that a gene very similar to Toll – dubbed the Toll-like receptor – plays a crucial role in the innate immune system of vertebrates, specifically in the response to a substance secreted by bacteria called lipopolysaccharide. Since then a number of Toll-like receptors have been found to play a variety of important roles in the innate immune system.
Bruce Beutler. Image courtesy of Mosimann for Balzan.
As the Nobel committee notes these discoveries have led to “an explosion of research in innate immunity” both on how it can be harnessed to fight infection, and how excessive innate immune system responses in events such as cytokine storms can be curbed.
Ralph Steinman’s prize is in recognition of the discoveries he made working with Zanvil A. Cohn at the Rockefeller University about the other main branch of the immune system, the adaptive immune system. In 1973 he identified a new cell type that he called the dendritic cell in cultured mouse cells, and subsequently demonstrated in live mice that dendritic cells stimulated T-cells to mount a strong immune response.
Ralph Steinman. Image courtesy of Rockefeller University Press
Since then Ralph Steinman has continued to push forward research at the Rockefeller University on the role of dendritic cells in several aspects of the immune response, including graft rejection, resistance to tumors, autoimmune disease and infections, work which has relied heavily on mouse studies. One exciting example of how knowledge of the role played by dendritic cells in the immune system is influencing medical research is in the field of HIV vaccine design, in 2010 researchers at Rockefeller announced that they were starting a clinical trial of a new type of vaccine that seeks out a protein called DEC 205 on the surface of the dendritic cell – originally identified 15 years ago through studies in mice – and then delivers a piece of HIV protein to it, which in turn stimulates the dendritic cell to interact with T-cells to target HIV.
This year’s Nobel Prizes once again recognize the value of basic biomedical research in stimulating medical advances, and once more highlight the crucial role played by animal research in making the Nobel-winning discoveries possible.
Addendum: We have just learned the sad news that Nobel laureate Ralph Steinman died last Friday 30 September after a four-year battle with pancreatic cancer. We would like to offer his family, friends and colleagues our condolences at this difficult time.
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Tagged adaptive immune system, adaptive immunity, aids, B-cell, Bruce Beutler, Dendritic cell, Drosophila melanogaster, fly, fruit fly, hiv, immune system, Innate immune system, innate immunity, Jules Hoffmann, Lasker prize, mice, mouse, Nobel Laureates, nobel prize, Nobel Prize in Physiology or Medicine, Ralph Steinman, Rockefeller University, T-cell, Toll receptor, Toll-like receptor, vaccine
There is encouraging news this week on the prospects for an effective vaccine against HIV. A research team led by Professor Mariano Esteban at the Spanish Superior Scientific Research Council (CSIC) have announced that the vaccine MVA-B elicited a persistent immune response against HIV in 85% of volunteers in a phase 1 clinical trial. MVA-B is a therapeutic vaccine, it is not intended to block infection but rather to keep HIV levels in the body at levels well below those at which the virus can cause illness.
As a CSIC press release published online on EureakAlert! notes the MVA-B vaccine, created by inserting four HIV genes from the B subtype of HIV – the subtype accounting for most HIV infections in Europe and North America – into a vector derived from the Modified Ankara Vaccinia virus (a smallpox vaccine and shown to be safe in both animal studies and extensive human use), notes that:
In 2008, MVA-B already showed very high efficiency in mice as well as macaque monkeys against Simian’s immunodeficiency virus (SIV). Due to it’s high immunological response in humans, Phase I clinic trials will be conducted with HIV infected volunteers, to test its efficiency as a therapeutic vaccine.”
This is indeed true, a 2007 study in mice revealed that the MVA-B vaccine induced a strong immune response , while a paper published in 2008 by the same group demonstrated that a very similar MVA vaccine was able to induce a robust response involving both the HIV-1-specific CD4+ helper T-cells and CD8+ cytotoxic T cells in Rhesus macaques, and was able to control virus levels in macaques infected with the SHIV 89.6P hybrid virus whereas in unvaccinated monkeys the levels of virus rose and most developed an AIDS-like illness.
There is a question over whether the immune response generated by the MVA-B vaccine will be able to restrict HIV in humans, after all the MRK-Ad5 vaccine which failed to restrict the HIV virus in human trials and the pathogenic SIV MAC239 – considered a better model for HIV infection than SHIV 89.6p – in macaque monkeys had successfully controlled SHIV 89.6P in earlier studies.
Some reassurance on this issue comes from a study at Oregon Health and Science University (OHSU) that was announced earlier this year, where a group led by Dr. Louis Picker used a different vaccine vector – one based on Cytomegalovirus – to elicit a very similar broad immune response , with strong memory T-cell involvement, to that induced by MVA-B, and found that it induced long-term control the highly pathogenic SIV MAC239 strain. This was the highest degree of control demonstrated to date against this SIV strain, and indeed the cytomegalovirus vaccine is one of the first to demonstrate any ability to control SIV MAC239 levels.
Professor Esteban and his colleagues are certainly not resting on their laurels either, further clinical trials of the MVA-B vaccine are planned, to determine whether it can protect against HIV. In the meantime they are also seeking to improve on this vaccine. Earlier this year they published a paper in the open-access journal PloS One where they deleted a gene in the MVA vector to yield a new MVA-B vaccine that showed in mice a substantial increase in the magnitude and breath of the immune response compared with their original MVA-B vaccine, and an even better memory T-cell response. They now plan to evaluate this improved vaccine in a non-human primate model of HIV infection, and it will be interesting to see if they choose to use a more stringent model of infection such as SIV MAC239 rather than SHIV-89.6P.
Despite the setbacks and disappointments over the past two decades, it is clear from the work being done at the CSIC and OHSU that real progress is being made towards the development of both prophylactic and therapeutic vaccines against HIV, and it is just as clear that animal research continues to play a vital role in that progress.
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Tagged aids, CSIC, hiv, HIV vaccine, immune response, immune system, Louis Picker, macaque, Mariano Esteban, mice, monkey, mouse, MVA-B, ohsu, Oregon Health and Science University, rhesus macaque, SHIV, SHIV-89.6P, SIV, SIV MAC239, Spanish Superior Scientific Research Council, T-cell, vaccine