Vaccination (or active immunization) entails the introduction of a foreign material (antigen) into an individual in order to produce protection (immunity) to a particular disease. In simple terms, vaccination works by priming the immune system to recognize a particular antigen. One of the primary goals of vaccination is to generate protective titers of antibody, as well as long-term protection through the creation of memory B cells that can protect against the infectious agent. Successful vaccines must generate neutralizing antibody responses as well as B cell memory toward a specific pathogen. However, successful vaccines are the exception: it has been difficult to create a protective vaccine for a great number of infectious diseases (e.g. HIV) or even long lasting, protective vaccines against common diseases (e.g. flu). Despite many years of basic research, the reasons why most vaccines fail are not understood. In recent years, passive immunization against non-communicable diseases has also shown great promise. (This is best illustrated in the context of cancer, where the non-proprietary name for a majority of new drugs ends in -mab;an acronym that indicates the monoclonal antibody source). Active immunization to raise therapeutic antibodies is the next logical step. Therefore, understanding how to make good vaccines is of therapeutic interest both in the traditional context of infectious diseases and in the context of non- communicable diseases, most of which are currently incurable. To address this acute need for successful vaccines in both contexts, we propose to approach vaccine design in a completely new manner: rather than attempt to engineer an immunogenic vector, we sought to exploit an organism that has an inherent ability to stimulate a very strong B cell response in an infected individual, that results in tremendous antibody production and B cell memory. We have created a novel vaccine vector using the coat of the African trypanosome Trypanosoma brucei, an extracellular parasite that lives in the bloodstream of the infected mammalian host. T.brucei is completely exposed to the immune system and to evade it, it uses its coat as a decoy: it promotes the generation of antibody responses to it, and then switches coats, starting the cycle again, and establishing a chronic infection. Exploitation of T.brucei 's ability to elicit strong neutralizing antibody responses (and B cell memory) to its coat makes it an optimal (though clearly completely unconventional) vaccine vector, and we propose herein to use this in the development of therapeutic vaccines toward Alzheimer's and also toward drugs of abuse (nicotine;opiates). Finally, we hope to learn from T.brucei, so that in the future we can develop designer vaccines that successively mimic what this organism has evolved to achieve.

Public Health Relevance

We have developed a way to display pieces of proteins, or even small molecules, in a way that these stimulate a strong antibody response. We propose here to use this new method as a therapeutic vaccine, to stimulate our bodies to generate specific antibodies against targets of medical relevance (such as protein aggregates in Alzheimer's disease, or drugs of abuse, in the case of addiction). If successful, our experiments have the potential to bring the promise of therapeutic vaccination to fruition and could thus have a profound impact on the way we treat a great many chronic diseases (not only the ones we will focus on here, but also cancer etc).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-A (51))
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Ferguson, Stacy E
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Rockefeller University
Other Domestic Higher Education
New York
United States
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Pinger, Jason; Chowdhury, Shanin; Papavasiliou, F Nina (2017) Variant surface glycoprotein density defines an immune evasion threshold for African trypanosomes undergoing antigenic variation. Nat Commun 8:828
Mugnier, Monica R; Stebbins, C Erec; Papavasiliou, F Nina (2016) Masters of Disguise: Antigenic Variation and the VSG Coat in Trypanosoma brucei. PLoS Pathog 12:e1005784
Mugnier, Monica R; Cross, George A M; Papavasiliou, F Nina (2015) The in vivo dynamics of antigenic variation in Trypanosoma brucei. Science 347:1470-3
Hovel-Miner, Galadriel; Mugnier, Monica; Papavasiliou, F Nina et al. (2015) A Host-Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei. Results Probl Cell Differ 57:23-46
Stavropoulos, Pete; Papavasiliou, F Nina (2010) Using T. brucei as a biological epitope-display platform to elicit specific antibody responses. J Immunol Methods 362:190-4