Development of Experimental Basis for a Malaria Vaccine

Ruth S. Nussenzweig, Doc en Med, PhD
CV Starr Professor of Medical and Molecular Parasitology

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In the mid 1970’s it was demonstrated, for the first time, that a malaria vaccine containing radiation attenuated parasites protects not only mice and monkeys, but also humans. This was later repeatedly conformed with the same results. However, this vaccine was far from practical and the infectious mosquito stages (sporozoites) do not multiply in vitro. Thus, the need for a subunit vaccine.

We had earlier characterized the CS protein as a protective antigen, abundant on the surface of sporozoites and highly immunogenic. The CS is present with a similar structure in all mammalian malaria species. CS protein or part of its sequence is currently the only parasite component present in the majority of candidate vaccines for humans. We and others have shown that viral vectors expressing the CS or its key sequences (epitopes) elicit complete protection against experimental malaria. However, this requires two or more immunizing doses and protection is of short duration in experimental animals and humans ( ? 2 months). Currently, we are investigating, for the first time, a new excellent viral vector system, the Yellow Fever vaccine of humans, which elicits protection for many years. We are using a recombinant Yellow Fever vaccine expressing key epitopes of a rodent malaria parasite. Administration of this virus results in a high level of protection, of long duration, after a single immunizing dose. (See further details in Ref. 1 of 2005). The same level of protection is also achieved by «DNA launch» which may not require a cold chain (to be published).

Selected Publications

1. Kumar KA, Sano G, Boscardin S, Nussenzweig RS, Nussenzweig MC, Zavala F, Nussenzweig V. The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature. 2006 Dec 14:444(7121);937-40.
2. Silvia B. Boscardin, Julius C.R. Hafalla, Alice O. Kamphorst, Revati F. Masilamani, Henry A. Zebroski, Alexandre Morrot, Fidel Zavala, Ralph M. Steinman, Ruth S. Nussenzweig and Michel C. Nussenzweig. Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses. J. Exp Med. 2006 Mar;203(3):599-606.
3. Oliveira GA, Wetzel K, Calvo-Calle JM, Nussenzweig R, Schmidt A, Birkett A, Dubovsky F, Tierney E, Gleiter CH, Boehmer G, Luty AJ, Ramharter M, Thornton GB, Kremsner PG, Nardin EH. Safety and enhanced immunogenicity of a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in adjuvant Montanide ISA 720 in a phase I trial. Infect Immun. 2005 Jun;73(6):3587-97.
4. Tao D, Barba-Spaeth G, Rai U. Nussenzweig V, Rice C and Nussenzweig R.S. Yellow Fever 17D as a vaccine vector for microbial CTL epitopes: Protection in a rodent malaria model. J Exp. Med. 2005;201(2):201-209.
5. Saul, A., Nussenzweig R.S. Rationale for Malaria Vaccine Development. In: 'Novel Vaccination Strategies', Edited by: Stefan H.E. Kaufmann, WILEY-VCH Verlag GmbH & Co. KGgA. Weinheim. 2004, pp 479-503.
6. Gonzalez-Aseguinolaza G, Nakaya Y, Molano A, Dy E, Esteban M, Rodriguez D, Rodriguez JR, Palese P, Garcia-Sastre A and Nussenzweig RS. Induction of protective immunity against malaria by priming-boosting immunization with recombinant cold-adapted influenza and modified vaccinia Ankara viruses expressing a CD8+-T-cell epitope derived from the circumsporozoite protein of Plasmodium yoelii. J Virol. 2003;77:11859-66.
7. Bonaldo MC, Garratt RC, Caufour PS, Freire MS, Rodrigues MM, Nussenzweig RS and Galler R. Surface expression of an immunodominant malaria protein B cell epitope by yellow fever virus. J Mol Biol. 2002;315:873-75.
8. Bruna-Romero, O., Gonzalez-Aseguinolaza, G., Hafalla, J., Tsuji, M., and Nussenzweig, RS. Complete, long lasting protection against malaria of mice primed and boosted with two distinct viral vectors expressing the same plasmodial antigen. Proc Natl Acad Sci. 2001;98:11491-11496.