Elizabeth Nardin PhD, Associate Professor

More info about me

Email me

Synthetic peptide and recombinant protein malaria vaccines are being developed to target the pre-erythrocytic stages of Plasmodium falciparum and prevent the 200-300 million infections that occur worldwide. The rational design of vaccines for Plasmodia, as well as other pathogens, requires an understanding of the immune mechanisms that can positively or negative modulate humoral and cellular responses. The key elements involve not only the choice of immunogen (i.e. type of antigen, delivery system), but also appropriate adjuvant formulation to stimulate the innate immune system and ensure effective presentation of antigen by dendritic cells (DC). Therefore, vaccine design must address issues of antigen uptake/processing, peptide/class II binding and DC antigen presentation to naïve T cells. These multiple factors can modulate DC function to stimulate development of antigen specific CD4+ T helper (Th) cells for long-lived immune responses, or T regulatory (Tr) cells that suppress antibody and cellular responses. Vaccines designed to target infectious organisms, by eliciting high levels of specific antibody or cells, must elicit strong Th and avoid induction of Tr responses. Conversely, therapeutic vaccines for class II associated diseases, such as diabetes or MS, are designed to elicit Tr cells that can downregulate the autoimmune CD4+ T cells responsible for pathology.

Our laboratory focuses on the circumsporozoite protein as both a key component for multistage malaria vaccines and as a model antigen to define the vaccine parameters required to elicit optimal antibody and CD4+ T cell responses. Phase I/II trials have demonstrated the feasibility of developing CS subunit vaccines. A major component of these vaccines is a B cell epitope from the repeat region of the circumsporozoite (CS) protein, an antigen expressed on the surface of the infectious sporozoite that is the target of protective antibodies. In Phase I trials, we have examined the T and B cell responses of volunteers immunized with irradiated P. falciparum sporozoites, synthetic peptide and virus like particle (VLP) vaccines containing P. falciparum CS repeats (Figure 1A, B) in an effort to understand the HLA class II associated immune mechanisms that function in immunity to sporozoites.

Fig 1. (A). P. falciparum CS protein (B) Hybrid HBV core antigen containing P. falciparum T and B cell epitopes

The immune response to the malaria pre-erythrocytic stages is multicomponent and antibodies, CD4+ and CD8+ T cells and IFN-γ have been shown to be protective in rodent malaria models. CD4+ Th cells play a critical role in protective immunity against sporozoite challenge. Both sporozoite and peptide induced anti-repeat antibody responses are T cell dependent, as is the CD8+ CTL response. Moreover, in animal models, immunization with peptides containing malaria Th epitopes can elicit protective CD4+ effector T cells that mediated IFN-γ dependent inhibition of parasite hepatic stages. A major focus of our laboratory is the analysis of the fine specificity and function of CD4+ T cells derived from preclinical animal studies and from volunteers in Phase I trials of various vaccine formulations.

Fig 2. Human CD4+ T cell

A critical component for successful vaccine development is the ability to determine whether manipulations of antigen configuration, adjuvant formulation and/or fine specificity of T and B cell responses have a positive or negative effect on protective immunity. The lack of correlates of protective immunity to sporozoite challenge in humans is a severe limitation for the design of efficacious vaccines. P. falciparum sporozoites are highly infectious only to humans, and alternative animal models require splenectomized chimpanzees or monkeys, a limited and expensive resource. Although anti-repeat immune responses in vaccinated volunteers can be measured by serologic or cellular assays, there is no safe, practical method to assay the protective capacity of these responses in vivo, except in expensive and potentially hazardous Phase II trials. In recent studies we have used a transgenic rodent malaria parasite genetically modified to express P. falciparum CS repeats (PfPb) to investigate the in vivo protective efficacy of P. falciparum vaccine-induced anti-repeat antibody and cellular responses. The PfPb /murine model is being used to evaluate protective efficacy of anti-P. falciparum repeat antibodies elicited in human vaccinees and for examining P. falciparum repeat specific humoral and cellular immunity elicited by new vaccine candidates and adjuvant formulations. Since the sporozoite challenge is in rodents, the EEF stages can be measured by PCR and partial or total protection quantified, which is not possible in human volunteers. The ability to study P. falciparum specific cellular and humoral immune responses in vivo in a small laboratory model may help identify quantitative correlates of protective immunity useful in assessment of immune responses in human vaccinees.

Selected Publications

1. Calvo-Calle, J.M., Oliveira, G.A., Othoro-Watta,C., Severow, J., Parra-Lopez, C., and Nardin, E.H.  A linear peptide containing minimal T and B cell epitopes of Plasmodium falciparum Circumsporozoite protein elicits protection against transgenic sporozoite challenge. Infect. Immun. 2006 Dec:74(12);6929-39.
2. Parra-Lopez, C., Calvo-Calle, J.M., Cameron, TO, Vargas LE, Salazar LM, Patarroyo ME, Nardin, E and Stern, LJ. Major histocompatibility complex and T cell interctions of a universal T cell epitope from Plasmodium falciparum circumsporozoite protein. J.Biol. Chem., 2006. 281:14907-17.
3. Calvo-Calle, J.M., Oliveira, G.A. and Nardin, E.H. Human CD4+ T cells induced by synthetic peptide malaria vaccine are comparable to cells elicited by attenuated P. falciparum sporozoites. J. Immunol. 2005 Dec 1;175(11):7575-85.
4. Langermans, J.A.M., Schmidt, A., Vervenne, R.A.W., Birkett, A.J., Calvo-Calle, J.M., Hensmann, M., Thornton, G.B., Dubovsky, F., Weiler, H., Nardin, E. and Thomas, A.W. Effect of adjuvant on reactogenicity and long-term immunogenicity of the malaria vaccine Icc-1132 in Macaques. Vaccine. 2005 Sept 3-;23(41):4935-43.
5. 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.
6. Frevert U, Nardin E. Arrest in the liver--a genetically defined malaria vaccine? N Engl J Med. 2005 Apr;352(15):1600-2.
7. Nardin, E.H., Oliveira, G.A., Calvo-Calle, J.M., Wetzel, K. Maier, C., Birkett, A.J., Sarpotdar, P., Corrado, M.L., Thorton, G.B. and A. Schmidt. Phase 1 testing of malaria vaccine comprised of hepatitis B virus core particles expressing P. falciparum Circumsporozoite epitopes. Infection and Immunity. 2004;72:6519-6527.
8. Kumar, K.A., Oliveira, G.A., Edelman, R., Nardin, E. and Nussenzweig, V. Quantitative Plasmodium sporozoite neutralization assay (T-SNA). J. Immunol. Methods. 2004;292:157-164.
9. Persson, C., Oliveira, G., Sultan, A.A., Bhanot, P., Nussenzweig, V. and Nardin, E.H. A new tool to evaluate the efficacy of human pre-erythrocytic malaria vaccines: rodent malaria parasites bearing a hybrid falciparum circumsporozoite protein. J. Immunology, Cutting Edge, 2002;169:6681-6685. (#J53422)
10. Birkett, A., Lyons , K., Schmidt, A., Boyd, D., Oliveira, G. A., Siddique, A., Nussenzweig, R., Calvo-Calle, J.M. and Nardin, E.H. Hepatitis B virus core antigen particle containing multiple epitopes of P. falciparum CS protein provides a highly immunogenic malaria vaccine in preclinical analyses in rodent and primate hosts. Infection and Immunity. 2002;70:6860-6870. (#J45416)
11. Nardin, E.H., Calvo-calle, J.M., Oliveira, G.A., Nussenzweig, R.S., Schneider, M., Tiercy, J.-M., Loutan, L., Hochstrasser, D. and Rose, K. A totally synthetic polyoxime malaria vaccine containing P. falciparum B cell and universal T cell epitopes elicits immune responses in volunteers of diverse HLA types. J. Immunol. 2001;166:481-489. (#J29160)
12. Nardin, E., Oliveira, G., Calvo-Calle, J., Castro, Z., Nussenzweig, R., Schmeckpeper, B., Hall, B.F., Diggs, C. Bodison, S. and Edelman, R. A synthetic malaria peptide vaccine elicits high levels of antibodies to P. falciparum sporozoites in vaccinees of defined HLA genotype. J. Inf. Dis. 2000;182:1486. (#J35241)