Title: Induction and persistence of memory T cells by candidate malaria vaccines
PhD Student: Anne Carola Teirlinck
Supervisors: Prof. Robert Sauerwein (Radboud University Nijmegen Medical Centre, the Netherlands) and Prof. Alan Thomas (BioMedical Primate Research Center, the Netherlands)
Collaborators: Dr. Rinaldo Zurbriggen (Pevion Biotech Ltd, Switzerland) and Dr. Roma Chilengi (African Malaria Network Trust, Tanzania)
Background: The essential biological objective of a malaria vaccine is induction of a sustained memory for protective immunity. Malaria vaccine development has so far primarily concentrated on identification and testing of appropriate Plasmodium antigens. There is no doubt that formulation and adjuvants are equally important since they play a key role in the nature and strength of the induced immune response. Adjuvants are compounds that interact with the innate immune system facilitating antigen uptake, processing and presentation by APC. The APC response orchestrates the downstream immune regulatory mechanisms and the specific immunity that develops after the first clonal expansion of T cells. The latter is a complex process that depends on MHC dependent antigen presentation, co-stimulatory molecule expression, and cytokines. Stimulatory pathways may be counter-regulated by suppressive signals from regulatory T cells. The outcome of this cascade of events on T cells is a key factor for the subsequent antibody profile and for protection.
Little is known on how adjuvantia operate at cellular level and such knowledge is important for a rational approach to vaccine formulation. Several formulations of AMA1 and MSP3-GLURP will be developed in the EMVDA program i.e. with IRIV or in combination with Alum hydrogel or DDA/TDB.
Aim of the project: To study the effect of different adjuvants and delivery systems on induction of central and effector T cell memory by AMA1 vaccine candidates. .
Methods: AMA1 formulated with influenza virus type particle (IRIV) or adjuvated with dimethyldioctadecylammonium (DDA)/TDB or Aluminumhydrogel will be studied for their capacity to induce central and effector memory T cells. Upstream immunological events will be included that may influence this induction such as activation of APC and subsets of CD4 cells (Th1, Th2, Tregs). Activation will be assessed by membrane surface marker expression and cytokine synthesis /profile as well as by functional in vitro assays. Studies, which also include longitudinal follow-up, will be conducted in animal models used for preclinical assessment of the vaccine candidates as well as with PBMC´s obtained from Phase Ia or Ib clinical trials.
Expected outcome: Understanding of the role and mechanisms of adjuvants on the induction of sustained memory T cells allowing a rational choice for clinical development of selected malaria vaccine candidates.