Title: Assessment of the immune responses to a malaria candidate vaccine in immunized volunteers and exposed populations

PhD Student: Micha Phill Grønholm Jepsen

Supervisors: Dr. Michael Theisen (Statens Serum Institut, Copenhagen, Denmark) and Dr. Benjamin Mordmüller (University of Tübingen, Institut für Tropenmedizin, Germany)

Collaborators: Prof. Peter G. Kremsner (University of Tübingen, Institut für Tropenmedizin, Germany), Dr. Saadou Issifou (Albert Sweitzer Hospital, Lamberene, Gabon), Dr. Rinaldo Zurbriggen (Pevion Biotech Ltd, Switzerland), Dr. Roma Chilengi (African Malaria Network Trust, Tanzania), Dr. Babatunde Imoukhuede and Dr. Odile Leroy (European Malaria Vaccine Initiative, Denmark).

Background: Both the quantitative and the qualitative response to immunizations is of importance. Thus, high titers against the immunogen may not always achieve the protective efficacy aimed at. The switch from IgM to IgG following booster immunizations is of paramount importance for a proper memory function. Besides the ability to recognize important epitopes on the vaccine immunogen the avidity of the antibodies raised seem to be crucially important. Thus, both proper T and B-cell stimulation by the immunogen has to be assured. Aluminium Hydroxide is the preferred adjuvant but it is uncertain whether this adjuvant can provide the required stimulation of the immune system especially when employing subunit vaccines.

Vaccines against infectious diseases are administered to the target population (infants / children) prior to exposure of the pathogen in question. Maternally derived antibodies are known to interfere with the development of proper immune response to measles and possibly also other infectious pathogens. For measles this has implication for the recommended immunization schedule especially in developing countries. Maternally derived antibodies against adenovirus might also influence the window of opportunity of immunization with Ad-vectored vaccines. Immunization against malaria should preferably be started as early as possibly before repeated exposure might possibly modify the immune response.

Aim of the project is: A comparative study of the immune response in non-exposed European volunteers employing different adjuvants and delivery systems, which will not only provide important information about the antigen used but might also provide information of importance for other vaccine constructs. In addition it is essential to compare with a non-adjuvanted delivery system such as the Virosome system. Further, a comparison between the response obtained in non-exposed volunteers and exposed adult volunteers may also provide information whether the desired immune response can be obtained in individuals who are already primed via exposure to the parasite. Finally, a comparison of the immune response in lightly exposed children to that of non-exposed adult volunteers might provide information on whether the reactivity in non-exposed adult individuals is likely to mimic the response in infants/children from malaria endemic areas.

To assess the window of opportunity for immunization with malaria sub-unit vaccine with an aim to investigate the possibility to finally include a malaria vaccine in the EPI programme.

Methods: It will be essential to develop micro assays for detection of specific antibodies in infants. Equipment for micro assays suitable for infant studies is available. IgM, IgG and IgG subclass responses, memory B-cell ELISPOT and IgG avidity kinetics against vaccine-antigens will be assessed. It is not known to what extent maternally derived antibodies against malaria might negatively influence immunizations with sub-unit vaccines.

Mother and cord blood samples will be used to assess the Ab profile and sampling three and 6 month later from the infants combined with clinical examination and microscopy of malaria smears will  provide information on specific antibody kinetics and the experience of clinical malaria. Active surveillance and assessment of antibody kinetics in micro assays will be the core activities.

Ongoing clinical trials as well as planned investigations within the European Malaria Vaccine Initiative (EMVI) and African Malaria Network Trust (AMANET) framework hold unique possibilities to systematically investigate immune responses against the same candidate antigen in different adjuvant formulations and delivery systems in exposed and non-exposed populations in different age groups. The project is embedded in current and future clinical trials in Tübingen and Lambaréné. Collaboration with other clinical trial sites will be solicited. 

Expected outcome:

-To develop micro assay for detection of specific antibodies and /or cytokines.

-To contribute to the evaluation of malaria clinical trials.