Experimental infection and protection against ... - TI Pharma

Summary, Samenvatting, List of publications, Dankwoord, C.V. 245
Summary
Plasmodium falciparum (Pf) malaria is one of the most frequent infectious
diseases and is responsible for severe malaria morbidity and mortality mainly
among young children in Sub-Saharan Africa. Humans are infected through the
bite of an infected Anopheles mosquito. An effective malaria vaccine is a key tool
of critical research that is needed to support malaria control and eradication.
Decades of research have led to the identification of approximately 36 antigens
that have been put forward as vaccine candidates. These antigens are grouped
according to their expression in the Pf lifecycle. Pre-erythrocytic antigens are
expressed in the sporozoite forms of the parasite that invade the human liver
causing subclinical infection. Blood stage antigens are expressed during the
parasite development within the host red blood cells, where they are
responsible for the clinical malaria disease, with fever, headache and myalgia.
Transmission blocking antigens are derived from the parasite’s sexual stages,
which will complete the lifecycle by reproduction within the mosquito host after
biting the infectious human.
This thesis focuses on the development of research tools that facilitate
immunological and vaccine research into human protection against Plasmodium
falciparum malaria in early stages of clinical development.
In section 1, we describe the safety and immunogenicity of the Apical
Membrane Antigen 1 (AMA1), which has been put forward as a promising blood
stage vaccine candidate (Chapter 2). We combined AMA1 with different
adjuvants, Alhydrogel, Montanide and AS02 and find distinct reactogenicity
profiles, with all vaccine formulations being immunogenic. The magnitude of the
humoral immune response can be enhanced by a more potent adjuvant, but
breadth and subclass distribution appear much less influenced by the adjuvant
(Chapter 3). We performed in depth analysis of the concentration and avidity of
AMA1 antibodies induced and found an inverse relation between these
parameters (Chapter 4). Since Phase II field efficacy trials with different AMA1
formulations have been unsuccessful in inducing protection so far, the
development of new adjuvants, delivery systems, strain covering approaches or
the combination of AMA1 with other antigens may provide a means by which
antibody responses can be boosted and animal results can be translated into
human efficacy.