Experimental infection and protection against ... - TI Pharma

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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.
246 Chapter 12 Controlled human malaria infections (CHMI) are trials in which healthy volunteers are exposed to malaria-infected mosquito bites, followed closely and treated as soon as blood-stage parasites are detected by microscopy. These studies are used to assess preliminary efficacy of primarily pre-erythrocytic vaccine candidates in a limited number of institutions worldwide. In section 2, we compared the safety and parasitological outcome of CHMI in different institutions and conclude that CHMI can be safely conducted, but will lead to grade 3 adverse events in a proportion of volunteers (Chapter 5). The primary parasitological outcome of such experiments is highly reproducible within institutions but may vary between trial centres. In addition, we evaluated the power of CHMI to detect vaccine efficacy of candidate malaria vaccines (Chapter 6) and found that CHMI can confidently assess a reduction in parasitemia for both pre-erythrocytic and blood stage vaccines, possibly broadening its application in malaria vaccine research. We subsequently improved the protocol of CHMI trials by increasing the portfolio of Pf parasites for CHMI with the successful establishment of a new Pf strain from Cambodia, NF135.C10 (Chapter 7). The availability of this strain allows for future assessment of cross-strain immunity induced by candidate vaccines through heterologous CHMI trials. Furthermore, we tested unattenuated cryopreserved sporozoites for their infectivity by intradermal injection, proving potency in five of six volunteers from each of three dose groups (Chapter 8). The needle administration of sporozoites has advantages over mosquito delivery, in terms of dosing and expanding the global capacity to perform CHMI trials. However, future studies will need to focus on improving the administration of these sporozoites in order to achieve 100% infection rates. Moreover, with an increasing number of CHMI centres being installed, priority should be given to initiatives to standardize challenge procedures in order to ensure comparability of results worldwide. In section 3 we show that viable intact sporozoites are capable of inducing protection to Pf malaria in humans very efficiently, if high levels of blood stage parasitemia and clinical disease are prevented by co-administration of the drug chloroquine (CPS, Chapter 9). Chloroquine kills blood stage parasites but does not affect the hepatic development of malaria parasites. A protocol in which we exposed healthy, malaria-naïve volunteers to the bites of infected mosquitoes under chloroquine prophylaxis on three occasions with monthly intervals, rendered 10 of 10 volunteers protected against subsequent controlled infection. We found that protection was associated with an increased response of
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Contents Contents 5 Chapter 1 - Int
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Introduction 9 Malaria Malaria is o
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Introduction 11 Preclinical Clinica
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Introduction 13 pipeline of clinica
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Introduction 15 The division of ant
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Introduction 17 Figure 4. Populatio
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Introduction 19 candidates. Initial
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Introduction 21 - to identify param
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Introduction 23 20. Nussenzweig RS,
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Introduction 25 50. Ouedraogo AL, R
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Introduction 27 RTS,S/AS02 in malar
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Chapter 2 Safety and Immunogenicity
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Safety and Immunogenicity of a Reco
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Chapter 3 Humoral immune responses
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Humoral immune responses to a singl
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Chapter 4 82 Abstract The functiona
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84 Chapter 4 Figure 1. Schematic re
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86 Chapter 4 Concentration (mg/ml,
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88 Chapter 4 Figure 4: Correlation
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90 Chapter 4 positively correlated
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92 Chapter 4 Acknowledgements The a
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94 Chapter 4 determinant of subsequ
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Chapter 5 Comparison of clinical an
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Comparison of clinical and parasito
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Chapter 6 Efficacy of pre-erythrocy
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Efficacy of pre-erythrocytic and bl
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Chapter 7 NF135.C10: a new Plasmodi
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NF135.C10: a new Plasmodium falcipa
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Chapter 8 Induction of malaria in v
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Induction of malaria in volunteers
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Section 3 Whole parasite inoculatio
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174 Chapter 9 Abstract An effective
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176 Chapter 9 Figure 1. Study desig
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178 Chapter 9 followed by five iden
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180 Chapter 9 Figure 2. Parasitemia
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182 Chapter 9 Test Day I-1 Day C-1
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184 Chapter 9 strain P. falciparum-
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186 Chapter 9 protective role in ot
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188 Chapter 9 References 1. Greenwo
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190 Chapter 9 27. Orjih AU. Acute m
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192 Chapter 9 medium A (Caltag Labo
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