Experimentally induced blood-stage malaria in Kenyan adults: understanding disease mechanisms and protection in the context of background immunity
Lead Research Organisation:
University of Oxford
Department Name: Tropical Medicine
Abstract
Plasmodium falciparum malaria causes an estimated 500 million cases per year and hundreds of thousands of deaths annually. Substantial morbidity and mortality occurs in Africa. An effective vaccine is needed, and vaccine development is essential to provide an effective sustainable and cost-effective control of disease. Rational vaccine development would be based on clearly described mechanisms that lead to clearance of parasites and the correlates of immunity.
The current lead vaccine, based on the first falciparum gene ever cloned, delivers ~30% protection over 4 years. An understanding and identification of the underlying mechanisms that lead to naturally acquired immunity has the potential to inform rational vaccine design. We need to identify the antigenic targets for protective immune responses; and the threshold required and functional properties.
The study of naturally acquired immunity has been conducted using observational field studies to date, based on surveillance of naturally exposed children. However, adults living in endemic areas acquire resistance to infection and/or disease with repeated exposure to malaria causing parasites. To understand how this immunity impacts infection, we recently conducted a deliberate infection study using parasite stages that are infective from the mosquito, sporozoites. Out of a total of 142 volunteers, 33 were observed to be malaria parasite free and remained uninfected throughout monitoring for infection in the study. These studies in non-endemic volunteers, with 100% developing infection, have recently been used to investigate pathophysiological mechanisms of disease utilising the stage of the parasite responsible for disease, blood stages i.e. deliberate infection with parasite infected red blood cells.
We now propose to deliberately infect volunteers who we found to be previously malaria-free with parasite-infected red blood cells that directly results in the signs and symptoms associated with disease. We intend to evaluate pathophysiological mechanisms of disease and determine the contribution and mechanisms of immunity resulting from the disease stage of infection. We will adopt a biomarker and systems immunology approach to identify mechanisms associated with disease outcome including detailed characterisation of biomarkers of immune activation including endothelial activation and microvascular function; typing of antibody specificities and function, analysis of cellular immunity; and analysis of the metabolome. This study will define mechanisms associated with disease in the context of pre-existing immunity and help inform targets for the next generation blood-stage vaccines.
The current lead vaccine, based on the first falciparum gene ever cloned, delivers ~30% protection over 4 years. An understanding and identification of the underlying mechanisms that lead to naturally acquired immunity has the potential to inform rational vaccine design. We need to identify the antigenic targets for protective immune responses; and the threshold required and functional properties.
The study of naturally acquired immunity has been conducted using observational field studies to date, based on surveillance of naturally exposed children. However, adults living in endemic areas acquire resistance to infection and/or disease with repeated exposure to malaria causing parasites. To understand how this immunity impacts infection, we recently conducted a deliberate infection study using parasite stages that are infective from the mosquito, sporozoites. Out of a total of 142 volunteers, 33 were observed to be malaria parasite free and remained uninfected throughout monitoring for infection in the study. These studies in non-endemic volunteers, with 100% developing infection, have recently been used to investigate pathophysiological mechanisms of disease utilising the stage of the parasite responsible for disease, blood stages i.e. deliberate infection with parasite infected red blood cells.
We now propose to deliberately infect volunteers who we found to be previously malaria-free with parasite-infected red blood cells that directly results in the signs and symptoms associated with disease. We intend to evaluate pathophysiological mechanisms of disease and determine the contribution and mechanisms of immunity resulting from the disease stage of infection. We will adopt a biomarker and systems immunology approach to identify mechanisms associated with disease outcome including detailed characterisation of biomarkers of immune activation including endothelial activation and microvascular function; typing of antibody specificities and function, analysis of cellular immunity; and analysis of the metabolome. This study will define mechanisms associated with disease in the context of pre-existing immunity and help inform targets for the next generation blood-stage vaccines.
Technical Summary
Plasmodium falciparum malaria causes substantial morbidity and mortality in Africa. A high-efficacy vaccine is essential. The current lead malaria vaccine confers ~30% protection over 4 years and is based on the major antigen on the surface of pre-erythrocytic sporozoite parasite stages. An attractive strategy to build on this partial efficacy is a multi-stage vaccine including immunity against blood-stages of the parasites. However, there is no analogous single major antigen for blood stage parasites, and vaccines based on several different blood stage antigens have not been successful. Adults in endemic areas acquire immunity to blood-stage parasites after repeated malaria exposure. Identifying the underlying mechanisms of naturally acquired immunity has the potential to inform rational vaccine design e.g. antigen selection. We recently completed controlled human malaria infection (CHMI) studies in Kenyan adults using cryopreserved sporozoites (PfSPZ) and identified 33 out of 142 volunteers who remained uninfected by sensitive blood PCR for malaria parasites. The PCR negative volunteers are likely to have high levels of acquired immunity, and imply an excellent model for vaccine development. However the protection may have resulted either from immunity to pre-erythrocytic or to blood-stage parasites. The distinction is critical for further study and vaccine design. We now propose a blood-stage challenge experiment for these previously protected volunteers since this will bypass pre-erythrocytic stages to determine the contribution of blood-stage immunity and mechanisms. We aim to: (a) test whether a key component of malaria immunity is through an immune response to blood-stage infection; and (b) test whether individuals who are especially immune are able to control higher inoculums of parasites; and (c) define immunological mechanisms associated protection and/or disease pathogenesis to inform the development of the next generation of blood-stage malaria vaccines.
Description | IBSM - Pathogenesis and Analysis |
Organisation | Imperial College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Contributed intellectual input and expertise for the design, development, and implementation of the project. |
Collaborator Contribution | The collaborations/partnerships have contributed towards study design and development including potential analysis and interpretation. |
Impact | Participation in consultative workshop with key stakeholders. |
Start Year | 2022 |
Description | IBSM - Pathogenesis and Analysis |
Organisation | QIMR Berghofer Medical Research Institute |
Country | Australia |
Sector | Academic/University |
PI Contribution | Contributed intellectual input and expertise for the design, development, and implementation of the project. |
Collaborator Contribution | The collaborations/partnerships have contributed towards study design and development including potential analysis and interpretation. |
Impact | Participation in consultative workshop with key stakeholders. |
Start Year | 2022 |
Description | IBSM - Pathogenesis and Analysis |
Organisation | University of Melbourne |
Department | Melbourne Medical School |
Country | Australia |
Sector | Academic/University |
PI Contribution | Contributed intellectual input and expertise for the design, development, and implementation of the project. |
Collaborator Contribution | The collaborations/partnerships have contributed towards study design and development including potential analysis and interpretation. |
Impact | Participation in consultative workshop with key stakeholders. |
Start Year | 2022 |
Description | IBSM - Pathogenesis and Analysis |
Organisation | University of Oxford |
Department | Department of Paediatrics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Contributed intellectual input and expertise for the design, development, and implementation of the project. |
Collaborator Contribution | The collaborations/partnerships have contributed towards study design and development including potential analysis and interpretation. |
Impact | Participation in consultative workshop with key stakeholders. |
Start Year | 2022 |
Description | Consultative workshop with Community Members |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | The plans of the project are to conduct a challenge study using malaria blood-stage infected red blood cells. Being a new area, where participants will receive malaria infected blood, consultative workshops were conducted to seek the views of community members. Thirty (30) KEMRI Community Representatives (KCRs) were invited for a 2-day deliberative workshop in 2 groups of 15 each, being careful to group them according to their community experience in participating in challenge studies. Group 1 consisted of KCRs from Junju, Pingilikani, Ngerenya locations (areas where participants for challenge studies have been recruited from); and Group 2 Kilifi Township, Mtwapa, Jaribuni, Kauma, Vyambani, Ziani, Chasimba, Takaungu, Tezo, Matsangoni, Jaribuni, Gede, Sokoke and Roka (challenge studies naïve communities that is areas where participants have never been recruited from). The meetings were held on 12th to 13th and 14th to 15th July 2022. Those who attended were 26 KCR; 16 male and 10 female, 12 in Group 1 and 14 in Group 2. The first day of the meeting covered various topics which aimed at creating a mutual environment for learning as well as seeking consent for multimedia (photography and video recording). The other sessions were mainly provision of information including refreshing participants knowledge on KEMRI and its roles, research and research review process as well as building their knowledge on Human Infection studies including Malaria blood stage Human Infection Studies. Day 2 focused on recapping on the Malaria Blood-stage Studies to set the pace for the focus group discussions. The 15 representatives were then sub-divided into two groups of 7-8 participants then proceeded to the Focus Group Discussion (FGD) on Malaria blood-stage Study. Informed consent was obtained. Each participant signed and dated the informed consent form to confirm acceptance to participate in the discussions, and a copy of the same was issued to the participants. The discussions were recorded, and notes taken for transcription and data analysis. |
Year(s) Of Engagement Activity | 2022 |
Description | Consultative workshop with key stakeholders |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was a consultative meeting that involved collaborators, ethics and regulatory authority committee member representatives (3 different national organisations were identified for representation), and regional scientists who have undertaken this type of studies. This event also brought together the community members who had been previously engaged in 2022. Aspects of the study design and implementation were presented and discussed with the stakeholders giving feedback on best practices for implementation. |
Year(s) Of Engagement Activity | 2023 |