Malaria immunology

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

A search for therapies for cerebral malaria in African children Plasmodium falciparum malaria is a potentially fatal infectious disease caused by mosquito-transmitted parasites. Last year P. falciparum infections caused over 219 million cases of malaria and 435 thousand deaths, the vast majority of which were among young African children. The deadliest complication of infection is cerebral malaria (CM), causing greater than 90% of malarial fatalities. The mortality for CM is high, estimated to be 15-25%, despite treatment with highly effective anti-malarial drugs. Tragically, many children that survive CM suffer from life-long sequelae, including debilitating cognitive, hearing, and vision impairments. Critically, there are currently no adjunctive CM therapies to combine with rapid-acting antimalarial drugs. Given the global burden of severe malaria, the development of a CM therapy is a public health and humanitarian priority. At present our knowledge of the cellular and molecular mechanisms that underlie CM disease pathology is incomplete. Heavy iRBC sequestration in the cerebrovasculature of children who died of CM is often accompanied by intra- and perivascular pathology, including ring hemorrhages. These observations led to the generally accepted hypothesis that iRBC sequestration in the cerebrovasculature and the resulting sequelae including mechanical obstruction, inflammation, impaired vasoregulation, and BBB dysregulation may cause this clinical syndrome . Unfortunately, various therapies attempting to target this mechanism (at least 17 clinical trials of 11 therapies) have not shown efficacy. An existing mouse model for CM, experimental CM (ECM) shares many features with the human disease. Indeed, several studies including our own using MRI provided evidence of vasogenic brain swelling, blood-brain barrier dysfunction, and fatal brainstem herniation in ECM, similar to that observed in children with CM by MRI. However, the mouse model suggests an alternative mechanism of pathology. ECM requires cross-presentation of parasite antigens on MHC-I by the brain vasculature and targeting of this vasculature by CD3+CD8+ T cells. However, the presence or nature of immune cell infiltrates into the brains of children who dies of CM has not been rigorously determined. Thus, a critical gap in our knowledge of CM in children is whether a pattern of CD3+CD8+ T cell accumulation, which resembles that observed in the murine model of CM, exists in the brains of children who died of CM. We recently provided definitive evidence that CD3+CD8+ T cells are present in the brains of children who died of CM. CD3+CD8+ T cells were present in both the lumen of the venous vasculature in close association with the endothelium as well as on the abluminal side of vessels in the perivascular spaces. The number of CD3+CD8+ T cells is even greater in HIV-infected children with CM, suggesting that HIV coinfection can influence this disease. These observations open new avenues for adjunctive treatment for CM that involve modulating CD3+CD8+ T cells with a wealth of available T cell targeting therapeutics. A phase I/IIa clinical trial to test the safety of DON as an effective conjunctive therapy for CM in African children Based on the findings described above, in 2019, we initiated plans to carry out a phase I/IIa clinical trial of DON as an adjunctive therapy for African children with CM (entitled: DON in pediatric cerebral malaria: a phase I/IIa dose-escalation safety study). Our clinical trial team included Louis Miller (senior scientist LMVR), Brittany Riggle (Research Fellow LIG) and Doug Postels (Children’s Hospital/GW Medical School). We succeeded in putting all the necessary pieces together required for our trial and that began in January 2023. In summary we: identified a well-equipped site in Malawi headed by Terrie Taylor to carry out our trial; received IRB approval for our clinical protocol with Dr. Postels as PI in the U.S. and in Malawi; obtained from NCI a sufficient quantity of cGGP DON for our studies that was successfully filled and finished and shipped to Malawi for the start of our trial and to a facility in Frederick, MD for storage; submitted an IND application to the FDA and received permission to proceed with the adult arm of our study and obtained funding to support the clinical trial from DMID, NIAID with Dr. Postels as PI. We completed the first two adult arms of our Phase I/IIa clinical trial in June 2023 and submitted our PK and safety data to the FDA that showed DON to be safe in adults and requested FDA permission to proceed to the children’s arm of our study in which children with cerebral malaria are recruited to participate in a placebo-controlled dose escalation of DON. I retired at the end of December 2024 and the progress described was accomplished October 1- December 31, 2024.