Embark on a groundbreaking journey through the landscape of malaria defense with Robert Seder and Peter Crompton from the esteemed National Institutes of Health (NIH). Explore their cutting-edge work harnessing the potential of monoclonal antibodies (mAbs) to combat malaria. Delve into the journey of how monoclonal antibodies were isolated and characterized structurally against novel epitopes against a conserved protein expressed on the infecting sporozoite. The monoclonal antibody has multi-functional effects by limiting motility of the sporozoites in the skin following mosquito bite as well as enhancing their destruction in the blood and preventing their infection in the liver, the key initiating event of the infection. This provides the optimal approach to prevent infection which would limit the clinical manifestations leading to such a high burden of morbidity and mortality in infants and young children. This strategy can also be useful for elimination of malaria. Witness how their exceptional breakthrough emerges as a transformative force in the global battle against this enduring threat.
Which wall does your research break?
Malaria remains a major public health threat, with nearly half of the world’s population at risk of infection. In 2021, this disease killed 619,000 people – including half a million children in Africa – despite widespread use of currently available countermeasures. Children under five years old and pregnant women bear the greatest burden of this disease. Current interventions have contributed greatly to the considerable gains made against malaria; however, progress has stalled and malaria incidence is increasing. New interventions are urgently needed to maintain progress and accelerate malaria elimination. Recently, the first malaria vaccine has been approved by the WHO for infants 5-17 months of age and others are in the pipeline. The efficacy of this vaccine is ~ 40% after 4 years. Our teams at the NIAID Vaccine Research Center (VRC) and the NIAID Division of Intramural Research (DIR) developed and tested monoclonal antibodies (mAbs) as a potential new tool to provide high level protection by preventing infection and clinical disease across all age groups including pregnant women. The advantages of using mAbs for malaria prevention are many – mAbs have an excellent safety profile and, unlike vaccines that require multiple doses and take time to have an effect, mAbs can be immediately effective upon administration of a single dose and can be used in all age groups. The first mAb our team isolated was CIS43, which was identified in people who had taken part in a vaccine trial overseen by Seder. Our team added the LS mutation to CIS43, greatly extending its durability in vivo and creating the first mAb tested in clinical trials – CIS43LS. We later discovered another mAb, L9 that was found to be 2-3 times more potent than CIS43 in animal studies. A more potent mAb could increase cost-effectiveness and scalability, better enabling global access to this important tool. LS was also added to L9 to create L9LS to prolong its durability in vivo. The initial clinical trials led by VRC and tested in US adults demonstrated that intravenous administration of CIS43LS was safe and mediated high-level protection against controlled human malaria infection. To extend these findings to the field, investigators at the DIR and colleagues in Mali showed that a single intravenous dose of CIS43LS was safe and 88% protective against malaria infection in adults over a 6-month period of intense malaria transmission in Mali. Additional trials found that both CIS43LS and L9LS protect against controlled malaria infection in U.S. adults at low doses and via subcutaneous injection, a simpler administration method that would be important for widespread application. Ongoing clinical trials in Africa (Mali and Kenya) are testing the efficacy of a single dose of L9LS administered subcutaneously to infants and children over 6-12 months against seasonal or perennial malaria transmission.
What inspired or motivated you to work on your current research or project?
- Seder: I have spent the last 25 years working on vaccines against HIV, TB and more recently, malaria. These three infections have had the most dramatic effects on morbidity and mortality worldwide, and developing effective ways to prevent them would dramatically impact both health and economic well-being globally. With regard to malaria, having worked in Africa for many years, I was able to directly experience the extraordinary effects that malaria has on impacting the health of infants and small children and the hardship this has created on their extended family.
- Crompton: I have studied malaria in Africa for over 15 years and have seen its tragic effects firsthand, so I feel a sense of urgency to work with my colleagues at the NIH and in Africa to develop new tools to fight this terrible disease. Our recent work in Mali showed that monoclonal antibodies are among the most promising new tools in the development pipeline for malaria prevention, so I wake up each day feeling highly motivated to move this research forward as efficiently as possible.
In what ways does society benefit from your research?
Our initial trials provide hope that VRC-developed mAbs will be a powerful tool for preventing malaria infection, clinical disease and onward malaria transmission in all age groups, improving health and economic well-being globally. mAbs could be transformative in our efforts to prevent the devastating impacts of malaria on women and children living in endemic communities. In 2021, approximately three-quarters of malaria deaths were in children under five years old, particularly in Sub-Saharan Africa. Malaria can have negative long-term neurological, cognitive and developmental impacts on children who experience infection under five years of age. Malaria in pregnancy is also a strong risk factor for maternal mortality, neonatal death, and poor birth outcomes. The benefits of such a tool that provides potent protection against malaria during high-risk periods such as seasonal malaria and pregnancy, go beyond saving lives lost to a preventable and treatable disease – malaria also has significant societal and economic costs on communities affected by the disease. The direct costs of malaria are estimated to be at least USD$12 billion annually and the cost of lost economic growth in malaria-endemic countries is many times more. As an example, repeated malaria infections in childhood is associated with as much as a 50% reduction in adult income earning potential. Absenteeism from work and school due to illness caused by malaria results in reduced worker productivity and educational attainment. It is also important to consider the potential cost savings to public health systems due to this tool. A highly effective antibody that prevents malaria infection could decrease the use of drugs and other healthcare resources that are needed to care for a person who becomes sick with malaria.
Looking ahead, what are your hopes or aspirations for the future based on your research or project?
The long-term goal of this research is to ensure access to a new and promising tool that is safe and highly effective at blocking malaria infection and onward transmission with the potential for needing only one interaction with the health system per year. This would contribute to malaria control and elimination efforts by preventing disease and loss of life with fewer opportunities to miss delivery of critical interventions to those at risk. We are also continuing to iterate this work to develop mAbs, with greater potency and then we will focus on optimizing commercial production to further reduce cost. Our ultimate goal would be to build manufacturing facilities to control costs and ensure global equity of access to this promising new tool. Further, as we continue innovating and further develop these monoclonal antibodies to protect against malaria, we are also working to build a foundation that will enable us to more rapidly develop safe and effective tools to use mAbs to fight emerging diseases of pandemic potential.