Age-dependent antibody profiles to plasmodium antigens are differentially associated with two artemisinin combination therapy outcomes in high transmission setting

Ben Andagalu; Pinyi Lu; Irene Onyango; Elke Bergmann-Leitner; Ruth Wasuna; Geoffrey Odhiambo; Lorna J Chebon-Bore; Luicer A Ingasia; Dennis W Juma; Benjamin Opot; Agnes Cheruiyot; Redemptah Yeda; Charles Okudo; Raphael Okoth; Gladys Chemwor; Joseph Campo; Anders Wallqvist; Hoseah M Akala; Daniel Ochiel; Bernhards Ogutu; Sidhartha Chaudhury; Edwin Kamau

doi:10.3389/fmed.2022.991807

Age-dependent antibody profiles to plasmodium antigens are differentially associated with two artemisinin combination therapy outcomes in high transmission setting

Front Med (Lausanne). 2022 Oct 13:9:991807. doi: 10.3389/fmed.2022.991807. eCollection 2022.

Authors

Ben Andagalu¹, Pinyi Lu^{2

3}, Irene Onyango¹, Elke Bergmann-Leitner⁴, Ruth Wasuna¹, Geoffrey Odhiambo¹, Lorna J Chebon-Bore¹, Luicer A Ingasia¹, Dennis W Juma¹, Benjamin Opot¹, Agnes Cheruiyot¹, Redemptah Yeda¹, Charles Okudo¹, Raphael Okoth¹, Gladys Chemwor¹, Joseph Campo⁵, Anders Wallqvist², Hoseah M Akala¹, Daniel Ochiel¹, Bernhards Ogutu⁶, Sidhartha Chaudhury^{2

7}, Edwin Kamau^{1

8

9}

Affiliations

¹ Department of Emerging and Infectious Diseases (DEID), United States Army Medical Research Directorate-Africa (USAMRD-A), Kenya Medical Research Institute (KEMRI)/Walter Reed Project, Kisumu, Kenya.
² Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, United States.
⁴ Biologics Research and Development, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
⁵ Antigen Discovery Inc., Irvine, CA, United States.
⁶ Kenya Medical Research Institute (KEMRI), Nairobi, Kenya.
⁷ Center for Enabling Capabilities, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
⁸ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
⁹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Abstract

The impact of pre-existing immunity on the efficacy of artemisinin combination therapy is largely unknown. We performed in-depth profiling of serological responses in a therapeutic efficacy study [comparing artesunate-mefloquine (ASMQ) and artemether-lumefantrine (AL)] using a proteomic microarray. Responses to over 200 Plasmodium antigens were significantly associated with ASMQ treatment outcome but not AL. We used machine learning to develop predictive models of treatment outcome based on the immunoprofile data. The models predict treatment outcome for ASMQ with high (72-85%) accuracy, but could not predict treatment outcome for AL. This divergent treatment outcome suggests that humoral immunity may synergize with the longer mefloquine half-life to provide a prophylactic effect at 28-42 days post-treatment, which was further supported by simulated pharmacokinetic profiling. Our computational approach and modeling revealed the synergistic effect of pre-existing immunity in patients with drug combination that has an extended efficacy on providing long term treatment efficacy of ASMQ.

Keywords: artemether-lumefantrine; artemisinin combination therapy; artesunate-mefloquine; computational analysis; immunoprofiling; machine learning; malaria; modeling.

Copyright © 2022 Andagalu, Lu, Onyango, Bergmann-Leitner, Wasuna, Odhiambo, Chebon-Bore, Ingasia, Juma, Opot, Cheruiyot, Yeda, Okudo, Okoth, Chemwor, Campo, Wallqvist, Akala, Ochiel, Ogutu, Chaudhury and Kamau.