TY - JOUR
T1 - Anti-Gametocyte Antigen Humoral Immunity and Gametocytemia During Treatment of Uncomplicated Falciparum Malaria
T2 - A Multi-National Study
AU - O’Flaherty, Katherine
AU - Chan, Jo-Anne
AU - Cutts, Julia C.
AU - Zaloumis, Sophie G.
AU - Ashley, Elizabeth A.
AU - Phyo, Aung Pyae
AU - Drew, Damien R.
AU - Dondorp, Arjen M.
AU - Day, Nicholas P.
AU - Dhorda, Mehul
AU - Fairhurst, Rick M.
AU - Lim, Pharath
AU - Amaratunga, Chanaki
AU - Pukrittayakamee, Sasithon
AU - Hien, Tran Tinh
AU - Htut, Ye
AU - Mayxay, Mayfong
AU - Faiz, M. Abul
AU - Mokuolu, Olugbenga A.
AU - Onyamboko, Marie A.
AU - Fanello, Caterina
AU - Takashima, Eizo
AU - Tsuboi, Takafumi
AU - Theisen, Michael
AU - Nosten, Francois
AU - Beeson, James G.
AU - Simpson, Julie A.
AU - White, Nicholas J.
AU - Fowkes, Freya J. I.
N1 - Funding Information: This work was supported by the National Health and Medical Research Council of Australia (project grant 1060785 [to FF, JS, and FN], program grant 637406 [to JB], 1166753 Career Development Fellowship [to FF], and investigator grants 1173046 [to JB] and 1196068 [to JS]), the Australian Centre for Research Excellence in Malaria Elimination (1134989), the Ramaciotti Foundation (Establishment Grant 3245/2011), the Ian Potter Foundation (grant to FF), the Victorian State Government (Operational Infrastructure Support grant), the United Kingdom Department for International Development, with additional support from the Worldwide Antimalarial Resistance Network, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Wellcome Trust of Great Britain (support to the Wellcome Trust Mahidol Oxford Tropical Medicine Research Programme). This research was funded in part by the Wellcome Trust [220211]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: Copyright © 2022 O’Flaherty, Chan, Cutts, Zaloumis, Ashley, Phyo, Drew, Dondorp, Day, Dhorda, Fairhurst, Lim, Amaratunga, Pukrittayakamee, Hien, Htut, Mayxay, Faiz, Mokuolu, Onyamboko, Fanello, Takashima, Tsuboi, Theisen, Nosten, Beeson, Simpson, White and Fowkes.
PY - 2022/4/7
Y1 - 2022/4/7
N2 - Introduction: Understanding the human immune response to Plasmodium falciparum gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates. Methods: In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant P. falciparum gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates Pfs230 (Pfs230c and Pfs230D1M) and Pfs48/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment. Results: Microscopy detectable gametocytemia was observed in 11% (127/1,114) of participants at enrolment, and an additional 9% (95/1,114) over the follow-up period (up to day 42) (total 20% of participants [222/1,114]). IgG levels in response to Pfs230c, Pfs48/45 and Pfs230D1M varied across study sites at enrolment (p < 0.001), as did IgG seroprevalence for anti-Pfs230c and D1M IgG (p < 0.001), but not for anti-Pfs48/45 IgG (p = 0.159). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens (Pfs230c OR [95% CI], p: 1.70 [1.10, 2.62], 0.017; Pfs48/45: 1.45 [0.85, 2.46], 0.174; Pfs230D1M: 1.70 [1.03, 2.80], 0.037), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density Pfs230c OR [95% CI], p: 1.09 [1.02, 1.17], 0.008; Pfs48/45: 1.05 [0.98, 1.13], 0.185; Pfs230D1M: 1.07 [0.99, 1.14], 0.071). Conclusion: Pfs230 and Pfs48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant P. falciparum.
AB - Introduction: Understanding the human immune response to Plasmodium falciparum gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates. Methods: In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant P. falciparum gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates Pfs230 (Pfs230c and Pfs230D1M) and Pfs48/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment. Results: Microscopy detectable gametocytemia was observed in 11% (127/1,114) of participants at enrolment, and an additional 9% (95/1,114) over the follow-up period (up to day 42) (total 20% of participants [222/1,114]). IgG levels in response to Pfs230c, Pfs48/45 and Pfs230D1M varied across study sites at enrolment (p < 0.001), as did IgG seroprevalence for anti-Pfs230c and D1M IgG (p < 0.001), but not for anti-Pfs48/45 IgG (p = 0.159). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens (Pfs230c OR [95% CI], p: 1.70 [1.10, 2.62], 0.017; Pfs48/45: 1.45 [0.85, 2.46], 0.174; Pfs230D1M: 1.70 [1.03, 2.80], 0.037), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density Pfs230c OR [95% CI], p: 1.09 [1.02, 1.17], 0.008; Pfs48/45: 1.05 [0.98, 1.13], 0.185; Pfs230D1M: 1.07 [0.99, 1.14], 0.071). Conclusion: Pfs230 and Pfs48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant P. falciparum.
KW - antibodies
KW - clinical malaria
KW - epidemiogy
KW - falciparum malaria
KW - gametocyte
KW - immunity
KW - malaria
UR - http://www.scopus.com/inward/record.url?scp=85128699175&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fcimb.2022.804470
DO - https://doi.org/10.3389/fcimb.2022.804470
M3 - Article
C2 - 35463638
VL - 12
JO - Frontiers in Cellular and Infection Microbiology
JF - Frontiers in Cellular and Infection Microbiology
SN - 2235-2988
M1 - 804470
ER -