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 - 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

Y1 - 2022

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, Protozoan

KW - Antigens, Protozoan

KW - Humans

KW - Immunity, Humoral

KW - Immunoglobulin G

KW - Malaria

KW - Malaria, Falciparum/drug therapy

KW - Plasmodium falciparum

KW - Seroepidemiologic Studies

U2 - 10.3389/fcimb.2022.804470

DO - 10.3389/fcimb.2022.804470

M3 - Journal article

C2 - 35463638

VL - 12

SP - 804470

JO - Frontiers in Cellular and Infection Microbiology

JF - Frontiers in Cellular and Infection Microbiology

SN - 2235-2988

ER -