AUTHOR=O’Flaherty Katherine , Chan Jo-Anne , Cutts Julia C. , Zaloumis Sophie G. , Ashley Elizabeth A. , Phyo Aung Pyae , Drew Damien R. , Dondorp Arjen M. , Day Nicholas P. , Dhorda Mehul , Fairhurst Rick M. , Lim Pharath , Amaratunga Chanaki , Pukrittayakamee Sasithon , Hien Tran Tinh , Htut Ye , Mayxay Mayfong , Faiz M. Abul , Mokuolu Olugbenga A. , Onyamboko Marie A. , Fanello Caterina , Takashima Eizo , Tsuboi Takafumi , Theisen Michael , Nosten Francois , Beeson James G. , Simpson Julie A. , White Nicholas J. , Fowkes Freya J. I. 

TITLE=Anti-Gametocyte Antigen Humoral Immunity and Gametocytemia During Treatment of Uncomplicated Falciparum Malaria: A Multi-National Study

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.804470

DOI=10.3389/fcimb.2022.804470

ISSN=2235-2988

ABSTRACT=<sec><title>Introduction</title><p>Understanding the human immune response to <italic>Plasmodium falciparum</italic> gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates.</p></sec><sec><title>Methods</title><p>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 <italic>P. falciparum</italic> gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates <italic>Pf</italic>s230 (<italic>Pf</italic>s230c and <italic>Pf</italic>s230D1M) and <italic>Pf</italic>s48/45 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.</p></sec><sec><title>Results</title><p>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 <italic>Pf</italic>s230c, <italic>Pf</italic>s48/45 and <italic>Pf</italic>s230D1M varied across study sites at enrolment (<italic>p &lt; 0.001</italic>), as did IgG seroprevalence for anti-<italic>Pf</italic>s230c and D1M IgG (<italic>p &lt; 0.001</italic>), but not for anti-<italic>Pf</italic>s48/45 IgG (<italic>p = 0.159</italic>). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens (<italic>Pf</italic>s230c OR [95% CI], <italic>p</italic>: 1.70 [1.10, 2.62], <italic>0.017</italic>; <italic>Pf</italic>s48/45: 1.45 [0.85, 2.46], <italic>0.174</italic>; <italic>Pf</italic>s230D1M: 1.70 [1.03, 2.80], <italic>0.037</italic>), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density <italic>Pf</italic>s230c OR [95% CI], <italic>p</italic>: 1.09 [1.02, 1.17], <italic>0.008</italic>; <italic>Pf</italic>s48/45: 1.05 [0.98, 1.13], <italic>0.185</italic>; <italic>Pf</italic>s230D1M: 1.07 [0.99, 1.14], <italic>0.071</italic>).</p></sec><sec><title>Conclusion</title><p><italic>Pf</italic>s230 and <italic>Pf</italic>s48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant <italic>P. falciparum</italic>.</p></sec>