{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T09:28:16Z","timestamp":1768642096034,"version":"3.49.0"},"reference-count":43,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"3_Suppl","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,9]]},"abstract":"<jats:title>ABSTRACT.<\/jats:title>\n<jats:p>In the early 1980s, Richard Carter was among the first researchers to identify the sexual stage-specific Pfs48\/45 protein, leading to the identification of target epitopes. Carter predicted its tertiary conformation while involved in a number of studies on naturally acquired sexual stage-specific antibodies. Pfs48\/45 is a cysteine-rich surface protein of sexual stages of <jats:italic>Plasmodium falciparum<\/jats:italic> that plays a critical role in male gamete fertility. Antibodies against Pfs48\/45 prevent parasite development in the mosquito vector, and therefore prevent the spread of malaria in the population. Since the gene was sequenced in the early 1990s, Pfs48\/45 has been considered a prime target candidate for a malaria transmission-blocking vaccine. However, major manufacturing challenges\u2014in particular, difficulty realizing satisfactory yields of a properly folded protein for the induction of functional antibodies\u2014delayed clinical development significantly. These challenges were met roughly 20 years later. The first clinical trial with a Pfs48\/45 subunit vaccine (R0.6C) was started in the Netherlands in early 2021. The excellent contributions to the long and winding path of Pfs48\/45 research by Richard Carter are well recognized and are an integrated part of his seminal contributions to unraveling <jats:italic>Plasmodium<\/jats:italic> sexual stage biology.<\/jats:p>","DOI":"10.4269\/ajtmh.21-1320","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T12:36:39Z","timestamp":1657542999000},"page":"22-26","source":"Crossref","is-referenced-by-count":15,"title":["40 Years of Pfs48\/45 Research as a Transmission-Blocking Vaccine Target of Plasmodium falciparum Malaria"],"prefix":"10.4269","volume":"107","author":[{"given":"Robert W.","family":"Sauerwein","sequence":"first","affiliation":[{"name":"TropIQ Health Sciences, Nijmegen, The Netherlands;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan","family":"Plieskatt","sequence":"additional","affiliation":[{"name":"Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Theisen","sequence":"additional","affiliation":[{"name":"Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark;"},{"name":"Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2795","reference":[{"key":"b1","series-title":"Philos Trans R Soc Lond B Biol Sci","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1098\/rstb.1984.0120","article-title":"Target antigens in malaria transmission blocking immunity","volume":"307","author":"Carter","year":"1984"},{"key":"b2","series-title":"J Immunol","first-page":"2557","article-title":"Monoclonal antibodies against surface determinants on gametes of Plasmodium gallinaceum block transmission of malaria parasites to mosquitoes","volume":"131","author":"Kaushal","year":"1983"},{"key":"b3","series-title":"J Exp Med","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1084\/jem.162.5.1460","article-title":"Sequential expression of antigens on sexual stages of Plasmodium falciparum accessible to transmission-blocking antibodies in the mosquito","volume":"162","author":"Vermeulen","year":"1985"},{"key":"b4","series-title":"Mol Biochem Parasitol","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/0166-6851(86)90027-7","article-title":"Characterization of Plasmodium falciparum sexual stage antigens and their biosynthesis in synchronised gametocyte cultures","volume":"20","author":"Vermeulen","year":"1986"},{"key":"b5","series-title":"Mol Biochem Parasitol","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0166-6851(93)90158-T","article-title":"Cloning and expression of the gene coding for the transmission blocking target antigen Pfs48\/45 of Plasmodium falciparum.","volume":"61","author":"Kocken","year":"1993"},{"key":"b6","series-title":"Parasite Immunol","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/j.1365-3024.1987.tb00511.x","article-title":"Target antigens of malaria transmission blocking immunity exist as a stable membrane bound complex","volume":"9","author":"Kumar","year":"1987"},{"key":"b7","series-title":"Cell","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/S0092-8674(01)00199-4","article-title":"A central role for P48\/45 in malaria parasite male gamete fertility","volume":"104","author":"van Dijk","year":"2001"},{"key":"b8","series-title":"Mol Biochem Parasitol","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/0166-6851(94)00054-Q","article-title":"Predicted disulfide-bonded structures for three uniquely related proteins of Plasmodium falciparum, Pfs230, Pfs48\/45 and Pf12","volume":"71","author":"Carter","year":"1995"},{"key":"b9","series-title":"Pharm Res","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1007\/s11095-017-2208-1","article-title":"Expression, purification and characterization of GMZ2\u2032.10C, a complex disulphide-bonded fusion protein vaccine candidate against the asexual and sexual life-stages of the malaria-causing Plasmodium falciparum parasite","volume":"34","author":"Mistarz","year":"2017"},{"key":"b10","series-title":"Nat Commun","doi-asserted-by":"publisher","first-page":"4458","DOI":"10.1038\/s41467-018-06742-9","article-title":"Structural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48\/45","volume":"9","author":"Kundu","year":"2018"},{"key":"b11","series-title":"Proc Natl Acad Sci USA","doi-asserted-by":"publisher","first-page":"6692","DOI":"10.1073\/pnas.1204363109","article-title":"Structure of the Plasmodium 6-cysteine s48\/45 domain","volume":"109","author":"Arredondo","year":"2012"},{"key":"b12","series-title":"Proc Natl Acad Sci USA","doi-asserted-by":"publisher","first-page":"13598","DOI":"10.1073\/pnas.0502378102","article-title":"Structural models for the protein family characterized by gamete surface protein Pfs230 of Plasmodium falciparum.","volume":"102","author":"Gerloff","year":"2005"},{"key":"b13","series-title":"J Biol Chem","doi-asserted-by":"publisher","first-page":"17148","DOI":"10.1074\/jbc.M700948200","article-title":"Epitope analysis of the malaria surface antigen pfs48\/45 identifies a subdomain that elicits transmission blocking antibodies","volume":"282","author":"Outchkourov","year":"2007"},{"key":"b14","series-title":"Parasite Immunol","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1111\/j.1365-3024.1990.tb00990.x","article-title":"Properties of epitopes of Pfs 48\/45, a target of transmission blocking monoclonal antibodies, on gametes of different isolates of Plasmodium falciparum.","volume":"12","author":"Carter","year":"1990"},{"key":"b15","series-title":"Exp Parasitol","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1006\/expr.2000.4586","article-title":"Plasmodium falciparum: production and characterization of rat monoclonal antibodies specific for the sexual-stage Pfs48\/45 antigen","volume":"97","author":"Roeffen","year":"2001"},{"key":"b16","series-title":"Proc Natl Acad Sci USA","doi-asserted-by":"publisher","first-page":"4301","DOI":"10.1073\/pnas.0800459105","article-title":"Correctly folded Pfs48\/45 protein of Plasmodium falciparum elicits malaria transmission-blocking immunity in mice","volume":"105","author":"Outchkourov","year":"2008"},{"key":"b17","series-title":"Nat Commun","doi-asserted-by":"publisher","first-page":"3822","DOI":"10.1038\/s41467-018-06340-9","article-title":"Structural basis for recognition of the malaria vaccine candidate Pfs48\/45 by a transmission blocking antibody","volume":"9","author":"Lennartz","year":"2018"},{"key":"b18","series-title":"Parasite Immunol","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1111\/j.1365-3024.1988.tb00215.x","article-title":"Antibodies to Plasmodium falciparum gamete surface antigens in Papua New Guinea sera","volume":"10","author":"Graves","year":"1988"},{"key":"b19","series-title":"Front Immunol","doi-asserted-by":"publisher","first-page":"2480","DOI":"10.3389\/fimmu.2019.02480","article-title":"Immune responses to gametocyte antigens in a malaria endemic population: the African falciparum context: a systematic review and meta-analysis","volume":"10","author":"Muthui","year":"2019"},{"key":"b20","series-title":"PLoS One","doi-asserted-by":"publisher","first-page":"e14114","DOI":"10.1371\/journal.pone.0014114","article-title":"The dynamics of naturally acquired immune responses to Plasmodium falciparum sexual stage antigens Pfs230 & Pfs48\/45 in a low endemic area in Tanzania","volume":"5","author":"Bousema","year":"2010"},{"key":"b21","series-title":"Res Immunol","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/0923-2494(91)90150-H","article-title":"Transmission blocking immunity may provide clues that antimalarial immunity is largely T-independent","volume":"142","author":"Mendis","year":"1991"},{"key":"b22","series-title":"Am J Trop Med Hyg","doi-asserted-by":"publisher","first-page":"711","DOI":"10.4269\/ajtmh.1992.46.711","article-title":"Human antibody responses to epitopes on the Plasmodium falciparum gametocyte antigen Pfs 48\/45 and their relationship to infectivity of gametocyte carriers","volume":"46","author":"Graves","year":"1992"},{"key":"b23","series-title":"J Infect","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.jinf.2015.03.007","article-title":"Naturally acquired antibody responses to recombinant Pfs230 and Pfs48\/45 transmission blocking vaccine candidates","volume":"71","author":"Jones","year":"2015"},{"key":"b24","series-title":"Infect Immunol","doi-asserted-by":"publisher","first-page":"4957","DOI":"10.1128\/IAI.05288-11","article-title":"Naturally acquired immune responses to Plasmodium falciparum sexual stage antigens Pfs48\/45 and Pfs230 in an area of seasonal transmission","volume":"79","author":"Ou\u00e9draogo","year":"2011"},{"key":"b25","series-title":"Parasitology","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1017\/S0031182015001341","article-title":"Naturally acquired immunity to sexual stage P. falciparum parasites","volume":"143","author":"Stone","year":"2016"},{"key":"b26","series-title":"Parasite Immunol","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/j.1365-3024.1994.tb00302.x","article-title":"Plasmodium falciparum malaria transmission-blocking immunity under conditions of low endemicity as in Sri Lanka","volume":"16","author":"Premawansa","year":"1994"},{"key":"b27","series-title":"Nat Commun","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1038\/s41467-017-02646-2","article-title":"Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity","volume":"9","author":"Stone","year":"2018"},{"key":"b28","series-title":"Curr Mol Med","doi-asserted-by":"publisher","first-page":"223","DOI":"10.2174\/156652406776055140","article-title":"Sexual-stage antibody responses to P. falciparum in endemic populations","volume":"6","author":"Bousema","year":"2006"},{"key":"b29","series-title":"Immunol Rev","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1111\/imr.12828","article-title":"Immunity against sexual stage Plasmodium falciparum and Plasmodium vivax parasites","volume":"293","author":"de Jong","year":"2020"},{"key":"b30","series-title":"Mol Biochem Parasitol","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/S0166-6851(01)00278-X","article-title":"Extreme geographical fixation of variation in the Plasmodium falciparum gamete surface protein gene Pfs48\/45 compared with microsatellite loci","volume":"115","author":"Conway","year":"2001"},{"key":"b31","series-title":"Am J Trop Med Hyg","doi-asserted-by":"publisher","first-page":"143","DOI":"10.4269\/ajtmh.15-0571","article-title":"Pooled amplicon deep sequencing of candidate Plasmodium falciparum transmission-blocking vaccine antigens","volume":"94","author":"Juliano","year":"2016"},{"key":"b32","series-title":"Sci Transl Med","first-page":"2ra5","article-title":"Extreme polymorphism in a vaccine antigen and risk of clinical malaria: implications for vaccine development","volume":"1","author":"Takala","year":"2009"},{"key":"b33","series-title":"NPJ Vaccines","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41541-021-00366-9","article-title":"Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes","volume":"6","author":"de Jong","year":"2021"},{"key":"b34","series-title":"Expert Rev Vaccines","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1080\/14760584.2017.1276833","article-title":"Towards clinical development of a Pfs48\/45-based transmission blocking malaria vaccine","volume":"16","author":"Theisen","year":"2017"},{"key":"b35","series-title":"Vaccine","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.1016\/j.vaccine.2014.03.020","article-title":"A multi-stage malaria vaccine candidate targeting both transmission and asexual parasite life-cycle stages","volume":"32","author":"Theisen","year":"2014"},{"key":"b36","series-title":"Expert Rev Vaccines","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1080\/14760584.2017.1355246","article-title":"The GMZ2 malaria vaccine: from concept to efficacy in humans","volume":"16","author":"Theisen","year":"2017"},{"key":"b37","series-title":"Microb Cell Fact","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s12934-017-0710-0","article-title":"Construct design, production, and characterization of Plasmodium falciparum 48\/45 R0.6C subunit protein produced in Lactococcus lactis as candidate vaccine","volume":"16","author":"Singh","year":"2017"},{"key":"b38","series-title":"Vaccine","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1016\/j.vaccine.2015.02.040","article-title":"A Plasmodium falciparum 48\/45 single epitope R0.6C subunit protein elicits high levels of transmission blocking antibodies","volume":"33","author":"Singh","year":"2015"},{"key":"b39","series-title":"Front Immunol","doi-asserted-by":"publisher","first-page":"606266","DOI":"10.3389\/fimmu.2020.606266","article-title":"A reproducible and scalable process for manufacturing a Pfs48\/45 Based Plasmodium falciparum transmission-blocking vaccine","volume":"11","author":"Singh","year":"2021"},{"key":"b40","series-title":"Clin Vaccine Immunol","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1128\/CVI.05104-11","article-title":"N-terminal prodomain of Pfs230 synthesized using a cell-free system is sufficient to induce complement-dependent malaria transmission-blocking activity","volume":"18","author":"Tachibana","year":"2011"},{"key":"b41","series-title":"Front Immunol","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.3389\/fimmu.2019.01256","article-title":"Pfs230 and Pfs48\/45 fusion proteins elicit strong transmission-blocking antibody responses against Plasmodium falciparum.","volume":"10","author":"Singh","year":"2019"},{"key":"b42","series-title":"NPJ Vaccines","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41541-021-00383-8","article-title":"Preclinical development of a Pfs230-Pfs48\/45 chimeric malaria transmission-blocking vaccine","volume":"6","author":"Singh","year":"2021"},{"key":"b43","doi-asserted-by":"publisher","year":"2017","DOI":"10.1098\/rstb.1984.0120"}],"container-title":["The American Journal of Tropical Medicine and Hygiene"],"original-title":[],"link":[{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/107\/3_Suppl\/article-p22.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/107\/3_Suppl\/article-p22.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/107\/3_Suppl\/article-p22.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T14:22:18Z","timestamp":1662733338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/107\/3_Suppl\/article-p22.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,9]]},"references-count":43,"journal-issue":{"issue":"3_Suppl"},"URL":"https:\/\/doi.org\/10.4269\/ajtmh.21-1320","relation":{},"ISSN":["0002-9637","1476-1645"],"issn-type":[{"value":"0002-9637","type":"print"},{"value":"1476-1645","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,9]]}}}