{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:05:03Z","timestamp":1768565103053,"version":"3.49.0"},"posted":{"date-parts":[[2024,5,12]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":121,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    \u2019s life cycle.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We analyzed 325\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Rdatabase. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>\n                    Among the ten antigens analyzed, only three in the transmission-blocking vaccine category display\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    3D7 as the dominant haplotype. The antigens\n                    <jats:italic>\n                      AMA1, CSP, MSP1\n                      <jats:sub>19<\/jats:sub>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>CelTOS,<\/jats:italic>\n                    are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast,\n                    <jats:italic>Rh5<\/jats:italic>\n                    , a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for\n                    <jats:italic>CelTOS<\/jats:italic>\n                    , the transmission-blocking antigens\n                    <jats:italic>Pfs25<\/jats:italic>\n                    ,\n                    <jats:italic>Pfs48\/45<\/jats:italic>\n                    ,\n                    <jats:italic>Pfs230<\/jats:italic>\n                    ,\n                    <jats:italic>Pfs47<\/jats:italic>\n                    , and\n                    <jats:italic>Pfs28<\/jats:italic>\n                    exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretations<\/jats:title>\n                  <jats:p>\n                    These findings offer valuable insights into the selection of optimal vaccine candidates against\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    . Based on our results, we recommend prioritizing conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>Purdue Department of Biological Sciences; Puskas Memorial Fellowship; National Institute of Allergy and Infectious Diseases (U19AI089680).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in context<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Evidence before this study<\/jats:title>\n                    <jats:p>\n                      Decades of research on the most virulent malaria parasite,\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      , have yielded multiple antigen candidates of pre-erythrocytic, blood-stage, and transmission-blocking vaccines in varying stages of development from preclinical development to more advanced clinical trials. The malaria vaccine, RTS,S\/AS01, which was constructed using the C-terminal and NANP repeat region of the Circumsporozoite Protein (\n                      <jats:italic>CSP<\/jats:italic>\n                      ) from the African reference strain 3D7, was approved and recommended for use in 2021. However, the vaccine\u2019s lower efficacy is likely a result of the genetic polymorphism of the target antigen shown by studies on natural variation in\n                      <jats:italic>CSP<\/jats:italic>\n                      . Similarly, another more recent pre-erythrocytic vaccine, R21\/Matrix-M, showed great promise in clinical trials and was recommended in late 2023 by the WHO for use for prevention of malaria in children, but is also multi-dose and\n                      <jats:italic>CSP<\/jats:italic>\n                      -based. To maximize vaccine efficacy, it would be more strategic to first understand diversity and variation of antigens across the three types of vaccine classes, targeting various stages of the\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      life cycle. Previous studies have reported analyses of vaccine candidate antigens but were mostly limited to pre-erythrocytic and blood-stage antigens, with less focus on transmission-blocking antigens. These studies revealed that most of the pre-erythrocytic and blood-stage antigens are of high diversity due to balancing selection, posing challenges for vaccine design to encompass the antigenic variation.\n                    <\/jats:p>\n                    <jats:p>\n                      A search conducted on PubMed on April 1, 2024, for relevant published research which used the terms \u201cmalaria vaccine\u201d, \u201c\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      \u201d [not \u201c\n                      <jats:italic>vivax<\/jats:italic>\n                      \u201d], \u201cselection\u201d and \u201cdiversity\u201d yielded 48 studies between 1996 and the present day, with only 14 published studies in the past 3 years. This emphasizes the need for more studies assessing genetic diversity and selection of potential\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      vaccine candidates to aid in more effective vaccine development efforts. A similar search with the terms \u201ctransmission-blocking vaccine\u201d, \u201cmalaria\u201d, \u201c\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      \u201d, not \u201c\n                      <jats:italic>vivax<\/jats:italic>\n                      \u201d, \u201cselection\u201d and \u201cdiversity\u201d without any date or language restrictions revealed three relevant studies. This warrants future studies to explore transmission-blocking vaccines in this context.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Added value of this study<\/jats:title>\n                    <jats:p>\n                      By comparing the genetic and structural analyses of transmission-blocking antigens with pre-erythrocytic and blood-stage antigens, we identify promising\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      vaccine antigens characterized by their conservation with low balancing selection and the presence of infection\/transmission-blocking epitopes, which are essential for informing the development of new malaria vaccines. This comprehensive workflow can be adopted for studying the genetic and structural variation of other\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      vaccine targets before developing the next generation of malaria vaccines for effectiveness against natural parasite populations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications of this study<\/jats:title>\n                    <jats:p>\n                      Our suggested strategies for designing malaria vaccines include two possible approaches. We emphasize the development of a multi-stage vaccine that combines critical components such as anti-merozoite (\n                      <jats:italic>Rh5<\/jats:italic>\n                      ) and transmission-blocking antigens (\n                      <jats:italic>Pfs25<\/jats:italic>\n                      ,\n                      <jats:italic>Pfs28<\/jats:italic>\n                      ,\n                      <jats:italic>Pfs48\/45<\/jats:italic>\n                      ,\n                      <jats:italic>Pfs230<\/jats:italic>\n                      ). Alternatively, we suggest the creation of transmission-blocking vaccines specifically targeting\n                      <jats:italic>Pfs25<\/jats:italic>\n                      ,\n                      <jats:italic>Pfs28<\/jats:italic>\n                      and\n                      <jats:italic>Pfs48\/45<\/jats:italic>\n                      . These innovative approaches show great potential in advancing the development of more potent and effective malaria vaccines for the future.\n                    <\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2024.05.11.24307175","type":"posted-content","created":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T03:25:17Z","timestamp":1715570717000},"source":"Crossref","is-referenced-by-count":1,"title":["Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates in\n                  <i>Plasmodium falciparum<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6549-0771","authenticated-orcid":false,"given":"Ilinca I.","family":"Ciubotariu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley K.","family":"Broyles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaojun","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyothi","family":"Thimmapuram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mulenga C.","family":"Mwenda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brenda","family":"Mambwe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conceptor","family":"Mulube","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Japhet","family":"Matoba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Schue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6579-3513","authenticated-orcid":false,"given":"William J.","family":"Moss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Bridges","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1696-8203","authenticated-orcid":false,"given":"He","family":"Qixin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8137-6285","authenticated-orcid":false,"given":"Giovanna","family":"Carpi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024051507250850000_2024.05.11.24307175v1.1","doi-asserted-by":"publisher","DOI":"10.1586\/erv.12.92"},{"issue":"3","key":"2024051507250850000_2024.05.11.24307175v1.2","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3390\/vaccines8030400","article-title":"Pre-Erythrocytic Vaccines against Malaria","volume":"8","year":"2020","journal-title":"Vaccines"},{"issue":"1","key":"2024051507250850000_2024.05.11.24307175v1.3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41541-020-0196-3","article-title":"Malaria vaccines since 2000: progress, priorities, products","volume":"5","year":"2020","journal-title":"npj Vaccines"},{"issue":"1","key":"2024051507250850000_2024.05.11.24307175v1.4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s12936-020-3141-z","article-title":"Plasmodium falciparum pre-erythrocytic stage vaccine development","volume":"19","year":"2020","journal-title":"Malaria Journal"},{"key":"2024051507250850000_2024.05.11.24307175v1.5","unstructured":"WHO. 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