Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice
BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in...
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| Veröffentlicht in: | The Journal of clinical investigation 2021-04, Vol.131 (7), p.1-9 |
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| creator | Healy, Sara A Anderson, Charles Swihart, Bruce J Mwakingwe, Agnes Gabriel, Erin E Decederfelt, Hope Hobbs, Charlotte V Rausch, Kelly M Zhu, Daming Muratova, Olga Herrera, Raul Scaria, Puthupparampil V MacDonald, Nicholas J Lambert, Lynn E Zaidi, Irfan Coelho, Camila H Renn, Jonathan P Wu, Yimin Narum, David L Duffy, Patrick E |
| description | BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. |
| doi_str_mv | 10.1172/JCI146221 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_464455</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A657723646</galeid><sourcerecordid>A657723646</sourcerecordid><originalsourceid>FETCH-LOGICAL-c685t-297b378a20842da4b5d51499104dd9424cf480ee8aba444c6c4bce96e0c194893</originalsourceid><addsrcrecordid>eNqNkktv1DAQxyMEoqVw4AsgS0gIDim24zj2pVK14rGoUhGvq-U4k8Rt1i6xs7DfHq-6bBu0B-SDrZnf_MfzyLLnBJ8SUtG3nxZLwjil5EF2TMpS5IIW4mF2jDEluawKcZQ9CeEKY8JYyR5nR0VRcoIJP87gcxtogdHGwtAE1NuuhxGt9KBHq1EctQsrG4L1Lq8Hb66t69BaG2MdIG2iXdu4QbHXDm2FSmQd6qdVikL1FJHzEa2sgafZo1YPAZ7t7pPs-_t33xYf84vLD8vF-UVuuChjTmVVF5XQFAtGG83qsikJk5Jg1jSSUWZaJjCA0LVmjBluWG1AcsCGSCZkcZLlt7rhF9xMtboZ7UqPG-W1VTvTdXqBYjx1okz82S2fPCtoDLhU8TALm3uc7VXn10pgQoQQSeD1TmD0PycIUaVuGRgG7cBPQVEmBJFY8m2ul_-gV34aXWqHoiWWFZaCyzuq0wMo61qf8pqtqDrnZVXRgjN-V-eM6sBB-qR30NpknvGnB_h0GkjjORjwZhaQmAi_Y6enENTy65f_Zy9_zNlX99ge9BD74IcppgULB0XN6EMYod0PhWC1XXq1X_rEvrg_xT35d8uLP4-p9_o</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2509709869</pqid></control><display><type>article</type><title>Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>SWEPUB Freely available online</source><creator>Healy, Sara A ; Anderson, Charles ; Swihart, Bruce J ; Mwakingwe, Agnes ; Gabriel, Erin E ; Decederfelt, Hope ; Hobbs, Charlotte V ; Rausch, Kelly M ; Zhu, Daming ; Muratova, Olga ; Herrera, Raul ; Scaria, Puthupparampil V ; MacDonald, Nicholas J ; Lambert, Lynn E ; Zaidi, Irfan ; Coelho, Camila H ; Renn, Jonathan P ; Wu, Yimin ; Narum, David L ; Duffy, Patrick E</creator><creatorcontrib>Healy, Sara A ; Anderson, Charles ; Swihart, Bruce J ; Mwakingwe, Agnes ; Gabriel, Erin E ; Decederfelt, Hope ; Hobbs, Charlotte V ; Rausch, Kelly M ; Zhu, Daming ; Muratova, Olga ; Herrera, Raul ; Scaria, Puthupparampil V ; MacDonald, Nicholas J ; Lambert, Lynn E ; Zaidi, Irfan ; Coelho, Camila H ; Renn, Jonathan P ; Wu, Yimin ; Narum, David L ; Duffy, Patrick E</creatorcontrib><description>BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI146221</identifier><identifier>PMID: 33561016</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Antibodies ; Antigens ; Biomedical research ; Clinical Medicine ; Clinical trials ; Control ; Disease transmission ; Enzyme-linked immunosorbent assay ; Experiments ; Health aspects ; Immune response ; Immunogenicity ; Malaria ; Membrane proteins ; Mosquitoes ; Parasite vaccines ; Parasites ; Pharmaceutical research ; Proteins ; Vaccines</subject><ispartof>The Journal of clinical investigation, 2021-04, Vol.131 (7), p.1-9</ispartof><rights>COPYRIGHT 2021 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Apr 2021</rights><rights>2021 Healy et al. 2021 Healy et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c685t-297b378a20842da4b5d51499104dd9424cf480ee8aba444c6c4bce96e0c194893</citedby><cites>FETCH-LOGICAL-c685t-297b378a20842da4b5d51499104dd9424cf480ee8aba444c6c4bce96e0c194893</cites><orcidid>0000-0003-3041-5402 ; 0000-0002-4483-5005 ; 0000-0001-9161-2050 ; 0000-0002-8162-4514 ; 0000-0002-7885-9996</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011888/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011888/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33561016$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:146617085$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Healy, Sara A</creatorcontrib><creatorcontrib>Anderson, Charles</creatorcontrib><creatorcontrib>Swihart, Bruce J</creatorcontrib><creatorcontrib>Mwakingwe, Agnes</creatorcontrib><creatorcontrib>Gabriel, Erin E</creatorcontrib><creatorcontrib>Decederfelt, Hope</creatorcontrib><creatorcontrib>Hobbs, Charlotte V</creatorcontrib><creatorcontrib>Rausch, Kelly M</creatorcontrib><creatorcontrib>Zhu, Daming</creatorcontrib><creatorcontrib>Muratova, Olga</creatorcontrib><creatorcontrib>Herrera, Raul</creatorcontrib><creatorcontrib>Scaria, Puthupparampil V</creatorcontrib><creatorcontrib>MacDonald, Nicholas J</creatorcontrib><creatorcontrib>Lambert, Lynn E</creatorcontrib><creatorcontrib>Zaidi, Irfan</creatorcontrib><creatorcontrib>Coelho, Camila H</creatorcontrib><creatorcontrib>Renn, Jonathan P</creatorcontrib><creatorcontrib>Wu, Yimin</creatorcontrib><creatorcontrib>Narum, David L</creatorcontrib><creatorcontrib>Duffy, Patrick E</creatorcontrib><title>Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.</description><subject>Antibodies</subject><subject>Antigens</subject><subject>Biomedical research</subject><subject>Clinical Medicine</subject><subject>Clinical trials</subject><subject>Control</subject><subject>Disease transmission</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Experiments</subject><subject>Health aspects</subject><subject>Immune response</subject><subject>Immunogenicity</subject><subject>Malaria</subject><subject>Membrane proteins</subject><subject>Mosquitoes</subject><subject>Parasite vaccines</subject><subject>Parasites</subject><subject>Pharmaceutical research</subject><subject>Proteins</subject><subject>Vaccines</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>D8T</sourceid><recordid>eNqNkktv1DAQxyMEoqVw4AsgS0gIDim24zj2pVK14rGoUhGvq-U4k8Rt1i6xs7DfHq-6bBu0B-SDrZnf_MfzyLLnBJ8SUtG3nxZLwjil5EF2TMpS5IIW4mF2jDEluawKcZQ9CeEKY8JYyR5nR0VRcoIJP87gcxtogdHGwtAE1NuuhxGt9KBHq1EctQsrG4L1Lq8Hb66t69BaG2MdIG2iXdu4QbHXDm2FSmQd6qdVikL1FJHzEa2sgafZo1YPAZ7t7pPs-_t33xYf84vLD8vF-UVuuChjTmVVF5XQFAtGG83qsikJk5Jg1jSSUWZaJjCA0LVmjBluWG1AcsCGSCZkcZLlt7rhF9xMtboZ7UqPG-W1VTvTdXqBYjx1okz82S2fPCtoDLhU8TALm3uc7VXn10pgQoQQSeD1TmD0PycIUaVuGRgG7cBPQVEmBJFY8m2ul_-gV34aXWqHoiWWFZaCyzuq0wMo61qf8pqtqDrnZVXRgjN-V-eM6sBB-qR30NpknvGnB_h0GkjjORjwZhaQmAi_Y6enENTy65f_Zy9_zNlX99ge9BD74IcppgULB0XN6EMYod0PhWC1XXq1X_rEvrg_xT35d8uLP4-p9_o</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Healy, 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yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice</title><author>Healy, Sara A ; Anderson, Charles ; Swihart, Bruce J ; Mwakingwe, Agnes ; Gabriel, Erin E ; Decederfelt, Hope ; Hobbs, Charlotte V ; Rausch, Kelly M ; Zhu, Daming ; Muratova, Olga ; Herrera, Raul ; Scaria, Puthupparampil V ; MacDonald, Nicholas J ; Lambert, Lynn E ; Zaidi, Irfan ; Coelho, Camila H ; Renn, Jonathan P ; Wu, Yimin ; Narum, David L ; Duffy, Patrick E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c685t-297b378a20842da4b5d51499104dd9424cf480ee8aba444c6c4bce96e0c194893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antibodies</topic><topic>Antigens</topic><topic>Biomedical research</topic><topic>Clinical Medicine</topic><topic>Clinical trials</topic><topic>Control</topic><topic>Disease transmission</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Experiments</topic><topic>Health aspects</topic><topic>Immune response</topic><topic>Immunogenicity</topic><topic>Malaria</topic><topic>Membrane proteins</topic><topic>Mosquitoes</topic><topic>Parasite vaccines</topic><topic>Parasites</topic><topic>Pharmaceutical research</topic><topic>Proteins</topic><topic>Vaccines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Healy, Sara A</creatorcontrib><creatorcontrib>Anderson, Charles</creatorcontrib><creatorcontrib>Swihart, Bruce J</creatorcontrib><creatorcontrib>Mwakingwe, Agnes</creatorcontrib><creatorcontrib>Gabriel, Erin E</creatorcontrib><creatorcontrib>Decederfelt, Hope</creatorcontrib><creatorcontrib>Hobbs, Charlotte V</creatorcontrib><creatorcontrib>Rausch, Kelly M</creatorcontrib><creatorcontrib>Zhu, Daming</creatorcontrib><creatorcontrib>Muratova, Olga</creatorcontrib><creatorcontrib>Herrera, Raul</creatorcontrib><creatorcontrib>Scaria, Puthupparampil 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investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Healy, Sara A</au><au>Anderson, Charles</au><au>Swihart, Bruce J</au><au>Mwakingwe, Agnes</au><au>Gabriel, Erin E</au><au>Decederfelt, Hope</au><au>Hobbs, Charlotte V</au><au>Rausch, Kelly M</au><au>Zhu, Daming</au><au>Muratova, Olga</au><au>Herrera, Raul</au><au>Scaria, Puthupparampil V</au><au>MacDonald, Nicholas J</au><au>Lambert, Lynn E</au><au>Zaidi, Irfan</au><au>Coelho, Camila H</au><au>Renn, Jonathan P</au><au>Wu, Yimin</au><au>Narum, David L</au><au>Duffy, Patrick E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2021-04-01</date><risdate>2021</risdate><volume>131</volume><issue>7</issue><spage>1</spage><epage>9</epage><pages>1-9</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>33561016</pmid><doi>10.1172/JCI146221</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-3041-5402</orcidid><orcidid>https://orcid.org/0000-0002-4483-5005</orcidid><orcidid>https://orcid.org/0000-0001-9161-2050</orcidid><orcidid>https://orcid.org/0000-0002-8162-4514</orcidid><orcidid>https://orcid.org/0000-0002-7885-9996</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2021-04, Vol.131 (7), p.1-9 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_464455 |
| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; SWEPUB Freely available online |
| subjects | Antibodies Antigens Biomedical research Clinical Medicine Clinical trials Control Disease transmission Enzyme-linked immunosorbent assay Experiments Health aspects Immune response Immunogenicity Malaria Membrane proteins Mosquitoes Parasite vaccines Parasites Pharmaceutical research Proteins Vaccines |
| title | Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T05%3A02%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pfs230%20yields%20higher%20malaria%20transmission-blocking%20vaccine%20activity%20than%20Pfs25%20in%20humans%20but%20not%20mice&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Healy,%20Sara%20A&rft.date=2021-04-01&rft.volume=131&rft.issue=7&rft.spage=1&rft.epage=9&rft.pages=1-9&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI146221&rft_dat=%3Cgale_swepu%3EA657723646%3C/gale_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2509709869&rft_id=info:pmid/33561016&rft_galeid=A657723646&rfr_iscdi=true |