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Transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of Plasmodium falciparum AMA1
Apical membrane antigen 1 (AMA1) is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human and...
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| Published in: | PloS one 2011-06, Vol.6 (6), p.e20977 |
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| creator | Biswas, Sumi Dicks, Matthew D J Long, Carole A Remarque, Edmond J Siani, Loredana Colloca, Stefano Cottingham, Matthew G Holder, Anthony A Gilbert, Sarah C Hill, Adrian V S Draper, Simon J |
| description | Apical membrane antigen 1 (AMA1) is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human and simian adenoviral (AdHu5 and ChAd63) and orthopoxviral (MVA) vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1).
AdHu5-MVA prime-boost vaccination in mice and rabbits using these vectors encoding the 3D7 allele of PfAMA1 induced cellular immune responses as well as high-titer antibodies that showed growth inhibitory activity (GIA) against the homologous but not heterologous parasite strains. In an effort to overcome the issues of PfAMA1 antigenic polymorphism and pre-existing immunity to AdHu5, a simian adenoviral (ChAd63) vector and MVA encoding two alleles of PfAMA1 were developed. This antigen, composed of the 3D7 and FVO alleles of PfAMA1 fused in tandem and with expression driven by a single promoter, was optimized for antigen secretion and transmembrane expression. These bi-allelic PfAMA1 vaccines, when administered to mice and rabbits, demonstrated comparable immunogenicity to the mono-allelic vaccines and purified serum IgG now showed GIA against the two divergent strains of P. falciparum encoded in the vaccine. CD8(+) and CD4(+) T cell responses against epitopes that were both common and unique to the two alleles of PfAMA1 were also measured in mice.
Optimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. These data support the further clinical development of these vaccine candidates in Phase I/IIa clinical trials. |
| doi_str_mv | 10.1371/journal.pone.0020977 |
| format | article |
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AdHu5-MVA prime-boost vaccination in mice and rabbits using these vectors encoding the 3D7 allele of PfAMA1 induced cellular immune responses as well as high-titer antibodies that showed growth inhibitory activity (GIA) against the homologous but not heterologous parasite strains. In an effort to overcome the issues of PfAMA1 antigenic polymorphism and pre-existing immunity to AdHu5, a simian adenoviral (ChAd63) vector and MVA encoding two alleles of PfAMA1 were developed. This antigen, composed of the 3D7 and FVO alleles of PfAMA1 fused in tandem and with expression driven by a single promoter, was optimized for antigen secretion and transmembrane expression. These bi-allelic PfAMA1 vaccines, when administered to mice and rabbits, demonstrated comparable immunogenicity to the mono-allelic vaccines and purified serum IgG now showed GIA against the two divergent strains of P. falciparum encoded in the vaccine. CD8(+) and CD4(+) T cell responses against epitopes that were both common and unique to the two alleles of PfAMA1 were also measured in mice.
Optimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. These data support the further clinical development of these vaccine candidates in Phase I/IIa clinical trials.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0020977</identifier><identifier>PMID: 21698193</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenoviridae - genetics ; Adenoviruses ; Alleles ; Amino acids ; Animals ; Antibodies ; Antigenic determinants ; Antigens ; Apical membrane antigen 1 ; Avian flu ; Biology ; CD4 antigen ; CD8 antigen ; Clinical trials ; Coding ; Deoxyribonucleic acid ; DNA ; Drug dosages ; Drug therapy ; Encephalitis ; Epitopes ; Expression vectors ; Genetic Vectors ; Homology ; Immune response ; Immune response (cell-mediated) ; Immunity ; Immunization ; Immunogenicity ; Immunoglobulin G ; Immunoglobulins ; Infectious diseases ; Inserts ; Lymphocytes ; Lymphocytes T ; Malaria ; Malaria Vaccines - genetics ; Malaria Vaccines - immunology ; Malaria, Falciparum - prevention & control ; Medical research ; Medicine ; Mice ; Monkeys ; Optimization ; Orthopoxvirus - genetics ; Parasites ; Parasitology ; Plasmodium falciparum ; Plasmodium falciparum - genetics ; Plasmodium falciparum - immunology ; Polymorphism ; Proteins ; Rabbits ; Studies ; T cells ; Transgenes ; Vaccination ; Vaccines ; Vector-borne diseases</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e20977</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-a892be91528118fc111ec85ee4f16d6a39c0e714d0611508468ed230b947fd2d3</citedby><cites>FETCH-LOGICAL-c725t-a892be91528118fc111ec85ee4f16d6a39c0e714d0611508468ed230b947fd2d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1304043909/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1304043909?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21698193$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Moorthy, Vasee</contributor><creatorcontrib>Biswas, Sumi</creatorcontrib><creatorcontrib>Dicks, Matthew D J</creatorcontrib><creatorcontrib>Long, Carole A</creatorcontrib><creatorcontrib>Remarque, Edmond J</creatorcontrib><creatorcontrib>Siani, Loredana</creatorcontrib><creatorcontrib>Colloca, Stefano</creatorcontrib><creatorcontrib>Cottingham, Matthew G</creatorcontrib><creatorcontrib>Holder, Anthony A</creatorcontrib><creatorcontrib>Gilbert, Sarah C</creatorcontrib><creatorcontrib>Hill, Adrian V S</creatorcontrib><creatorcontrib>Draper, Simon J</creatorcontrib><title>Transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of Plasmodium falciparum AMA1</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Apical membrane antigen 1 (AMA1) is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human and simian adenoviral (AdHu5 and ChAd63) and orthopoxviral (MVA) vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1).
AdHu5-MVA prime-boost vaccination in mice and rabbits using these vectors encoding the 3D7 allele of PfAMA1 induced cellular immune responses as well as high-titer antibodies that showed growth inhibitory activity (GIA) against the homologous but not heterologous parasite strains. In an effort to overcome the issues of PfAMA1 antigenic polymorphism and pre-existing immunity to AdHu5, a simian adenoviral (ChAd63) vector and MVA encoding two alleles of PfAMA1 were developed. This antigen, composed of the 3D7 and FVO alleles of PfAMA1 fused in tandem and with expression driven by a single promoter, was optimized for antigen secretion and transmembrane expression. These bi-allelic PfAMA1 vaccines, when administered to mice and rabbits, demonstrated comparable immunogenicity to the mono-allelic vaccines and purified serum IgG now showed GIA against the two divergent strains of P. falciparum encoded in the vaccine. CD8(+) and CD4(+) T cell responses against epitopes that were both common and unique to the two alleles of PfAMA1 were also measured in mice.
Optimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. These data support the further clinical development of these vaccine candidates in Phase I/IIa clinical trials.</description><subject>Adenoviridae - genetics</subject><subject>Adenoviruses</subject><subject>Alleles</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigenic determinants</subject><subject>Antigens</subject><subject>Apical membrane antigen 1</subject><subject>Avian flu</subject><subject>Biology</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Clinical trials</subject><subject>Coding</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Encephalitis</subject><subject>Epitopes</subject><subject>Expression vectors</subject><subject>Genetic Vectors</subject><subject>Homology</subject><subject>Immune response</subject><subject>Immune response (cell-mediated)</subject><subject>Immunity</subject><subject>Immunization</subject><subject>Immunogenicity</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulins</subject><subject>Infectious diseases</subject><subject>Inserts</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Malaria</subject><subject>Malaria Vaccines - genetics</subject><subject>Malaria Vaccines - immunology</subject><subject>Malaria, Falciparum - prevention & control</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Monkeys</subject><subject>Optimization</subject><subject>Orthopoxvirus - genetics</subject><subject>Parasites</subject><subject>Parasitology</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - genetics</subject><subject>Plasmodium falciparum - immunology</subject><subject>Polymorphism</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Studies</subject><subject>T cells</subject><subject>Transgenes</subject><subject>Vaccination</subject><subject>Vaccines</subject><subject>Vector-borne diseases</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk22L1DAQx4so3nn6DUQDgiC4a9K0TfpGWA4fFk5O9PRtSNNpN0ub9JJ0vfUz-KHNur1jFxRMXmSY-c0_wzCTJE8JnhPKyJu1HZ2R3XywBuYYp7hk7F5ySkqazooU0_sH9knyyPs1xjnlRfEwOUlJUfIYPU1-XTlpfAsGkB2C7vVPGbQ1r5Hu-9HYGNBKhy2SpkbaoI0OziJoGq2k2iLbRI-THdqACtZBjTZSKW3AI7gZHHivTYvCD4tk10EX3THjcyd9b2s99qiRndKDdNFcfFqQx8mD6PHwZHrPkm_v312df5xdXH5Yni8uZoqleZhJXqYVlCRPOSG8UYQQUDwHyBpS1IWkpcLASFbjgpAc86zgUKcUV2XGmjqt6VnyfK87dNaLqZFeEIoznNESl5FY7onayrUYnO6l2wortfjjsK4V0gWtOhBAgJTxAK2qLFZS0TIaGYsPI4zSqPV2-m2seqgVmBBbdiR6HDF6JVq7EZSQgmc8CryYBJy9HsGHf5Q8Ua2MVWnT2Cimeu2VWGSs4JzxvIjU_C9UvDX0WsVRanT0HyW8OkqITICb0MrRe7H8-uX_2cvvx-zLA3YFsgsrb7txN33-GMz2oHLWewfNXecIFrtNuO2G2G2CmDYhpj077Ppd0u3o09_JfAWn</recordid><startdate>20110616</startdate><enddate>20110616</enddate><creator>Biswas, Sumi</creator><creator>Dicks, Matthew D J</creator><creator>Long, Carole A</creator><creator>Remarque, Edmond J</creator><creator>Siani, Loredana</creator><creator>Colloca, Stefano</creator><creator>Cottingham, Matthew G</creator><creator>Holder, Anthony A</creator><creator>Gilbert, Sarah C</creator><creator>Hill, Adrian V S</creator><creator>Draper, Simon J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110616</creationdate><title>Transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of Plasmodium falciparum AMA1</title><author>Biswas, Sumi ; Dicks, Matthew D J ; Long, Carole A ; Remarque, Edmond J ; Siani, Loredana ; Colloca, Stefano ; Cottingham, Matthew G ; Holder, Anthony A ; Gilbert, Sarah C ; Hill, Adrian V S ; Draper, Simon J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c725t-a892be91528118fc111ec85ee4f16d6a39c0e714d0611508468ed230b947fd2d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adenoviridae - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Biswas, Sumi</au><au>Dicks, Matthew D J</au><au>Long, Carole A</au><au>Remarque, Edmond J</au><au>Siani, Loredana</au><au>Colloca, Stefano</au><au>Cottingham, Matthew G</au><au>Holder, Anthony A</au><au>Gilbert, Sarah C</au><au>Hill, Adrian V S</au><au>Draper, Simon J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of Plasmodium falciparum AMA1</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-06-16</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e20977</spage><pages>e20977-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><notes>Conceived and designed the experiments: SB MGC AVSH SJD. Performed the experiments: SB MDJD CAL EJR LS SJD. Analyzed the data: SB CAL EJR. Contributed reagents/materials/analysis tools: SC AAH SCG. Wrote the paper: SB AVSH SJD.</notes><abstract>Apical membrane antigen 1 (AMA1) is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human and simian adenoviral (AdHu5 and ChAd63) and orthopoxviral (MVA) vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1).
AdHu5-MVA prime-boost vaccination in mice and rabbits using these vectors encoding the 3D7 allele of PfAMA1 induced cellular immune responses as well as high-titer antibodies that showed growth inhibitory activity (GIA) against the homologous but not heterologous parasite strains. In an effort to overcome the issues of PfAMA1 antigenic polymorphism and pre-existing immunity to AdHu5, a simian adenoviral (ChAd63) vector and MVA encoding two alleles of PfAMA1 were developed. This antigen, composed of the 3D7 and FVO alleles of PfAMA1 fused in tandem and with expression driven by a single promoter, was optimized for antigen secretion and transmembrane expression. These bi-allelic PfAMA1 vaccines, when administered to mice and rabbits, demonstrated comparable immunogenicity to the mono-allelic vaccines and purified serum IgG now showed GIA against the two divergent strains of P. falciparum encoded in the vaccine. CD8(+) and CD4(+) T cell responses against epitopes that were both common and unique to the two alleles of PfAMA1 were also measured in mice.
Optimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. These data support the further clinical development of these vaccine candidates in Phase I/IIa clinical trials.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21698193</pmid><doi>10.1371/journal.pone.0020977</doi><tpages>e20977</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-06, Vol.6 (6), p.e20977 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1304043909 |
| source | Open Access: PubMed Central; Publicly Available Content Database |
| subjects | Adenoviridae - genetics Adenoviruses Alleles Amino acids Animals Antibodies Antigenic determinants Antigens Apical membrane antigen 1 Avian flu Biology CD4 antigen CD8 antigen Clinical trials Coding Deoxyribonucleic acid DNA Drug dosages Drug therapy Encephalitis Epitopes Expression vectors Genetic Vectors Homology Immune response Immune response (cell-mediated) Immunity Immunization Immunogenicity Immunoglobulin G Immunoglobulins Infectious diseases Inserts Lymphocytes Lymphocytes T Malaria Malaria Vaccines - genetics Malaria Vaccines - immunology Malaria, Falciparum - prevention & control Medical research Medicine Mice Monkeys Optimization Orthopoxvirus - genetics Parasites Parasitology Plasmodium falciparum Plasmodium falciparum - genetics Plasmodium falciparum - immunology Polymorphism Proteins Rabbits Studies T cells Transgenes Vaccination Vaccines Vector-borne diseases |
| title | Transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of Plasmodium falciparum AMA1 |
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