{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:53:19Z","timestamp":1790635999077,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010016","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37AI080289"],"award-info":[{"award-number":["R37AI080289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ragon Institute Sundry"},{"name":"SAMANA Kay MGH Research Scholar Program"},{"DOI":"10.13039\/100000865","name":"Gates Foundation","doi-asserted-by":"crossref","award":["OPP1151840"],"award-info":[{"award-number":["OPP1151840"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MGH ECOR Scholars Program"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1\/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime\/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA\/vector, vector\/vector and DNA\/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA\/rAd5 and rAd35\/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies.<\/jats:p>\n<jats:p><jats:bold>Trial registration<\/jats:bold>: ClinicalTrials.gov <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00801697\" xlink:type=\"simple\">NCT00801697<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00961883\" xlink:type=\"simple\">NCT00961883<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02207920\" xlink:type=\"simple\">NCT02207920<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00125970\" xlink:type=\"simple\">NCT00125970<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02852005\" xlink:type=\"simple\">NCT02852005<\/jats:ext-link>).<\/jats:p>","DOI":"10.1371\/journal.ppat.1010016","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T18:52:27Z","timestamp":1638211947000},"page":"e1010016","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2307-3379","authenticated-orcid":true,"given":"Stephanie","family":"Fischinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3231-7726","authenticated-orcid":true,"given":"Deniz","family":"Cizmeci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5310-5883","authenticated-orcid":true,"given":"Davy","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon P.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1298-3676","authenticated-orcid":true,"given":"Nicole","family":"Frahm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2276-7117","authenticated-orcid":true,"given":"Julie","family":"McElrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1013-5107","authenticated-orcid":true,"given":"Jonathan","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7685-8968","authenticated-orcid":true,"given":"Pierre-Alexandre","family":"Bart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pantaleo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Keefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"O. Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Rouphael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Churchyard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-2001","authenticated-orcid":true,"given":"Zoe","family":"Moodie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeycy","family":"Donastorg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0335-6390","authenticated-orcid":true,"given":"Hendrik","family":"Streeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7680-9215","authenticated-orcid":true,"given":"Galit","family":"Alter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"ppat.1010016.ref001","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1056\/NEJMoa1600693","article-title":"Antiretroviral Therapy for the Prevention of HIV-1 Transmission","volume":"375","author":"MS Cohen","year":"2016","journal-title":"N Engl J Med"},{"key":"ppat.1010016.ref002","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1097\/QAD.0000000000001145","article-title":"Effectiveness and safety of oral HIV preexposure prophylaxis for all populations","volume":"30","author":"VA Fonner","year":"2016","journal-title":"AIDS"},{"key":"ppat.1010016.ref003","unstructured":"UNAIDS. 2017 Global HIV Statistics. Fact sheet. 2018."},{"key":"ppat.1010016.ref004","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1056\/NEJMp1312711","article-title":"The Quest for an HIV-1 Vaccine\u2014Moving Forward","volume":"369","author":"DH Barouch","year":"2013","journal-title":"N Engl J Med"},{"key":"ppat.1010016.ref005","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1056\/NEJMoa0908492","article-title":"Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand","volume":"361","author":"S Rerks-Ngarm","year":"2009","journal-title":"N Engl J Med"},{"key":"ppat.1010016.ref006","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S1473-3099(12)70088-9","article-title":"Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B\/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144.","volume":"12","author":"ML Robb","year":"2012","journal-title":"Lancet Infect Dis."},{"key":"ppat.1010016.ref007","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1056\/NEJMoa1113425","article-title":"Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial","volume":"366","author":"BF Haynes","year":"2012","journal-title":"N Engl J Med"},{"key":"ppat.1010016.ref008","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0075665","article-title":"Plasma IgG to Linear Epitopes in the V2 and V3 Regions of HIV-1 gp120 Correlate with a Reduced Risk of Infection in the RV144 Vaccine Efficacy Trial.","volume":"8","author":"R Gottardo","year":"2013","journal-title":"PLoS One"},{"key":"ppat.1010016.ref009","doi-asserted-by":"crossref","first-page":"228ra39","DOI":"10.1126\/scitranslmed.3007730","article-title":"Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination.","volume":"6","author":"NL Yates","year":"2014","journal-title":"Sci Transl Med."},{"key":"ppat.1010016.ref010","doi-asserted-by":"crossref","first-page":"e87572","DOI":"10.1371\/journal.pone.0087572","article-title":"Vaccine-Induced IgG Antibodies to V1V2 Regions of Multiple HIV-1 Subtypes Correlate with Decreased Risk of HIV-1 Infection.","volume":"9","author":"S Zolla-Pazner","year":"2014","journal-title":"PLoS One."},{"key":"ppat.1010016.ref011","unstructured":"National Institutes of Health. Experimental HIV Vaccine Regimen Ineffective in Preventing HIV. In: www.nih.gov. 2020."},{"key":"ppat.1010016.ref012","doi-asserted-by":"crossref","first-page":"4838","DOI":"10.1172\/JCI126391","article-title":"Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk","volume":"129","author":"SD Neidich","year":"2019","journal-title":"J Clin Invest"},{"key":"ppat.1010016.ref013","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1089\/aid.2016.0204","article-title":"Comparison of Antibody Responses Induced by RV144, VAX003, and VAX004 Vaccination Regimens","volume":"33","author":"C Karnasuta","year":"2017","journal-title":"AIDS Res Hum Retroviruses"},{"key":"ppat.1010016.ref014","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1126\/scitranslmed.3007736","article-title":"Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines.","volume":"6","author":"AW Chung","year":"2014","journal-title":"Sci Transl Med"},{"key":"ppat.1010016.ref015","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.135057","article-title":"Protein-based, but not viral vector alone, HIV vaccine boosting drives an IgG1-biased polyfunctional humoral immune response.","volume":"5","author":"S Fischinger","year":"2020","journal-title":"JCI Insight."},{"key":"ppat.1010016.ref016","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1182\/blood-2006-06-027136","article-title":"Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-\u03b2","volume":"109","author":"J Zhu","year":"2007","journal-title":"Blood"},{"key":"ppat.1010016.ref017","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1128\/JVI.02386-13","article-title":"The Canarypox Virus Vector ALVAC Induces Distinct Cytokine Responses Compared to the Vaccinia Virus-Based Vectors MVA and NYVAC in Rhesus Monkeys","volume":"88","author":"JE Teigler","year":"2014","journal-title":"J Virol"},{"key":"ppat.1010016.ref018","doi-asserted-by":"crossref","first-page":"4843","DOI":"10.1172\/JCI75894","article-title":"HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial","volume":"124","author":"P-A Bart","year":"2014","journal-title":"J Clin Invest"},{"key":"ppat.1010016.ref019","doi-asserted-by":"crossref","first-page":"e45840","DOI":"10.1371\/journal.pone.0045840","article-title":"Heterologous Prime-Boost Regimens Using rAd35 and rMVA Vectors Elicit Stronger Cellular Immune Responses to HIV Proteins Than Homologous Regimens","volume":"7","author":"S Ratto-Kim","year":"2012","journal-title":"PLoS One."},{"key":"ppat.1010016.ref020","doi-asserted-by":"crossref","first-page":"11434","DOI":"10.1128\/JVI.78.20.11434-11438.2004","article-title":"Heterologous Human Immunodeficiency Virus Type 1 Priming-Boosting Immunization Strategies Involving Replication-Defective Adenovirus and Poxvirus Vaccine Vectors","volume":"78","author":"DR Casimiro","year":"2004","journal-title":"J Virol"},{"key":"ppat.1010016.ref021","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.4161\/hv.20778","article-title":"Poxvirus vectors as HIV\/AIDS vaccines in humans","volume":"8","author":"C Elena G\u00f3mez","year":"2012","journal-title":"Hum Vaccin Immunother"},{"key":"ppat.1010016.ref022","doi-asserted-by":"crossref","first-page":"8525","DOI":"10.1128\/JVI.01265-15","article-title":"Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates","volume":"89","author":"J Garc\u00eda-Arriaza","year":"2015","journal-title":"J Virol"},{"key":"ppat.1010016.ref023","article-title":"Developments in Viral Vector-Based Vaccines.","author":"T Ura","year":"2014","journal-title":"Vaccines"},{"key":"ppat.1010016.ref024","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1517\/14712598.8.9.1347","article-title":"Replicating adenovirus vector prime\/protein boost strategies for HIV vaccine development","volume":"8","author":"LJ Patterson","year":"2008","journal-title":"Expert Opin Biol Ther"},{"key":"ppat.1010016.ref025","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1126\/science.1070441","article-title":"Diversity Considerations in HIV-1 Vaccine Selection.","volume":"296","author":"B. 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