{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:47:08Z","timestamp":1790801228575,"version":"4.1.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Stabilized HIV envelope (Env) trimeric protein immunogens have been shown to induce strong autologous neutralizing antibody response. However, there is limited data on the immunogenicity and efficacy of stabilized Env expressed by a viral vector-based immunogen. Here, we compared the immunogenicity and efficacy of two modified vaccinia Ankara (MVA) vaccines based on variable loop 2 hotspot (V2 HS) optimized C.1086 envelope (Env) sequences, one expressing the membrane anchored gp150 (MVA-150) and the other expressing soluble uncleaved pre-fusion optimized (UFO) gp140 trimer (MVA-UFO) in a DNA prime\/MVA boost approach against heterologous tier 2 SHIV1157ipd3N4 intrarectal challenges in rhesus macaques (RMs). Both MVA vaccines also expressed SIVmac239 Gag and form virus-like particles. The DNA vaccine expressed SIVmac239 Gag, C.1086 gp160 Env and rhesus CD40L as a built-in adjuvant. Additionally, all immunizations were administered intradermally (ID) to reduce induction of vaccine-specific IFN\u03b3+ CD4 T cell responses. Our results showed that both MVA-150 and MVA-UFO vaccines induce comparable Env specific IgG responses in serum and rectal secretions. The vaccine-induced serum antibody showed ADCC and ADCVI activities against the challenge virus. Comparison with a previous study that used similar immunogens <jats:italic>via<\/jats:italic> intramuscular route (IM) showed that ID immunizations induced markedly lower SHIV specific CD4 and CD8 T cell responses compared to IM immunizations. Following challenge, MVA-UFO vaccinated animals showed a significant delay in acquisition of SHIV1157ipd3N4 infection but only in Mamu-A*01 negative macaques with an estimated vaccine efficacy of 64% per exposure. The MVA-150 group also showed a trend (p=0.1) for delay in acquisition of SHIV infection with an estimated vaccine efficacy of 57%. The vaccine-induced IFN\u03b3 secreting CD8 T cell responses showed a direct association and CD4 T cells showed an inverse association with delay in acquisition of SHIV infection. These results demonstrated that both MVA-150 and MVA-UFO immunogens induce comparable humoral and cellular immunity and the latter provides marginally better protection against heterologous tier 2 SHIV infection. They also demonstrate that DNA\/MVA vaccinations delivered by ID route induce better antibody and lower CD4 and CD8 T cell responses compared to IM.<\/jats:p>","DOI":"10.3389\/fimmu.2022.914969","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T08:28:50Z","timestamp":1658478530000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["V2 hotspot optimized MVA vaccine expressing stabilized HIV-1 Clade C envelope Gp140 delays acquisition of heterologous Clade C Tier 2 challenges in Mamu-A*01 negative Rhesus Macaques"],"prefix":"10.3389","volume":"13","author":[{"given":"Tiffany M.","family":"Styles","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sailaja","family":"Gangadhara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep B. J.","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusmita","family":"Sahoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayalensh","family":"Shiferaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Welbourn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela A.","family":"Kozlowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Derdeyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayakumar","family":"Velu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama Rao","family":"Amara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908492","article-title":"Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand","volume":"361","author":"Rerks-Ngarm","year":"2009","journal-title":"New Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00934-19","article-title":"Human immunodeficiency virus C.1086 envelope Gp140 protein boosts following DNA\/Modified vaccinia virus Ankara vaccination fail to enhance heterologous anti-V1V2 antibody response and protection against clade c simian-human immunodeficiency virus challenge","volume":"93","author":"Styles","year":"2019","journal-title":"J Virol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.immuni.2021.02.001","article-title":"A modified vaccinia Ankara vector-based vaccine protects macaques from SARS-CoV-2 infection, immune pathology, and dysfunction in the lungs","volume":"54","author":"Routhu","year":"2021","journal-title":"Immunity"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.12.026","article-title":"SIVmac239 MVA vaccine with and without a DNA prime, similar prevention of infection by a repeated dose SIVsmE660 challenge despite different immune responses","volume":"30","author":"Lai","year":"2012","journal-title":"Vaccine"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03527-14","article-title":"CD40L-adjuvanted DNA\/modified vaccinia virus Ankara simian immunodeficiency virus (SIV) vaccine enhances protection against neutralization-resistant mucosal SIV infection","volume":"89","author":"Kwa","year":"2015","journal-title":"J Virol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2007.07.017","article-title":"GM-CSF DNA: An adjuvant for higher avidity IgG, rectal IgA, and increased protection against the acute phase of a SHIV-89.6P challenge by a DNA\/MVA immunodeficiency virus vaccine","volume":"369","author":"Lai","year":"2007","journal-title":"Virology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1038\/s41467-019-08739-4","article-title":"HIV-1 vaccination by needle-free oral injection induces strong mucosal immunity and protects against SHIV challenge","volume":"10","author":"Jones","year":"2019","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01163-16","article-title":"Virus-like particles displaying trimeric simian immunodeficiency virus (SIV) envelope Gp160 enhance the breadth of DNA\/Modified vaccinia virus Ankara SIV vaccine-induced antibody responses in rhesus macaques","volume":"90","author":"Iyer","year":"2016","journal-title":"J Virol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1126\/science.292.5514.69","article-title":"Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA\/MVA vaccine","volume":"292","author":"Amara","year":"2001","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","first-page":"994","DOI":"10.4049\/jimmunol.1500083","article-title":"Codelivery of envelope protein in alum with MVA vaccine induces CXCR3-biased CXCR5+ and CXCR5- CD4 T cell responses in rhesus macaques","volume":"195","author":"Iyer","year":"2015","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/jia2.25793","article-title":"Current approaches to HIV vaccine development: a narrative review","author":"Kim","year":"2021","journal-title":"J Int AIDS Soc"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12481","article-title":"Native-like env trimers as a platform for HIV-1 vaccine design","volume":"275","author":"Sanders","year":"2017","journal-title":"Immunol Rev"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2020.1745093","article-title":"Stabilized diverse HIV-1 envelope trimers for vaccine design","volume":"9","author":"Wang","year":"2020","journal-title":"Emerg Microbes Infect"},{"key":"B14","doi-asserted-by":"publisher","first-page":"101470","DOI":"10.1016\/j.smim.2021.101470","article-title":"HIV Vaccinology: 2021 update","volume":"51","author":"Lee","year":"2021","journal-title":"Semin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/jia2.25797","article-title":"Structure-guided envelope trimer design in HIV-1 vaccine development: A narrative review","author":"Derking","year":"2021","journal-title":"J Int AIDS Soc"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003618","article-title":"A next-generation cleaved, soluble HIV-1 env trimer, BG505 SOSIP.664 Gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies","volume":"9","author":"Sanders","year":"2013","journal-title":"PLoS Pathog"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03473-14","article-title":"A native-like SOSIP.664 trimer based on an HIV-1 subtype b env gene","volume":"89","author":"Pugach","year":"2015","journal-title":"J Virol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02652-15","article-title":"Structure-guided redesign increases the propensity of HIV env to generate highly stable soluble trimers","volume":"90","author":"Guenaga","year":"2015","journal-title":"J Virol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1507793112","article-title":"Design and structure of two HIV-1 clade c SOSIP.664 trimers that increase the arsenal of native-like env immunogens","volume":"112","author":"Julien","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2515135520957763","DOI":"10.1177\/2515135520957763","article-title":"Efficiently cleaved HIV-1 envelopes: Can they be important for vaccine immunogen development","volume":"8","author":"Das","year":"2020","journal-title":"Ther Adv Vaccines Immunother"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.03.047","article-title":"Cleavage-independent HIV-1 env trimers engineered as soluble native spike mimetics for vaccine design","volume":"11","author":"Sharma","year":"2015","journal-title":"Cell Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"12040","DOI":"10.1038\/ncomms12040","article-title":"Uncleaved prefusion-optimized Gp140 trimers derived from analysis of HIV-1 envelope metastability","volume":"7","author":"Kong","year":"2016","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3324","DOI":"10.1016\/j.celrep.2018.08.051","article-title":"Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers","volume":"24","author":"Aldon","year":"2018","journal-title":"Cell Rep"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0108446","article-title":"Cryptic determinant of Alpha4beta7 binding in the V2 loop of HIV-1 Gp120","volume":"9","author":"Tassaneetrithep","year":"2014","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav1800","article-title":"Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy","volume":"11","author":"Chamcha","year":"2019","journal-title":"Sci Transl Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00975-14","article-title":"CD40L-adjuvanted DNA\/modified vaccinia virus Ankara simian immunodeficiency virus SIV239 vaccine enhances SIV-specific humoral and cellular immunity and improves protection against a heterologous SIVE660 mucosal challenge","volume":"88","author":"Kwa","year":"2014","journal-title":"J Virol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.11.011","article-title":"Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2","volume":"38","author":"Liao","year":"2013","journal-title":"Immunity"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3051","article-title":"Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 env","volume":"22","author":"Kwon","year":"2015","journal-title":"Nat Struct Mol Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.056","article-title":"Immunogenicity of stabilized HIV-1 envelope trimers with reduced exposure of non-neutralizing epitopes","volume":"163","author":"de Taeye","year":"2015","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"110436","DOI":"10.1016\/j.celrep.2022.110436","article-title":"Structure-guided changes at the V2 apex of HIV-1 clade c trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies","volume":"38","author":"Sahoo","year":"2022","journal-title":"Cell Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00558-06","article-title":"Molecularly cloned SHIV-1157ipd3n4: A highly replication- competent, mucosally transmissible R5 simian-human immunodeficiency virus encoding HIV clade c env","volume":"80","author":"Song","year":"2006","journal-title":"J Virol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1097\/00042560-200008010-00001","article-title":"Modified wick method using weck-cel sponges for collection of human rectal secretions and analysis of mucosal HIV antibody","volume":"24","author":"Kozlowski","year":"2000","journal-title":"J Acquir Immune Defic Syndr"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180245","article-title":"Differences in serum IgA responses to HIV-1 Gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy","volume":"12","author":"Nabi","year":"2017","journal-title":"PLoS One"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02173-08","article-title":"Preclinical studies of human immunodeficiency Virus\/AIDS vaccines: Inverse correlation between avidity of anti-env antibodies and peak postchallenge viremia","volume":"83","author":"Zhao","year":"2009","journal-title":"J Virol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01650-12","article-title":"A novel assay for antibody-dependent cell-mediated cytotoxicity against HIV-1- or SIV-infected cells reveals incomplete overlap with antibodies measured by neutralization and binding assays","volume":"86","author":"Alpert","year":"2012","journal-title":"J Virol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600629","article-title":"High doses of GM-CSF inhibit antibody responses in rectal secretions and diminish modified vaccinia Ankara\/Simian immunodeficiency virus vaccine protection in TRIM5alpha-restrictive macaques","volume":"197","author":"Kannanganat","year":"2016","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01846-18","article-title":"Clade c HIV-1 envelope vaccination regimens differ in their ability to elicit antibodies with moderate neutralization breadth against genetically diverse tier 2 HIV-1 envelope variants","volume":"93","author":"Burton","year":"2019","journal-title":"J Virol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009257","article-title":"The C3\/465 glycan hole cluster in BG505 HIV-1 envelope is the major neutralizing target involved in preventing mucosal SHIV infection","volume":"17","author":"Charles","year":"2021","journal-title":"PLoS Pathog"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01221-14","article-title":"Characterization and implementation of a diverse simian immunodeficiency virus SIVsm envelope panel in the assessment of neutralizing antibody breadth elicited in rhesus macaques by multimodal vaccines expressing the SIVmac239 envelope","volume":"89","author":"Kilgore","year":"2015","journal-title":"J Virol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1509731112","article-title":"Breakthrough of SIV strain Sme660 challenge in SIV strain Mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses","volume":"112","author":"Burton","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00295-10","article-title":"Nonpathogenic simian immunodeficiency virus infection of sooty mangabeys is not associated with high levels of autologous neutralizing antibodies","volume":"84","author":"Li","year":"2010","journal-title":"J Virol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/pbi.12670","article-title":"Coordinated protein Co-expression in plants by harnessing the synergy between an intein and a viral 2A peptide","volume":"15","author":"Zhang","year":"2017","journal-title":"Plant Biotechnol J"},{"key":"B43","doi-asserted-by":"publisher","first-page":"3123","DOI":"10.1016\/j.celrep.2018.11.058","article-title":"V2-directed vaccine-like antibodies from HIV-1 infection identify an additional K169-binding light chain motif with broad ADCC activity","volume":"25","author":"van Eeden","year":"2018","journal-title":"Cell Rep"},{"key":"B44","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.ebiom.2018.02.025","article-title":"Correlates of protection against SIVmac251 infection in rhesus macaques immunized with chimpanzee-derived adenovirus vectors","volume":"31","author":"Tuyishime","year":"2018","journal-title":"EBioMedicine"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000751","article-title":"Preexisting vaccinia virus immunity decreases SIV-specific cellular immunity but does not diminish humoral immunity and efficacy of a DNA\/MVA vaccine","volume":"185","author":"Kannanganat","year":"2010","journal-title":"J Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.15.7625-7631.2002","article-title":"Different patterns of immune responses but similar control of a simian-human immunodeficiency virus 89.6P mucosal challenge by modified vaccinia virus Ankara (MVA) and DNA\/MVA vaccines","volume":"76","author":"Amara","year":"2002","journal-title":"J Virol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1128\/JVI.76.1.292-302.2002","article-title":"ALVAC-SIV-Gag-Pol-Env-Based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency","volume":"76","author":"Pal","year":"2002","journal-title":"J Virol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nri2357","article-title":"Impact of MHC class I diversity on immune control of immunodeficiency virus replication","volume":"8","author":"Goulder","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.4.2736-2740.2003","article-title":"Expression of the major histocompatibility complex class I molecule mamu-A*01 is associated with control of simian immunodeficiency virus SIVmac239 replication","volume":"77","author":"Mothe","year":"2003","journal-title":"J Virol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.19.12321-12331.2005","article-title":"Vectored gag and env but not tat show efficacy against simian-human immunodeficiency virus 89.6P challenge in mamu-A*01-Negative rhesus monkeys","volume":"79","author":"Liang","year":"2005","journal-title":"J Virol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000997","article-title":"Contributions of mamu-A*01 status and TRIM5 allele expression, but not CCL3L copy number variation, to the control of SIVmac251 replication in Indian-origin rhesus monkeys","volume":"6","author":"Lim","year":"2010","journal-title":"PLoS Genet"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008764","article-title":"Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge","volume":"16","author":"Om","year":"2020","journal-title":"PLoS Pathog"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03176","article-title":"Human dendritic cells: Their heterogeneity and clinical application potential in cancer immunotherapy","volume":"9","author":"Patente","year":"2018","journal-title":"Front Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030448","article-title":"Regulation of dendritic cell migration to the draining lymph node: Impact on T lymphocyte traffic and priming","volume":"198","author":"MartIn-Fontecha","year":"2003","journal-title":"J Exp Med"},{"key":"B55","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41577-018-0088-1","article-title":"Dendritic cell subsets in T cell programming: Location dictates function","volume":"19","author":"Eisenbarth","year":"2019","journal-title":"Nat Rev Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.914969\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T08:28:53Z","timestamp":1658478533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.914969\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,22]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2022.914969"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.914969","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,22]]},"article-number":"914969"}}