PMID- 34168657 OWN - NLM STAT- MEDLINE DCOM- 20211027 LR - 20211027 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Bridging Computational Vaccinology and Vaccine Development Through Systematic Identification, Characterization, and Downselection of Conserved and Variable Circumsporozoite Protein CD4 T Cell Epitopes From Diverse Plasmodium falciparum Strains. PG - 689920 LID - 10.3389/fimmu.2021.689920 [doi] LID - 689920 AB - An effective malaria vaccine must prevent disease in a range of populations living in regions with vastly different transmission rates and protect against genetically-diverse Plasmodium falciparum (Pf) strains. The protective efficacy afforded by the currently licensed malaria vaccine, Mosquirix, promotes strong humoral responses to Pf circumsporozoite protein (CSP) 3D7 but protection is limited in duration and by strain variation. Helper CD4 T cells are central to development of protective immune responses, playing roles in B cell activation and maturation processes, cytokine production, and stimulation of effector T cells. Therefore, we took advantage of recent in silico modeling advances to predict and analyze human leukocyte antigen (HLA)-restricted class II epitopes from PfCSP - across the entire PfCSP 3D7 sequence as well as in 539 PfCSP sequence variants - with the goal of improving PfCSP-based malaria vaccines. Specifically, we developed a systematic workflow to identify peptide sequences capable of binding HLA-DR in a context relevant to achieving broad human population coverage utilizing cognate T cell help and with limited T regulatory cell activation triggers. Through this workflow, we identified seven predicted class II epitope clusters in the N- and C-terminal regions of PfCSP 3D7 and an additional eight clusters through comparative analysis of 539 PfCSP sequence variants. A subset of these predicted class II epitope clusters was synthesized as peptides and assessed for HLA-DR binding in vitro. Further, we characterized the functional capacity of these peptides to prime and activate human peripheral blood mononuclear cells (PBMCs), by monitoring cytokine response profiles using MIMIC((R)) technology (Modular IMmune In vitro Construct). Utilizing this decision framework, we found sufficient differential cellular activation and cytokine profiles among HLA-DR-matched PBMC donors to downselect class II epitope clusters for inclusion in a vaccine targeting PfCSP. Importantly, the downselected clusters are not highly conserved across PfCSP variants but rather, they overlap a hypervariable region (TH2R) in the C-terminus of the protein. We recommend assessing these class II epitope clusters within the context of a PfCSP vaccine, employing a test system capable of measuring immunogenicity across a broad set of HLA-DR alleles. CI - Copyright (c) 2021 Noe, Terry, Schanen, Sassano, Hindocha, Phares, Moise, Christen, Tucker, Kotraiah, Drake, Martin, De Groot and Gutierrez. FAU - Noe, Amy R AU - Noe AR AD - Leidos Life Sciences, Leidos Inc., Frederick, MD, United States. FAU - Terry, Frances E AU - Terry FE AD - EpiVax Inc., Providence, RI, United States. FAU - Schanen, Brian C AU - Schanen BC AD - Sanofi Pasteur, VaxDesign Campus, Orlando, FL, United States. FAU - Sassano, Emily AU - Sassano E AD - Sanofi Pasteur, VaxDesign Campus, Orlando, FL, United States. FAU - Hindocha, Pooja AU - Hindocha P AD - EpiVax Inc., Providence, RI, United States. FAU - Phares, Timothy W AU - Phares TW AD - Leidos Life Sciences, Leidos Inc., Frederick, MD, United States. FAU - Moise, Leonard AU - Moise L AD - EpiVax Inc., Providence, RI, United States. FAU - Christen, Jayne M AU - Christen JM AD - Leidos Life Sciences, Leidos Inc., Frederick, MD, United States. FAU - Tucker, Kenneth D AU - Tucker KD AD - Leidos Life Sciences, Leidos Inc., Frederick, MD, United States. FAU - Kotraiah, Vinayaka AU - Kotraiah V AD - Leidos Life Sciences, Leidos Inc., Frederick, MD, United States. FAU - Drake, Donald R 3rd AU - Drake DR 3rd AD - Sanofi Pasteur, VaxDesign Campus, Orlando, FL, United States. FAU - Martin, William D AU - Martin WD AD - EpiVax Inc., Providence, RI, United States. FAU - De Groot, Anne S AU - De Groot AS AD - EpiVax Inc., Providence, RI, United States. AD - University of Georgia Center for Vaccines and Immunology, Athens, GA, United States. FAU - Gutierrez, Gabriel M AU - Gutierrez GM AD - Leidos Life Sciences, Leidos Inc., Frederick, MD, United States. LA - eng PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20210608 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, Protozoan) RN - 0 (Cytokines) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-DR Antigens) RN - 0 (Malaria Vaccines) RN - 0 (Peptide Fragments) RN - 0 (Protozoan Proteins) RN - 0 (circumsporozoite protein, Protozoan) SB - IM MH - Antigens, Protozoan/immunology/*pharmacology MH - CD4-Positive T-Lymphocytes/*drug effects/immunology/parasitology MH - Cells, Cultured MH - Computer-Aided Design MH - Cytokines/metabolism MH - *Drug Design MH - Epitopes, T-Lymphocyte/*immunology MH - HLA-DR Antigens/immunology MH - High-Throughput Screening Assays MH - Host-Parasite Interactions MH - Humans MH - Lymphocyte Activation/drug effects MH - Malaria Vaccines/immunology/*pharmacology MH - Malaria, Falciparum/immunology/parasitology/*prevention & control MH - Peptide Fragments/immunology/pharmacology MH - Plasmodium falciparum/*immunology/pathogenicity MH - Protozoan Proteins/immunology/*pharmacology MH - Vaccinology MH - Workflow PMC - PMC8217813 OTO - NOTNLM OT - CSP OT - HLA-DR OT - TH2R OT - cross-strain OT - in silico epitope prediction OT - malaria OT - multifunctional cytokine response COIS- AN, TP, KT, VK, JC, and GG are employees of Leidos, Inc., prime contractor for USAID Malaria Vaccine Development Program (MVDP) Contract AID-OAA-C-15-00071, and hold Leidos stock and/or stock options. FT, LM, WM, and ADG are employees of EpiVax, Inc., an MVDP subcontractor. PH was a previous employee of EpiVax, Inc. BS, ES, and DD are employees of Sanofi Pasteur, an MVDP subcontractor, and hold Sanofi Pasteur stock and/or stock options. EDAT- 2021/06/26 06:00 MHDA- 2021/10/28 06:00 PMCR- 2021/01/01 CRDT- 2021/06/25 06:50 PHST- 2021/04/01 00:00 [received] PHST- 2021/05/06 00:00 [accepted] PHST- 2021/06/25 06:50 [entrez] PHST- 2021/06/26 06:00 [pubmed] PHST- 2021/10/28 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.689920 [doi] PST - epublish SO - Front Immunol. 2021 Jun 8;12:689920. doi: 10.3389/fimmu.2021.689920. eCollection 2021.