title: A Novel Prime and Boost Regimen of HIV Virus-Like Particles with TLR4 Adjuvant MPLA Induces Th1 Oriented Immune Responses against HIV.
abstract: HIV virus-like particles (VLPs) present the HIV envelope protein in its native conformation, providing an ideal vaccine antigen. To enhance the immunogenicity of the VLP vaccine, we sought to improve upon two components; the route of administration and the additional adjuvant. Using HIV VLPs, we evaluated sub-cheek as a novel route of vaccine administration when combined with other conventional routes of immunization. Of five combinations of distinct prime and boost sequences, which included sub-cheek, intranasal, and intradermal routes of administration, intranasal prime and sub-cheek boost (IN+SC) resulted in the highest HIV-specific IgG titers among the groups tested. Using the IN+SC regimen we tested the adjuvant VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV) + monophosphoryl lipid A (MPLA) at MPLA concentrations of 0, 7.5, 12.5, and 25 μg/dose in combination with our VLPs. Mice that received 12.5 or 25 μg/dose MPLA had the highest concentrations of Env-specific IgG2c (20.7 and 18.4 μg/ml respectively), which represents a Th1 type of immune response in C57BL/6 mice. This was in sharp contrast to mice which received 0 or 7.5 μg MPLA adjuvant (6.05 and 5.68 μg/ml of IgG2c respectively). In contrast to IgG2c, MPLA had minor effects on Env-specific IgG1; therefore, 12.5 and 25 μg/dose of MPLA induced the optimal IgG1/IgG2c ratio of 1.3. Additionally, the percentage of germinal center B cells increased significantly from 15.4% in the control group to 31.9% in the CALV + 25 μg MPLA group. These mice also had significantly more IL-2 and less IL-4 Env-specific CD8+ T cells than controls, correlating with an increased percentage of Env-specific central memory CD4+ and CD8+ T cells. Our study shows the strong potential of IN+SC as an efficacious route of administration and the effectiveness of VLPs combined with MPLA adjuvant to induce Env specific Th1-oriented HIV-specific immune responses.
authors: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, 77030, United States of America.
authors: Ethan
authors: E
authors: Poteet
authors: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, 77030, United States of America.
authors: Phoebe
authors: P
authors: Lewis
authors: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, 77030, United States of America.
authors: Feng
authors: F
authors: Li
authors: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, 77030, United States of America.
authors: Sheng
authors: S
authors: Zhang
authors: Houston Methodist Research Institute, Houston, TX, 77030, United States of America.
authors: Jianhua
authors: J
authors: Gu
authors: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, 77030, United States of America.
authors: Changyi
authors: C
authors: Chen
authors: Molecular Express, Inc., Rancho Domínguez, CA, 90220, United States of America.
authors: Sam On
authors: SO
authors: Ho
authors: Molecular Express, Inc., Rancho Domínguez, CA, 90220, United States of America.
authors: Thai
authors: T
authors: Do
authors: Molecular Express, Inc., Rancho Domínguez, CA, 90220, United States of America.
authors: SuMing
authors: S
authors: Chiang
authors: Molecular Express, Inc., Rancho Domínguez, CA, 90220, United States of America.
authors: Gary
authors: G
authors: Fujii
authors: Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, 77030, United States of America; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX, 77030, United States of America.
authors: Qizhi
authors: Q
authors: Yao
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000281:Administration, Intranasal; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004333:Drug Administration Routes; D005260:Female; D015497:HIV-1 / Q000276:immunology / Q000648:ultrastructure; D007117:Immunization, Secondary / Q000379:methods*; D007074:Immunoglobulin G / Q000276:immunology; D007271:Injections, Intradermal; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives; D008810:Mice, Inbred C57BL; D010316:Particle Size; D018800:Thy-1 Antigens / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D007074:Immunoglobulin G; D008050:Lipid A; D018800:Thy-1 Antigens; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C048436:monophosphoryl lipid A