Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity.
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2010-08-10
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BACKGROUND: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). METHODS: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. RESULTS: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. CONCLUSIONS: The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000886.
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Graham, Barney S, M Juliana McElrath, Michael C Keefer, Kyle Rybczyk, David Berger, Kent J Weinhold, Janet Ottinger, Guido Ferarri, et al. (2010). Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity. PLoS One, 5(8). p. e11995. 10.1371/journal.pone.0011995 Retrieved from https://hdl.handle.net/10161/4559.
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Kent James Weinhold
The Weinhold Laboratory is currently focused on utilizing a comprehensive repertoire of highly standardized and formerly validated assay platforms to profile the human immune system in order to identify immunologic signatures that predict disease outcomes. These ongoing studies span a broad range of highly relevant clinical arenas, including: 1) cancer (non-small cell lung cancer, head and neck cancer, glioblastoma neoforme, ovarian cancer, and prostate cancer), 2) autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosis, multiple sclerosis, and myasthenia gravis), 3) pulmonary disease (idiopathic pulmonary fibrosis), 4) solid organ transplantation (lung, kidney, liver, and heart), and 5) inflammatory disorders.
Two of the areas that have been especially active over the past few years include the comprehensive immunologic profiling of cancer patients receiving so-called ‘immune checkpoint blockade’ therapies and the search for immune signatures in lung transplant recipients that track with resistance to CMV infection. The laboratory conducted immune monitoring studies associated with a Phase I trial of Ipilimumab (anti-CTLA-4) in a neoadjuvant setting for the treatment of non-small cell lung cancer (NSCLC). For this trial we extensively utilized several high parameter flow cytometry (PFC) platforms to follow activation, maturation, exhaustion, and proliferation patterns within CD4+ and CD8+ subsets of T-cells. We are also utilizing an intracellular cytokine staining (ICS) platform in efforts to detect anti-tumor associated antigen (TAA) responses by CD4+ and CD8+ T cells from peripheral blood mononuclear cells as well as lymphocytes infiltrating the patients’ tumor. These assays are designed to measure antigen-driven intracellular production of IFN-γ, TNF-α, and IL-2, as well as the degranulation marker CD107a. This strategy enables us to not only document individual cytokine responses, but to also assess (through Boolean gating) changes in relative polyfunctionality of the responses. We have also performed similar immune monitoring of a Phase II trial evaluating nivolumab (anti-PD-1) alone vs. combined nivolumamb + ipilimumab vs. avastin (bevacizamab) alone in patients with glioblastomas. In both studies, we are seeking to identify pharmacodynamics markers and immune correlates predictive of clinical responses. In completed studies of a cohort of lung transplant recipients, we identified specific polyfunctional signatures in CD4+ and CD8+ subsets against CMV pp65 and IE-1 antigens that tracked with resistance to CMV infection (manuscript in preparation). These findings now serve as the basis for a Phase I clinical trial to compare conventional 6-month chemoprophylaxis in lung transplant recipients versus a regimen dictated by the presence or absence of the predictive signatures. This trial is the principal component of a recently awarded Clinical Trials in Organ Transplantation or CTOT award made from the NIH to Duke (Scott Palmer, PI). Ongoing studies will test the hypothesis that these signatures that have been validated in lung transplant recipients will also predict resistance to CMV infection in the context of other solid organ transplants such as kidney, liver, and heart.Future studies will also attempt to identify predictive signatures for resistance to BK polyomavirus, the cause of graft threatening nephritis in kidney transplant recipients and cystitis in bone marrow transplant recipients.
Recent publications
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Yi, J.S., Ready, N., Healy, P., Dumbauld, C., Berry, M., Shoemaker, D., Clarke, J., Crawford, J., Tong, B.C., Harpole, D., D’Amico, T.A., McSherry, F., Dunphy, F., McCall, S.J., Christensen, J.D., Wang, X, and Weinhold, K.J. Immune activation in early stage non-small cell lung cancer patients receiving neoadjuvant chemotherapy plus ipilimumab. Clin. Cancer Res. 23(24):7474-7482, 2017. PMCID: PMC5732888.
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Woroniecka, K., Chongsathidkiet, P., Rhodin, K., Kemeny, H., Dechant, C., Elsamadicy, A.A., Koyama, S., Jackson, C., Farber, H.S., Elsamadicy, A.A., Cui, X., Koyama, S., Jackson, C., Hansen, L., Bigner, D.D., Giles, A., Healy, P., Dranoff, G., Weinhold, K.J., Dunn, G.P., and Fecci, P.E. T cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin. Cancer Res. Sep 1;24(17)4175-4186, 2018. PMCID: PMC6081269.
Weinhold, K.J., Bukowski, J.F., Brennan, T.V., Noveck, R.J., Staats, J.S., Lin, L., Stempora, L., Hammond, C., Wouters, A., Mojcik, C.F., Cheng, J., Collinge, M., Jesson, M.I., Hazra, A., Biswas, P., Lan, S., Clark, J.D., and Hodge, J.A. Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers. Clin. Immunology 191:10-20, June 19, 2018. PMCID: PMC6036921.
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Berger, M., Murdoch, D., Staats, J., Chan, C., Thomas J., Garrigues, G., Browndyke, J., Cooter, M., Quinones, Q., Matthew, J., and Weinhold, K.J. Flow cytometry characterization of cerebrospinal fluid monocytes in patients with postoperative cognitive dysfunction (POCD): A pilot study. Anesthesia & Analgesia May 3, 2019 doi: 10.1213/ANE. PMCID: PMC6800758.
Nyanhete, T.E., Frisbee, A., Bradley, T., Faison, W.J., Robins, E., Payne, T.,Freel, S.A., Sawant, S., Weinhold, K.J., Wiehe, K., Haynes, B.F., Ferrari, G., Li, Q-J., Moody, M.A., and Tomaras, G.D. HLA class II-restricted CD8+T cells in HIV-1 virus controllers. Nat. Sci. Rep. 9(1):10165, 2019; PMCID: PMC6629643.
Yi, J.S., Rosa-Bray, M., Staats, J., Zakroysky, P., Chan, C., Russo, M., Dumbauld, C., White, S., Gierman, T., Weinhold, K.J., and Guptill, J.T. Establishment of normative ranges of the healthy immune system with comprehensive polychromatic flow cytometry profiling. PLoS One 14(12):e0225512, Dec.11, 2019. PMCID: PMC6905525.
Healy, Z.R., Weinhold, K.J., and Murdoch D.M. Transcriptional profiling of CD8+ CMV-specific T cell functional subsets obtained using a method for isolating high-quality RNA from fixed and permeabilized cells. Frontiers in Immunology 11:1859, Sep. 2, 2020. PMCID: PMC7492549.
Zhang, T., Harrison, M.R., O’Donnell, P.H., Ajjai, A., Hahn, N.M., Appleman, L.J., Cetnar, J., Burke, J.M., Fleming, M., Miloswsky. M., Mortazavi, A., Shore, N., Sonapavde, G., Schmidt, E., Bitman, B., Munugalavadla, V., Izumi, P., Patel, P., Staats, J., Chan, C., Weinhold, K.J.*and George, D.J.,*senior co-authors. A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer. Cancer Oct.15, 2020 126(20):4485-4497. PMCID: PMC7590121
Salama, A.K.S., Palta, M., Rushing, C.N., Selim, M.A., Linnet, K.N., Czito, B.G., Yoo, D.S., Hanks, B.A., Beasley, G.M., Mosca, P., Dumbauld, C., Steadman, K.N., Yi, J.S., Weinhold, K.J., Tyler, D.S., Lee, W.T., and Brizel, D.M. Ipilimumab and radiation in patients with high risk resected or regionally advanced melanoma. Clin. Cancer Res. 1 March, 2021 27(5):1287-1295. PMCID: PMC8759408.
Li, Y., Yi, J.S., Russo, M.., Rosa-Bray, M., Weinhold. K.J., and Guptill, J.T. Normative dataset for plasma cytokines in healthy human adults. Data Brief 2021 Feb. 9;35:106857. PMCID: PMC7900339
White, S., Quinn, J., Enzor, E., Staats, J., Mosier, S.M., Almarode, J., Denny, T.N., Weinhold, K., Ferrari, G., and Chan, C. FlowKit: A Python toolkit for integrated manual and automated cytometry analysis workflows. Frontiers in Immunology 12:768541,Nov. 5, 2021. PMCID: PMC8602902.
Sung, B-Y., Lin, Y-H., Shah, P.D., Bieler, J.G., Palmer, S., Weinhold, K.J., Chang, H-R., Huang, H., Avery, R.K., Schneck, J., and Chiu, Y-L. Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1. J. Clin. Invest. 132(2):e140508, January 18, 2022. PMCID: PMC8759796.
Lusk, J.B., Quinones, Q.J., Staats, J.S., Weinhold, K.J., Grossi, P.M., Laskowitz, D.T., and James, M.L. Coupling hematoma evacuation with immune profiling for analysis of neuroinflammation after primary intracerebral hemorrhage: a pilot study. World Neurosurg. 2022 May;161:162-168 PMCID:PMID:35217228.
Brown, Landon C., Halabi, S., Somarelli, J., Humeniuk, M., Wu, Y., Oyekunle, T., Howard, L., Huang, J., Anand, M., Davies, C., Patel, P., Staats, J., Weinhold, K.J., Harrison, M.R., Zhang, T., George, D.J., and Armstrong, A.J. A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer. Prostate Cancer and Prostatic Diseases 25(4):762-769, 2022. PMCID: PMC8933335.
Khatri, A., Todd, J.L., Kelly, F.L., Nagler, A., Ji, Z., Jain, V., Gregory, S..G., Weinhold, K.J., and Palmer, S.M. JAK-STAT activation in basal cells contributes to cytotoxic T-cell mediated basal cell death in human chronic lung allograft dusfunction. JCI Insight 8(6) March 22, 2023 PMCID:PMC pending.
Zaffiri, L., Messinger, M., Staats, J.S., Patel, P., Palmer, S.M., Weinhold, K.J., Snyder, L.D., and Luftig, M.A. Evaluation of host cellular responses to Epstein-Barr virus (EBV) in adult lung transplant recipients with EBV-associated diseases. J. Med. Virol. 95(4):e28724, 2023.
David Charles Montefiori
Dr. Montefiori is Professor and Director of the Laboratory for HIV and COVID-19 Vaccine Research & Development in the Department of Surgery, Division of Surgical Sciences at Duke University Medical Center. His major research interests are viral immunology and HIV and COVID-19 vaccine development, with a special emphasis on neutralizing antibodies.
Multiple aspects of HIV-1 neutralizing antibodies are studied in his laboratory, including mechanisms of neutralization and escape, epitope diversity among the different genetic subtypes and geographic distributions of the virus, neutralizing epitopes, requirements to elicit protective neutralizing antibodies by vaccination, optimal combinations of neutralizing antibodies for immunoprophylaxis, and novel vaccine designs for HIV-1. Dr. Montefiori also directs large vaccine immune monitoring programs funded by the NIH and the Bill & Melinda Gates Foundation that operate in compliance with Good Clinical Laboratory Practices and has served as a national and international resource for standardized assessments of neutralizing antibody responses in preclinical and clinical trials of candidate HIV vaccines since 1988.
At the onset of the COVID-19 pandemic he turned his attention to SARS-CoV-2, with a special interest in emerging variants and how they might impact transmission, vaccines and immunotherapeutics. His rapid response to emerging SARS-CoV-2 variants of concern provided some of the earliest evidence of the potential risk the variants pose to vaccines. In May 2020, his laboratory was recruited by the US Government to lead the national neutralizing antibody laboratory program for COVID-19 vaccines.
His laboratory utilizes FDA approved validated assay criteria to facilitate regulatory approvals of COVID-19 vaccines. He has published over 750 original research papers that have helped shape the scientific rationale for antibody-based vaccines.
Barton Ford Haynes
Barton F. Haynes, M.D. is the Frederic M. Hanes Professor of Medicine and Immunology, and Director of the Duke Human Vaccine Institute. Prior to leading the DHVI, Dr. Haynes served as Chief of the Division of Rheumatology, Allergy and Clinical Immunology, and later as Chair of the Department of Medicine. As Director of the Duke Human Vaccine Institute, Bart Haynes is leading a team of investigators working on vaccines for emerging infections, including tuberculosis, pandemic influenza, emerging coronaviruses, and HIV/AIDS.
To work on the AIDS vaccine problem, his group has been awarded two large consortium grants from the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) known as the Center for HIV/AIDS Vaccine Immunology (CHAVI) (2005-2012), and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) (2012-2019) to conduct discovery science to speed HIV vaccine development. In July 2019, his team received the third of NIH “CHAVI” awards to complete the HIV vaccine development work - CHAV-D.
Since the beginning of the COVID-19 pandemic, Haynes and the DHVI Team has been working non-stop to develop vaccines, rapid and inexpensive tests and therapeutics to combat the pandemic. Since March 2020, he has served as a member of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) committee to advise on COVID-19 vaccine development, and served as the co-chair of the ACTIV subcommittee on vaccine safety. Haynes is the winner of the Alexander Fleming Award from the Infectious Disease Society of America and the Ralph Steinman Award for Human Immunology Research from the American Association of Immunologists. He is a member of the National Academy of Medicine, National Academy of Inventors and the American Academy of Arts and Sciences.
About the Haynes LaboratoryThe Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases.
Mucosal Immune Responses in Acute HIV Infection
The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the development of an HIV vaccine. The lab has developed a novel approach to define the B cell repertories in AHI in order to find neutralizing antibodies against the virus. This approach uses linear Immunoglobulin (Ig) heavy and light chain gene expression cassettes to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. This strategy was used to characterize the Ig repertoire of plasma cells/plasmablasts in AHI and to produce recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination.
The lab is also studying the earliest effect HIV-1 has on B cells. Analyzing blood and gut-associated lymphoid tissues (GALT) during acute HIV infection, they have found that as early as 17 days after transmission HIV-1 induces B cell class switching and 47 days after transmission, HIV-1 causes considerable damage to GALT germinal centers. They found that in AHI, GALT memory B cells induce polyclonal B cell activation due to the presence of HIV-1-specific, influenza-specific, and autoreactive antibodies. The team concluded from this study that early induction of polyclonal B cell differentiation, along with follicular damage and germinal center loss, may explain why HIV-1 induced antibody responses decline rapidly during acute HIV infection and why plasma antibody responses are delayed.
The lab is also looking at ways of generating long-lived memory B cell responses to HIV infection, another major hurdle in the development of a successful HIV-1 vaccine. The lab has found that in HIV-1 gp120 envelope vaccination and chronic HIV-1 infection, HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma antibodies.
Immunogen Design
To overcome the high level of genetic diversity in HIV-1 envelope genes, the Haynes lab is developing strategies to induce antibodies that cross-react with multiple strains of HIV. The lab has designed immunogens based on transmitted founder Envs and mosaic consensus Envs in collaboration with Dr. Bette Korber at Los Alamos National Laboratory. These immunogens are designed to induce antibodies that cross-react with a multiple subtype Env glycoproteins. The goal is to determine if cross-reactive mAbs to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced. The team recently characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env protein. Two of the mAbs cross-reacted with all tested Env proteins, including SIVcpzUS Env and bound Env proteins with high affinity.
Mucosal Immune Responses in TB and Influenza
The Haynes lab is helping to develop novel approaches to TB vaccine development. The current therapeutic vaccine for TB, called BCG, may prevent complications from TB in children, but offers little protection against infection and disease in adults. The lab is focused on using live attenuated Mycobacterium tuberculosis mutants as vaccine candidates and is currently evaluating this approach in non-human primate studies. As part of the DHVI Influenza program, they are studying the B cell response to influenza in order to generate a “universal” flu vaccine. They are currently trying to express more highly conserved influenza antigens in recombinant vesicular stomatitis virus (rVSV) vectors in order to elicit robust T cell and antibody responses to those antigens.
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