Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity.

Abstract

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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Published Version (Please cite this version)

10.1371/journal.pone.0011995

Publication Info

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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Scholars@Duke

Weinhold

Kent James Weinhold

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery

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


Zidar, D.A., Mudd, J.C., Juchnowski, S., Lopes, J.P., Sparks, S., Park, S.S., Ishikawa, M., Osborne, R., Washam, J.B., Chan, C., Funderburg, N.T., Owoyele, A., Alaiti, M.A., Mayuga, M., Orringer, C., Costa, M.A., Simon, D.I., Tatsuoka, C., Califf, R.M., Newby, L.K., Lederman, M.M., and Weinhold, K.J.  Altered maturation status and possible immune exhaustion of CD8 T lymphocytes in the peripheral blood of patients presenting with acute coronary syndromes. Arterioscler., Thromb., and Vasc. Biol. 36(2): 389-397, Feb. 2016 PMID: 26663396

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.

Reap, E., Suryadevera, C., Batuch, K., Sanchez-Perez, L., Archer, G., Schmittling, R., Norberg, P., Herndon II, J., Healy, P., Congdon, K., Gedeon, P., Campbell, O., Swartz, A., Riccione, K., Yi, J., Hossain-Ibrahim, M., Saraswathula, A., Nair, S., Anastasie, A., Broome, T., Weinhold, K.J., Desjardins, A., Vlahoviv, G., Mclendon, R., Firedman, H., Bigner, D., Fecci, P., Mitchell, D., and Sampson, J. Dendritic cells enhance polyfunctionality of adoptively transferred T cells which target cytomegalovirus in glioblastoma. Cancer Research 78(1):256-264, 2018. PMCID: PMC5754236.

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.

Berger, M., Oyeyemi, D, Olurinde, M.O., Whitson, H.E., Weinhold, K.J., Woldorff, M.G., Lipsitz, L.A., Moretti, E., Giattino, C.M., Rpberts, K.C., Zhou, J., Bunning, T., Ferrandino, M., Scheri, R.P., Cooter, M., Chan, C., Cabeza, R., Browndyke, J.N., Murdoch, D.M., Devinney, M.J., Shaw, L.M., Cohen, H.J., Mathew, J.P., and the INTUIT Investigators. The INTUIT Study: Investigating neuroinflammation underlying postoperative cognitive dysfunction. J. American Geriatrics Society 67940;794-798, 2019. PMCID: PMC6688749.

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.



Montefiori

David Charles Montefiori

Professor in Surgery

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.


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