CBER Expertise
HIV and smallpox vaccines: Development of new assays and animal models for evaluation of vaccine safety and efficacy
Principal Investigator: H. Golding, PhD
Office / Division / Lab: OVRR / DVP / LR
Overview
Public Health Issue: Identifying biomarkers of efficacy of HIV vaccines poses a specific challenge, in that many of the current vaccine candidates contain multiple antibody-inducing genes from HIV and determining which, or which types of antibodies in what proportion, correspond to clinical efficacy can be difficult. Moreover, HIV vaccinated individuals generate anti-HIV antibodies that react in currently licensed HIV detection kits to give a “positive” result, even though these vaccinees are not infected. Therefore, it is important to develop new diagnostic tests that can help to distinguish antibody responses from true HIV infections (i.e., vaccine failure) from those uninfected individual with vaccine-induced HIV antibodies (i.e., vaccine response). These assays will also reduce potential social harms to vaccine trial participants and will help to retain them in the pools of blood and plasma donors. In the case of smallpox vaccines, since smallpox vaccine efficacy trials are not feasible or ethical, both in vitro assays and new animal models are needed to utilize the Animal Efficacy Rule allowing animal studies to supplant clinical trials for efficacy for the licensure of new vaccines. Finally, rapid test development for evaluating vaccine potency and consistency of manufacture are important issues for more efficient vaccine review.
Regulatory Contribution: The assays and animal models under development will provide new tools to sponsors of HIV and smallpox vaccines for measuring immune responses, differentiating them from infections, evaluating unexpected adverse reactions, and evaluating manufacturing consistency and quality.
Research Approach: The research program uses cutting edge technologies to advance the following topics related to vaccine evaluations: (1) HIV Vaccines: A) Identifying peptides for a new assay for rapidly distinguishing HIV infections from vaccine- induced HIV antibody responses. B) Development of quantitative analytical assays to be applied as potency assays for lot release and long term stability testing. (2) Smallpox vaccines: A) Development of high throughput vaccinia neutralization assay, based on a reporter gene, for evaluation of vaccine induced antibodies and new Vaccinia Immune Globulin preparations (VIGIV). B) Development of animal models to follow vaccinia dissemination to internal organs (vaccine-safety evaluation) and testing of new anti-viral interventions. C) Establishment of correlates of protection against monkeypox challenge of primates. This model will be used for licensure of new smallpox vaccines.
Mission Relevance and Outcomes: The assays developed in this laboratory have a significant and continuing impact on vaccine evaluations. The vaccinia neutralization assay developed in this laboratory was selected by an HHS working group as the assay of choice for all government sponsored clinical trials of new smallpox vaccines. The assay was also transferred to outside laboratories in industry and academia for their pre-clinical and clinical development of smallpox vaccines and VIGIV. The vaccinia dissemination assay will shed light on the unexpected cardio toxicity reported in some recipients of the current smallpox vaccine. It will be used for evaluation of post-exposure treatments designed to alleviate vaccine- related complications. The new HIV diagnostic kit is resolving a major regulatory concern within studies HIV prophylactic vaccines. It may be incorporated in phase II/III trials (after validation) in the near future.
Publications
J Infect Dis 2007 Oct 1;196(7):1026-32
Antibodies to the A27 Protein of Vaccinia Virus Neutralize and Protect against Infection but Represent a Minor Component of Dryvax Vaccine-Induced Immunity.
He Y, Manischewitz J, Meseda CA, Merchlinsky M, Vassell RA, Sirota L, Berkower I, Golding H, Weiss CD
AIDS 2007 Feb 19;21(4):521-4
Durable neutralizing antibodies after remote smallpox vaccination among adults with and without HIV infection.
Kan VL, Manischewitz J, King LR, Golding H
J Acquir Immune Defic Syndr 2006 Nov 1;43(3):304-12
Novel Approach for Differential Diagnosis of HIV Infections in the Face of Vaccine-Generated Antibodies: Utility for Detection of Diverse HIV-1 Subtypes.
Khurana S, Needham J, Park S, Mathieson B, Busch MP, Nemo G, Nyambi P, Zolla-Pazner S, Laal S, Mulenga J, Chomba E, Hunter E, Allen S, McIntyre J, Hewlett I, Lee S, Tang S, Cowan E, Beyrer C, Altfeld M, Yu XG, Tounkara A, Koita O, Kamali A, Nguyen N, Graham BS, Todd D, Mugenyi P, Anzala O, Sanders E, Ketter N, Fast P, Golding H
J Immunol 2006 Aug 15;177(4):2552-64
Subunit recombinant vaccine protects against monkeypox.
Heraud JM, Edghill-Smith Y, Ayala V, Kalisz I, Parrino J, Kalyanaraman VS, Manischewitz J, King LR, Hryniewicz A, Trindade CJ, Hassett M, Tsai WP, Venzon D, Nalca A, Vaccari M, Silvera P, Bray M, Graham BS, Golding H, Hooper JW, Franchini G
J Virol 2006 Mar;80(5):2092-9
Human Immunodeficiency Virus (HIV) Vaccine Trials: a Novel Assay for Differential Diagnosis of HIV Infections in the Face of Vaccine-Generated Antibodies.
Khurana S, Needham J, Mathieson B, Rodriguez-Chavez IR, Catanzaro AT, Bailer RT, Kim J, Polonis V, Cooper DA, Guerin J, Peterson ML, Gurwith M, Nguyen N, Graham BS, Golding H
Clin Infect Dis 2006 Feb 15;42(4):e16-20
Clinical and immunological comparison of smallpox vaccine administered to the outer versus the inner upper arms of vaccinia-naive adults.
Waibel KH, Golding H, Manischewitz J, King LR, Tuchscherer M, Topolski RL, Walsh DS
J Leukoc Biol 2005 Dec;78(6):1306-17
Increased CXCR4-dependent HIV-1 fusion in activated T cells: role of CD4/CXCR4 association.
Zaitseva M, Romantseva T, Manischewitz J, Wang J, Goucher D, Golding H
Virology 2005 Sep 1;339(2):164-75
Enhanced immunogenicity and protective effect conferred by vaccination with combinations of modified vaccinia virus Ankara and licensed smallpox vaccine Dryvax in a mouse model.
Meseda CA, Garcia AD, Kumar A, Mayer AE, Manischewitz J, King LR, Golding H, Merchlinsky M, Weir JP
Nat Med 2005 Jul;11(7):740-7
Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus.
Edghill-Smith Y, Golding H, Manischewitz J, King LR, Scott D, Bray M, Nalca A, Hooper JW, Whitehouse CA, Schmitz JE, Reimann KA, Franchini G
J Virol 2005 Jun;79(11):6791-800
Identification of a Linear Peptide Recognized by Monoclonal Antibody 2D7 Capable of Generating CCR5-Specific Antibodies with Human Immunodeficiency Virus-Neutralizing Activity.
Khurana S, Kennedy M, King LR, Golding H
J Biol Chem 2005 Jun 23; [Epub ahead of print]
CCR5 N-terminal region plays a critical role in HIV-1 inhibition by toxoplasma gondii derived cyclophilin-18.
Golding H, Khurana S, Yarovinsky F, King LR, Abdoulaeva G, Antonsson L, Owman C, Platt EJ, Kabat D, Andersen JF, Sher A
Biotechnol Bioeng 2005 Jun 20;90(6):663-74
Production of recombinant proteins by vaccinia virus in a microcarrier based mammalian cell perfusion bioreactor.
Bleckwenn NA, Golding H, Bentley WE, Shiloach J
J Infect Dis 2005 Feb 1;191(3):372-81
Smallpox vaccine does not protect macaques with AIDS from a lethal monkeypox virus challenge.
Edghill-Smith Y, Bray M, Whitehouse CA, Miller D, Mucker E, Manischewitz J, King LR, Robert-Guroff M, Hryniewicz A, Venzon D, Meseda C, Weir J, Nalca A, Livingston V, Wells J, Lewis MG, Huggins J, Zwiers SH, Golding H, Franchini G.
J Biol Chem 2004 Dec 17;279(51):53635-42
Structural determinants of the anti-HIV activity of a CCR5 antagonist derived from Toxoplasma gondii.
Yarovinsky F, Andersen JF, King LR, Caspar P, Aliberti J, Golding H, Sher A
J Med Primatol 2004 Aug;33(4):167-74
Systemic and mucosal immunity in rhesus macaques immunized with HIV-1 peptide and gp120 conjugated to Brucella abortus.
Eller N, Golding H, Inoue S, Beining P, Inman J, Matthews N, Scott DE, Golding B
Vox Sang 2004 Feb;86(2):125-9
Intravenous immunoglobulin products contain neutralizing antibodies to vaccinia.
Goldsmith JC, Eller N, Mikolajczyk M, Manischewitz J, Golding H, Scott DE