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  1. Biologics Research Projects

HIV, Influenza, 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


General Overview

Industry and academic researchers are developing new vaccines against viruses, including HIV, pandemic influenza strains of avian origin(H5N1, H7N7, H7N9, H9N9), respiratory syncyia virus (RSV), Ebola, smallpox and the Zika virus. Novel "Universal Influenza Vaccines" are also under development. Many of these vaccines are being developed and tested together with novel adjuvants (agents that stimulate or increase immune response to vaccines).

Therefore, in addition to evaluating the safety and efficacy of the vaccine itself, FDA must also evaluate the combination of vaccine and its adjuvant. Moreover, evaluation of each viral vaccine presents unique challenges that agency regulators must address individually.

The goal of our program is to develop new and improved tools for monitoring vaccine safety and efficacy. FDA will then share these new tools with the regulated industry to enable use of these tools in their research and development efforts.

The availability of new tools could reduce the time it takes to develop new vaccines against HIV, influenza, RSV, Ebola, smallpox, and Zika and help FDA to recognize quickly potential safety problems with vaccines that use new adjuvants. Thus, our work will contribute significantly to public health in the US and globally by facilitating development and approval of new vaccines that prevent serious diseases.


Scientific Overview

Our laboratory is working to generate effective vaccines against highly pathogenic avian influenza (H5, H7 H7, H9, H2) based on the globular head of the influenza hemagglutinin (HA) form the corresponding viruses.We are also exploring new protective targets in RSV, Ebola, and in the future, Zika virus.

Future vaccines for influenza strains with pandemic potential will likely be combined with adjuvants in order to improve their immunogenicity, to generate heterosubtypic neutralizing activity, and to reduce the amount of antigen required for vaccination--an important advantage for global vaccination campaigns.

In parallel with vaccine development, we are working to improve the analytical tools available for comparing immune responses generated by different vaccine candidates. Our laboratory initiated the use of whole genome phage display libraries (GFPDL)to screen antibody repertoires, and surface plasmon resonance to measure antibody binding to properly folded viral surface proteins and to measure antibody affinity maturation. These tools are used to screen convalescent sera, monoclonal antibodies, and to compare immune sera from recipients of unadjuvanted vaccines with that of recipients of adjuvanted vaccines.

The same tools have been developed for RSV, which causes high morbidity in newborn children and in frail old individuals. New RSV vaccines are in advance development to be evaluated in the very old, the very young (newborn infants) and pregnant mothers.

The Ebola pandemic in West Africa required concerted efforts to stop the outbreaks in several countries and to rapidly develope and test new vaccines, which are currently being evlauted in clinical trials. We are developing novel methods to better explore the antibody reperoires following Ebola infection and vaccination.

The new analytical tools developed in our lab will help to find the correlates of protection against influenza, RSV, Ebola (and Zika), could contribute to the design of improved vaccines with broad cross-protection potentital.

Some new adjuvants contain components that can cause unacceptable reactogenicity and systemic adverse reactions. Often these adverse reactions are undetectable in pre-clinical toxicity studies in small animals due to species differences in the cellular receptor targeted by the novel adjuvants or because of their lower sensitivity to drug-associated toxicities. Therefore, we are developing rapid in vitro screening assays based on human cells to evaluate the activity of new adjuvants and to identify parameters that will predict unacceptable toxicities including fever in humans.

Our program is also continuing in the application of whole-body bioimaging of animals challenged with recombinant vaccinia-luciferase. This new approach, in addition to the use of advanced statistic tools, provides a practical, quantitative, and humane approach to following virus dissemination in animal models and for evaluating the efficacy of novel vaccines and therapies for smallpox.


Publications

  1. iScience 2020 Mar 27;23(3):100920
    Human antibody repertoire following Ebola virus infection and vaccination.
    Fuentes S, Ravichandran S, Coyle EM, Klenow L, Khurana S
  2. Cell Host Microbe 2020 Feb 12;27(2):262-76
    Longitudinal human antibody repertoire against complete Ebola virus proteome following natural infection reveals immune markers of protection.
    Khurana S, Ravichandran S, Hahn M, Coyle EM, Spencer SW, Zak SE, Kindrachuk J, Davey Jr. RT, Dye JM, Chertow DS
  3. J Infect Dis 2020 Feb 3;221(4):636-46
    Antigenic fingerprinting of RSV-A infected hematopoietic cell transplant recipients reveals importance of mucosal anti-RSV-G antibodies in control of RSV infection in humans.
    Fuentes S, Hahn M, Chilcote K, Chemaly RF, Shah DP, Ye X, Avadhanula V, Piedra PA, Golding H, Khurana S
  4. Vaccine 2020 Jan 22;38(4):800-7
    Expansion of the 1st WHO international standard for antiserum to respiratory syncytial virus to include neutralisation titres against RSV subtype B: an international collaborative study.
    McDonald JU, Rigsby P, Atkinson E, Engelhardt OG, Study Participants
  5. Lancet Respir Med 2019 Nov;7(11):951-63
    Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
    Davey RT Jr, Fernandez-Cruz E, Markowitz N, Pett S, Babiker AG, Wentworth D, Khurana S, Engen N, Gordin F, Jain MK, Kan V, Polizzotto MN, Riska P, Ruxrungtham K, Temesgen Z, Lundgren J, Beigel JH, Lane HC, Neaton JD
  6. Sci Signal 2019 Oct 8;12(602):eaat6023
    T cell-derived soluble glycoprotein GPIbalpha mediates PGE2 production in human monocytes activated with the vaccine adjuvant MDP.
    Liu F, Endo Y, Romantseva T, Wu WW, Akue A, Shen RF, Golding H, Zaitseva M
  7. NPJ Vaccines 2019 Oct 14;4:42
    Harmonization of Zika neutralization assays by using the WHO International Standard for anti-Zika virus antibody.
    Mattiuzzo G, Knezevic I, Hassall M, Ashall J, Myhill S, Faulkner V, Hockley J, Rigsby P, Wilkinson DE, Page M, collaborative study participants
  8. Cell 2019 Sep 5;178(6):1313-28
    Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans.
    Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, Das J, Wang H, Guthmiller J, Zheng NY, Huang M, Uphadhyay AA, Gardinassi L, Petitdemange C, McCullough MP, Johnson SJ, Gill K, Cervasi B, Zou J, Bretin A, Hahn M, Gewirtz AT, Bosinger SE, Wilson PC, Li S, Alter G, Khurana S, Golding H, Pulendran B
  9. Proc Natl Acad Sci U S A 2019 Jul 23;116(30):15194-9
    Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics.
    Winarski KL, Tang J, Klenow L, Lee J, Coyle EM, Manischewitz J, Turner HL, Takeda K, Ward AB, Golding H, Khurana S
  10. Nat Commun 2019 Jul 26;10(1):3338
    Repeat vaccination reduces antibody affinity maturation across different influenza vaccine platforms in humans.
    Khurana S, Hahn M, Coyle EM, King LR, Lin TL, Treanor J, Sant A, Golding H
  11. Nat Commun 2019 Apr 26;10(1):1943
    Differential human antibody repertoires following Zika infection and the implications for serodiagnostics and disease outcome.
    Ravichandran S, Hahn M, Belaunzaran-Zamudio PF, Ramos-Castaneda J, Najera-Cancino G, Caballero-Sosa S, Navarro-Fuentes KR, Ruiz-Palacios G, Golding H, Beigel JH, Khurana S
  12. J Virol 2019 Apr 3;93(8):e00169-19
    Broad hemagglutinin-specific memory B cell expansion by seasonal influenza virus infection reflects early-life imprinting and adaptation to the infecting virus.
    Tesini BL, Kanagaiah P, Wang J, Hahn M, Halliley JL, Chaves FA, Nguyen PQT, Nogales A, DeDiego ML, Anderson CS, Ellebedy AH, Strohmeier S, Krammer F, Yang H, Bandyopadhyay S, Ahmed R, Treanor JJ, Martinez-Sobrido L, Golding H, Khurana S, Zand MS, Topham DJ, Sangster MY
  13. J Infect Dis 2018 Nov 22;218(Suppl. 5):S636-48
    Fully human immunoglobulin G from transchromosomic bovines treats nonhuman primates infected with Ebola virus Makona isolate.
    Luke T, Bennett RS, Gerhardt DM, Burdette T, Postnikova E, Mazur S, Honko AN, Oberlander N, Byrum R, Ragland D, St Claire M, Janosko KB, Smith G, Glenn G, Hooper J, Dye J, Pal S, Bishop-Lilly KA, Hamilton T, Frey K, Bollinger L, Wada J, Wu H, Jiao JA, Olinger GG, Gunn B, Alter G, Khurana S, Hensley LE, Sullivan E, Jahrling PB
  14. J Infect Dis 2018 Nov 22;218(Suppl. 5):S597-602
    Antibody repertoire of human polyclonal antibodies against Ebola virus glycoprotein generated after deoxyribonucleic acid and protein vaccination of transchromosomal bovines.
    Fuentes S, Ravichandran S, Khurana S
  15. NPJ Vaccines 2018 Oct 1;3:40
    AS03-adjuvanted H5N1 vaccine promotes antibody diversity and affinity maturation, NAI titers, cross-clade H5N1 neutralization, but not H1N1 cross-subtype neutralization.
    Khurana S, Coyle EM, Manischewitz J, King LR, Gao J, Germain RN, Schwartzberg PL, Tsang JS, Golding H, CHI Consortium
  16. PLoS Pathog 2018 Aug 24;14(8):e1007262
    Protective antigenic sites in respiratory syncytial virus G attachment protein outside the central conserved and cysteine noose domains.
    Lee J, Klenow L, Coyle EM, Golding H, Khurana S
  17. Vaccine 2018 Jul 25;36(31):4657-62
    Improving ability of RSV microneutralization assay to detect G-specific and cross-reactive neutralizing antibodies through immortalized cell line selection.
    Boukhvalova MS, Mbaye A, Kovtun S, Yim KC, Konstantinova T, Getachew T, Khurana S, Falsey AR, Blanco JCG
  18. Cold Spring Harb Perspect Biol 2018 Apr 2;10(4):a029132
    What is the predictive value of animal models for vaccine efficacy in humans? The importance of bridging studies and species-independent correlates of protection.
    Golding H, Khurana S, Zaitseva M
  19. Vaccines 2018 Apr 27;6(2):24
    Development and regulation of novel influenza virus vaccines: a United States young scientist perspective.
    Khurana S
  20. J Virol 2018 Jan 30;92(4):e01588-17
    Comparison of the efficacy of N9 neuraminidase-specific monoclonal antibodies against influenza A(H7N9) virus infection.
    Wan H, Qi L, Gao J, Couzens LK, Jiang L, Gao Y, Sheng ZM, Fong S, Hahn M, Khurana S, Taubenberger JK, Eichelberger MC
  21. Cell Host Microbe 2017 Oct 11;22(4):471-83.e5
    A potent germline-like human monoclonal antibody targets a pH-sensitive epitope on H7N9 influenza hemagglutinin.
    Yu F, Song H, Wu Y, Chang SY, Wang L, Li W, Hong B, Xia S, Wang C, Khurana S, Feng Y, Wang Y, Sun Z, He B, Hou D, Manischewitz J, King LR, Song Y, Min JY, Golding H, Ji X, Lu L, Jiang S, Dimitrov DS, Ying T
  22. Antiviral Res 2017 Aug;144:8-20
    Development of an animal model of progressive vaccinia in nu/nu mice and the use of bioluminescence imaging for assessment of the efficacy of monoclonal antibodies against vaccinial B5 and L1 proteins.
    Zaitseva M, Thomas A, Meseda CA, Cheung CYK, Diaz CG, Xiang Y, Crotty S, Golding H
  23. J Transl Med 2017 Jul 10;15(1):155
    Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy.
    Goswami M, Prince G, Biancotto A, Moir S, Kardava L, Santich BH, Cheung F, Kotliarov Y, Chen J, Shi R, Zhou H, Golding H, Manischewitz J, King L, Kunz LM, Noonan K, Borrello IM, Smith BD, Hourigan CS
  24. Clin Vaccine Immunol 2017 Mar 6;24(3):e00498-16
    Preexisting immunity not frailty phenotype predicts influenza post vaccination titers among older veterans.
    Van Epps P, Tumpey T, Pearce MB, Golding H, Higgins P, Hornick T, Burant C, Wilson BM, Banks R, Gravenstein S, Canaday DH
  25. Sci Rep 2017 Feb 10;7:42428
    Preclinical evaluation of bacterially produced RSV-G protein vaccine: Strong protection against RSV challenge in cotton rat model.
    Fuentes S, Klenow L, Golding H, Khurana S
  26. Vaccine 2017 Jan 23;35(4):694-702
    Development of bioluminescence imaging of respiratory syncytial virus (RSV) in virus-infected live mice and its use for evaluation of therapeutics and vaccines.
    Fuentes S, Arenas D, Moore MM, Golding H, Khurana S
  27. Nat Med 2016 Dec;22(12):1439-47
    Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies.
    Khurana S, Fuentes S, Coyle EM, Ravichandran S, Davey RT Jr, Beigel JH
  28. J Virol 2016 Sep 29;90(20):9383-93
    Antigenic fingerprinting of antibody response following highly pathogenic H7N7 avian influenza virus exposure in humans: Evidence for anti-PA-X antibodies.
    Khurana S, Chung KY, Coyle EM, Meijer A, Golding H
  29. Sci Rep 2016 May 27;6:26494
    ICOS(+)PD-1(+)CXCR3(+) T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination.
    Bentebibel SE, Khurana S, Schmitt N, Kurup P, Mueller C, Obermoser G, Palucka AK, Albrecht RA, Garcia-Sastre A, Golding H, Ueno H
  30. Sci Rep 2016 Apr 25;6:24897
    Production of potent fully human polyclonal antibodies against Ebola Zaire virus in transchromosomal cattle.
    Dye JM, Wu H, Hooper JW, Khurana S, Kuehne AI, Coyle EM, Ortiz RA, Fuentes S, Herbert AS, Golding H, Bakken RA, Brannan JM, Kwilas SA, Sullivan EJ, Luke TC, Smith G, Glenn G, Li W, Ye L, Yang C, Compans RW, Tripp RA, Jiao JA
  31. PLoS Pathog 2016 Apr 21;12(4):e1005554
    Antigenic fingerprinting following primary RSV infection in young children identifies novel antigenic sites and reveals unlinked evolution of human antibody repertoires to fusion and attachment glycoproteins.
    Fuentes S, Coyle EM, Beeler J, Golding H, Khurana S
  32. Neurol Neuroimmunol Neuroinflamm 2016 Jan 27;3(1):e196
    Patients with MS under daclizumab therapy mount normal immune responses to influenza vaccination.
    Lin YC, Winokur P, Blake A, Wu T, Manischewitz J, King LR, Romm E, Golding H, Bielekova B
  33. J Infect Dis 2015 Oct 15;212(8):1270-8
    High affinity H7 head and stalk domain-specific antibody responses to an inactivated influenza H7N7 vaccine after priming with live attenuated influenza vaccine.
    Halliley JL, Khurana S, Krammer F, Fitzgerald T, Coyle EM, Chung KY, Baker SF, Yang H, Martínez-Sobrido L, Treanor JJ, Subbarao K, Golding H, Topham DJ, Sangster MY
  34. MBio 2015 Aug 4;6(4):e01156-15
    A simple flow-cytometric method measuring B cell surface immunoglobulin avidity enables characterization of affinity maturation to influenza A virus.
    Frank GM, Angeletti D, Ince WL, Gibbs JS, Khurana S, Wheatley AK, Max EE, McDermott AB, Golding H, Stevens J, Bennink JR, Yewdell JW
  35. J Virol 2015 Mar 15;89(6):3295-307
    Post-challenge administration of Brincidofovir protects normal and immune-deficient mice reconstituted with limited numbers of T cells from lethal challenge with IHD-J-Luc vaccinia virus.
    Zaitseva M, McCullough KT, Cruz S, Thomas A, Diaz CG, Keilholz L, Grossi IM, Trost LC, Golding H
  36. PLoS One 2015 Jan 28;10(1):e0115476
    Oral priming with replicating adenovirus serotype 4 followed by subunit H5N1 vaccine boost promotes antibody affinity maturation and expands H5N1 cross-clade neutralization.
    Khurana S, Coyle EM, Manischewitz J, King LR, Ishioka G, Alexander J, Smith J, Gurwith M, Golding H
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