Passive Immunotherapies Protect WRvFire and IHD-J-Luc Vaccinia Virus-Infected Mice from Lethality by Reducing Viral Loads in the Upper Respiratory Tract and Internal Organs

ABSTRACT Whole-body bioimaging was employed to study the effects of passive immunotherapies on lethality and viral dissemination in BALB/c mice challenged with recombinant vaccinia viruses expressing luciferase. WRvFire and IHD-J-Luc vaccinia viruses induced lethality with similar times to death following intranasal infection, but WRvFire replicated at higher levels than IHD-J-Luc in the upper and lower respiratory tracts. Three types of therapies were tested: licensed human anti-vaccinia virus immunoglobulin intravenous (VIGIV); recombinant anti-vaccinia virus immunoglobulin (rVIG; Symphogen, Denmark), an investigational product containing a mixture of 26 human monoclonal antibodies (HuMAbs) against mature virion (MV) and enveloped virion (EV); and HuMAb compositions targeting subsets of MV or EV proteins. Bioluminescence recorded daily showed that pretreatment with VIGIV (30 mg) or with rVIG (100 μg) on day −2 protected mice from death but did not prevent viral replication at the site of inoculation and dissemination to internal organs. Compositions containing HuMAbs against MV or EV proteins were protective in both infection models at 100 μg per animal, but at 30 μg, only anti-EV antibodies conferred protection. Importantly, the t statistic of the mean total fluxes revealed that viral loads in surviving mice were significantly reduced in at least 3 sites for 3 consecutive days (days 3 to 5) postchallenge, while significant reduction for 1 or 2 days in any individual site did not confer protection. Our data suggest that reduction of viral replication at multiple sites, including respiratory tract, spleen, and liver, as monitored by whole-body bioluminescence can be used to predict the effectiveness of passive immunotherapies in mouse models.

[1]  Christine G. Casey,et al.  Smallpox Vaccination and Adverse Reactions , 2011 .

[2]  S. K. Rasmussen,et al.  Capturing the Natural Diversity of the Human Antibody Response against Vaccinia Virus , 2010, Journal of Virology.

[3]  J. Weir,et al.  Third-generation smallpox vaccines: challenges in the absence of clinical smallpox. , 2010, Future microbiology.

[4]  Barney S. Graham,et al.  Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo , 2010, Proceedings of the National Academy of Sciences.

[5]  T. P. Frandsen,et al.  Development of mass spectrometry based techniques for the identification and determination of compositional variability in recombinant polyclonal antibody products. , 2010, Analytical chemistry.

[6]  Geoffrey L. Smith,et al.  Repulsion of Superinfecting Virions: A Mechanism for Rapid Virus Spread , 2010, Science.

[7]  Senta M Kapnick,et al.  Application of Bioluminescence Imaging to the Prediction of Lethality in Vaccinia Virus-Infected Mice , 2009, Journal of Virology.

[8]  F. Ennis,et al.  Comparison of the safety and immunogenicity of ACAM1000, ACAM2000 and Dryvax in healthy vaccinia-naive adults. , 2009, Vaccine.

[9]  J. Cohen,et al.  Progressive vaccinia in a military smallpox vaccinee - United States, 2009. , 2009, MMWR. Morbidity and mortality weekly report.

[10]  M. R. Benhnia,et al.  Vaccinia Virus Extracellular Enveloped Virion Neutralization In Vitro and Protection In Vivo Depend on Complement , 2008, Journal of Virology.

[11]  J. Héraud,et al.  Differential Antigen Requirements for Protection against Systemic and Intranasal Vaccinia Virus Challenges in Mice , 2008, Journal of Virology.

[12]  J. Kennedy,et al.  ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine , 2008, Expert opinion on investigational drugs.

[13]  Alessandro Sette,et al.  Redundancy and Plasticity of Neutralizing Antibody Responses Are Cornerstone Attributes of the Human Immune Response to the Smallpox Vaccine , 2008, Journal of Virology.

[14]  I. Berkower,et al.  Antibodies to the A27 protein of vaccinia virus neutralize and protect against infection but represent a minor component of Dryvax vaccine--induced immunity. , 2007, The Journal of infectious diseases.

[15]  C. Midgley,et al.  Quantification of antibody responses against multiple antigens of the two infectious forms of Vaccinia virus provides a benchmark for smallpox vaccination , 2006, Nature Medicine.

[16]  B. Moss,et al.  Vaccinia Virus Entry into Cells via a Low-pH-Dependent Endosomal Pathway , 2006, Journal of Virology.

[17]  D. Venzon,et al.  Subunit Recombinant Vaccine Protects against Monkeypox1 , 2006, The Journal of Immunology.

[18]  P. S. Andersen,et al.  Isolation of human antibody repertoires with preservation of the natural heavy and light chain pairing. , 2006, Journal of molecular biology.

[19]  R. Wittek.  Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy. , 2006, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[20]  Christiana N. Fogg,et al.  Combinations of Polyclonal or Monoclonal Antibodies to Proteins of the Outer Membranes of the Two Infectious Forms of Vaccinia Virus Protect Mice against a Lethal Respiratory Challenge , 2005, Journal of Virology.

[21]  Siddiqua Hirst,et al.  Vaccinia Virus H3L Envelope Protein Is a Major Target of Neutralizing Antibodies in Humans and Elicits Protection against Lethal Challenge in Mice , 2005, Journal of Virology.

[22]  M. Law,et al.  An investigation of the therapeutic value of vaccinia-immune IgG in a mouse pneumonia model. , 2005, The Journal of general virology.

[23]  Christiana N. Fogg,et al.  Synergistic neutralizing activities of antibodies to outer membrane proteins of the two infectious forms of vaccinia virus in the presence of complement. , 2004, Virology.

[24]  T. Monath,et al.  ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain) – a second-generation smallpox vaccine for biological defense , 2004, International Journal of Infectious Diseases.

[25]  Christiana N. Fogg,et al.  Protective Immunity to Vaccinia Virus Induced by Vaccination with Multiple Recombinant Outer Membrane Proteins of Intracellular and Extracellular Virions , 2004, Journal of Virology.

[26]  J. Robinson,et al.  Differential efficacy of vaccinia virus envelope proteins administered by DNA immunisation in protection of BALB/c mice from a lethal intranasal poxvirus challenge. , 2004, Vaccine.

[27]  John D Lambris,et al.  Antibodies against the extracellular enveloped virus B5R protein are mainly responsible for the EEV neutralizing capacity of vaccinia immune globulin. , 2004, Virology.

[28]  P. Jahrling,et al.  Smallpox DNA Vaccine Protects Nonhuman Primates against Lethal Monkeypox , 2004, Journal of Virology.

[29]  J. Cleveland,et al.  Guidelines for infection control in dental health-care settings--2003. , 2003, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[30]  T. Monath,et al.  Development of a novel vaccinia-neutralization assay based on reporter-gene expression. , 2003, The Journal of infectious diseases.

[31]  L. Rotz,et al.  Recommendations for using smallpox vaccine in a pre-event vaccination program. Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Healthcare Infection Control Practices Advisory Committee (HICPAC). , 2003, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[32]  Joanne Cono,et al.  Smallpox vaccination and adverse reactions. Guidance for clinicians. , 2003, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[33]  M. Law,et al.  The formation and function of extracellular enveloped vaccinia virus. , 2002, The Journal of general virology.

[34]  D. A. Dotson,et al.  Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. , 2001, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[35]  J. Modlin,et al.  Vaccinia (Smallpox) Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001 , 2001 .

[36]  C. Schmaljohn,et al.  DNA vaccination with vaccinia virus L1R and A33R genes protects mice against a lethal poxvirus challenge. , 2000, Virology.

[37]  R. Wittek,et al.  Neutralizing and protective antibodies directed against vaccinia virus envelope antigens. , 1999, Virology.

[38]  Geoffrey L. Smith,et al.  Antibodies against vaccinia virus do not neutralize extracellular enveloped virus but prevent virus release from infected cells and comet formation. , 1997, The Journal of general virology.

[39]  R. Harpaz,et al.  Prevention of plague: recommendations of the Advisory Committee on Immunization Practices (ACIP). , 1996, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[40]  B. Moss,et al.  Role of cell-associated enveloped vaccinia virus in cell-to-cell spread , 1992, Journal of virology.

[41]  Geoffrey L. Smith,et al.  A constitutively expressed vaccinia gene encodes a 42-kDa glycoprotein related to complement control factors that forms part of the extracellular virus envelope. , 1992, Virology.

[42]  L. Payne.  Significance of extracellular enveloped virus in the in vitro and in vivo dissemination of vaccinia. , 1980, The Journal of general virology.

[43]  L. Payne.  Identification of the vaccinia hemagglutinin polypeptide from a cell system yielding large amounts of extracellular enveloped virus , 1979, Journal of virology.