Establishment of Markers of Viral Vaccine Safety and Efficacy

Principal Investigator: Steven Rubin, MD
Office / Division / Lab: OVRR / DVP / LMD

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Overview

Public Health Issue: Use of live, attenuated vaccines is one of the most effective means of protecting individuals from disease and death following virus infection. Live, attenuated vaccines are weakened versions of viruses intended to stimulate protective immune responses. Attenuation is typically achieved by repeated passage of the wild type virus under unnatural conditions (different substrates, temperatures, etc). There is no established number of passages required for attenuation. Insufficient attenuation can result in a vaccine with potentially adverse health outcomes, while excessive attenuation can result in an ineffective vaccine. Development of tests capable of correctly assessing a candidate vaccine's attenuation profile is therefore essential to the licensure of safe and effective vaccines.

Regulatory Contribution: It is important to be able to predictably evaluate new candidate vaccines for potential safety and efficacy concerns before widespread use in humans, as well as be able to evaluate consistent manufacturing and safety profiles of licensed vaccines, as needed.

Research Approach: This research program supports vaccine safety and efficacy concerns through: (1) Development of in vivo, in vitro and molecular tests for assessing the safety of vaccines for the nervous system, including mumps vaccine, live influenza vaccine and vaccinia-based smallpox vaccines and using these tests to identify the mechanism/basis of vaccine virus virulence, and (2) Identification of surrogate immunological markers of protective efficacy and assessments of persistence of immunity.

Mission Relevance & Outcomes: These studies will provide the knowledge and tools for evaluating and supporting the development of safe and effective vaccines.

 

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Publications

J Med Virol 2009 Jan;81(1):130-8
Identification of genetic mutations associated with attenuation and changes in tropism of Urabe mumps virus.
Shah D, Vidal S, Link MA, Rubin SA, Wright KE

Clin Infect Dis 2008 Dec 1;47(11):1458-67
Mumps Outbreaks in Vaccinated Populations: Are Available Mumps Vaccines Effective Enough to Prevent Outbreaks?
Dayan GH, Rubin S

J Neuroinflammation 2008 Nov 11;5:50
Astrocytes play a key role in activation of microglia by persistent Borna disease virus infection.
Ovanesov MV, Ayhan Y, Wolbert C, Moldovan K, Sauder C, Pletnikov MV

J Infect Dis 2008 Aug 15;198(4):508-515
Antibody Induced by Immunization with the Jeryl Lynn Mumps Vaccine Strain Effectively Neutralizes a Heterologous Wild-Type Mumps Virus Associated with a Large Outbreak.
Rubin SA, Qi L, Audet SA, Sullivan B, Carbone KM, Bellini WJ, Rota PA, Sirota L, Beeler J

J Infect Dis 2008 Jun 15;197(12):1662-8
Long-term persistence of mumps antibody after receipt of 2 measles-mumps-rubella (MMR) vaccinations and antibody response after a third MMR vaccination among a university population.
Date AA, Kyaw MH, Rue AM, Klahn J, Obrecht L, Krohn T, Rowland J, Rubin S, Safranek TJ, Bellini WJ, Dayan GH

J Immunol 2008 Jun 15;180(12):8231-40
Immunotherapy with CpG oligonucleotides and antibodies to TNF-alpha rescues neonatal mice from lethal arenavirus-induced meningoencephalitis.
Pedras-Vasconcelos JA, Puig M, Sauder C, Wolbert C, Ovanesov M, Goucher D, Verthelyi D

J Neurovirol 2008 Apr;14(2):136-42
Genetic contributions to influenza virus attenuation in the rat brain.
Qi L, Carbone KM, Ye Z, Liu T, Ovanesov M, Pletnikov M, Sauder C, Rubin SA

Vaccine 2008 Apr 16;26(17):2111-8
Measles cases in highly vaccinated population of Novosibirsk, Russia, 2000-2005.
Atrasheuskaya AV, Kulak MV, Neverov AA, Rubin S, Ignatyev GM

Lancet 2008 Mar 15;371(9616):932-44
Mumps.
Hviid A, Rubin S, Mühlemann K

Cytokine 2008 Feb;41(2):182-6
The IP10 (CXCL10) specific cDNA probe of the mCK-5c multiprobe RNase protection assay kit carries two nucleotide insertions that complicate the interpretation of results.
Sauder C, Pedras-Vasconcelos J, Puig M, Verthelyi D

J Neurovirol 2007 Dec;13(6):513-21
A single nucleotide change in the mumps virus F gene affects virus fusogenicity in vitro and virulence in vivo.
Malik T, Sauder C, Wolbert C, Zhang C, Carbone KM, Rubin S

J Gen Virol 2007 Sep;88(Pt 9):2533-41
Functional consequences of attenuating mutations in the haemagglutinin neuraminidase, fusion and polymerase proteins of a wild-type mumps virus strain.
Malik T, Wolbert C, Mauldin J, Sauder C, Carbone KM, Rubin SA

Clin Microbiol Infect 2007 Jul;13(7):670-6
Mumps vaccine failure investigation in Novosibirsk, Russia, 2002-2004.
Atrasheuskaya AV, Kulak MV, Rubin S, Ignatyev GM

Vaccine 2007 Jun 11;25(24):4651-8
Investigation of mumps vaccine failures in Minsk, Belarus, 2001-2003.
Atrasheuskaya AV, Blatun EM, Kulak MV, Atrasheuskaya A, Karpov IA, Rubin S, Ignatyev GM

J Virol 2006 Dec;80(24):12141-8
Activation of microglia by Borna Disease Virus infection: an in vitro study.
Ovanesov MV, Sauder C, Rubin SA, Richt J, Nath A, Carbone KM, Pletnikov MV

Vaccine 2006 Mar 24;24(14):2662-8
Serological and phylogenetic evidence of monotypic immune responses to different mumps virus strains.
Rubin S, Mauldin J, Chumakov K, Vanderzanden J, Iskow R, Carbone K

Vaccine 2006 Mar 6;24(10):1530-6
Horizontal transmission of the Leningrad-3 live attenuated mumps vaccine virus.
Atrasheuskaya AV, Neverov AA, Rubin S, Ignatyev GM

J Clin Microbiol 2005 Sep;43(9):4847-51
Mumps virus-specific antibody titers from pre-vaccine era sera: comparison of the plaque reduction neutralization assay and enzyme immunoassays.
Mauldin J, Carbone K, Hsu H, Yolken R, Rubin S

Bioinformatics 2005 Aug 1;21(15):3248-54
A quantitative determination of multi-protein interactions by the analysis of confocal images using a pixel-by-pixel assessment algorithm.
Goucher DR, Wincovitch SM, Garfield SH, Carbone KM, Malik TH

J Infect Dis 2005 Apr 1;191(7):1123-8
The rat-based neurovirulence safety test for the assessment of mumps virus neurovirulence in humans: an international collaborative study.
Rubin SA, Afzal MA, Powell CL, Bentley ML, Auda GR, Taffs RE, Carbone KM

Psychiatry Res 2005 Mar 30;134(1):105
Detection of anti-Borna disease virus antibodies by Western blot analysis.
Ghosh M, Sauder C, Carbone KM, Malik TH

Arch Virol 2004 Nov;149(11):2171-86
Susceptibility of Borna disease virus to the antiviral action of gamma-interferon: evidence for species-specific differences.
Sauder C, Herpfer I, Hassler C, Staeheli P

J Neurovirol 2004 Oct;10(5):305-14
Wild-type and attenuated influenza virus infection of the neonatal rat brain.
Rubin S, Liu D, Pletnikov M, McCullers J, Ye Z, Levandowski R, Johannessen J, Carbone K

J Neurovirol 2004 Oct;10(5):267-77
Developmental alterations in serotoninergic neurotransmission in Borna disease virus (BDV)-infected rats: a multidisciplinary analysis.
Dietz D, Vogel M, Rubin S, Moran T, Carbone K, Pletnikov M

Vaccine 2004 Mar 29;22(11-12):1486-93
Mouse neurotoxicity test for vaccinia-based smallpox vaccines.
Li Z, Rubin SA, Taffs RE, Merchlinsky M, Ye Z, Carbone KM