Evaluation of Safety and Potency of Viral Vaccines Based on Analysis of Molecular Consistency

Principal Investigator: Konstantin M. Chumakov, PhD
Office / Division / Lab: OVRR / DVP / LMD

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Overview

Public Health Issue: Ensuring safety and efficacy of biological products is at the core of CBER mission. Evaluation of new products and quality control of the licensed ones involves rigorous testing that often requires use of animals and other costly and laborious procedures. Evaluation and implementation of state-of-the-art techniques available in the field may lead to reduction in cost or time and therefore, should be carefully tested for applicability to regulatory evaluation of vaccines. New molecular methods provide tools for in-depth characterization of vaccines that could be used for monitoring consistency of product manufacture, thereby ensuring product safety and efficacy. Introduction of these new methods across the industry requires leadership from scientists in thepublic sector. FDA researchers are uniquely positioned to support improved efficiency and continuous modernization of testing by creating and validating new methods for assessment of vaccine safety and efficacy.

Regulatory Contribution: This research is aimed at introduction of new concepts of regulatory evaluation of vaccines and a new generation of test procedures based on cutting-edge scientific approaches. Use of molecular characterization of vaccines could significantly improve their quality and reduce the time needed for new vaccine development and regulatory approval. The new molecular approaches are especially important for new products for which direct clinical evaluation of efficacy is not possible, and therefore licensure decisions must be based on surrogate biomarkers and the "Animal Rule" (http://www.fda.gov/cber/rules/humeffic.htm).

Research Approach: Our research program has developed novel methods for monitoring the molecular consistency of the genetic stability of live poliovirus vaccine. We have now expanded our method development to include other viral vaccines, such as West Nile Virus vaccine, Influenza vaccine, and others, thereby guiding rational vaccine design. Advanced immunological procedures are being developed for detailed profiling of the antigenic structure of viruses and vaccines, as well as of the immune response in vaccine recipients and laboratory animals. These methods could help identify biomarkers of protection of a new generation of Inactivated Poliovirus Vaccine (IPV). Monitoring molecular consistency of these biomarkers could be a way to ensure vaccine efficacy. Other directions include the use of transgenic animals susceptible to human infectious agents for evaluation of the safety and efficacy of human vaccines.

Mission Relevance & Outcomes: Creation of the new generation of test methods could only be done with active leadership of FDA regulatory scientists working in collaboration with WHO and international regulatory authorities. This laboratory has a long track record of introducing novel molecular techniques for evaluation of safety and efficacy of viral vaccines.

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Publications

J Virol Methods 2008 Dec;154(1-2):27-40
Microarray-based assay for the detection of genetic variations of structural genes of West Nile virus.
Grinev A, Daniel S, Laassri M, Chumakov K, Chizhikov V, Rios M

Blood Coagul Fibrinolysis 2008 Sep;19(6):543-555
Interaction of coagulation factor VIII with members of the low-density lipoprotein receptor family follows common mechanism and involves consensus residues within the A2 binding site 484-509.
Ananyeva NM, Makogonenko YM, Sarafanov AG, Pechik IV, Gorlatova N, Radtke KP, Shima M, Saenko EL

Virology 2008 Aug 15;378(1):118-22
Cleavage of eukaryotic initiation factor eIF5B by enterovirus 3C proteases.
de Breyne S, Bonderoff JM, Chumakov KM, Lloyd RE, Hellen CU

Lancet 2008 Apr 19;371(9621):1385-7
Immunisation against poliomyelitis: moving forward.
Ehrenfeld E, Glass RI, Agol VI, Chumakov K, Dowdle W, John TJ, Katz SL, Miller M, Breman JG, Modlin J, Wright P

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

DNA Cell Biol 2008 Apr;27(4):191-8
Quercetinase pirin makes poliovirus replication resistant to flavonoid quercetin.
Neznanov N, Kondratova A, Chumakov KM, Neznanova L, Kondratov R, Banerjee AK, Gudkov AV

Virology 2008 Jan 5;370(1):63-76
Recovery of strains of the polyomavirus SV40 from rhesus monkey kidney cells dating from the 1950s to the early 1960s.
Peden K, Sheng L, Omeir R, Yacobucci M, Klutch M, Laassri M, Chumakov K, Pal A, Murata H, Lewis AM Jr

Nat Rev Microbiol 2007 Dec;5(12):952-8
Vaccination against polio should not be stopped.
Chumakov K, Ehrenfeld E, Wimmer E, Agol VI

J Infect Dis 2007 Sep 1;196(5):692-8
Randomized trial of inactivated and live polio vaccine schedules in guatemalan infants.
Asturias EJ, Dueger EL, Omer SB, Melville A, Nates SV, Laassri M, Chumakov K, Halsey NA

J Med Virol 2007 Apr 24;79(6):791-802
Microarray assay for evaluation of the genetic stability of modified vaccinia virus Ankara B5R gene.
Laassri M, Meseda CA, Williams O, Merchlinsky M, Weir JP, Chumakov K

J Med Virol 2006 Oct;78(10):1325-40
Microarray assay for detection and discrimination of Orthopoxvirus species.
Ryabinin VA, Shundrin LA, Kostina EB, Laassri M, Chizhikov V, Shchelkunov SN, Chumakov K, Sinyakov AN

J Clin Microbiol 2006 Oct;44(10):3752-9
Genotyping of measles virus in clinical specimens on the basis of oligonucleotide microarray hybridization patterns.
Neverov AA, Riddell MA, Moss WJ, Volokhov DV, Rota PA, Lowe LE, Chibo D, Smit SB, Griffin DE, Chumakov KM, Chizhikov VE

J Infect Dis 2006 Sep 15;194(6):804-7
Further development of a new transgenic mouse test for the evaluation of the immunogenicity and protective properties of inactivated poliovirus vaccine.
Dragunsky EM, Ivanov AP, Abe S, Potapova SG, Enterline JC, Hashizume S, Chumakov KM

J Infect Dis 2006 May 15;193(10):1344-9
Analysis of reversions in the 5'-untranslated region of attenuated poliovirus after sequential administration of inactivated and oral poliovirus vaccines.
Laassri M, Lottenbach K, Belshe R, Rennels M, Plotkin S, Chumakov K

J Virol 2006 Mar;80(6):2641-53
Antigenic evolution of vaccine-derived polioviruses: changes in individual epitopes and relative stability of the overall immunological properties.
Yakovenko ML, Cherkasova EA, Rezapkin GV, Ivanova OE, Ivanov AP, Eremeeva TP, Baykova OY, Chumakov KM, Agol VI

J Infect Dis 2006 Feb 15;193(4):598-600
1,25-dihydroxyvitamin d3 enhances systemic and mucosal immune responses to inactivated poliovirus vaccine in mice.
Ivanov AP, Dragunsky EM, Chumakov KM

J Infect Dis 2005 Dec 15;192(12):2092-2098
Effect of Different Vaccination Schedules on Excretion of Oral Poliovirus Vaccine Strains.
Laassri M, Lottenbach K, Belshe R, Wolff M, Rennels M, Plotkin S, Chumakov K

Cancer Res 2005 Nov 15;65(22):10273-9
Some oral poliovirus vaccines were contaminated with infectious SV40 after 1961.
Cutrone R, Lednicky J, Dunn G, Rizzo P, Bocchetta M, Chumakov K, Minor P, Carbone M

J Virol Methods 2005 Jun;126(1-2):45-52
Determination of poliovirus-specific IgA in saliva by ELISA tests.
Ivanov A, Dragunsky E, Ivanova O, Rezapkin G, Potapova S, Chumakov K

J Clin Microbiol 2005 Jun;43(6):2886-94
Genomic analysis of vaccine-derived poliovirus strains in stool specimens by combination of full-length PCR and oligonucleotide microarray hybridization.
Laassri M, Dragunsky E, Enterline J, Eremeeva T, Ivanova O, Lottenbach K, Belshe R, Chumakov K

Nature 2005 Jun 16;435(7044):881
Don't drop current vaccine until we have new ones.
Agol VI, Chumakov K, Ehrenfeld E, Wimmer E

J Biol Chem 2005 Jun 24;280(25):24153-8
Proteolytic cleavage of the p65-RelA subunit of NF-kappaB during poliovirus infection.
Neznanov N, Chumakov KM, Neznanova L, Almasan A, Banerjee AK, Gudkov AV

Expert Rev Vaccines 2005 Apr;4(2):167-72
ELISA as a possible alternative to the neutralization test for evaluating the immune response to poliovirus vaccines.
Ivanov AP, Dragunsky EM

Biologicals 2005 Mar;33(1):17-27
Improved ELISA test for determination of potency of Inactivated Poliovirus Vaccine (IPV).
Rezapkin G, Dragunsky E, Chumakov K

Biologicals 2005 Mar;33(1):29-39
Analysis of antigenic profiles of inactivated poliovirus vaccine and vaccine-derived polioviruses by block-ELISA method.
Rezapkin G, Martin J, Chumakov K

J Virol 2005 Jan;79(2):1062-70
Spread of vaccine-derived poliovirus from a paralytic case in an immunodeficient child: an insight into the natural evolution of oral polio vaccine.
Cherkasova EA, Yakovenko ML, Rezapkin GV, Korotkova EA, Ivanova OE, Eremeeva TP, Krasnoproshina LI, Romanenkova NI, Rozaeva NR, Sirota L, Agol VI, Chumakov KM

J Clin Microbiol 2004 Dec;42(12):5793-801
Mapping of genomic segments of influenza B virus strains by an oligonucleotide microarray method.
Ivshina AV, Vodeiko GM, Kuznetsov VA, Volokhov D, Taffs R, Chizhikov VI, Levandowski RA, Chumakov KM

J Infect Dis 2004 Oct 15;190(8):1404-12
Evaluation of immunogenicity and protective properties of inactivated poliovirus vaccines: a new surrogate method for predicting vaccine efficacy.
Dragunsky EM, Ivanov AP, Wells VR, Ivshina AV, Rezapkin GV, Abe S, Potapova SG, Enterline JC, Hashizume S, Chumakov KM

J Virol 2004 Oct;78(20):11097-107
Molecular mechanisms of attenuation of the Sabin strain of poliovirus type 3.
Guest S, Pilipenko E, Sharma K, Chumakov K, Roos RP