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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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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


General Overview

FDA carefully evaluates the safety and effectiveness of vaccines, both before and after they reach the market. These evaluations, which are done in both "test tube" studies as well as in animal models, are often labor- intensive and time-consuming.

Our laboratory is adapting cutting-edge tools of biotechnology to make the design and evaluation of new vaccines more efficient. We will use these technologies to get more detailed knowledge of the structure and properties of vaccines. Such knowledge will help to improve the design and manufacture of vaccines, making them significantly safer and more effective.

The design and manufacturing of vaccines is done mainly by the vaccine industry, and to a lesser extent by academic researchers. However, FDA scientists can lead and coordinate this work, making the results publicly available to the entire industry and general public. This will maximize the efficiency of these efforts and thus facilitate FDA regulatory evaluation of these products, reducing the time needed to approve vaccines and make them available to the public.

Our research program focuses on creating, validating, and using new biotechnology tools for in-depth studies of the molecular makeup of vaccines and for studying how people respond to vaccines. We base our approach to this research on the concept of molecular consistency; that is, on ensuring that manufacture of vaccines results in products that are uniform in their molecular makeup. Using this approach, FDA regulators will work to ensure that vaccines conform to the highest standards of quality, based on their molecular consistency.

The program is pursuing several strategies to achieve this goal: 1) analyzing how likely it is that vaccines made from live viruses will undergo gene mutations that degrade their safety and effectiveness; 2) determining which molecular parts of the vaccines are responsible for triggering immune system responses and studying in detail those immune system responses; and 3) creating new ways to evaluate both the inactive components of vaccines used to increase vaccine potency (e.g. adjuvants) and ways to prevent or mitigate adverse reactions caused by those components.

Since animal testing is likely to remain the gold standard for many products, this program seeks to improve this technique by using genetically modified mice. We are also trying to incorporate new imaging techniques and other technologies to study the effect of vaccines on these mice. Our aim is to reduce the number of animals that must be used while significantly increasing the amount and precision of scientific information produced by these studies.


Scientific Overview

We are analyzing the molecular consistency of vaccines in a variety of ways. First, we monitor the genetic stability of live viral vaccines through sensitive analysis of their genetic composition. This approach is based on the quasi-species concept that natural viral populations (including stocks of live viral vaccines) contain a wide variety of mutants. Even though most such mutants are present at a very low level, together they can significantly affect biological properties of vaccines. Therefore, one of our objectives is to create methods for characterizing and quantifying small quantities of mutants that have potentially deleterious properties. The techniques developed to monitor genomic consistency of vaccines can also be used to investigate cases of vaccine-induced adverse reactions.

A second strategy we are pursuing to analyze molecular consistency of vaccines is the development of new methods for detailed characterization of the immunochemical properties of vaccines and the immune responses to them. This includes creating ways to determine the repertoire of epitopes (epitope profiles) that inactivated vaccines contain, and analyzing the repertoire of antibodies (paratope profiles) in sera of vaccine recipients.

We are also pursuing immunological characterization of new vaccine products by developing novel immunization-challenge methods using transgenic mouse models. This is especially important in the case of poliovirus vaccines, for which the only natural model are primates. Specifically, we use transgenic mice susceptible to poliomyelitis to compare the efficacy of different products containing inactivated poliovirus vaccine. The program also aims to analyze results of clinical trials of new vaccines, including studies in special populations, such as premature infants. We are also developing new methods to analyze clinical samples that improve the power of vaccine clinical trials.

In addition, our program is studying certain adverse reactions caused by oral polio vaccine (OPV) that require treatment. OPV can trigger emergence of circulating vaccine-derived polioviruses (cVDPV) and can also establish persistent infections in immunocompromised individuals who subsequently excrete vaccine derived viruses (VDPV). One of the objectives of this program is to create ways to assess the efficacy of methods designed to mitigate adverse consequences of OPV vaccination. We use methods based on transgenic mouse models to assess the efficacy of anti-poliovirus drugs and human monoclonal antibodies proposed for treating chronically infected individuals, and to stop outbreaks caused by VDPV.

Finally, since new vaccines increasingly contain adjuvants added to improve their efficacy and modify the immune response, we are developing new methods for preclinical and clinical evaluation of vaccines containing adjuvants. Our goal is to be able to analyze the consistency of adjuvanted vaccines using cutting-edge molecular approaches such as in vivo models of human immune system (MIMIC®), and to use the FACTORIAL® protocol to analyze the activity of cellular signal transduction pathways (transcription factors activity profiles).


Publications

Pediatr Infect Dis J 2012 Feb;31(2):176-180
Immunologic Response to Oral Polio Vaccine in Human Immunodeficiency Virus-infected and Uninfected Zimbabwean Children.
Gnanashanmugam D, Troy SB, Musingwini G, Huang C, Halpern MS, Stranix-Chibanda L, Shetty AK, Kouiavskaia D, Nathoo K, Chumakov K, Maldonado YA

Antivir Ther 2011;16(7):999-1004
Immunological and pathogenic properties of poliovirus variants selected for resistance to antiviral drug V-073.
Kouiavskaia DV, Dragunsky EM, Liu HM, Oberste MS, Collett MS, Chumakov KM

Vaccine 2011 Sep 2;29(38):6432-6
WHO Working Group discussion on revision of the WHO recommendations for the production and control of poliomyelitis vaccines (oral): TRS Nos. 904 and 910. Report of Meeting held on 20-22 July 2010, Geneva, Switzerland.
Martin J, Milne C, Minor P, Chumakov K, Baca-Estrada M, Caruana JF, Zhou T

Clin Vaccine Immunol 2011 Aug;18(8):1387-90
Immunogenicity of inactivated polio vaccine with concurrent antiviral V-073 administration in mice.
Kouiavskaia D, Collett MS, Dragunsky EM, Sarafanov A, Chumakov KM

J Virol Methods 2011 Jul;175(1):14-9
MAPREC assay for quantitation of mutants in a recombinant flavivirus vaccine strain using near-infrared fluorescent dyes.
Bidzhieva B, Laassri M, Chumakov K

J Med Virol 2011 May;83(5):910-20
Microarray hybridization for assessment of the genetic stability of chimeric West Nile/dengue 4 virus.
Laassri M, Bidzhieva B, Speicher J, Pletnev AG, Chumakov K

J Virol 2011 May;85(9):4354-62
Chimpanzee-human monoclonal antibodies for treatment of chronic poliovirus excretors and emergency postexposure prophylaxis.
Chen Z, Chumakov K, Dragunsky E, Kouiavskaia D, Makiya M, Neverov A, Rezapkin G, Sebrell A, Purcell R

PLoS One 2011 Apr 29;6(4):e17529
Universal oligonucleotide microarray for sub-typing of influenza a virus.
Ryabinin VA, Kostina EV, Maksakova GA, Neverov AA, Chumakov KM, Sinyakov AN

OMICS 2011 Mar;15(3):105-12
Biomarkers in the age of omics: time for a systems biology approach.
Abu-Asab MS, Chaouchi M, Alesci S, Galli S, Laassri M, Cheema AK, Atouf F, Vanmeter J, Amri H

J Virol Methods 2010 Nov;169(2):322-31
Repertoire of antibodies against type 1 poliovirus in human sera.
Rezapkin G, Neverov A, Cherkasova E, Vidor E, Sarafanov A, Kouiavskaia D, Dragunsky E, Chumakov K

Proc Natl Acad Sci U S A 2010 Nov 16;107(46):20063-8
Massively parallel sequencing for monitoring genetic consistency and quality control of live viral vaccines.
Neverov A, Chumakov K

J Infect Dis 2010 Jan 15;201(2):214-22
Preterm Infants' T Cell Responses to Inactivated Poliovirus Vaccine.
Klein NP, Gans HA, Sung P, Yasukawa LL, Johnson J, Sarafanov A, Chumakov K, Hansen J, Black S, Dekker CL

Expert Rev Vaccines 2009 Jul;8(7):899-905
Future of polio vaccines.
Ehrenfeld E, Modlin J, Chumakov K

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):543-55
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

Hum Vaccin 2005 May-Jun;1(3):102-5
Poliovirus-Binding Inhibition ELISA for Evaluation of Immune Response to Oral Poliovirus Vaccine: A Possible Alternative to the Neutralization Test.
Ivanov AP, Dragunsky EM, Ivanova OE, Rezapkin GV, Potapova SG, Chumakov KM

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

 

 

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