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  1. Biologics Research Projects

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).


NPJ Vaccines 2020 Mar 20;5:26
Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization.
Konopka-Anstadt JL, Campagnoli R, Vincent A, Shaw J, Wei L, Wynn NT, Smithee SE, Bujaki E, Te Yeh M, Laassri M, Zagorodnyaya T, Weiner AJ, Chumakov K, Andino R, Macadam A, Kew O, Burns CC

Vaccines 2020 Mar 5;8(1):pii. E120
Multiplex PCR-based neutralization (MPBN) assay for titers determination of the three types of anti-poliovirus neutralizing-antibodies.
Manukyan H, Petrovskaya S, Chumakov K, Laassri M

J Infect Dis 2020 Feb 3;221(4):504-5
Sabin strain inactivated polio vaccine for the polio endgame.
Modlin J, Chumakov K

J Virol Methods 2020 Feb;276:113785
Universal ELISA for quantification of D-antigen in inactivated poliovirus vaccines.
Kouiavskaia D, Devudu Puligedda R, Dessain SK, Chumakov K

Antibodies 2020 Feb 28;9(1):5
Human IgA monoclonal antibodies that neutralize poliovirus produced by hybridomas and recombinant expression.
Puligedda RD, Vigdorovich V, Kouiavskaia D, Kattala CD, Zhao JY, Al-Saleem FH, Chumakov K, Sather DN, Dessain SC

PLoS One 2020 Jan 30;15(1):e0228006
A novel gamma radiation-inactivated sabin-based polio vaccine.
Tobin GJ, Tobin JK, Gaidamakova EK, Wiggins TJ, Bushnell RV, Lee WM, Matrosova VY, Dollery SJ, Meeks HN, Kouiavskaia D, Chumakov K, Daly MJ

Virol J 2019 Oct 28;16(1):122
Multiplex PCR-based titration (MPBT) assay for determination of infectious titers of the three Sabin strains of live poliovirus vaccine.
Manukyan H, Rodionova E, Zagorodnyaya T, Lin TL, Chumakov K, Laassri M

MABS 2019 Apr;11(3):546-58
Capture and display of antibodies secreted by hybridoma cells enables fluorescent on-cell screening.
Puligedda RD, Sharma R, Al-Saleem FH, Kouiavskaia D, Velu AB, Kattala CD, Prendergast GC, Lynch DR, Chumakov K, Dessain SK

J Am Acad Dermatol 2019 Mar;80(3):804-6
Possible long-term sequelae in hand, foot, and mouth disease caused by Coxsackievirus A6.
Broccolo F, Drago F, Ciccarese G, Genoni A, Porro A, Parodi A, Chumakov K, Toniolo A

J Clin Virol 2019 Jan;110:1-6
Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6: clinical presentation and phylogenesis of CV-A6 strains.
Broccolo F, Drago F, Ciccarese G, Genoni A, Puggioni A, Rosa GM, Parodi A, Manukyan H, Laassri M, Chumakov K, Toniolo A

Biologicals 2018 Sep;55:63-70
Detection of bovine viral diarrhoea virus nucleic acid, but not infectious virus, in bovine serum used for human vaccine manufacture.
Laassri M, Mee ET, Connaughton SM, Manukyan H, Gruber M, Rodriguez-Hernandez C, Minor PD, Schepelmann S, Chumakov K, Wood DJ

J Virol 2018 Aug 16;92(17):e00976-18
Newcastle disease virus-based vectored vaccine against poliomyelitis.
Viktorova EG, Khattar SK, Kouiavskaia D, Laassri M, Zagorodnyaya T, Dragunsky E, Samal S, Chumakov K, Belov GA

Biologicals 2018 May;53:30-8
Assessing the potency and immunogenicity of inactivated poliovirus vaccine after exposure to freezing temperatures.
White JA, Estrada M, Weldon WC, Chumakov K, Kouiavskaia D, Fournier-Caruana J, Stevens E, Gary HE Jr, Maes EF, Oberste MS, Snider CJ, Anand A, Chen D

PLoS Pathog 2018 Mar 19;14(3):e1006943
Evolution of echovirus 11 in a chronically infected immunodeficient patient.
Laassri M, Zagorodnyaya T, Hassin-Baer S, Handsher R, Sofer D, Weil M, Karagiannis K, Simonyan V, Chumakov K, Shulman L

Nucleic Acids Res 2017 Nov 2;45(19):10989-1003
Separation and assembly of deep sequencing data into discrete sub-population genomes.
Karagiannis K, Simonyan V, Chumakov K, Mazumder R

Viruses 2017 Nov 22;9(11):353
Pressure for pattern-specific intertypic recombination between Sabin polioviruses: evolutionary implications.
Korotkova E, Laassri M, Zagorodnyaya T, Petrovskaya S, Rodionova E, Cherkasova E, Gmyl A, Ivanova OE, Eremeeva TP, Lipskaya GY, Agol VI, Chumakov K

Vaccine 2017 Oct 4;35(41):5455-62
Characterization of human monoclonal antibodies that neutralize multiple poliovirus serotypes.
Puligedda RD, Kouiavskaia D, Al-Saleem FH, Kattala CD, Nabi U, Yaqoob H, Bhagavathula VS, Sharma R, Chumakov K, Dessain SK

Sci Rep 2017 Jul 10;7(1):5013
Revealing enterovirus infection in chronic human disorders: An integrated diagnostic approach.
Genoni A, Canducci F, Rossi A, Broccolo F, Chumakov K, Bono G, Salerno-Uriarte J, Salvatoni A, Pugliese A, Toniolo A

Genomics 2017 Jul;109(3-4):131-40
HIVE-heptagon: a sensible variant-calling algorithm with post-alignment quality controls.
Simonyan V, Chumakov K, Donaldson E, Karagiannis K, Lam PV, Dingerdissen H, Voskanian A

J Virol 2017 Jun 26;91(14):e02310-16
Pathogenic events in a nonhuman primate model of oral poliovirus infection leading to paralytic poliomyelitis.
Shen L, Chen CY, Huang D, Wang R, Zhang M, Qian L, Zhu Y, Zhang AZ, Yang E, Qaqish A, Chumakov K, Kouiavskaia D, Vignuzzi M, Nathanson N, Macadam AJ, Andino R, Kew O, Xu J, Chen ZW

Plant Biotechnol J 2016 Nov;14(11):2190-2200
Cold chain and virus free chloroplast-made booster vaccine to confer immunity against different polio virus serotypes.
Chan HT, Xiao Y, Weldon WC, Oberste SM, Chumakov K, Daniell H

J Virol Methods 2018 Sep;259:74-80
Quantitative multiplex one-step RT-PCR assay for identification and quantitation of Sabin strains of poliovirus in clinical and environmental specimens.
Manukyan H, Zagorodnyaya T, Ruttimann R, Manor Y, Bandyopadhyay A, Shulman L, Chumakov K, Laassri M

MBio 2016 Aug 23;7(4):e01114-16
A full-length infectious cDNA clone of Zika virus from the 2015 epidemic in Brazil as a genetic platform for studies of virus-host interactions and vaccine development.
Tsetsarkin KA, Kenney H, Chen R, Liu G, Manukyan H, Whitehead SS, Laassri M, Chumakov K, Pletnev AG

Euro Surveill 2016 Apr 14;21(15):30193
Environmental surveillance of viruses by tangential flow filtration and metagenomic reconstruction.
Furtak V, Roivainen M, Mirochnichenko O, Zagorodnyaya T, Laassri M, Zaidic SZ, Rehman L, Alam MM, Chizhikov V, Chumakov K

Methods Mol Biol 2016;1387:263-77
Methods to monitor molecular consistency of oral polio vaccine.
Chumakov KM

Database 2016 Mar 17;2016:baw022
High-performance integrated virtual environment (HIVE): a robust infrastructure for next-generation sequence data analysis.
Simonyan V, Chumakov K, Dingerdissen H, Faison W, Goldweber S, Golikov A, Gulzar N, Karagiannis K, Vinh Nguyen Lam P, Maudru T, Muravitskaja O, Osipova E, Pan Y, Pschenichnov A, Rostovtsev A, Santana-Quintero L, Smith K, Thompson EE, Tkachenko V, Torcivia-Rodriguez J, Voskanian A, Wan Q, Wang J, Wu TJ, Wilson C, Mazumder R

PLoS One 2016 Feb 10;11(2):e0144261
Fluorescence adherence inhibition assay: a novel functional assessment of blocking virus attachment by vaccine-induced antibodies.
Asati A, Kachurina O, Karol A, Dhir V, Nguyen M, Parkhill R, Kouiavskaia D, Chumakov K, Warren W, Kachurin A

Science 2016 Jan 22;351(6271):348
Eradicating polio: a balancing act.
Agol V, Cello J, Chumakov K, Ehrenfeld E, Wimmer E

PLoS One 2015 Sep 25;10(9):e0138650
Deep sequencing for evaluation of genetic stability of influenza A/California/07/2009 (H1N1) vaccine viruses.
Majid L, Zagorodnyaya T, Plant EP, Petrovskaya S, Bidzhieva B, Ye Z, Simonyan V, Chumakov K

J Infect Dis 2015 Jun 15;211(12):1969-76
Comparison of the immunogenicity of various inactivated polio vaccine booster doses by intradermal versus intramuscular routes in HIV-infected adults.
Troy SB, Kouiavskaia D, Siik J, Kochba E, Beydoun H, Mirochnitchenko O, Levin Y, Khardori N, Chumakov K, Maldonado Y

J Infect Dis 2015 May 1;211(9):1447-50
Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.
Kouiavskaia D, Mirochnitchenko O, Dragunsky E, Kochba E, Levin Y, Troy S, Chumakov K

J Clin Virol 2015 Apr;65:32-37
A single chimpanzee-human neutralizing monoclonal antibody provides post-exposure protection against type 1 and type 2 polioviruses.
Kouiavskaia D, Chen Z, Dragunsky E, Mirochnitchenko O, Purcell R, Chumakov K

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