Evaluation of the Quality of Viral Vaccines Based on Molecular Consistency
Konstantin M. Chumakov, PhD
Office of Vaccines Research and Review
Division of Viral Products
Laboratory of Method Development
Konstantin.Chumakov@fda.hhs.gov
Biosketch
Dr. Konstantin Chumakov is a graduate of Moscow State University (1973) and holds a Ph.D. degree in virology (1979) and Doctor of Sciences degree in molecular biology (1987) from the same university. In 1973-1987, he was a Research Scientist at the Laboratory of Molecular Biology and Bioorganic Chemistry of Moscow State University. From 1987 to 1989 he was Chief of the Laboratory of Bacterial Genetics at the Institute of Microbiology of the Soviet Academy of Sciences in Moscow. Dr. Chumakov moved to the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research (CBER) in 1989, where he is a Principal Investigator and Laboratory Chief in the Division of Viral Products. Since 2008, he has served as Associate Director for Research in the CBER’s Office of Vaccines Research and Review. He is also an Adjunct Professor at George Washington University and the University of Maryland, and the Director of the Global Virus Network Center of Excellence. He is an advisor to the World Health Organization and a member of WHO Polio Research Committee. His scientific interests are in poliovirus biology and bioinformatics, as well as creation of molecular methods for evaluation and quality control of vaccines and other biological products.
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 use these technologies to gain more detailed knowledge of the structure and properties of vaccines. Such knowledge helps to improve the design and manufacture of vaccines, making them significantly safer, effective, and affordable. Moreover, FDA’s proactive research also greatly facilitates 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 and reproducible 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) dissecting the details of immune responses and finding new ways to enhance protection; and 3) creating new ways to evaluate and increase vaccine potency (e.g., new potency tests, use of adjuvants, new routes of administration, etc.) and ways to prevent or mitigate adverse reactions caused by vaccines.
Since animal testing is continues to be applicable to some products, this program seeks to improve this technique by using genetically modified mice. Our aim is to reduce the number of animals used while significantly increasing the amount and precision of scientific information produced by these studies, and to ultimately replace their use with new molecular protocols.
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 understanding that natural viral populations (including stocks of live viral vaccines) contain a wide variety of mutants. Even though most such mutants are present at very low levels, 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 to analyze molecular consistency of vaccines is developing 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, as well as analyzing the repertoire of antibodies (paratope profiles) in sera of vaccine recipients. This approach is closely integrated with efforts to develop new ways to determine vaccine potency and to standardize potency testing of new and existing vaccines. Studies of the repertoire of antibodies are linked to the isolation, cloning, and characterization of human monoclonal antibodies that serve not only as valuable reagents for characterization of vaccines, but also could be used as new therapeutic tools.
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 vaccines, and to assess residual neurovirulence of live poliovirus vaccines. The program also aims to analyze results of clinical trials of new vaccines, including vaccines with improved genetic stability and safety profiles. We are also developing new methods to analyze clinical samples that improve the power of vaccine clinical trials. The next generation sequencing and qPCR-based methods developed in our lab for monitoring genetic stability of attenuated viruses in vaccine recipients were used in support of the first-ever WHO Emergency Use Listing of a vaccine (the novel oral polio vaccine type 2).
In addition, we are studying adverse reactions caused by oral polio vaccine (OPV) and ways to mitigate them. OPV can trigger emergence of circulating vaccine-derived polioviruses 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 approaches designed to mitigate adverse consequences of OPV vaccination. We use transgenic mouse models to assess the efficacy of anti-poliovirus drugs and human monoclonal antibodies that are proposed to treat chronically infected individuals and to stop outbreaks caused by VDPV.
Finally, monitoring vaccine performance in the field involves analyses of the circulation of wild and vaccine-derived viruses. We are developing new methods for environmental and clinical surveillance, based on metagenomic studies using next generation sequencing technologies.
Important Links
- Innovation and Regulatory Science- Research Summary: Universal test for assessing potency of inactivated poliovirus vaccines could facilitate their global production and availability ; FDA poliovirus assay is faster and more versatile than current assays used in vaccine development and environmental surveillance
- ORCID ID: 0000-0003-3002-6247
Publications
- Proc Natl Acad Sci U S A 2021 May 25;118(21):e2101718118
Old vaccines for new infections: Exploiting innate immunity to control COVID-19 and prevent future pandemics.
Chumakov K, Avidan MS, Benn CS, Bertozzi SM, Blatt L, Chang AY, Jamison DT, Khader SA, Kottilil S, Netea MG, Sparrow A, Gallo RC - Int J Syst Evol Microbiol 2021 May;71(5)
Streptococcus vicugnae sp. nov., isolated from faeces of alpacas (Vicugna pacos) and cattle (Bos taurus), Streptococcus zalophi sp. nov., and Streptococcus pacificus sp. nov., isolated from respiratory tract of California sea lions (Zalophus californianus).
Volokhov DV, Zagorodnyaya TA, Shen Z, Blom J, Furtak VA, Eisenberg T, Fan P, Jeong KC, Gao Y, Zhang S, Amselle M - Risk Anal 2021 Feb;41(2):387-8
Letter to the editor.
Chumakov K, Jamison DT, Aaby P, Benn CS, Gallo RC - J Infect Dis 2020 Dec 1;222(11):1920-7
The use of next generation sequencing for the quality control of live-attenuated polio vaccines.
Charlton B, Hockley J, Laassri M, Wilton T, Crawt L, Preston M, NGS Study Group, Rigsby P, Chumakov K, Martin J - J Appl Ecol 2021 Apr;58(4):879-89
Disentangling interactions among mercury, immunity, and infection in a neotropical bat community.
Becker DJ, Speer KA, Korstian JM, Volokhov DV, Droke HF, Brown AM, Baijnauth CL, Padgett-Stewart T, Broders HG, Plowright RK, Rainwater TR, Fenton MB, Simmons NB, Chumchal MM - Transbound Emerg Dis 2020 Nov 19 [Epub ahead of print]
Worldwide occurrence of hemoplasmas in wildlife: insights into the patterns of infection, transmission, pathology, and zoonotic potential.
Millán J, Di Cataldo S, Volokhov DV, Becker DJ - Science 2020 Jun 12;368(6496):1187-8
Can existing live vaccines prevent COVID-19?
Chumakov K, Benn CS, Aaby P, Kottilil S, Gallo R - 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 15;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 Sep;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 - J Virol 2017 Jul;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 - 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 - 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