Keith Peden, PhD
Office of Vaccines Research and Review
Division of Viral Products
Laboratory of DNA Viruses
Dr. Keith Peden obtained his Ph.D. from the MRC Mammalian Genome Unit, Department of Zoology, University of Edinburgh, UK. He then carried out post-doctoral research in the Department of Molecular Biology, University of Edinburgh, UK, and at the Department of Molecular Biology and Genetics with Dan Nathans at the Johns Hopkins University School of Medicine, Baltimore. Following postdoctoral training, Dr. Peden spent a year at the Pasteur Institute (1988/89) with Luc Montagnier working on HIV. The work involved generating infectious molecular clones of HIV-1 and HIV-2 and initiating studies on the viral accessory genes. He then spent 5 years at the NIH continuing work on HIV-1 and HIV-2 before moving to CBER/FDA in 1994.
Dr. Peden’s research at CBER first focused on HIV but turned to addressing perceived safety issues with the use of tumorigenic cell substrates for the manufacture of vaccines against viral diseases. Currently, he is Chief of the Laboratory of DNA Viruses in the Division of Viral Products, Office of Vaccines Research and Review, CBER, FDA, where the major focus of his research continues to address safety issues associated with cell substrates for vaccine production. More recently, he has been developing of micro-neutralization assays to assess the effectiveness of vaccines. The overall aims of both areas of research are to facilitate the introduction of effective vaccines against viral diseases.
Viral vaccines are produced in animal cells called “cell substrates.” Therefore, the characteristics of these cell substrates affect the quality of the vaccine. Our division regulates vaccines against infectious diseases caused by viruses, and our research program is directed at both developing new tools that could be used to evaluate the safety of cell substrates used to produce viral vaccines and developing methods to evaluate the effectiveness of vaccines.
A number of vaccines protect the public against viral diseases such as polio, influenza, measles, mumps, rubella, varicella, smallpox, and rotavirus. These vaccines, which are made in monkey, chick, or human cell substrates, are safe and effective. However, not all vaccines can be manufactured in current cell substrates for two reasons: 1) the vaccine viruses may not be able to grow in these cells; 2) the yield of virus may be too low for the product to be commercially viable. Nevertheless, because new vaccines are required to combat emerging and re-emerging infectious viruses (e.g., pandemic influenza viruses, Ebola virus, MERS coronavirus, Zika virus, and Lassa virus) and also against HIV/AIDS, new cell substrates are necessary.
The reason that only a limited variety of cell substrates are used is that scientists in the 1950s concluded that cell lines established from human tumors should not be used to make preventative vaccines. The rationale for this decision was based on the concern that if a cell substrate were derived from a human tumor, or was shown experimentally to be able to form a tumor in an animal (i.e., the cells were tumorigenic), then components from those cells could be present in vaccines manufactured in them and these components might be able to induce cancer or other diseases in recipients of the vaccines.
However, the growth of some viruses requires the use of these kinds of cells, and as a consequence, using these cells to develop new vaccines remains of interest. Over the past several decades, researchers have learned much about how cancer develops, and this knowledge has allowed FDA to reopen the question about the safety concerns with using tumorigenic cells for vaccine production and to address these concerns in a mechanistic and data-driven manner. Our laboratory is developing new approaches, using rodent models as well as in vitro studies, to investigate whether the use of tumorigenic cells or cells derived from human tumors for vaccine production poses safety concerns to the recipients of those vaccines.
An additional component of our work is developing assays that can measure neutralizing antibodies induced by vaccines and that can be adapted to high throughput. Because most vaccines owe their effectiveness to eliciting neutralizing antibodies, which are proteins that block infection and/or production of the virus, determining whether neutralizing antibodies are induced following vaccination is an important component of determining whether the vaccine is effective. Additionally, developing novel neutralization assays might aid the evaluation of the effectiveness of vaccines and thus facilitate their licensure.
The variety of cell substrates used to manufacture licensed vaccines has been limited to primary avian or monkey cells, human diploid cells, and the VERO cell line. This repertoire is insufficient for the production of the next generation of vaccines. All mammalian cell substrates being evaluated are neoplastic, since they are immortal, and some are tumorigenic. The fear that components from the cell substrate could induce cancer in vaccine recipients was the main reason that tumorigenic cells were originally prohibited for vaccine manufacture in the 1950s. Several expert panels have concluded that the major concerns with using these types of cells are the potential presence of adventitious agents and the unavoidable presence of small quantities of residual cell substrate DNA in vaccines. Our laboratory is developing assays to evaluate the safety of novel cell substrates with respect to the latter issue, namely, whether residual cellular DNA could pose a safety risk. The potential risk from DNA comes from its known biological activities: cell-substrate DNA may encode an infectious genome (the infectivity activity of DNA), and DNA may encode dominant activated oncogenes that could transform the vaccine recipient’s cells to become cancerous (the oncogenic activity of DNA). To evaluate DNA oncogenicity, we are developing in vivo assays to quantify the oncogenicity of DNA. These assays involve identifying sensitive rodent systems that can detect oncogenic activity of positive-control expression plasmids for dominant oncogenes. If such rodent systems can be identified, then DNA from the cell substrate will be assessed for its oncogenic activity in these systems. These studies could allow us to estimate the oncogenic risks from DNA. The resulting estimates will be conservative, since they will be based on the most sensitive assays available.
A second project is to identify the mechanism by which cells become tumorigenic. Many mammalian cell substrates (VERO, MDCK, CHO) were derived from primary cells by passage in culture. These cells became immortal, i.e., capable of indefinite passaging, but sometimes with further passaging they become tumorigenic. We are investigating the mechanism by which this occurs, in order to determine whether there is a risk from using tumorigenic cells for vaccine production.
A third project is to develop quantitative high-throughput micro-neutralization assays to detect neutralizing antibodies to viruses. Because most licensed vaccines are effective through eliciting neutralizing antibodies, methods that can quantify these antibodies are critical to vaccine development. When a human pathogenic virus cannot be propagated under standard laboratory conditions and requires high containment (e.g., Ebola, Lassa, and Nipah viruses), and even for viruses that require BSL-3 containment (e.g., SARS-CoV, MERS-CoV, and the recently isolated SARS-CoV-2), evaluating neutralizing antibodies against such viruses is complicated. We have been exploring alternative methodologies that can be used in standard BSL-2 laboratories to quantify neutralizing antibodies, such as using replication-competent hybrid viruses. In addition, the hybrid viruses can themselves be used to study the biology of the original virus and also to generate reagents for the development of vaccines.
Innovation and Regulatory Science - Research Summary: FDA develops rapid and sensitive assay to assess antibody response to Ebola virus vaccine without using the virus
Vaccines 2021 Jan 23;9(2):81
Development of mRNA vaccines: scientific and regulatory issues.
Knezevic I, Liu MA, Peden K, Zhou T, Kang HN
Curr Top Microbiol Immunol 2020 Jul 8 [Epub ahead of print]
Regulatory considerations on the development of mRNA vaccines.
Naik R, Peden K
NPJ Vaccines 2020 Jun 18;5:52
WHO informal consultation on the guidelines for evaluation of the quality, safety, and efficacy of DNA vaccines, Geneva, Switzerland, December 2019.
Sheets R, Kang HN, Meyer H, Knezevic I, Sheets R, Kang HN, Meyer H, Knezevic I, Abwao E, Alali M, Aprea P, Bae C, Blades CDRZ, Boyer J, Broderick KE, Duffy P, Farnsworth A, Gangakhedkar J, Gutsch D, Hafiz RA, Jackson N, Kaslow D, Khan AS, Ledgerwood J, Liu MA, Maslow J, Nkansah E, Park Y, Patel A, Peden K, Racine T, Rose N, Roy P, Song M, Wei W
Vaccine 2020 Feb 18;38(8):1869-80
The science of vaccine safety: summary of meeting at Wellcome Trust.
Plotkin SA, Offit PA, DeStefano F, Larson HJ, Arora NK, Zuber PLF, Fombonne E, Sejvar J, Lambert PH, Hviid A, Halsey N, Garcon N, Peden K, Pollard AJ, Markowitz LE, Glanz J
NPJ Vaccines 2019 Oct 14;4:42
Harmonization of Zika neutralization assays by using the WHO International Standard for anti-Zika virus antibody.
Mattiuzzo G, Knezevic I, Hassall M, Ashall J, Myhill S, Faulkner V, Hockley J, Rigsby P, Wilkinson DE, Page M, collaborative study participants
Vaccine: X 2019 Apr 11;(1):100004
Responsiveness to basement membrane extract as a possible trait for tumorigenicity characterization.
Murata H, Omeir R, Tu W, Lanning L, Phy K, Foseh G, Lewis AM Jr, Peden K
Vaccine 2017 Oct 4;35(41):5481-6
Development of a micro-neutralization assay for ebolaviruses using a replication-competent vesicular stomatitis hybrid virus and a quantitative PCR readout.
Lee SS, Phy K, Peden K, Sheng-Fowler L
Vaccine 2015 Dec 16;33(51):7254-61
RT-qPCR-based microneutralization assay for human cytomegalovirus using fibroblasts and epithelial cells.
Wang X, Peden K, Murata H
Chromosome Res 2015 Dec;23(4):663-80
A novel canine kidney cell line model for the evaluation of neoplastic development: karyotype evolution associated with spontaneous immortalization and tumorigenicity.
Omeir R, Thomas R, Teferedegne B, Williams C, Foseh G, Macauley J, Brinster L, Beren J, Peden K, Breen M, Lewis AM Jr