Zahradnik J, Starr S, Plotkin S (2001) A canarypox vector-expressing cytomegalovirus (cmv) phosphoprotein 65 induces long-lasting cytotoxic t cell responses in ...
Medical Microbiology and Immunology Stanley Plotkin: The Bright Spark of Cytomegalovirus Vaccines --Manuscript Draft-Manuscript Number:
MMIM-D-14-00158R1
Full Title:
Stanley Plotkin: The Bright Spark of Cytomegalovirus Vaccines
Article Type:
S.I. : Cytomegalovirus 2015
Keywords:
none - Introduction
Corresponding Author:
Edward S. Mocarski UNITED STATES
Corresponding Author Secondary Information: Corresponding Author's Institution: Corresponding Author's Secondary Institution: First Author:
Edward S. Mocarski
First Author Secondary Information: Order of Authors:
Edward S. Mocarski
Order of Authors Secondary Information: Abstract:
none - This is an Introduction to the presentation/review by Staley Plotkin.
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Response to Editor’s comments: (1) As a legend to the photograph portrait of Stanley you may include a text like this: Lecture given by Dr. Plotkin at the symposium „Margaret Gladys Smith 60th Anniversary of Cytomegalovirus Isolation, Waldthausen Castle, Germany, Nov. 21, 2014 (photograph by courtesy of Dipl. Ing. Michael Reddehase). Response: Included (2) on the 2nd text page, first line, I feel it should read: "Dr. Plotkin's research efforts with....". Response: Corrected (3) on the last text page, line 7, it currently reads " moderate butl but poorly..". I guess, the "butl" is not as meant. Response: Corrected
In addition, I made a few edits to bring greater clarity to the text.
Manuscript Click here to download Manuscript: Mocarski Plotkin Introduction.docx Click here to view linked References
Stanley Plotkin: The Bright Spark of Cytomegalovirus Vaccines Introduction given by Edward S. Mocarski Department of Microbiology and Immunology Emory Vaccine Center Emory University School of Medicine Atlanta, Georgia 30322 USA
Special acknowledgement to Eva Gonczol, Ph.D., Virology National Center for Epidemiology Budapest, Hungary
It is a tremendous pleasure and indeed honor for me to introduce Dr. Stanley Plotkin, a living legend in the world of vaccines, who will present a personal view of the current state of affairs in cytomegalovirus (CMV) vaccine development. Dr. Plotkin, more than any other individual, has contributed to the progress in vaccine research and development since the idea of universal vaccination to prevent CMV congenital disease was proposed nearly 50 years ago. After completing his medical training just about the time CMV was first isolated, and following a few years working for the Centers for Disease Control in the Epidemic Intelligence Service, from 1960 to 1991, he directed a vaccine research group at the Wistar Institute, and maintained clinical affiliations with The University of Pennsylvania and Children’s Hospital of Philadelphia. Dr. Plotkin is most renowned and recognized for his pioneering work on viral vaccines. His research expanded the portfolio of children’s vaccines currently available to combat widespread infectious diseases, including rubella, polio, rabies, rotavirus diarrhea and varicella (chicken pox). His success in the development of a live-attenuated rubella vaccine, currently in use worldwide, prompted a follow-up focus to address the need for a CMV vaccine, most likely due to the many common attributes between German measles-associated congenital disease and patterns of CMV disease, despite their marked differences in biology.
Dr. Plotkin probably never envisaged a life-long courtship with CMV vaccine initiatives when he began investigating CMV some 45 years ago. His initial focus was, of course, the liveattenuated Towne vaccine, which he escorted through clinical development that included, (i) the demonstration of safety and efficacy in solid organ transplant recipients [4], (ii) the hallmark demonstration that the vaccine strain was unable to reactivate and so lacked the biological property of latency [5] and (iii) a test of safety and efficacy against experimental challenge with the limited-passage Toledo strain [3]. He chose to recruit Catholic monks as vaccinees, thus there was no harm for pregnant women or children after infectious challenge with the Toledo strain. These important milestones in the 1970’s and 1980’s engaged many talented
associates and envisaged eventual success for this vaccine strategy. His research led to the first contemporary concepts of CMV vaccination, including the importance of cellular immunity to the conservation of protective antigens amongst circulating strains and the benefit of natural and experimental challenge [1-3]. These concepts challenged the conventional confidence in antiviral antibody as the sole mediator of immunity, a theme that continues to be debated today. Along the way, his report of a vaccine efficacy against CMV-associated opportunistic disease in solid organ transplant recipients [4] was an accomplishment as the first success of a vaccine for an opportunistic infectious disease. Ultimately, Towne vaccine was effective in kidney transplant patients, but proved less potent than natural infection in women of childbearing age when they were evaluated for resistance to natural mucosal acquisition of virus (reinfection) [6]. These studies portrayed an opportunity that has been pursued with other vaccine strategies, both live and non-live, while Towne vaccine has been sidelined.
Whereas, over the years he dedicated his research enterprise to establishing a CMV live attenuated vaccine platform, he is also acknowledged for numerous contributions to the basic understanding of CMV biology long before this became a defined field. Dr. Plotkin has received many accolades and honors that acknowledge his accomplishments, including election to the Institute of Medicine of the National Academy of Sciences (USA), the Sabin Gold Medal Award, the French Legion of Honor Medal, and the Maxwell Finland Award for Scientific Achievement from the Infectious Disease Society. From 1991, after retiring from active academic research, Dr. Plotkin took on the roles of chief protagonist and statesman of CMV vaccines, first as Medical and Scientific Director at Pasteur Mérieux Connaught and later becoming consultant to Sanofi Pasteur. Today, he is consultant to the world. It is fair to say that no CMV vaccine candidate comes to light without the benefit of his publications and personal guidance. A biography accompanying the Maxwell Finland Award is a source record of Dr. Plotkin’s career (http://www.nfid.org/awards/finland).
Dr. Plotkin’s research efforts with Dr. Toru Furukawa resulted in seminal contributions to the basic biology of CMV, including the initial reports that characterized the remarkable ability of this herpesvirus to stimulate cellular metabolism, along with driving dramatic expansion of mitochondrial DNA, and the ability of viral structural components to meter cellular stimulation [712]. This effort included the ability to stimulate a co-infecting RNA virus [13]. At about the same time he was running complex vaccine trials, Dr. Plotkin published hallmark observations with Dr. Eva Gonczol that brought to light the dependence of CMV replication on the differentiation state of cells [14-16] and stimulation of human immunodeficiency virus upon co-infection [17]. In addition to these key observations, Dr. Plotkin made his laboratory a CMV hub, helping investigators interested in taking up the study of CMV and providing viral strains that have helped define the characteristics of virulence and attenuation. Very importantly, after being nucleated through Dr. Plotkin’s direct research, these basic questions have remained at the center of CMV biology in the decades since his seminal contributions appeared.
Throughout the years, preclinical evaluation of live-attenuated, non-live and vectored CMV vaccine candidates have been undertaken by Dr. Plotkin's research group [18-24]. Pioneering virological and immunological properties as well as practical assay endpoints have been the consistent output from this research. Throughout his career, though, Dr. Plotkin retained fixed interest in the live-attenuated Towne vaccine candidate he first brought onto the scene almost 40 years ago [25]. As the pioneer in the area of CMV vaccine development, Dr. Plotkin applied skills he had honed in the successful control of rubella virus to bear, including the use of secondary cultures of human fetal fibroblasts as a substrate for propagation of the vaccine. Dr. Plotkin supported decades-old efforts to “dial-up” Towne efficacy through the construction and evaluation of Towne-Toledo chimeras by Aviron (now MedImmune, a subsidiary of AstraZeneca) or the more recent introduction of the gH/gL pentamer into a replication defective
AD169 strain taken into clinical trials by Merck. He has also supported budding efforts to “dialdown” a clinical strain as possible vaccine vector platform that may well see the light of clinical trials. This long-term relationship with such a complex virus may be considered “Stanley’s mistress” in one view. Dr. Plotkin certainly got a firsthand taste of the duplicitous nature of this relationship, reporting the first hint of immune modulation by CMV by characterizing of the viral IgG Fc receptor [26]. He has also kept the light on for non-live vaccine strategies such as the MF-59 adjuvanted gB subunit vaccine that gave moderate, but poorly durable success [27]. This vaccine was transferred from Chiron to Sanofi Pasteur in the early 1990’s under Dr. Plotkin’s executive guidance.
Dr. Plotkin will now impart his considerable understanding of the breadth of issues related to long-needed universal CMV vaccine for prevention of congenital disease. He still imagines this goal achievable within his lifetime, leading all in the field to wish him a very long life!
1. Starr SE, Dalton B, Garrabrant T, Paucker K, Plotkin SA (1980) Lymphocyte blastogenesis and interferon production in adult human leukocyte cultures stimulated with cytomegalovirus antigens. Infect Immun 30 (1):135-139 2. Quinnan GV, Jr., Delery M, Rook AH, Frederick WR, Epstein JS, Manischewitz JF, Jackson L, Ramsey KM, Mittal K, Plotkin SA, et al. (1984) Comparative virulence and immunogenicity of the Towne strain and a nonattenuated strain of cytomegalovirus. Annals of Internal Medicine 101 (4):478-483 3. Plotkin SA, Starr SE, Friedman HM, Gonczol E, Weibel RE (1989) Protective effects of Towne cytomegalovirus vaccine against low-passage cytomegalovirus administered as a challenge. J Infect Dis 159 (5):860-865 4. Plotkin SA, Smiley ML, Friedman HM, Starr SE, Fleisher GR, Wlodaver C, Dafoe DC, Friedman AD, Grossman RA, Barker CF (1984) Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants. Lancet 1 (8376):528-530 5. Plotkin SA, Huang ES (1985) Cytomegalovirus vaccine virus (Towne strain) does not induce latency. J Infect Dis 152 (2):395-397 6. Adler SP, Starr SE, Plotkin SA, Hempfling SH, Buis J, Manning ML, Best AM (1995) Immunity induced by primary human cytomegalovirus infection protects against secondary infection among women of childbearing age. J Infect Dis 171 (1):26-32 7. Furukawa T, Fioretti A, Plotkin S (1973) Growth characteristics of cytomegalovirus in human fibroblasts with demonstration of protein synthesis early in viral replication. J Virol 11 (6):991997 8. Furukawa T, Tanaka S, Plotkin SA (1975) Restricted growth of human cytomegalovirus in UV-irradiated WI-38 human fibroblasts. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine (New York, NY) 148:1249-1251 9. Furukawa T, Tanaka S, Plotkin SA (1975) Stimulation of macromolecular synthesis in guinea pig cells by human CMV. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine (New York, NY) 148 (1):211-214 10. Tanaka S, Furukawa T, Plotkin SA (1975) Human cytomegalovirus stimulates host cell RNA synthesis. J Virol 15 (2):297-304 11. Furukawa T, Sakuma S, Plotkin SA (1976) Human cytomegalovirus infection of WI-38 cells stimulates mitochondrial DNA synthesis. Nature 262 (5567):414-416 12. Hirai K, Furukawa T, Plotkin SA (1976) Induction of DNA Polymerase in WI-38 and guinea pig cells infected with human cytomegalovirus (HCMV). Virology 70 (1):251-255 13. Furukawa T, Jean JH, Plotkin SA (1978) Enhanced poliovirus replication in cytomegalovirusinfected human fibroblasts. Virology 85 (2):622-625 14. Gonczol E, Andrews PW, Plotkin SA (1984) Cytomegalovirus replicates in differentiated but not in undifferentiated human embryonal carcinoma cells. Science 224 (4645):159-161 15. Gonczol E, Andrews PW, Plotkin SA (1985) Cytomegalovirus infection of human teratocarcinoma cells in culture. J Gen Virol 66:509-515 16. Andrews PW, Gonczol E, Fenderson BA, Holmes EH, O'Malley G, Hakomori S, Plotkin S (1989) Human cytomegalovirus induces stage-specific embryonic antigen 1 in differentiating human teratocarcinoma cells and fibroblasts. J Exp Med 169 (4):1347-1359 17. Hirka G, Prakash K, Kawashima H, Plotkin SA, Andrews PW, Gonczol E (1991) Differentiation of human embryonal carcinoma cells induces human immunodeficiency virus permissiveness which is stimulated by human cytomegalovirus coinfection. J Virol 65 (5):27322735 18. Furukawa T, Gonczol E, Starr S, Tolpin MD, Arbeter A, Plotkin SA (1984) HCMV envelope antigens induce both humoral and cellular immunity in guinea pigs. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine (New York, NY) 175 (2):243-250
19. Hudecz F, Gonczol E, Plotkin SA (1985) Preparation of highly purified human cytomegalovirus envelope antigen. Vaccine 3 (3):300-304 20. Marshall GS, Ricciardi RP, Rando RF, Puck J, Ge RW, Plotkin SA, Gonczol E (1990) An adenovirus recombinant that expresses the human cytomegalovirus major envelope glycoprotein and induces neutralizing antibodies. J Infect Dis 162 (5):1177-1181 21. Gonczol E, deTaisne C, Hirka G, Berencsi K, Lin WC, Paoletti E, Plotkin S (1991) High expression of human cytomegalovirus (HCMV)-gB protein in cells infected with a vaccinia-gB recombinant: the importance of the gB protein in HCMV immunity. Vaccine 9 (9):631-637 22. Wang JB, Adler SP, Hempfling S, Burke RL, Duliege AM, Starr SE, Plotkin SA (1996) Mucosal antibodies to human cytomegalovirus glycoprotein B occur following both natural infection and immunization with human cytomegalovirus vaccines. J Infect Dis 174 (2):387-392 23. Berencsi K, Gyulai Z, Gonczol E, Pincus S, Cox WI, Michelson S, Kari L, Meric C, Cadoz M, Zahradnik J, Starr S, Plotkin S (2001) A canarypox vector-expressing cytomegalovirus (cmv) phosphoprotein 65 induces long-lasting cytotoxic t cell responses in human cmv-seronegative subjects. J Infect Dis 183 (8):1171-1179. 24. Bernstein DI, Schleiss MR, Berencsi K, Gonczol E, Dickey M, Khoury P, Cadoz M, Meric C, Zahradnik J, Duliege AM, Plotkin S (2002) Effect of previous or simultaneous immunization with canarypox expressing cytomegalovirus (CMV) glycoprotein B (gB) on response to subunit gB vaccine plus MF59 in healthy CMV-seronegative adults. J Infect Dis 185 (5):686-690. 25. Plotkin SA, Furukawa T, Zygraich N, Huygelen C (1975) Candidate cytomegalovirus strain for human vaccination. Infect Immun 12 (3):521-527 26. Sakuma S, Furukawa T, Plotkin SA (1977) The characterization of IgG receptor induced by human cytomegalovirus. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine (New York, NY) 155 (2):168-172 27. Pass RF (2009) Development and evidence for efficacy of CMV glycoprotein B vaccine with MF59 adjuvant. J Clin Virol 46 Suppl 4:S73-76. doi:S1386-6532(09)00324-2 [pii] 10.1016/j.jcv.2009.07.002 [doi]
Figure Legends Figure 1. Lecture given by Dr. Stanley Plotkin at the symposium “Margaret Gladys Smith 60th Anniversary of Cytomegalovirus Isolation”, Waldthausen Castle, Germany, Nov. 21, 2014 (photograph by courtesy of Dipl. Ing. Michael Reddehase).
Figure Click here to download high resolution image
