Lawrence Corey (born February 14, 1947) is professor of Medicine and Laboratory Medicine at the University of Washington, a member of the Vaccine and Infectious Disease Division and past president and director of Fred Hutchinson Cancer Research Center[1] in Seattle, Washington. He also serves as the founding director and co-principal investigator of the HIV Vaccine Trials Network. The American physician-scientist is an internationally recognized expert in virology, immunology and vaccine development.[2] His discoveries over the past 30 years are cited as having deepened the understanding of both the pathogenesis and treatment of diseases caused by viruses, especially human immunodeficiency virus (HIV) and herpes viruses.[3] Corey has pioneered some of the most significant advances in the creation of safe and effective antivirals for herpes viruses and HIV, the testing of experimental vaccines for HIV and genital herpes, and the designing of new methods for diagnosing and monitoring therapies for viral infections.[4]

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Education

Corey received his Bachelor of Science and M.D. from the University of Michigan in Ann Arbor, Michigan, and received postgraduate training at the University of Michigan, the US Centers for Disease Control and Prevention, and University of Washington.

Research and career

In the early 1980s, Corey worked with Nobel Prize-winning biochemist and pharmacologist Dr. Gertrude Elion to demonstrate that an antiviral that was selective and specific for a viral-specified enzyme could be safely and effectively administered to control a chronic viral infection (herpes simplex virus type 2 or HSV-2). Corey first conceived of and demonstrated the core concepts and direct line association between quantitative viral load reduction and clinical benefit using topical, intravenous and oral formulations of acyclovir in classic studies performed between 1980 and 1984.[5][6][7] Acyclovir was the first antiviral drug to get rapid approval from the FDA, and it was Corey's studies that defined its use in genital herpes. These studies led to the licensure for acyclovir in a wide variety of infections such as HSV-1, HSV-2 and varicella chickenpox virus, including the first use of an antiviral for daily long term use. Acyclovir and its derivatives valacyclovir and famciclovir are the most prescribed antivirals in the world: over 400 million people have HSV-2 infection. These early studies led by Corey were directly responsible for the subsequent successful involvement of the pharmaceutical and medical sciences communities to develop effective antiviral therapy for HIV and hepatitis B.

In 1987, Corey directed the NIH supported AIDS Clinical Trials Group (ACTG), which was established to test antivirals to HIV-1, and conducted pivotal clinical trials demonstrating the use of the antiretroviral drug AZT to reduce maternal-fetal transmission of HIV and the usefulness of combinations of antiretrovirals to prolong survival from HIV.[8] During this time, his laboratory demonstrated that HIV circulated in plasma well before the development of AIDS.[9] The ACTG subsequently demonstrated that the initiation of therapy early during asymptomatic stages of HIV infection reduced progression to HIV[10] and that combinations of antiretrovirals (3>2>1 drug) were critical to the control of HIV replication and management; the result being that HIV control has enabled life expectancy to increase globally.[11] Triple combination therapy with two nucleosides and a protease inhibitor demonstrated a marked reduction in viral load, increase in CD4+ T-cell count and lowering of activation markers with the addition of the protease inhibitor.[12] Through the ACTG, he also was the first to lead the integration of community members into clinical research activities.[13]

In the mid-1990s, Corey increasingly focused his work in the area of vaccine development, and in 1998 worked with the US National Institute of Allergy and Infectious Diseases to develop a global clinical trials group to speed the development of HIV vaccines. In 2002, Corey became the major driver in conceiving of the Global HIV Vaccine Enterprise. The Enterprise is one of the few scientific programs that is overseen by leaders of the major industrialized countries of the world.

One of Corey's major scientific initiatives has been to study and develop better therapy for the treatment and prevention of infectious disease associated cancers such as Kaposi sarcoma and Burkitt lymphoma.[14] In the mid-2000s, that led Corey to launch a partnership between Fred Hutchinson Cancer Research Center and the Uganda Cancer Institute.[15] On July 30, 2010, Dr. Corey was named the fourth president of the Fred Hutchinson Cancer Research Center.[16] One of his major initiatives was to increase the strength of the Fred Hutch's translational research programs and its commitment to bring better therapies and preventions for cancer to the developing world. In May 2015, the Fred Hutch/UCI partnership led to the opening of the first comprehensive cancer center jointly constructed by US and African institutions in sub-Saharan Africa: the UCI-Fred Hutch Cancer Centre.[17] In 2013, as an outgrowth of his work in T-cell immunology, Corey became a cofounder of Juno Therapeutics, a company devoted to using genetically engineered T cells to fight cancer.[18]

Corey's early research dealt with herpes simplex viruses and he headed several landmark studies defining the disease and leading the licensure of acyclovir and valacyclovir for its treatment.[19][20] This included a study to reduce acquisition among sexual partners. Between 1988 and 1998, Corey published a series of key studies showing the association between infection with HSV-2 and HIV-1.[21][22] These studies led to pilot and large sale clinical trials of anti-HSV-2 therapy to reduce HIV acquisition and transmission.[23] In 2000, Corey conducted the first discordant couple study using antiviral therapy for HSV-2. His publication in 2004 on reduction of transmission of HSV-2 was the first to demonstrate that antivirals could reduce transmission of infections to others (treatment as prevention),[24] a concept subsequently utilized by the HPTN 052 protocol team using continuous ART to reduce transmission of HIV to discordant couples. This latter approach is one of the current cornerstones of public health practices for reducing the morbidity and potentially the transmission of HIV-I.[25]

More recently, his research group has shown the importance of the mucosal immune system in controlling HSV reactivation, leading to current momentum to try to develop novel vaccines for treating genital herpes. Previously, the scientific consensus for HSV-2 pathogenesis was that virus reactivation was infrequent and determined by virus-neuronal interactions at the ganglion level and that most reactivations resulted in genital lesions.

Corey has been a central figure in the field of HIV vaccine development.[3] The HIV Vaccine Trials Network (HVTN) now includes investigators on five continents spanning more than 30 cities[26] and is leading the research for phase 1–3 clinical trials of candidate HIV vaccines globally. The HVTN as of 2018 is conducting 4 large scale efficacy trials in North America, South America and several countries in sub-Saharan Africa. On Dec. 1, 2015 the work of Corey and HTVN scientists pursuing a vaccine to potentially halt HIV and AIDS was highlighted in an HBO/VICE special report titled "Countdown to Zero."[27]

Honors

Corey was a member of the editorial board of the New England Journal of Medicine. He is a fellow of the Infectious Diseases Society of America and a member of the American Epidemiological Society, American Society for Clinical Investigation, and the Association of American Physicians. In addition, he is the recipient of the Pan American Society's Clinical Virology Award, the American Sexually Transmitted Diseases Association's Parran Award, and the University of Michigan Medical School's Distinguished Alumnus Award.[28] In 2008, he was elected to the National Academy of Medicine and in 2012 elected a Member of the American Academy of Arts and Sciences. He has published over 900 scientific publications and editorials (as of 2018).

Selected works

• Corey, L.; Nahmias, A. J.; Guinan, M. E.; Benedetti, J. K.; Critchlow, C. W.; Holmes, K. K. (1982-06-03). "A trial of topical acyclovir in genital herpes simplex virus infections". The New England Journal of Medicine. 306 (22): 1313–1319. doi:10.1056/NEJM198206033062201. ISSN 0028-4793. PMID 6280052.

• Corey L, Fife KH, Benedetti JK, Winter C, Fahnlander A, Connor JD, Hintz MA, Holmes KK. Intravenous acyclovir for the treatment of primary genital herpes. Ann Intern Med. 1983 Jun;98(6):914-21.

• Coombs RW, Collier AC, Allain J-P, Nikora B, Leuther M, Gjerset GF, Corey L. Plasma viremia in human immunodeficiency virus infection. N Engl J Med. 1989 Dec 14;321(24):1626-31.

• Volberding PA, Lagakos SW, Koch MA, Petinelli C, Myers MW, Booth DK, Balfour HH, Reichman RC, Bartlett JA, Hirsch MS, Murphy RL, Hardy WD, Soeiro R, Fischl MA, Bartlett JG, Merigan TC, Hyslop NE, Richman DD, Valentine FT, Corey L, and the ACTG. Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection — A Controlled Trial in Persons with Fewer Than 500 CD4-Positive Cells per Cubic Millimeter. N Engl J Med. 1990 Apr 5;322(14):941-9.

• Cooney EL, McElrath MJ, Corey L, Hu SL, Collier A, Arditti D, Hoffman M, Coombs RW, Smith GE, Greenberg PD. Enhanced immunity to HIV envelope elicited by a combined vaccine regimen consisting of priming with a vaccinia recombinant expressing HIV envelope and boosting with gp160 protein. Proc Natl Acad Sci USA. 1993 Mar 1;90(5):1882–1886.

• Schacker T, Collier ACC, Hughes J, Shea T, Corey L. The clinical and epidemiological features of primary HIV infection. Ann Intern Med. 1996 Aug 15;125(4):257-64.

• Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc Natl Acad Sci USA. 1998 Jul 21;95(15):8869-73.

• Wald A, Zeh J, Selke S, Warren T, Ryncarz AJ, Ashley R, Krieger JN, Corey L. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000 Mar 23;342(12):844-50.

• Wald A, Langenberg AGM, Link K, Izu A, Ashley R, Warren T, Tyring S, Douglas JM, Corey L. Effect of condoms on reducing the transmission of herpes simplex virus type-2 from men to women. JAMA. 2001 Jun 27;285(24):3100-6.

• Klausner RD, Fauci AS, Corey L, Nabel GJ, Gayle H, Berkley S, Haynes BF, Baltimore D, Collins C, Douglas RG, Esparza J, Francis DP, Ganguly NK, Gerberding JL, Johnston MI, Kazatchkine MD, McMichael AJ, Makgoba MW, Pantaleo G, Piot P, Shao Y, Tramont E, Varmus H, Wasserheit JN. The need for a global HIV vaccine enterprise. Science. 2003 Jun 27;300(5628):2036–2039.

• Corey L, Wald A, Celum C, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr. 2004 Apr 15;35(5):435-45.

• Zerr DM, Meier AS, Selke SS, Frenkel LM, Huang ML, Wald A, Rhoads M, Nguy L, Bornemann R, Morrow RA, Corey L. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. 2005 Feb 24;352(8):768-76.

• Zhu J, Hladik F, Woodward A, Klock A, Peng T, Johnston C, Remington M, Magaret A, Koelle DM, Wald A, Corey L. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat Med. 2009 Aug;15(8):886-92. PMC 2723183

• Schiffer JT, Abu-Raddad L, Mark KE, Zhu J, Selke S, Koelle DM, Wald A, Corey L. Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18973-8. PMC 2973882

• Corey L, McElrath MJ. HIV vaccines: mosaic approach to virus diversity. Nat Med. 2010 Mar;16(3):268-70.

• Chapuis A, Casper C, Kuntz S, Zhu J, Tjernlund A, Diem K, Turtle C, Cigal M, Velez R, Riddell SR, Corey L, Greenberg PD. HIV-specific CD8+ T-cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo. Blood. 2011 May 19;117(20):5391-5402. PMC 3109713

• Zhu J, Peng T, Johnston C, Phasouk K, Kask AS, Klock A, Jin L, Diem K, Koelle DM, Wald A, Robins H, Corey L. Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection. Nature. 2013 May 23;497(7450):494-7. PMC 3663925

• Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, Dejesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB; the HVTN 505 Study Team. Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine. N Engl J Med. 2013 Nov 28;369(22):2083-92.

• Johnston C, Zhu J, Jing L, Laing K, McClurkan C, Klock A, Diem K, Stanaway J, Tronstein E, Kwok WW, Huang ML, Selke S, Fong Y, Magaret A, Koelle DM, Wald A, and Corey L. Virologic and immunologic evidence of multifocal genital herpes simplex virus type 2 infection. J. Virol. 2014 May;88(9):4921-31.

• Wald A, Corey L, Timmler B, Magaret A, Warren T, Tyring S, Johnston C, Kriesel J, Fife K, Galitz L, Stoelben S, Huang M-L, Selke S, Stobernack H-P, Ruebsamen-Schaeff H and Birkmann A. Helicase-Primase Inhibitor Pritelivir for HSV-2 infection. N Eng J Med 2014 Jan 16;370(3):201-10.

• Jin X, Morgan C, Yu X, DeRosa S, Tomaras GD, Montefiori DC, Kublin J, Corey L, Keefer MC; NIAID HIV Vaccine Trials Network. Multiple factors affect immunogenicity of DNA plasmid HIV vaccines in human clinical trials. Vaccine. 2015 May 11;33(20):2347-53.

• Diem K, Magaret A, Klock A, Jin L, Zhu J, Corey L. Image analysis for accurately counting CD4+ and CD8+ T cells in human tissue. J Virol Methods. 2015 Sep 15;222:117-21.

• Janes H, Herbeck JT, Tovanabutra S, Thomas R, Frahm N, Duerr A, Hural J, Corey L, Self SG, Buchbinder SP et al. HIV-1 infections with multiple founders are associated with higher viral loads than infections with single founders. Nat Med. 2015 Oct;21(10):1139-41.

• Dimitrov D, Kublin JG, Ramsey S and Corey L. Are clade specific HIV vaccines a necessity? An analysis based on mathematical models. EBioMedicine. 2015 Dec;2(12):2062-2069.

• Tjernlund A, Burgener A, Lindvall JM, Peng T, Zhu J, Öhrmalm L, Picker LJ, Broliden K, McElrath MJ, Corey L. In Situ Staining and Laser Capture Microdissection of Lymph Node Residing SIV Gag-Specific CD8+ T cells-A Tool to Interrogate a Functional Immune Response Ex Vivo. PLoS One. 2016 Mar 17;11(3):e0149907. PMC4795610

• Joshua T Schiffer; David A Swan; Amalia Magaret; Anna Wald; Lawrence Corey. Mathematical Modeling Predicts that Increased HSV-2 Shedding in HIV-1 Infected Persons is Due to Poor Immunologic Control in Both Ganglia and Genital Mucosa. PLOS One. 2016 Jun 10;11(6):e0155124.

• Churchyard G, Mlisana K, Karuna S, Williamson AL, Williamson C, Morris L, Tomaras GD, De Rosa SC, Gilbert PB, Gu N, Yu C, Mkhize NN, Hermanus T, Allen M, Pensiero M, Barnett SW, Gray G, Bekker LG, Montefiori DC, Kublin J, Corey L. Sequential Immunization with gp140 Boosts Immune Responses Primed by Modified Vaccinia Ankara or DNA in HIV-Uninfected South African Participants. PLoS One. 2016 Sep 1;11(9):e0161753.

• Huang Y, Zhang L, Ledgerwood J, Grunenberg N, Bailer R, Isaacs A, Seaton K, Mayer KH, Capparelli E, Corey L, Gilbert PB. Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults. MAbs. 2017 Jul;9(5):792-800.

References

• ^ "Larry Corey to step down as president of Fred Hutch to focus on vaccine research". Puget Sound Business Journal.

• ^ "Cell & Gene Therapy for HIV Cure 2014".

• ^ 

• Jump up to:

• a b "Larry Corey, Virus Hunter".

• ^ "Pub Facts: Publications authored by Lawrence Corey".

• ^ Corey L, Nahmias AJ, Guinan ME, Benedetti JK, Critchlow CW, Holmes KK. A trial of topical acyclovir in genital herpes simplex infections. N Engl J Med 1982;306:1313-19.

• ^ Corey L, Fife KH, Benedetti JK, Winter C, Fahnlander A, Connor JD, Hintz MA, Holmes KK. Intravenous acyclovir for the treatment of primary genital herpes. Ann Intern Med. 1983;98:914-21.

• ^ Douglas JM, Critchlow C, Benedetti J, Mertz GJ, Connor JD, Hintz MA, Fahnlander A, Remington M, Winter C, Corey L. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med 1984;310:1551-56.

• ^ "What Will it Take to Achieve an AIDS-free World?". The Lancet.

• ^ Coombs RW, Collier AC, Allain J-P, Nikora B, Leuther M, Gjerset GF, Corey L. Plasma viremia in human immunodeficiency virus infection. N Engl J Med. 1989;321:1626-31.

• ^ Volberding PA, Lagakos SW, Koch MA, Petinelli C, Myers MW, Booth DK, Balfour HH, Reichman RC, Bartlett JA, Hirsch MS, Murphy RL, Hardy WD, Soeiro R, Fischl MA, Bartlett JG, Merigan TC, Hyslop NE, Richman DD, Valentine FT, Corey L, and the ACTG. Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection — A Controlled Trial in Persons with Fewer Than 500 CD4-Positive Cells per Cubic Millimeter. N Engl J Med. 1990 Apr 5;322(14):941-9.

• ^ Collier AC, Coombs RW, Fischl MA, Skolnik PR, Northfelt D, Boutin P, Hooper CJ, Kaplan LD, Volberding PA, Davis LG, Henrard DR, Weller S, Corey L. Combination therapy with zidovudine and didanosine compared to zidovudine alone in HIV-1 infection. Ann Intern Med. 1993 Oct 15;119(8):786-93.

• ^ Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, Jones M, Facey K, Whitacre C, McAuliffe VJ, Friedman HM, Merigan TC, Reichman RC, Hooper C, Corey L and the AIDS Clinical Trials Group. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N Engl J Med. 1996 Apr 18;334(16):1011-7.

• ^ "History of the ACTG".

• ^ "Part IV: The Infectious Connection". PRI.

• ^ "The Hutch, Uganda get creative in cancer fight". Seattle Times.

• ^ "Past Presidents & Directors".

• ^ "Fred Hutch broadens global reach with Uganda cancer center". Puget Sound Business Journal.

• ^ "New cancer research startup Juno Therapeutics raises $134M to push total funding past $300M". geekwire.com.

• ^ Corey L, Nahmias AJ, Guinan ME, Benedetti JK, Critchlow CW, Holmes KK. A trial of topical acyclovir in genital herpes simplex virus infections. N Engl J Med. 1982 Jun 3;306(22):1313-9.

• ^ Douglas JM, Critchlow C, Benedetti J, Mertz GJ, Connor JD, Hintz MA, Fahnlander A, Remington M, Winter C, Corey L. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med. 1984 Jun 14;310(24):1551-6.

• ^ Stamm WE, Handsfield HH, Rompalo AM, Ashley RL, Roberts PL, Corey L. The association between genital ulcer disease and acquisition of HIV infection in homosexual men. JAMA. 1988 Sep 9;260(10):1429-33.

• ^ Schacker T, Ryncarz AJ, Goddard J, Diem K, Shaughnessy M, Corey L. Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA. 1998 Jul 1;280(1):61-6.

• ^ Nagot N, Ouedraogo A, Foulongne V, et al. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007;356:790-799.

• ^ Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, Douglas JM, Paavonen J, Ashley Morrow R, Beutner KR, Stratchounsky LS, Keene ON, Watson HA, Tait D, Vargas-Cortez M, for the Valacyclovir HSV Transmission Study Group. Once daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004 Jan 1;350(1):11-20.

• ^ Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Fleming TR; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493-505.

• ^ "An HIV vaccine: the world's best long-term hope for ending AIDS". vaccinenews.net.

• ^ "Fred Hutch featured in HBO documentary on HIV vaccine". Seattle Times.

• ^ "Larry Corey, xconomy.com".

External links

• Lawrence Corey, Official web page as Principal Investigator of the HIV Vaccine Trials Network

• [...]

Text from "Discussion" : 

Our initial study of HIV infection in prostitutes in Nairobi found that HIV-seropositive women were more likely to have genital ulcers than were seronegative women [1]. Studies of men attending an STD clinic in Nairobi found an association between HIV antibody and both current and prior genital ulceration [2, 3]. More conclusive evidence for the association between genital ulcer disease and HIV transmission has come from two prospective studies of high-risk heterosexual populations in Nairobi.

Genital ulcers were identified as an independent risk factor for HIV seroconversion in a cohort of prospectively followed prostitutes (adjusted odds ratio, 3.7; P < .03) [4]. In addition, among men with a recent history of prostitute contact, seen at an STD clinic, initially seronegative men presenting with genital ulcer disease were more likely to seroconvert than were men presenting with urethritis (adjusted risk ratio, 4.7; P< .02) [5]. These studies suggested that genital ulcers might serve to increase the efficiency of HIV transmission during sexual intercourse and prompted us to determine whether we could isolate HIV from genital ulcer exudates.

We isolated HIV from the surface of 4 of 36 genital ulcers. In 2 of the 4 women, HIV was not isolated from the cervical os, which suggested that contamination of the ulcer base with cervical secretionswas not responsible for the positive ulcer cultures in at least 2 cases. Isolation ofHIV from ulcers suggests that contact with genital lesions in HIV-seropositive individuals may be one means by which HIV is transmitted during sexual intercourse. It is also possible that seronegative individuals with genital ulcers are at increased risk ofHIV infection when sexually exposed to a seropositive partner. We postulate that genital ulceration, with disruption of the intact epithelial barrier and presence of lymphocytes and mononuclear cells within the lesion [10-12], in either seropositive source partners or seronegative exposed partners could facilitate HIV transmission.

Several studies in the USA have found a similar association between genital or anorectal ulcerogenic pathogens and risk ofHIV infection in homosexual men. In an early case control study of AIDS in homosexual men in the USA, a history of syphilis or a positive serologic test for T. pallidum was associated with AIDS [13, 14]. A retrospective study of two populations of homosexual men in Seattle found an association between HIV antibody and a history of anogenital or oral herpes, a history of syphilis, antibody to HSV-2, or a positive serologic test for syphilis, after controlling for sexual activity [15].A study of HIV seroconversion in homosexual men in San Francisco also found an association between

HSV-2 antibody and HIV infection [16]. The high incidence of genital ulcer disease in male homosexuals and in African prostitutes and their sex partners may in part explain the rapid dissemination of HIV infection within these populations. In our initial survey of this community of Nairobi prostitutes, 550/0 of women had a positive serologic test for syphilis and 42070 had genital ulcers, 500/0 of which were culture-positive for H. ducreyi [1]. In the current study, infection with herpes simplex virus was universal, with 1000/0 of women having antibodies to HSV-l or -2. Most ulcers appeared to be chancroid on clinical grounds, although the H. ducreyi isolation rate was only 23%, perhaps reflecting increased antibiotic use in this population. Chancroid results in extensive ulceration that usually requires several weeks for healing, even with appropriate antibiotic treatment. Although such ulcers are painful, the women included in this study continued to practice prostitution.

It is not yet known whether HIV infection increases susceptibility to H. ducreyi, but HIV-seropositive individuals with chancroid ulcers have a higher rate of microbiologic treatment failure than do seronegative individuals; this suggests that a further increase in the current epidemic of chancroid in areas of high HIV prevalence in Africa might be predicted in the absence of behavior change [17]. Mucocutaneous HSV infections are more extensive and prolonged in HIV-infected persons, and the transmission of both pathogens to sexual partners may thus be facilitated [18]. In this manner, the epidemics of HIV and of ulcer-causing STDs may augment one another synergistically.

Could genital ulcers become a factor in heterosexual transmission of HIV in the developed world? In a study of STD clinic patients in Baltimore, a history of syphilis or a positive syphilis serology was associated with HIV infection in men, after controlling for homosexual activity [19]. In a second study limited to heterosexual patients, HSV-2 antibody and a positive RPR test were independently associated with HIV antibody [20]. Both syphilis and chancroid are increasing at epidemic rates in the USA; the greatest increases are occurring in heterosexuals, in minority races, and in geographic areas where there is a high incidence of AIDS in heterosexuals attributable to prostitution and intravenous drug abuse, such as New York City and Florida [21, 22].

HSV infection remains highly endemic in the USA, with the prevalence of antibody to HSV-2 ranging from 5% of female college students to nearly 500/0 of female STD patients in Seattle (L. Koutsky, K. K. H., L. C., unpublished data).

The identification of modifiable cofactors for HIV transmission has important implications for control programs. Current recommendations for preventing sexual transmission of HIV include mutual monogamy, avoidance of high-risk sexual activities, and the use of condoms. Public health education campaigns should also include a warning that genital ulcers may enhance susceptibility to and transmission ofAIDS. In addition, improved strategies for the prevention, diagnosis, and treatment of sexually transmitted ulcerative disease, particularly syphilis and chancroid and particularly in underdeveloped countries, should be an integral part of AIDS control programs.

PREPARATIONT O receive such an honor as the Thomas Parran Award I an inlereslmg process. Initially. Lhere is exciLement and nervousness: eventually Lhese feelings are replaced by lhe fear of deciding what to ay. Such an event requires a real speech. not a slide pre~ntation. Moreover it is an award bu~ed on '"lifetime achievement" and named after a person of history. One's c;elf-perception i not to feel thal you have much hi\lory - let alone be told you've been around a field long enough lo be called historical. However. the "lifeume achie\'ement'" designation does serve a purpose ... to look back and reflect on what :,-ou have been doing for the last 20 )Cars. Self-reflecuon is not an activil) that our !>oc1ety of rei.carcher,, rewards very often. After all, we are given public monies to pum the envelope of l.nowledge forward. to i,eek oul new problems, new issues, new technologies. We are rewarded for lhe new. not lhe old. Each box of slides i!. to depict something different. Each imitation to lecture demands something innovative. "Take few pri oners. wall.. foN an.I. Okay. :,-ou can Ii I lee\.\ard or starboard a l1ule. but don't bore U'> w1Lh the old o;tuff:'

I promi!.e not to bore you tonight-cenainly King Holmes, in hi-. introduction, has warmed up the crowd! But the caJI from Julie Schachter infonning me of the comrnittcc ·s deci,ion regarding the Parran award has brought with it all ,on-. of reflecrion!> FiN was a perhaps pre cient connection. one that my mother-an-la"' made "'hen she first heard of the Parran Award years ago. Thomas Parran's brolher "'as the obstetrician in Wa.<Jtington. DC. who delivCl'l..-- dm y \\-ifc Amy. ow. th1, could he taken several way . ~I) interpretation i~ that thL<p;o rtended Amy'i. role as ·The ,hado"' on m} land .. - ponending her role 10 the furtherance of my career. initially. as lhe person who would sit at Lhe dining room Lable (we never hod a house with a study until much fater) and work with me in constructing the line listings on the patients enrolled in my early tudie of Reye's syndrome and genital herpes. 1-6 Amy's handwriting, unlike mine. was legible. This allowed some semblance of consistency in resulu. as one poured lhrough each recitation of lhe listing . This "keeping the data honest" was a function later taken over by computers and most imponamly b:,--Ors. Jackie Benedelli and Judith 2.eh who are the doctoral level statisticians 10 our viral dhease research projecu. in Seanle and who e vigilance and intelligence have been a comcr<; tone of our work.

The reflections from the call also brought a flood of memories on which I "'ill digress becau e they mcludc so many people in\'olved in this society. Ye .... it took a whole village 10 rajse this imcstigator.

How Did It Start

How did I even get to this place? Well, it staned with a friendship for over 25 years now with Walt and Pegg) Stamm. Walt and 1 met as Epidemic Intelligence Service (EIS) officers at the Centers for Disease Control and Prevention (CDC) where ""e investigated an outbreak of hepatitis in a hemodialysis unit in Valhalla, NY. My first Nel~ Englm,d Journal of Medicine paper described this \\Ork.' It was Walt who told me to look at the infectious disease program in Seaccle. and it was Marvin Turck who recruited me to Seattle when r anended my fim lnterscieoce Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Chicago in 1974.11 This led to my first momentous meeting with King Holmes, my postdoctoral mentor at the University of Washington.

It was for me a moment indelibly inscribed in my memory bank. King's reputation as a hard-driving raconteur preceded him. 1 myself was nervous and excited as all new fellows are in embarking on their future lifelong career. [ did not really question the wisdom or choice of my elders in assigning me to King; I was assured that "mother university'' would take care of me during these 2 10 3 years of training. I popped my head into his office on July I, 1975 - said "Hello, rm Larry Corey." I was pleased he at least recognized the name and he said "Let's have lunch." His office had a spectacular view of ML Rainier. Later I learned that it was of enormous utility to King because it gave his advisees something to look at as they sat next to him while he trashed every other sentence that lhey wrote, every paper they wrote. For many years, he diligently rewrote all my carefully crafted sentences; sentences that he called ''old world dribble.'' Of course my fellows believe that I do the same thing that King did to me, but without the view!!!

Anyway, there wru. small talk m, we rode down the elevator. We entered the typical hospital lunch line. k I pushed the plastic tray through the line, King asked his first question, ''What were my interests." I answered, "Viral diseases." He looked back at me quizzically. (l imagined he was thinking, ''Where did Marvin Turck get this guy?") I plowed forward with "There aren't many internal medicine virologists so I thought that would be a good career niche."

King looked at me, paused, and said-laconically, I might add-"Sex is my career niche."

I paled ... the memory is still indelible. Kosher home, grandfather's a rabbi in the old cow1try ... swdious ... basical/ y a nerd, moved to a city without comed beef. barely a bagel i11s ight, and rhen going to work on sexually transmirred diseases (STDs). My mocher wa.s telfing people f 1,·cis going to be a cardiologist. What am I doing here!!

But what I was doing was learning the tools of one of the world's best trades, academic infectious diseases, from one of the \\Orld's best craftsmen and teachers. A-,, a mentor. King wa-,, unparalleled. He led by example. had unending energy and patience. He opened door.., watched me walk and then run through them. He was first teacher, then colleague. and now a most dear friend.

The training atmosphere in Seattle was unparalleled. My felJowship colleagues were Gary Schoolnik. Walt Stamm. Joel Meyecs, Bob Jones. Bill Bowie. Luci Tomkins. and Henry Rosen. The faculty included Bill Kirby. Bob Petersdorf. Paul Beeson. John Sherris, Seymour Klebanoff. Harry Beaty, George Ray. and Russ Alexander. All were there to teach and help. I learned ( I) that to cooperate meant quicker progress: (2) not 10 be afraid Lo solve problems quickly, you'U have more ideas than energy: and (3) when asked to participate in a program, say }es. Tm happy to help you do this project.'' and ''Yes, I think we can do this stud}' ...

There was enthusiasm and a feeling that the opportunities were large. Establish a cohort. study a disease. and -,,ucces-,, would follow. Collaborate - learn co write and follow-up on your patients. In an understated manner King said at that first lunch. 'There's this viral disease called genital herpes that no one knows much about. let's study it.'' Harry Adams had staned to study genital herpes I.he year before I arrived. 9 King introduced me to a physician's assistant named Michael Remington who taught me about clinical STDs and introduced me tO the clinic and disease that has occupied much of my career. We started together in 1975 and have been together since. Mike has seen more genital herpes simplex virus (HSV) than anyone on this planet. and I teamed then and now to listen to him. Parenthetica.lJy we have named our new disease management clinic devoted to herpes ''the Remington Clinic."

These ··early years"- as I will term them. were also marked with other major mentors: one in particular is not very well known to this audience. His name is Paul Strandjord. and he was chair of the Department of Laboratory Medicine at the University of Washington and my direct '·boss·· for over 16 years until he retired in 1995. It was Paul who 1aught me how to administratively be a leader and who conceptualized the administrative struccure of the medical virology division within the University of Washington School of Medicine. We developed a "vertically integrated" division -that is, a division within clinical pathology that not only ran a vigorous diagnostics di,,ision but also encompassed a far-reaching clinical and laboratory investigative program. This integration be1ween research clinics and labor,uorie!. would speed transfer of laboratory discoveries to the clinic. Investigative cohorts would assess new laboratory assays quicker than traditional methods. These itleai. were prophetic, and this structure has been perhap the single most imponam ingredient in the Seattle viral disease success story.

However, other ingredients were also imponant. Chief among them were colJeagues and friends - both within the STD and herpe~ viru!t field. Some came to Seattle for their career sojourns. Tom Quinn, Peter Piot. Jonna Paavonen, Bob Brunham. Eric Sandstrom, Ned Hook. and Ann Rompalo helped expand the problems and perspective on HSV infections. Hunter Handsfield returned from San Diego to run the King County STD Clinic and became a critical colleague and dear friend. Zane Brown, who trained at Utah. came to the Department of Obstetrics and Gynecology as a faculty member and initiated a truly productive 20-year collaboration.

Collaborators within the field of genital and neonatal herpes included Steve Straus at the National Institutes of Health. Richard Whitle> at Alabama, Andre ahmias of Emory University, Ann Arvin and Charles Prober at Stanford. Yvonne Bry. oa al UniYen.ity of California. Lo Angeles. Ste,c Sack in Vancou,er. Larry Stanberr}' in Cincinnati, and Adrian Mindel in London and now Sydney. While "'e compered. \\.e also cooperated. There \\a. camaraderie to the field.

During the early 19 Os the STD field "'as a boom: Case rates \\.ere skyrocketing and new syndromes were being defined. 10- 12 My field of genjtal herpe led the \\lay. rt was the procorypical , ir.il SID - hepatitis B was created by gastroenterologisL'> who rud not want to admit their infection wa'i an SID. Cytomegalo, irus - well- it was for immunocompromised pen.ons and newborns. Human immunodeficiency virus (HIV) wa.<; not yet in the scene. and human papilloma virus (HPV) and cervical cancer were a nascent field. However, genital herpe was a clearly defined chronic STD. Merua and patient concerns "'ere beightened.'t. 15

I threw myself into the thick of this boiling pot. Perhaps it was not hard. Incidence rate were booming. and y.,e could ee two 10 three person daily with true primary infection. 16·1T7 hese patient . e pecially women. were ,ick with fever. chills, headache. dysuria. huge genital and/or pharyngeal le~ions. barely examinable whether male or female. Once monthly a case of herpes simplex virus type 2 (HSV- 2)-associated aseptic meningitis was admiued to the University of Wasb.ington hospitals.' 6 Primary genital herpes had replaced disseminated gonococcal infection as the ho pitalized STD. The rwo fellowi. in the Seattle program who bandied inpatienls were Dave Martin - iavestigaung Reiters Syndrome - and myself. seeing patients with aseptic meningitis caused by HSV, HSV eocephalitii.. and then neonalal herpes. My first faculty office was located at Lhe Children's Ho pita! & Medical Center. and we sa"" a Leady 1ream of cai.e of neonatal HSV, nearly one a month. 1• :!11 Recently Zane Brown. my ob tetrical colleague, published a paper this past year on why \\.e saw !>O many neonatal HSV cases. 1t is because neonatal transmission occur, nearly exclu.i.ively among Lbo.,c \\Omen who acquire fir<.1e pisodes of HSV in the late third trimester.~• As such. 1t follows clo!>ely incident case" of HSV. Educational and medical trateg,ec; to attack neonatal herpes were not in place in the early 1980s. ln fact, 15 year later they are \till nol in place - an i">sue to which we hall return.

There were no therapies or cures. My fin,1 plenary talk a1 ICAAC re,iewing genital herpes had me sho'wing a blank slide for effecthe therapies of genital herpes.~ Albert Sabin espoused ether therapy. as if one could di . olve the virus 3\\.3).?. I conducled a rudy ofthh compound and produced a crying rate of 30% with application of thic; medication 10 genital le~ion . It produced another New England Journal of Medic111pea per, but it did little to my reputation in Seattle as a ''hcaler:·; 4 1ot everything that bums when it goes on works. I apologized to my patient:. profusely.

Shortly after thi, srudy. perhaps out of guilt, I started working on an idea for a patient advocacy or an educational effort for genital herpes. Two staffers with the American Social Health Association, Carla lf'mes and Sam Knox.. helped execute the idea and we e tablished the HELP organization now called the Herpes Resource Center.ms A. Martin Lerner of Wayne State University also helped in this endea,or. We imu:ued a quanerly aey.,sletter called the HELPER. which is now in its second decade of publication and has a circulation of over 20.000.Yi Charlie Ebel, who i in the audience today. was the medical writer for the HELPER and had the gift of being able to take arcane scientific topics <,ucb a<; subchmcal shedding and make it inLo understandable lay prose. The HELPER hos been the prototype for the detailed medical ncwsletten, on HIV and breast cancer that their advocacy groups now publish.

The Acyclovir Years

The real breal1.hrough in my career come in the early 1980 . Three things occurred: luck, great col leagues. and great postdoctoral fellows. I thin!-. almost everyone close to me has heard my admonition. '·tt is better to be lucky than good," or ha!> seen the small quilting on the wall of my office that says "If at first }'OU :.ucceed. try hard not to look astonished." Well. I was lucky- for the antiviral drug acyclovir was dropped into my lap.n The s~ were in the right order, we had spent the previous 3 years learning how to study a potential ther.ipy for genital herpe:,. ho"" to chart le\ions, culture the VUU!) from le!>ions. and record and analyze the mformation necessary to demon trate a potentially effective therapy. a ~-11>..4 Acyclovir brought working relation hips with Trudy Elion, David Barry, Dannie IGng. and Gray Davis from the Burroughs WelJcome Corporation. Planning and coordinating the studies of acyclovir for genital herpes was a true collabor-.uion. and we led acyclovir (actualJ>, I think the drug led us) 10 approval as the fin.t fast-tracked drug in infectious di ease.2' :1-1W ho would have predicted th.at this nucleo ide analog would be perhaps the safest anti-infective drug we currenlly have to treat an infectious disease?'~ One of the seminal tudie in this journey ~as one u mg intravenous (IV) therapy for severe genital herpes. a i,tudy Ken Ftfc and I conducted at the University or Wa!>hlngton Clinical Research Center. 29 The tnal was a double-blinded trial in which patients with severe primary genital herpes 'were admitted for 5 day-. of rv therap}' or alme placebo. It became very clear to u that omethmg very momentous was happening to half of the patients. Yes. ~hen you have a dramatic therapy. the double blind does not always hold. 29

This study charted the course for the re t of the acyclovir development program. Once \\.e knew what the compound could do. it became easier to do more far-reaching studies. Or.ii therapy for pnmary mfection 11.u and daily therapy for suppression quickly moved forward.'ll 7 The concept of using an antiviral on a daily basis in healthy people was mind boggling to most physicians and scientisls. There were W'cllllings of dire consequences from several colleagues. More than once. I was pulled aside at meerings and lectured about the danger of our daily suppression studies of oral acyclovir. e peciaJly concern about fulure malignancies or sterility. 3839 What moved these studies forward quickly but metbodicaJJy was enthusiastic and clever postdoctora1 felloy, s: Ken Fife, John Douglas, Greg Mertz, Rhoda Ashley, and John Sullivan-Bolyai. Each brought their intellect and hard work 10 these early studies of the therapy of genital and neonatal herpes. J think that we cut a wide swath in the field of genital herpes therapy in a very short time period. Within 4 years it was largely over - oral therapy emerged as an effective form of therapy for first infection, recurrenl infections, and suppression. Studies of JV therapy for treatment of encephalitis and the neonate were being led by Rich Whitley and Ann Arvin. 40.41 Licensure and press conferences took place; the studies made it on to the CDC STD guidelines. 41 There ea.sued a pause or perhaps even a malaise. During my morning run I'd bemoan "what do l do nextT'-the excitement seemed to have ended ...

But the malaise was short-lived because HIV arrived. In 1985, Bob Coombs came to Seattle as a postdoctoral fellow to work on HPV. The immunodeficiency syndrome of gay men was being tracked by [Dr. Ann Cornwall Collier (born 1953)] and Hunter Handsfield in Seattle, and it became clear that we needed to initiate a virological program in HIV. Shortly after HIV was identified, Bob went to Martin Hirsch's laboratory at Massachusetts General Hospital to learn how to culture HIV. From 1986 until my sabbatical in 1993 with Ed Mocarski at Stanford, HIV was a constant preoccupation [43-47].  It is still one as we in our group struggle on the difficult issues of how to develop an effective HlV-1 vaccine [48-53].

With [Dr. Ann Cornwall Collier (born 1953)], I established the University of Washington ACTU, one of the original 14. My colleagues graced me with chairing the executive committee of the largest clinical trials program in history. It grew from 14 LO over 53 academic medical center .

The years between 1988 and 1991 were tumultuous ones for me personally. As chair of the AIDS Clinical Trials Unit Executive Committee, there was consiant travel to the other Washington and exposure to the difficuJt is ues between researchers and HIV activists. Perhaps my early years deaJing wilb the frustration of ineffective therapy with genital herpes helped in this area. The issues of an activist's role in designing clinical trials and scientific agendas are complicated and clearly worthy of reflection. Jt is an area of interest thac one day l have vowed to write about. but not tonight.

Research Findings and Public Health Programs

Tonight. J want to talk about the extension of research mes.sages into the clinical care and public health sector.

For. while we as researchers have our insular meetings and our own standards of accolades. the purpose of dollars from public monies to suppon medical re earch is to translate these research findings into an improved. public good. I will personalize this ancL as you might expect from the title of this talk, "Raising the Consciousness for Idencifying Viral STDs: Fears and Frustrations," the issue of translating clinical research in genitaJ herpes to public health control for genital herpes has been. for me, a convoluted and sometimes frustrating process.

The theme I will be espousing tonigbt is that translation of research findings into routine medical practice, and more importantly public health practice, is not straightforward and that we as medical researchers need co spend more time and effort in this arena. Let's look at our own work over the last 20 years and what it has done for the public health.

If J can toot our born a bit. we have spent the public monies given to us fairly effectively. We have accomplished the following goals:

I. Developed the curre□ Uy used serological and clinical classification for genital herpes. 1s-17

2. Defined the natural history of genital herpes, documenting its frequency. s.ite of reactivation, and a disconcertingly high reactivation rate. 34- 37

3. Demonstrated the role prior HSV-1 had on ameliorating first episode infection and increasing the frequency of the subclinical acquisition of HSV-2. u.16.2s7.ss

4. Showed the differences in the natural history of genital HSY-I and HSV-2 in the aduJt and the lower morbidity of HS V -I in the neonate. )9-60

5. Demonstrated the ftrst effective therapy for primary HSV-2 and conducted the first studies of long-term suppressive therapy for clinical recurrences. 28-31.33

6. Rhoda Ashley perfected the western blot serology that has become the gold standard for defining seroconverion to HSY-I and HSV-2 and for defining pasc HSV- 2 from HSY- I infection 30•61; Rhoda has led the fight to reduce the use of inaccurate commercially based enzyme immunoassay (ElA) serologies and bas pioneered the development of accurate commerciaJJy based. type-specific serological assays. 62-t.i

7. With Laura Koutsky, showed that most persons do not present with .. classic'" genital herpes but present with what has been labeled atypical lesions: these atypical lesions are a misnomer for in actuality these "atypical lesions°' are the most common manifestations of genital herpes. 65

8. Defined the natural history of subclinicaJ sheclding.6<H9 These studies showed that HSV reactivation is 5 to I 0 times more frequeOL than previously appreciated. When measured by PCR-based methods, HSV-2 can be detected on genital mucosa on average 20% of days.68.69 Thus, for teaching and epidemiological purposes. this make, genitaJ herpe, more akin to a per-istent rather than interrmttent infection. Thus. it appears lhat the exp<hure rate of neonates and sexuaJ partners of HSV 2 'iCropo~iti\'e per.one; are high: making the expo~ure per tran,mis,ion ratio aJso high (i.e .. a lower eflicienc) of tr.msm1s~iom, lhan pre, iou,ly appreciated)/' Our recent data suggest that the sexual 1r.1nsmis,. jon efhciency of HSV ,s about the same as HIV, about 5 per 10.000c oital even~ or .021Ko f se:\ual contacts.' 0 Allhough the transmi,sion rate per expo,ure ma) be lo\\. the high react1vauon rate ha, 1mpltcauons for the role ,ubclinical HSV o;hedding plays ~ a cofactor in HIV di. ease transmiNon and acquisition, an i,,ue I di cu,sed m the plcnaJ) ,es,ion yesterday.

9. In a ,1udy with Andria Langcnberg that hai. been large!) ignored by people in the public. health ~phere. we showed that mo,t HSV acquisitions arc really ,ymptomatic and lhat the ,a,1 maJ0nl}' of HSV-2 ~eropo itive per,on.c; ha,e unrecogmzed '}mptomatic infecuon. We demonstrated that \\ith n 15 minute counseling -.ession with a health educator. most persons can be taught to identify clinical recurrences '1 J will return 10 tb1s 1s,ue later.

10. ln ra:ent ,1udie led b} Anna Wald. ""e ha"'e in the lai,c 3 year, provided firm fooung to the concept that it is HSV-2 seropos,uvit} that is the lllilJOrd ri\er for mfecuousness and tran.,mission: our PCR-b~ed studies show that nearly all HSV-2 ,eropos1t1\eS. whether ~ymptomat1c or with unrecognized infecuons. shed ubcltnically.n.71 We and othe"' have hown that subclmical ,;heddmg accounts for nearly all the HSV-2 tran,;mis.,1on perinatally or .,e,uall) •~

11. Showed the benefits of daily acyclo\lr for reducing subeHnical ,hedding. suggesung that anu, iral ther:.1py can in ,elected ~ituauons be a tool for reducing transmission. 81.ll A mutucenter study to test this concept is about ready to '>tan Such a stud) is nece,saJ) 10 quan- 11tate the value of this approach. but it 1, difficult to conce1,e that the 95'; reduction that oral anu-HSV compound, produce in reducing subclinical ,bedding \\ill not tr.m-.latc mto some clinical reoeht.

12. With Ste,e Strau, and collaborators at Chiron Corporation, showed that immunothcrapy can affect a chronic viral di,easc in hurnans.0 .1-1

13. Our 15-ycar que,1 for an effecthe ,accinc against genital herpes ha, been to date un,ucces<,ful.ro.as. 90 Howe,er. Da\'1d Koelle and Chm Po\3,ad of our group have recogmzed that the critical immune re,pon,es 10 HSV are C)totox1c T cell,;, that the quantity of the HSY-specific CDS+ T celb influence the l.Cverity of di~ease in immunocompromised patients. and that infilm1tioo of ,ucb cells m genital lesions i a,'iOCiatedw ith viral clearance from lesioos."'•~1 QThese data lay the ground\\-Orl for greatly improved immunotherapeutic approache to herpesv,rus mfectioru.. The laboratof) is current!) attempting to identify the viral antigen 10 which these CDS+ T cells are directed."

Yet for all these re-.earch accompli hments, the objective data show that we have done little for the public health. Last \\eek's publication m the Nt!ll England Journal of Medicine by the CDC on the 31< "ti-ncrea.<;ien HSV-2 seroprevalence in the Umted States ha." aptly shown that little of this work has been tram,lated into even a nascent public health policy. "'

A Paradigm Shift

I would like to spend ume examimng this issue and perhaps ,ugge\t that we in the American STD As..ociauon and ISSTDR must lead a paradigm shifi about viral STDs. and I \\-ill contend that if we make lhi. paradigm shift \\e will reenergizc our public health program., and our own field 1lle shibboleth '"it"s too expensive and 100 hard to imtiate programs for viral STD-. with current strapped resources" is a ~elf-defeating prophecy and one that will forever mire us into what I wtll call the linoleum-like landscaping for STD control Franl..lv. I hke carpeung. and m} wife prefers marble. but my theme iomght 1, that we must argue both more broadly and persua.,i\el) for program, d~1gned to reduce the spread of viral STDs. For. if we look at ways to initiate new progrrum for, u-al STD control. r.ither than espousing excuses as to why we cannot do somethmg. \\C personal!}, and more importantly. the health of our constituency. will be improved. In fact. J passionatel) feel that if we do not move forward we will as a re..earch field and as a medical ,oc1ecyd ie.

I am not espousing a novel concept here. Thomas Porran, in hi<; book. A Shado1i on the LAnd, ~tated the folJo\\ ing:

Toe bril!hl ,ide of a career 'Cr\ ice in pub he lk~th 1, that an able m~n bas a considerable opponunity to give his whole mind 10 the learning and doing of hi, tru.k. The dark -.ide may be eitpressed by the much quoted saying tlul the ,trongel>ilm pu1'eo f the human race 1s" Just 10 ,it," Under tax lc.ider..hipe. very group with c1,il ,;cn1ce or other job procecuon tends to develop a cenain number or fat-headi. anti chaiM1,anner.T. he '>lUlle thtni,>,. , true of bu,ine~sa nd intlu'>tr).T he an,11.erf or II is energe11cJ eader~h,pu nder v.hicb men \\h0 are good to '>l3tl v.,th cannot degenerate mto drones."

Although ~ome of the terms used here are "dated." the idea is not. Parenthetically. one quick!} learns from reading cla,,;1caJ\ \Ori..... ho\\ bright our early brethren were and what differenuares them from us are our technological tools in problem ,oh mg. not our intellect. as demonstrated in the next quote from Dr. Parran:

So far as the 11.ell-bemocf the human race is concerned.I look upon the great quesuon of i.yphilis today as ... no longer a question of treatment. mercy or ao mercy, that time has passeda nd now ii is a questiono f preventiono r the protection of me well for the sick. 11 is no longer a question for the therapist but one for the public heallb.96

The similarities between Treponema pa/lidum control in the 193Os pre-penicillin and HSY. H[Y, and other viral STD control are remarkable. The basic concept is simple: The object of public health prevention is 10 reduce transmission or acquisition of an STD. and while the tools to do so may be imperfect, to not even attempt to muster a control program with available tools is just wrong public policy.

As shown in Table l. the clinical and epidemiological similarities between the acquisition of viral and bacterial STDs are similar. Both viral and bacterial STDs are usually acquired from an asymptomatic carrier. ln both, the source contact can often be identified - increasingly so in viral STDs, which are chronic and hence a major feature for social networks of persons with sequential monogamous sexual relationships.97 Clinical diagnoses are poor in both bacterial and viral STDs, and laboratory-based assays are required for an etiologic diagnosis. These laboratory assays precipitate case contact investigation. One difference is that most therapy for bacterial STDs are curative and viral STDs are not. In other words. viral STDs are analogous to bac1erial STDs in the Thomas Parran era. Lastly. as shown so frequently by papers presented at this meeting, both viral and bacterial STDs increase tJ1e risk of HlV tranSmission and acquisition.98- 105

Table 2 depicts the current model a1 STD clinics for control of bacterial STDs. Public STD clinics are geared to treating the symptomatic patient. They also have screening programs for identifying the asymptomatic carrier by either cu11ure or serology, whatever is more effective. Lastly, they engage in source conlact investigation. Yet despite the sunilarities between lhe acquisition, transmission. and diagnosis of viral and baccerial STDs in Table l, r know of no current program within public health departmenlS thar uses the concepts of Table 2 for the control of genital HSV infections. My dearest hope is lhat the Fleming paper and the CDC's recent commitment to initiate a program to monitor antiviral resistance to HSV-2 signal a new appreciation for these issues.94

You could ask what is required to develop an HSY control program. There are, in my opinion. two parts to this question: (I) Are the tools available to do it? and (2) Is there the will or desire to do it?

Lei's discuss part I: Are the tools available to initiate a screening program for HSY-I infection in STD clinics? Here the answer is clearly yes. Type-specific serological assays have been available in reference laboratories for a decade.106 Moreover. commercialization of these products bas occurred in the last 12 months. 6.1 Although laboratory assays such as viral cultures or antigen detection and accurate HSY serologies are going to cost more than a ThayerMartin place. they are similar in cost to a chlamydia ligase chain reaction (LCR). With high volume testing, the cost of a chlamydia LCR is about $13; this is similar to the estimated cost of an HSY specific serology by EIA.107 10~

How about part 2 of the query "Is there the will or desire to tackle this problem?" ln my opinion, herein is the issue. Lei's digress a bit and discuss the issues surrounding and identifying persons with unrecognized or subclinicaJ HSY. In other words, let's look at the medical and public health reasons to diagnose unrecognized genital herpes and change our current paradigm of "Ignorance is bliss." After all, why not let sleeping dogs lie?

The reasons for diagnosing HSY are clear and shown in Table 3: (I) Mos1 HSY-2 seroposi1ives are truly sympto-matic (80%) and with serological identification and a short counseling session can be ~hown to have clinical disease. 89-1(()21)} Moreover, emerging data indicate Lhat once told they have genital herpes. patients increase their condom use and the frequency of having sex during peri~ of lesions decreases. In a recent HSY-2 vaccine trial the transmi ion rate per contact event was reduced by half as counseling mei.~ages about transmission were ghcn.7° (3) Additionally. as shO\\n in our study by Langenberg et al., many of the women with unrecognized genital herpes with HSV episodes get misdiagnosedRSa s having yeast or other vaginal or bacterial infection!> and are given inappropriate therap). Our study on thh issue wru, conducted before overLhc- counter vaginal prescriptions were available. I suspect the figure in Table 3 is, in reality. even higher.

If we believe identificanon and counseling offer some public health benefil. it seems to me the ,ru.t weight of the evidence ~uggests that initiating control programs for genital HSY prevention via identification and counseling are both approachable. nece sary, and cost-beneficial.

Feasibility or a Serological creening Program

As discussed earlier. what makes a control program for HSY-2 po sible is the development and commercialization of type-speci lie serological assays, assayi. that allow for routine screening for HSV-2 in high-prevalence situations. The two areas I would first propose ~ demonstration projects for such a serological screening program are (I) STD clinici. and (2) Ob/Gyn practices in which serological screening for HSV would be performed in the third trimester (Table 4). Th,~ latter approach is directed at preventing neonutal HSV (albeit it will identify carriers and susceptible ). Here the iotervention would be to identify women \\ ho are !.Usceptible to acquiring HSY in the last trimester of pregnancy. Thus. the intervention would be to identify women who lack HSV-2 anubodies who are sexual panners of per!.ons who are HSY-2 seropos1tive (or HSV-1 seropositive in the HSY seronegat1ve women). The goal of screening and counseling i to prevent acquisition of HSV in the late trimester.11.110-11• As this occurs in only about 15% of couples. thh i<, in our opimon a \Cry definable obJective. ~• 10-1 1

For 1he STD field. I feel that a serological creening program to identify HSV-2 seropositives in STD clinici. 1s \\hat we must undertake. At this state of our knowledge. I cannot and should not state what is the "best or most correct" approach. Should all STD attendees be screened? Should only select h1gh-rbk one be screened in an attempt to b.eep HSY and Hrv from co-circulating in the ~me populations'? Studies on uch 1s ues need to be conducted. But action needs to be taken now. On an epidemiological ba is the HSV-2 epidemic has preceded the HIV epidemic in nearly all population groups.-u.1"' 1 J It is a dangerous situation to increase the efficiency of transmission of HIV by severalfold and acquisition by twofold. This is great for the RIV-I virlll> but bad public health policy for the populace.' i.m

Table 5 depict'> the reai.ons why a serological screening program for HSV-2 is likely to useful. First the "hit rate" will be higher than most other screening programs we initiate: in mo~t STD clinic • 3SCk 10 50'if of attendees who undergo testing will need to be .. counseled.·· To me thi-. makes it an obvious succe~s. However, to Thoma,; Parran "chair-warmen." it brings out such nervou, palpitations as to the amount of work it will take to identify so many people wi1h a chronic transmittable viral disease that the discussion gel~ mired not m public health gOO<bi.u t with the high cost of such a program and the difficulty in initiating coun:.eling messages. The simple fact of the matter i:, that there are substantive data to ,how that coumeling me,. age:. to per!,on, with viral STDs does produce some reduction in mk behavior. 11s-11C1e nainly this reduction isles!. than complete. but it is substantive.

Let's look at the potential scenarios of ,uch an effort from such a screening program in Seattle (Table 6). where the studies show the prevalence in the STD clinic m, 40% in women and 30% in men. Al> shown in Table 6. a scrolog1cal creeniJ1g program would. in a 2-year ume period (we ,ee 5,000 new women and 5000 men yearly). identify 3,400 and 2.650 HSY-2 .,eropo itives. As a comparative figure. the clinics now diagnose about 250 women and 150 men yearly (800 in 2 years) with genital herpes (80t?f HSV-2). Thui,. one would increa,c the STD diagnosis for herpes from 800 every 2 years to 6,000 every 2 ycan.. a 7.5-fold mcreac;e.

Yes. such a program would lake work. but it would al~o be good clinical practice becau<,e. a, cfucus-.ed earlier. 25% of these HSV-2 ,eropos111ve women with unrecognized HSV-2 thmk they have other maladies. u,ually unn3f) tract infections. vaginal yeast. and bacterial infection-,, and are getting ineffective and costly lherapies for their condition,;. MoreO\er. once the e people are identified and told about HSV-2. half of the women and a -.imilar figure in men will recognize they are really ymptomatic.71 As 75~ of such per;ons -,hed HSV-2 by viral isolation. they arc potential 1ransm1tters. The higher rates of <,bedding demo11,1rated by polymerru e chain reacuon tudies among these people are likely to dnve thb figure up C\en more.e·" So. at a minimum by !.erologicaJ screening we have identified a new clinically significant STD in 20% of aJI women and 15% of aJl new male attendees with an assay that is similar in cost to a chlamydial LCR.

To me Lbe cost-benefit in such an approach is so obvious thai I would rum Lhe quest.ion around- why aren't STD and 1•enereologyc linics clamoring to do rhis?

Clearly thfa approach will require resources. It would take time and money to spread the news about Lhis viral STD to large numbers of men and women. But how thi is done can also be innovative. I would like to remind the audience that the studies we published on identifying HSV-2 carriers were conducted with university students who used pictures and graphics that our professional staff developed for the expressed purpose of identifying genital herpes.71-73 We in Seattle have models for such educational materials, and I am certain otber organizations experienced in these areas can do even better. But one thing is clear, STD and venereology clinics need to develop better patient educational materials to perform the following: Describe genital herpes - what are its complications? How it is transmitted: how it can be treated; bow transmission can be decreased. Moreover, the~e materials must be available in differing media fonns such as CD-ROM. video. or audiotapes.

I see great opportunity in the field for health education in STD clinics. The paradigm of the one-on-one clinician visit to counsel persons on acquisition and transmis ion is inefficient. expensive, and frankJy not feasible for the effort. Just because Lhis approach is not feasible does not mean we abrogate our responsibilicy to do llealth education. What we need to do is develop new models; to deliver patient educa- 1ion materials such as video , interactive CD-ROMs, and group education sessions are all ways to deliver iofonnat.ion and 10 develop new types of employees for the STD field. We must acknowledge that reading pamphlets is not what mo)t of our cliemele best unden,tand or find palatable. [n my opinion, ''electronic media·· is the way LO help deliver the message; the electronic medicine can deliver a health message efficiently and cheaply. The purpose of my talk tonight is not to delve into the details of such an HSV control program but to make a single point. It seems 10 me that it does us all good to start to tackle the issues of how to cope with chronic viral STDs.

Again Dr. Parran was prophetic when he said, "The first job in syphilis control is to teach.'' 119

Next, I think we can also help public health control by paying attention to HSV more at the "point of service" (Table 7). This means more attention to diagnosis and more attention to the potential of using suppressive therapy to reduce transmission. Table 7 ilJustrates a few situations in which I feel we need to use suppression more frequently. Subclinical shedding is higb in the initial 6 months postacquisition. 67·1:!F0o r many persons. it would appear prudent to initiate therapy at diagnosis until education eEfons are embraced.

Too often we approach the viral STD with the attitude, "It's too expensive to trem, counsel and deal with Lhis. We in the public STD clinic are here for a quick pop-in and popout, we're public not private health care. Therefore, it must be cheap and quick." This pllilosophy is somewhat puzzling to me, as we do not see this in many other public health sections. Would we get far with immunization and tuberculosis control if long-term follow-up was not a part of the program? Acyclovir is now generic - it is affordable. 1 am not advocating spraying the clinic or spiking the water with antivirals - quite the conlr.U). But T am adHx:ating that identifying persons with an STD and treating ii is 001 a v. roog public health pohc).

Our current aversion to user serological screening to identify persons with symptomatic HSV-2 because it is expensive and might cause "psychological morbidity" to those who are HSV-2 seropositive but do not know they have the disease is terribly misguided and self-serving. People do not like to transmit infection =to others. Yes, it is difficult as a health professional to tell someone they have something they do not want to have II is made even worse when we as the health care provider<, cannot cure this pen,on of the malady and function m the role of "healer."' But isn't it more difficult to be accused of transmitting an infection that in 1% of person2 leaves them hospitalized, that in 20% to 40 will cause a woman to have a subsequent cesarean ection, and invariably leads to chronic morbidity?16 After all, haven't we learned enough from social networks that even if only 50% of genital HSV acquisitions are symptomatic, identifying the undiagnosed carrier will reduce symptomatic first-episode disease and medical morbidity in a large number of people.

Again Thomas Parran was right on two accords. His action plan for T. pallidum is pertinent today identifying the cause, identifying the contacts, treating the patient with the disease, and educating the patient as to the mechanism of transmission (Table 8). It 1s the public health agency that must be required to participate in these tasks. Moreover. his idea:-that 11 i'> government that must lead the way to public health control are also, in my opinion, correct. "In general, it may be ,aid that in no place in the world ha~ syphilis declined without active government interaction. A nationally coordinated attack upon it seems as necessary as upon an invading army" [121]

Closing

To date, an HSV vaccine has alluded us. However, I feel we should be optimistic that an effective vaccine wall eventually emerge, perhaps even with one of the products in clinical trials now. In the interim, we must develop a plan for reducing the skyrocketing rates of HSV-2 that are occurring worldwide. One of the functions of our society must be to initiate such demonstration programs. Current resources, while not perfect, are not trivial and are likely to have some success. With the seroprevalence of HSV-2 at such high rates ii will take time to see an effect. Perhaps the best we can expect would be a ,lowing of the rate of infection over the next few years.

Acknowledgements

In closing, I am greatly flattered by the Parran Award and appreciative of the opportunities the people of these two societies have given me. More importantly, I thank my collaborator; at the University of Washington, my mentors. Dn.. Holmes and Strandjord, and of coursee my friends. colleagues, and family who nurtured and supported me throughout my life. I am appreciative to this society for the nourishment it has given me throughout my career. May it continue to grow and thrive and may it develop the wherewithal to tackle all STDs. 

When Dr. Larry Corey taught medical students about AIDS at the University of Washington in the late 1980s, he always brought in someone living with HIV to put a human face on what the budding doctors were learning. But it was never the same person twice, he remembers, because the patient always died before the next year. There weren’t good treatments and science wasn’t fast enough then to save them.

For decades, Corey dedicated his career to unlocking the secrets of HIV and AIDS and other infectious diseases and finding treatments that have now saved countless lives. He put his own scientific work largely on pause when he accepted the job of president and director of Fred Hutchinson Cancer Research Center in 2011. Now he is again feeling the press of time and a desire to do what he can to help speed the science.

Thursday morning, he announced he is stepping down so that he can return to his passion – making a difference through hands-on research.

“There is a difference between administrative success and scientific significance,” he said. “What significant impact can you make on humanity? That’s where you define yourself.”

Starting June 30, he’ll be trading his seat in the director's office to work full-time with his lab and clinical collaborators in the Vaccine and Infectious Disease Division at Fred Hutch. He’ll be a member of the faculty and will have the title of president and director emeritus. Fred Hutch Deputy Director Dr. Mark Groudine will serve as interim president and director while the Board of Trustees launches a national search for Corey’s successor.

“The Hutch’s loss of Larry as president and director is a major gain for the field of HIV vaccine research,” said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Fauci and Corey have been close friends and colleagues for decades through their work in infectious diseases.

Corey, known around the world for his work in medical virology, particularly in the areas of HIV/AIDS and herpes, said his decision is the result of months of struggle as he increasingly felt himself pulled to return to science.

When he first took the job of director, he made a list of the goals he wanted to accomplish in his first five years. Recently he reviewed the list, he said, and realized he’d achieved all of them in just more than three. He’s been instrumental in revitalizing the center, hiring world-class faculty and invigorating solid tumor research, grown the Center’s endowment, birthed a state initiative that could help infuse millions of cancer-research dollars and more. All of that has helped infuse the Center with new energy.

“I’ve loved this job as president and director. The notion that cures start here now permeates the place,” he said. “We are no longer looking backward – we are looking forward.”

In recent months, Corey realized, he yearned to return to being a hands-on part of spurring new treatments, cures, and vaccines.

“The issue became do I want to spend the next five years being a scientific administrator or do I want to continue to make my mark in what has been my life-long career,” he said.

‘How many lives could you have saved?’

Corey was a young man when he first began to feel the urgency of science. He was 26 when his brother-in-law, Thomas Banks, who had Hodgkin’s Lymphoma, died of candida sepsis. Corey had known him since he was 10 years old and the two were really like brothers. Banks was a physician, an ophthalmologist, and had inspired Corey.

“He was the reason I went into medicine,” Corey remembers.

Only a few years later, as a physician scientist, Corey did research on antifungals that have now largely wiped out candida sepsis.

“It was a poignant reminder of the pace of science,” he said. “If you can move something along quicker by even a year, how many lives could you have saved?”

He still remembers the June morning in 1981 when he picked up a copy of the Center for Disease Control and Prevention’s Morbidity and Mortality Weekly Report and read about a small group of gay men who had died after developing pneumocystis carinii pneumonia. Mysteriously, all their CD4 T cells, essential to the immune system, had been destroyed.

Back then, he assumed whatever was that cause was would be identified and a treatment would be found. He had no idea that virus, now known as HIV, would become a large part of his life’s work.

At the time, he was at the pinnacle of success with acyclovir – the first antiviral that could be given to a human. He was getting excellent results using acyclovir to keep herpes in check and pioneered treatments using it with infants born with the virus. Today, the mortality rates for babies born with herpes has declined from 80 to 10 percent

“I see kids we saved then now become parents themselves,” he said.

Increasingly, he was drawn into work on HIV. Thousands were dying and there weren’t any good treatments.

“It was a traumatic time then,” he said quietly, remembering friends who died of AIDS.

Six years after reading that first report on HIV, he became the head of the AIDS Clinical Trials Group (ACTG) and worked to develop effective treatments. By that year, 1987, more than 50,000 cases of AIDS had been reported in the United States and more than 40,000 had died.

In one year alone, Corey flew back and forth 20 times from Seattle to Bethesda, Maryland, without ever staying the night for meetings about HIV at the National Institutes of Health. There was too much to do. Too many people were dying. Too many more would in the future unless something could be done, he knew.

The ACTG developed and tested combination drug therapies and then protease inhibitors that extended the life expectancy of people with HIV from between six and nine months to decades. 

He also moved forward a study to find out if giving AZT to HIV positive women could reduce the rate of transmission from mother to child. The study had been stalled for two years because a small group of activists felt AZT was poison that shouldn’t be given to pregnant women. Corey spun out the Pediatric AIDS Clinical Trials Group from the ACTG so the trial could proceed. The study, known as ACTG 076, eventually showed a 76 percent reduction of transmission and established the worldwide use of antiretrovirals for preventing maternal to child transmission of HIV.

“It was the study that changed the world,” he said. “It saved the lives of millions of babies.”

Targeting an AIDS-free world

Dr. Barb Berg, chief of staff at Fred Hutch, marvels at the pivotal role Corey has played in infectious diseases. “He has more energy than anyone I know. He’s had an enormous impact on the world. I’m so excited for his work to continue.”

Dr. Robert Day, former president and director of Fred Hutch, was one of the people who recruited Corey to the Center as a researcher in 1996.

“I’m a big fan of Larry. This is a very difficult time for biomedical research and he’s dealt with that difficulty very well,” he said. “He’s increased contributions for science and other purposes. He developed a Ugandan branch of the center for treating cancer. He’s brought in new contributors. Now he’ll be able to apply his full attention (to research) and I think it’s a good time for that. His contributions will be even bigger and broader than in the past because we know so much more.”

While better treatments have been developed for people living with AIDS, Corey has set his sights on a vaccine. He’s the founder and director of the HIV Vaccine Trials Network, a collaboration of scientists around the world working toward an HIV vaccine.

Today, outside the brightly lit Corey Lab at Fred Hutch, across the street from his current office, photos of people living with HIV line the wall. In one, a young woman looks into the camera. In another, a small child with a feeding tube rests against a chair.

“I want my grandchildren to grow up in the AIDS-free world that I did,” he said. “I want them to be able to get vaccinated for HIV and for herpes and to not have to worry. That’s the dream.”

He has other dreams as well. The quest to make a vaccine against herpes is closer than ever, he said. And last year he helped found Juno Therapeutics, a biotechnology company focused on novel immunotherapies for cancer using reprogrammed T cells that directly attack the malignancy while avoiding healthy tissue. 

“We want to make it the front-line treatment so people don’t have to go through chemotherapy and radiation and all of those side effects,” he said.

Groudine is eager for what’s ahead. “Corey has incredible vision and he is so full of ideas.”

There is much to do, and after all these years, Corey still feels the same sense of urgency and is eager to get back to it.

“Miracles really do happen in the labs,” he said.

The June morning in 1981 started out routinely enough. Coffee in hand, Dr. Larry Corey, then a young University of Washington medical virologist, picked up a copy of the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly report. What he read is as fixed in his memory as a specimen on a glass slide: Five previously healthy men, all of them gay, had fallen ill or died from a lung infection that typically affects only people with severely damaged immune systems.

Not that he or anyone realized what they were seeing at the time. Corey was on the brink of developing the first antiviral treatment for genital herpes, a feat that would seal his reputation as a force in the infectious disease field before he was even 35. He remembers feeling confident that the scientific community would figure out what was causing these mysterious infections and how to stop them.

They were, of course, the first reported cases of what would become known as AIDS. And that single report would shift the course of Corey’s career. Finding a way to treat, prevent and even cure HIV, the virus found to cause the global scourge, would become the focus of his life’s work over the next 35 years.

Now 69 and the past president and director of Fred Hutchinson Cancer Research Center, Corey was right on one level: Within three years, scientists identified HIV as the virus that hijacks and decimates its victims’ immune systems, leaving them vulnerable to infections they might otherwise have fought off. By another dozen years, they had developed lifesaving combination antiviral drugs to hold the virus in check, building on a road map that Corey created for developing antivirals for herpes virus infections.

What he and no one else foresaw was how rapidly the killer virus would spread or what damage it would cause, killing an estimated 25 million people worldwide, a pace that treatment has slowed but not halted. With an estimated 40 million people living with HIV today, Corey and many others see a vaccine as the best hope to get to an AIDS-free generation.

Today the founder and leader of the world’s largest HIV vaccine network, Corey will deliver a plenary talk on the state of HIV vaccine development at next month’s AIDS 2016 conference, [https://www.aids2016.org/] the biannual meeting of the International AIDS Society, in Durban, South Africa. In August, he will be the keynote speaker at the third Conference on Cell and Gene Therapy for HIV cure [ http://cgt4hivcure2016.org/ ] at Fred Hutch about an even more challenging goal: an HIV cure.

• [Notes - AIDS 2016 conference : https://www.aids2016.org/Portals/0/File/AIDS2016_Abstracts_LOW.pdf?ver=2016-08-10-154247-087 / 2016-aids2016-abstracts-low.pdf / https://drive.google.com/file/d/18kaau7_AFMRhKpkh6lbrsr9c5VbO1Pos/view?usp=sharing ]

• [Notes - PDF Booklet for The 2016 Conference on Cell and Gene Therapy for HIV Cure :   [HI003D][GDrive]  ]

The road to research

Growing up in Detroit, Corey and his two older sisters were the children of immigrants from Russia and Poland. Corey was the “Americanized one” who now kicks himself for never learning the Yiddish, Russian, Polish, Ukrainian and Hebrew languages that filled his household. His father was in the schmatte, or rag recycling, business well before recycling became profitable; his mother was a homemaker. He idolized his oldest sister, Sharon, and the husband she married when Corey was 10. That was when Corey decided to go into medicine because his new brother-in-law was training to be an ophthalmologist. His other sister, Roslyn, also married a physician, “so it was logical to want to be like them,” Corey said.

Collecting scholarships and skipping grades, he graduated from the University of Michigan at 20 to enter the university’s fast-tracked, three-year medical program. Along the way, he started dating Amy Glasser, whose father had supervised the field trials of the Salk polio vaccine. [Dr. Jonas Edward Salk (born 1914)] was a guest at their 1969 wedding.

When he met one of the great vaccine developers in history, Corey was leaning toward a career in cardiology. Then tragedy struck. His beloved brother-in-law, Dr. Thomas Banks, developed Hodgkin lymphoma. Chemotherapy suppressed his immune system, and he died, not of the cancer but of an infection. He was 37, Corey, 26.

“You could say I’ve never recovered from that,” Corey said. “He was like my brother.”

Infectious diseases became his new passion. After a stint as a public health officer investigating epidemic outbreaks at the CDC during the Vietnam War era, he came to the University of Washington in 1975 as a postdoctoral fellow to research viral infections. His mentor, the legendary [Dr. King Kennard Holmes (born 1937)], nudged him toward sexually transmitted diseases, specifically genital herpes, a lifelong, recurring infection with no cure and, at the time, no treatment.

Corey recalled turning pale at the suggestion.

“Kosher home, grandfather’s a rabbi in the old country … studious … basically a nerd … and then going to work on sexually transmitted diseases,” he wrote for a 1988 lecture on receiving an award for his work in precisely that area. “My mother was telling people I was going to be a cardiologist. What was I doing here!!” 

A herpes breakthrough

In 1982, the fear and stigma surrounding herpes landed the virus on the cover of Time magazine as that era’s “scarlet letter,” a foreshadowing of the even greater HIV fear and stigma to come. By then, Corey was working with biochemist Trudy Elion at Burroughs Wellcome (now GlaxoSmithKline) to show that acyclovir, a new type of drug invented by Elion and directed for the first time at an enzyme specific for a virus, could control and suppress a viral infection.

Half the scientists he knew not only doubted that an antiviral would work, they feared it would cause harm, attacking human cells rather than the virus and causing an autoimmune disorder or even cancer.

“I was young enough and bold enough to say, ‘Let’s see what this drug can do,’” he said of a clinical trial of intravenous acyclovir to treat severe infections. "After the third day, it was, ‘Wow, there’s something special going on here.’” Results were so spectacular that it was obvious who was getting the therapy and who the placebo, even though neither researchers nor patients in the double-blinded study knew.

It was a heady time, Corey said, when “everything you touched worked.”

Today, acyclovir and its successors have reduced mortality rates for babies born with herpes from 80 to 10 percent. Corey also studied the daily use of the antiviral to prevent transmission, an approach that would later be used for HIV. These early studies paved the way for antiviral therapies for HIV, as well as for the viral infections hepatitis B and C.

Buoyed by this early success, Corey started looking around at what to do next. By then, it was apparent that there would be no easy solutions to the mystery disease first reported on that June day in 1981.

He began to focus on HIV.

Early HIV research

Corey opened an HIV lab at UW in 1983. As a physician-scientist, he also treated people with HIV. Each year, he would invite some of them to speak to the virology class he taught for first-year medical students. In those still-early days, many people were afraid to even be in the same room with someone with HIV. Corey wanted to make sure that his students didn’t buy into that fear.

“I would break the class up into small groups and they would have some one-on-one with the person about what it was like to have AIDS,” he said. “They would see me shake hands with the person and hug the person. You don’t get the infection that way. And there’s a humanity aspect to this.”

What hit Corey hardest — the real “humanity aspect” — was that each year, he had to recruit new patients. “The patients I brought in to be with the class one year were never around the next year,” he said. “They all died before you could bring them back. Every single one.”

This was not the first time Corey had reached out to the community of people affected by a disease. As a herpes researcher, he worked with the American Sexual Health Association to establish The Helper newsletter in 1979 to give people with herpes unbiased, accurate information about a virus that until then had been treated with either silence or derision. Today, The Helper continues to provide information online.

But his record of reaching out to patients didn’t seem to count once he became head of a network overseeing clinical trials of HIV treatment and thus the public face of the government and scientific response to AIDS. He and other network leaders came under harsh attack by the AIDS activist group ACT UP in protests born of rage, frustration and grief at the number of people dying of HIV. 

The ‘Gang of Five’

Funded by the National Institutes of Health, the AIDS Clinical Trials Group, or ACTG, formed in 1987 to test therapies for HIV. Corey’s UW lab was part of the network, and he became the group’s chairman. With no budget for hotel stays, he would catch a red-eye flight in the early morning from Seattle to Washington D.C. to attend meetings at NIH headquarters in Bethesda, Maryland, returning home on the day’s last flight. In 1990 alone, he made the grueling trip 20 times.

So urgent was the need for therapies that study investigators routinely worked seven-day, 100-hour weeks. Their hard work paid off. The ACTG developed and tested combination drug therapies and then protease inhibitors that by 1996 extended the life expectancy of people with HIV from between six and nine months to 20 years. Today, those who have access to and can tolerate the treatment can live a nearly normal lifespan.

“I think it’s the most remarkable achievement in all of medicine,” Corey said “Just look at the number of lives saved, the number of young adults who are living.”

But in the years leading up to that breakthrough, with people in the hardest-hit cities attending multiple funerals a day, nothing seemed fast except death from AIDS. Protestors stormed AIDS conferences and insisted on a voice in research decisions. 

ACT UP protestors dubbed Corey and ACTG investigators Drs. Margaret Fischl of the University of Miami, Martin S. Hirsch of Harvard, Thomas Merigan of Stanford and Douglas Richman of the University of California at San Diego the “Gang of Five” and publicly accused them of “ignoring the anger and frustration of people whose lives are at stake.” In a mock trial on the streets of San Francisco, activists tried the five scientists for “their crimes against gay people.”

Dr. Tony Fauci, the director then and now of the National Institute of Allergy and Infectious Diseases, a part of NIH, scolded the activists in the pages of the Advocate newspaper, saying, “It is particularly devastating and unfair when scientists of good faith and enormous talent are singled out and publicly named as scoundrels.”

Fauci later suggested that community members be allowed to attend the ACTG’s meetings. By the end of 1990, each site sought the local community’s involvement when developing studies. Today, community advisory boards are the norm in HIV research and a model for other disease advocates.

Corey remains one of the staunchest advocates of patient and community involvement. But the bitterness of the protests took their toll.

“It was horrible,” he said, closing his eyes at the memory even more than two decades later. “I was working 100 hours a week, I was so driven. I was given the responsibility of running this organization that was visible to the activists. So it was difficult. I learned from it. I grew from it. This is a reason why we now have such strong community outreach programs at the HIV Vaccine Trials Unit and at Fred Hutch.”

Knowing that a pathway to drug development was in place, Corey abruptly switched fields. Jonas Salk may have had an influence after all: He decided to focus on finding a vaccine to prevent HIV.

In 1998, Fauci asked if he would develop and lead a second large network, this one to test HIV vaccines. Corey assembled a team to run the HIV Vaccine Trials Network, or HVTN, which would be based at Fred Hutch. One of the first people he hired was Steve Wakefield, who continues to work with Corey, to do community outreach.

Corey does not believe that he failed to involve the community before. But with the passage of time, he has tried to glean lessons from the earlier criticism, however painful.

“You sometimes have to have the maturity of age to step back and say, ‘Well, OK, you could have handled that better,’” he said. “It’s why I’ve involved community so much better in the HVTN, it’s why I’ve become sort of a better communicator, it’s why I’ve changed the way I do research. It helped me be a better president, director, leader. There is some wisdom that comes out of parts of your life where you get criticized. You learn from your experience.”

Said Wakefield of the man he’s worked with for decades now, “Larry has a deep moral conviction to take care of the world that he’s in with the talents that he has. But he didn’t get any recognition for the sacrifices that he’s made to solve this epidemic. Until he had grandchildren, I never remember him going on vacations. Now part of his drive to find a vaccine is so his grandchildren will never have to live with HIV.”

The search for an HIV vaccine

Corey was recruited to Fred Hutch in 1996 to lead what is now the Vaccine and Infectious Disease Division. Soon he was deep in the work of finding a vaccine for HIV, which mutates so rapidly even within a single person that antibodies can’t keep up with the changes. Promising trials led to deep disappointments.

His early success against herpes helped him weather the setbacks.

“If I’d known how hard it was going to be — if [the setbacks] had come first — maybe I’d feel differently,” he said. “But I’d had a lot of success and accolades, and it was sort of, OK, you can’t walk away. If you’re not willing to undertake a really tough challenge, who is?”

One of the deepest came in 2007 when a major trial had to be halted when it was found that the vaccine neither prevented HIV infection nor reduced the amount of virus in the blood among vaccine recipients who became infected with HIV. In some cases, it could make the recipient more susceptible to the virus. Corey got the news around the time of his son’s wedding, and not even that joyous event could ease his dismay.

But he and the team he’d built pressed on.

“In Julie [McElrath] and Peter [Gilbert] and Jim Kublin, Steve Wakefield — we have just incredible people,” Corey said. “We are working at the cutting edge of science. The technologies and the techniques and the insights we’re providing are spinning off to other fields.”

On the brink

In 2014, after having served as Hutch president and director for four years, he stepped down to return to hands-on research at a particularly exciting time in the field.

An experimental HIV vaccine regimen being tested in a small clinical trial in South Africa has met the benchmarks to expand into a large-scale trial that could lead to the first licensed vaccine against the virus that causes AIDS. That trial is scheduled to begin in November, with results expected in 2020.

Meanwhile, partnering with a sister network, the HIV Prevention Trials Network, the HVTN launched a clinical trial in April of a new approach called antibody mediated prevention, or AMP. If the experimental antibodies being tested in the AMP trial provide protection as hoped, information gleaned from the study could help scientists figure out how to reverse-engineer a vaccine to elicit the antibodies at the concentrations needed. Corey believes that the path to the promised land of a vaccine that is 80 percent to 90 percent effective may well end up combining both approaches.

Before leaving the Fred Hutch presidency, Corey helped found Juno Therapeutics, a biotechnology company focused on novel immunotherapies for cancer using reprogrammed T cells that directly attack the malignancy while avoiding healthy tissue. “On a pound-for-pound basis, it’s the most potent killer of cancer we as a scientific field have developed,” he said. “The years of work by my close friends Phil Greenberg and Stan Riddell have placed Fred Hutch at the forefront of this story.”

Corey has since dreamed of using this approach to attempt something that is even more remote than a vaccine: a cure for HIV, a topic he will address at the upcoming Conference on Cell and Gene Therapy for HIV Cure.

“It’s a science experiment,” he said. “Perhaps even a grand science experiment. It’s worthwhile doing.”

There is an unprecedented need to manufacture and distribute enough safe and effective vaccine to immunize an extraordinarily large number of individuals in order to protect the entire global community from the continued threat of morbidity and mortality from severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The global need for vaccine and the wide geographic diversity of the pandemic require more than one effective vaccine approach. Collaboration will be essential among biotechnology and pharmaceutical companies, many of which are bringing forward a variety of vaccine approaches (1). The full development pathway for an effective vaccine for SARS-CoV-2 will require that industry, government, and academia collaborate in unprecedented ways, each adding their individual strengths. We discuss one such collaborative program that has recently emerged: the ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) public-private partnership. Spearheaded by the U.S. National Institutes of Health (NIH), this effort brings together the strengths of all sectors at this time of global urgency. We further discuss a collaborative platform for conducting harmonized, randomized controlled vaccine efficacy trials. This mechanism aims to generate essential safety and efficacy data for several candidate vaccines in parallel, so as to accelerate the licensure and distribution of multiple vaccine platforms and vaccines to protect against COVID-19 (coronavirus disease 2019).

We currently know little about what constitutes a protective immune response against COVID-19. Data from SARS-CoV-1 patients as well as recently infected SARS-CoV-2 patients document relatively high levels of immune responses after infection, especially antibody responses to the surface (spike) protein that mediates entry into host cells. However, in vivo data on the type or level of immunity required to protect from subsequent re-infection, and the likely duration of that protection, are currently unknown. In animal models of SARS-CoV-1, immunization with recombinant subunit proteins and viral- and nucleic acid–vectored vaccines, as well as passive transfer of neutralizing antibodies to the spike protein, have been shown to be protective against experimental infection (2, 3). Endpoints vary from protection of infection to modification of viral replication and disease. These data bring optimism that a highly immunogenic vaccine will elicit the magnitude and quality of antibody responses required for protection. The role that T cell immunity plays in preventing acquisition or amelioration of early disease, either in animal challenge models or in human coronavirus disease, is unclear (4); this constitutes another reason why a diversity of vaccine approaches must be pursued.

• [ Note how the focus is the "spike", as if only the "spike" is what has created a virus that enters cells. Thus, the medical response (vaccine) also appears to focus only on "the spike" ]

A high degree of safety is a primary goal for any widely used vaccine, and there is theoretical risk that vaccination could make subsequent SARS-CoV-2 infection more severe. This has been reported for feline coronaviruses and has been observed in some vaccine-challenge animal models of SARS-CoV-1 (5). These preclinical data suggest that the syndrome of vaccine-associated enhanced respiratory disease results from a combination of poorly protective antibodies that produce immune complex deposition together with a T helper cell 2 (T H 2)–biased immune response. The potential mechanism behind vaccine-induced immune enhancement and the means to minimize this risk have recently been reviewed (6). It will be important to construct conformationally correct antigens to elicit functionally effective antibodies—a lesson learned from vaccine-induced enhanced lower respiratory illness among infants receiving a formalin-inactivated respiratory syncytial virus (RSV) vaccine. Animal models of SARS-CoV-2 infection are currently being developed, and these models can be used to better understand the immune responses associated with protection (7).

CLINICAL AND IMMUNOLOGICAL ENDPOINTS

The primary endpoint for defining the effectiveness of a COVID vaccine also requires discussion. The two most commonly mentioned are (i) protection from infection as defined by seroconversion, and (ii) prevention of clinically symptomatic disease, especially amelioration of disease severity, including the frequency of disease requiring high-intensity medical care with some assessment of a decrease in hospitalization. This requires the close evaluation of the effect of vaccination on the severity of COVID-19 disease in a wide variety of epidemiological and medical settings among both younger and elderly populations as well as underserved minorities. All of these issues need to be evaluated in the context of these initial efficacy trials. Achieving these endpoints could also be associated with reduced transmissibility on a population basis.

Primary endpoints that involve reduction of disease require greater numbers of enrollees into trials, given that asymptomatic infection is estimated to be 20 to 40% of total cases of COVID-19 (8). Initial efficacy trials may then require a large initial enrollment, with ongoing monitoring of both serologic and clinical endpoints. A major challenge leading to a degree of complexity in developing clinical trial protocols for serological endpoints is the lack of precise knowledge of incidence rates (9). A critical requirement for such a multi-trial strategy is the establishment of independent laboratories with similar or identical validated serologic assays to provide a harmonizing bridge between multiple vaccine products and multiple vaccine efficacy trials. The use of these laboratories for each clinical trial, or the sharing of critical specimens from a trial, should be required. Parameters that would distinguish the immune response resulting from vaccination versus from infection are under intense investigation, and there is an immediate need to develop assays to address this issue.

Efficacy trials need to be evaluated for both benefit and harm. The likelihood of SARSCoV- 2 re-exposure is much higher than that of SARS-CoV-1, which has disappeared from community circulation, and hence longer-term evaluation of potential enhancement with re-exposure is needed. This requirement does not preclude licensure based on the endpoints outlined above; however, it does indicate that more prolonged follow-up of the initial vaccine cohorts should be undertaken. The durability of clinical and serologic endpoints will also need to be explored, as waning of immunity is common with human coronavirus infections (10). Coronaviruses have a single-stranded RNA genome with a relatively high mutation rate. Although there has been some genetic drift during the evolution of the SARS-CoV-2 epidemic, major alterations in the spike protein are not extensive to date, especially in the regions thought to be important for neutralization; this enables cautious optimism that vaccines designed now will be effective against circulating strains 6 to 12 months in the future (11).

• [ Why the focus on "the spike protein" ? ]

The possibility of performing controlled human challenge trials, in which a small number of volunteers are vaccinated and subsequently challenged with SARS-CoV-2, has been suggested. Such experiments, if designed to define potential immune correlates or winnow out less effective vaccine approaches, may have utility. However, this approach has shortcomings with respect to pathophysiology and safety (12). Although the risk of severe disease or death in young healthy individuals from COVID-19 is quite low, it is not zero, and we do not yet have proven effective therapies for COVID-19 to rescue volunteers with complications from such a challenge. It is likely that a SARSCoV- 2 challenge strain will, by design, cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients. Moreover, partial efficacy in young healthy adults does not predict similar effectiveness among older adults with major cofactors associated with COVID-19 disease, nor would it prove reduction of transmissibility to major susceptibility groups. Whether such experiments may be worthy of pursuit or would have a beneficial impact on timelines for vaccine development needs careful evaluation by an independent panel of ethicists, clinical trialists, and experts on vaccine development.

VACCINE PLATFORMS

It is encouraging that vaccine development efforts have moved swiftly, and several major vaccine platforms are moving toward clinical evaluation. These include traditional recombinant protein, replicating and nonreplicating viral vectors, and nucleic acid DNA and mRNA approaches. Each of these vaccine platforms has advantages and limitations. Important characteristics include speed and flexibility of manufacture, safety and reactogenicity, the profile of humoral and cellular immunogenicity, durability of immunity, scale and cost of manufacturing, vaccine stability, and cold chain requirements. No single vaccine or vaccine platform alone is likely to meet the global need, and so a strategic approach to the multi-pronged endeavor is absolutely critical.

Several companies are developing nucleic acid–based vaccines, including Moderna, BioNTech/Pfizer, CureVac (mRNA-based), and Inovio (DNA-based). DNA- and mRNA-based vaccines can be generated quickly on the basis of viral sequence, which allows a rapid pathway to the clinic (13, 14). Currently, optimal immunogenicity of DNA requires an electroporation or an injector delivery device to facilitate DNA entry into cells. mRNA vaccines use lipid nanoparticles to protect and deliver the mRNA and effectively adjuvant the immunogen. The scalability of these lipid nanoparticles and their temperature stability are issues that need to be addressed. Although there is a wide body of early-phase clinical experience with nucleic acid vaccines, none are licensed for widespread usage. As such, the path forward is filled with optimism, but some uncertainty remains, requiring rapid assessment of these products’ immunogenicity and safety while addressing the lack of commercial experience with them.

Traditional recombinant protein technology can be used to express the spike protein (e.g., Sanofi, Novavax), and although the time to establish cell lines needed for manufacturing is longer than for nucleic acid vaccines, there is a robust commercial experience with protein and protein particle vaccines, including licensed vaccines for hepatitis B, human papillomavirus, varicella zoster, and influenza. Protein vaccines will require a potent adjuvant, which can be critical for inducing a predominantly T H 1-type immune response; however, the availability of certain adjuvants may be limited. Viral vector vaccines encode the viral gene of interest into one of several well-characterized vectors, including adenovirus (Ad) and vesicular stomatitis virus (VSV). The replication-defective adenovirus 26 (rAd26), recently shown to be safe and immunogenic in preventing Ebola virus infection (15), is being developed by Janssen Pharmaceuticals for COVID-19. This platform has the potential to be manufactured at large scale. Preexisting immunity to the specific viral vector can attenuate immunogenicity, and this needs to be addressed in early-stage trials. A recombinant chimpanzee Ad vector (ChAdOx1), developed by the University of Oxford and AstraZeneca, has also entered clinical trials. Similar versions of ChAd vaccine products have been tested in prior clinical trials and shown to be safe and immunogenic. The VSV vector vaccine platform is replication-competent and thus induces a robust, likely durable immune response with a single dose. A licensed VSV Ebola vaccine made by Merck is highly effective after a single dose, although its reactogenicity may be limiting in some populations. These diverse approaches provide the potential for scalable production required for widespread population use.

STRATEGIC COLLABORATIONS

Under the ACTIV public-private partnership, NIH has partnered with its sister agencies in the Department of Health and Human Services, including the Food and Drug Administration, Centers for Disease Control and Prevention, and Biomedical Advanced Research and Development Authority; other U.S. government departments including the Departments of Defense and Veterans Affairs; the European Medicines Agency; and representatives from academia, philanthropic organizations, more than 15 biopharmaceutical companies, and the Foundation for NIH. This forum allows for discussions and consensus on vaccine trial designs, rapid data sharing, and close collaborations between the public and private sectors to rapidly and efficiently conduct vaccine efficacy studies. There is an emerging consensus that vaccine trials need to either use common independent laboratories or contribute samples and data for the purpose of generating surrogate markers that ultimately speed licensure and an overall comparison of efficacy. A common Institutional Review Board as well as a common cross-trial Data and Safety Monitoring Board (DSMB) should be used so that the regulatory framework for the entire enterprise is coordinated and the regulatory agencies and the public can make objective assessment of the effect sizes between approaches. As vaccine candidates are poised to enter phase 1, the collective planning for phase 3 must be undertaken. Although much of this focus is on trials in the United States, the COVID-19 Prevention Networks established under the ACTIV program have a global focus, and coordination with the World Health Organization, [The Coalition for Epidemic Preparedness Innovations (CEPI)] , and other global philanthropic partners must also occur.

Harmonized master protocols will be needed to enable transparent evaluation of the relative effectiveness of each vaccine approach. This harmonization can best be achieved through public-private partnerships such as ACTIV, in which government-supported central laboratories and independent biostatisticians serve as key resources for efficacy trials, thereby providing a standardized way to assess the relative immune responses of different types of vaccines (see the figure). Such laboratories enhance the ability to define correlates of protection, which would speed licensure for all vaccines as well as define populations that will achieve protective immunity. Data should be shared among companies and be provided to independent statistical evaluation, allowing the early evaluation of a potential surrogate marker of protection, which would markedly speed licensure and distribution. Such data can only be obtained from harmonization and collaboration early on, during the planning of efficacy trials and the implementation of the collaboration described in the figure: the use of collaborating clinical trial sites, the monitoring of these efficacy trials through a common DSMB, independent statisticians having access to cross-trial data in real time, and centralized immune monitoring laboratories. These innovations in the process of vaccine development are required to achieve the rapid development of the platform technologies entering clinical trials. Global effort, global cooperation, and transparency are needed to maximize the speed, veracity, and decision-making required to deliver scientific advances to the global population in a timely fashion. Models for all of these programs exist, and rapid implementation of these ideas is essential if we are to succeed in the timelines required to return us to pre–COVID-19 social interactions.

SCALE UP

The ability to manufacture hundreds of millions to billions of doses of vaccine requires the vaccine-manufacturing capacity of the entire world. Although new technologies and factories can be developed to sustain production, there is an immediate need to fund the necessary bio-manufacturing infrastructure, including the fill/finish steps that provide vialed vaccine products for distribution. Cost, distribution system, cold chain requirements, and delivery of widespread coverage are all potential constriction points in the eventual delivery of vaccines to individuals and communities. All of these issues require global cooperation among organizations involved in health care delivery and economics.

To return to a semblance of previous normality, the development of SARS-CoV-2 vaccines is an absolute necessity. To achieve this goal, all the resources in the public, private, and philanthropic sectors need to participate in a strategic manner. The ACTIV public-private partnership and collaborative harmonized efficacy trials are enabling models to achieve our common goal. j