Lawrence Corey

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

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Publications (511)5595.89 Total impact

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    ABSTRACT: Phase IIb or III HIV-1 vaccine efficacy trials are generally large and operationally challenging. To mitigate this challenge, the HIV Vaccine Trials Network is designing a Phase IIb efficacy trial accommodating the evaluation of multiple vaccine regimens concurrently. As this efficacy trial would evaluate a limited number of vaccine regimens, there is a need to develop a framework for optimizing the strategic selection of regimens from the large number of vaccine candidates tested in Phase I/IIa trials. In this paper we describe the approaches for the selection process, including the choice of immune response endpoints and the statistical criteria and algorithms. We illustrate the selection approaches using data from HIV-1 vaccine trials.
    No preview · Article · Apr 2016 · Current Opinion in Virology
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    ABSTRACT: As HIV-1 envelope immune responses are critical to vaccine related protection, most candidate HIV vaccines entering efficacy trials are based upon a clade specific design. This need for clade specific vaccine prototypes markedly reduces the implementation of potentially effective HIV vaccines. We utilized a mathematical model to determine the effectiveness of immediate roll-out of a non-clade matched vaccine with reduced efficacy compared to constructing clade specific vaccines, which would take considerable time to manufacture and test in safety and efficacy trials. We simulated the HIV epidemic in San Francisco (SF) and South Africa (SA) and projected effectiveness of three vaccination strategies: i) immediate intervention with a 20–40% vaccine efficacy (VE) non-matched vaccine, ii) delayed intervention by developing a 50% VE clade-specific vaccine, and iii) immediate intervention with a non-matched vaccine replaced by a clade-specific vaccine when developed. Immediate vaccination with a non-clade matched vaccine, even with reduced efficacy, would prevent thousands of new infections in SF and millions in SA over 30years. Vaccination with 50% VE delayed for five years needs six and 12years in SA to break-even with immediate 20 and 30% VE vaccination, respectively, while not able to surpass the impact of immediate 40% VE vaccination over 30years. Replacing a 30% VE with a 50% VE vaccine after 5years reduces the HIV acquisition by 5% compared to delayed vaccination. The immediate use of an HIV vaccine with reduced VE in high risk communities appears desirable over a short time line but higher VE should be the pursued to achieve strong long-term impact. Our analysis illustrates the importance of developing surrogate markers (correlates of protection) to allow bridging types of immunogenicity studies to support more rapid assessment of clade specific vaccines.
    Full-text · Article · Nov 2015 · EBioMedicine
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    ABSTRACT: The Phase 2b double-blinded, randomized Phambili/HVTN 503 trial evaluated safety and efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine vs placebo in sexually active HIV-1 seronegative participants in South Africa. Enrollment and vaccinations stopped and participants were unblinded but continued follow-up when the Step study evaluating the same vaccine in the Americas, Caribbean, and Australia was unblinded for non-efficacy. Final Phambili analyses found more HIV-1 infections amongst vaccine than placebo recipients, impelling the HVTN 503-S recall study. HVTN 503-S sought to enroll all 695 HIV-1 uninfected Phambili participants, provide HIV testing, risk reduction counseling, physical examination, risk behavior assessment and treatment assignment recall. After adding HVTN 503-S data, HIV-1 infection hazard ratios (HR vaccine vs. placebo) were estimated by Cox models. Of the 695 eligible, 465 (67%) enrolled with 230 from the vaccine group and 235 from the placebo group. 38% of the 184 Phambili dropouts were enrolled. Enrollment did not differ by treatment group, gender, or baseline HSV-2. With the additional 1286 person years of 503-S follow-up, the estimated HR over Phambili and HVTN 503-S follow-up was 1.52 (95% CI 1.08-2.15, p = 0.02, 82 vaccine/54 placebo infections). The HR was significant for men (HR = 2.75, 95% CI 1.49, 5.06, p = 0.001) but not for women (HR = 1.12, 95% CI 0.73, 1.72, p = 0.62). The additional follow-up from HVTN 503-S supported the Phambili finding of increased HIV-1 acquisition among vaccinated men and strengthened the evidence of lack of vaccine effect among women. clinicaltrials.gov NCT00413725 SA National Health Research Database DOH-27-0207-1539.
    Full-text · Article · Sep 2015 · PLoS ONE
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    ABSTRACT: Three phase 2b, double-blind, placebo-controlled, randomized efficacy trials have tested recombinant Adenovirus serotype-5 (rAd5)-vector preventive HIV-1 vaccines: MRKAd5 HIV-1 gag/pol/nef in Step and Phambili, and DNA/rAd5 HIV-1 env/gag/pol in HVTN505. Due to efficacy futility observed at the first interim analysis in Step and HVTN505, participants of all three studies were unblinded to their vaccination assignments during the study but continued follow–up. Rigorous meta-analysis can provide crucial information to advise the future utility of rAd5-vector vaccines.
    Full-text · Article · Sep 2015 · PLoS ONE
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    ABSTRACT: Given the variation in the HIV-1 viral load (VL) set point across subjects, as opposed to a fairly stable VL over time within an infected individual, it is important to identify the characteristics of the host and virus that affect VL set point. Although recently infected individuals with multiple phylogenetically linked HIV-1 founder variants represent a minority of HIV-1 infections, we found-in two different cohorts-that more diverse HIV-1 populations in early infection were associated with significantly higher VL 1 year after HIV-1 diagnosis.
    No preview · Article · Aug 2015 · Nature medicine
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    ABSTRACT: An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1–reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1–reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.
    Full-text · Article · Aug 2015 · Science
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    ABSTRACT: Background: The management of respiratory virus infections prior to hematopoietic cell transplant (HCT) is difficult. We examined whether respiratory virus detection before HCT influenced the requirement for bronchoscopy, hospitalization, and overall survival following HCT. Methods: Pre-HCT and weekly post-HCT nasal washes were collected through day 100 from patients with and without symptoms. Samples were tested by multiplex polymerase chain reaction for respiratory syncytial virus, parainfluenza viruses 1-4, influenza A and B, human metapneumovirus, adenovirus, and human rhinoviruses, coronaviruses, and bocavirus. Results: Of 458 patients, 116 (25%) had respiratory viruses detected pre-HCT. Overall, patients with viruses detected pre-HCT had fewer days alive and out of the hospital and lower survival at day 100 (adjusted hazard ratio [aHR], 2.4; 95% confidence interval [CI], 1.3-4.5; P = .007) than patients with negative samples; this risk was also present with rhinovirus alone (aHR for mortality, 2.6; 95% CI, 1.2-5.5; P = .01). No difference in bronchoscopy incidence was seen in patients with and without respiratory viruses (aHR, 1.3; 95% CI, .8-2.0; P = .32). In symptomatic patients, those with respiratory viruses detected had increased overall mortality compared with patients without viruses detected (unadjusted HR, 3.5; 95% CI, 1.0-12.1; P = .05); among asymptomatic patients, detection of respiratory viruses was not associated with increased mortality. Conclusions: These data support routine testing for respiratory viruses among symptomatic patients before HCT, and delay of transplant with virus detection when feasible, even for detection of rhinovirus alone. Further study is needed to address whether asymptomatic patients should undergo screening for respiratory virus detection before HCT.
    No preview · Article · Apr 2015 · Clinical Infectious Diseases
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    ABSTRACT: Background: Despite major advances in the prevention of cytomegalovirus (CMV) disease, the treatment of CMV pneumonia in recipients of hematopoietic cell transplant remains a significant challenge. Methods: We examined recipient, donor, transplant, viral, and treatment factors associated with overall and attributable mortality using Cox regression models. Results: Four hundred twenty-one cases were identified between 1986 and 2011. Overall survival at 6 months was 30% (95% confidence interval [CI], 25%-34%). Outcome improved after the year 2000 (all-cause mortality: adjusted hazard ratio [aHR], 0.7 [95% CI, .5-1.0]; P = .06; attributable mortality: aHR, 0.6 [95% CI, .4-.9]; P = .01). Factors independently associated with an increased risk of all-cause and attributable mortality included female sex, elevated bilirubin, lymphopenia, and mechanical ventilation; grade 3/4 acute graft-vs-host disease was associated with all-cause mortality only. An analysis of patients who received transplants in the current preemptive therapy era (n = 233) showed only lymphopenia and mechanical ventilation as significant risk factors for overall and attributable mortality. Antiviral treatment with ganciclovir or foscarnet was associated with improved outcome compared with no antiviral treatment. However, the addition of intravenous pooled or CMV-specific immunoglobulin to antiviral treatment did not seem to improve overall or attributable mortality. Conclusions: Outcome of CMV pneumonia showed a modest improvement over the past 25 years. However, advances seem to be due to antiviral treatment and changes in transplant practices rather than immunoglobulin-based treatments. Novel treatment strategies for CMV pneumonia are needed.
    No preview · Article · Mar 2015 · Clinical Infectious Diseases
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    ABSTRACT: To evaluate the utility of quantitative herpes simplex virus (HSV) polymerase chain reaction (PCR) levels for prognosis and management of neonatal HSV disease. Clinical and virologic data were abstracted by medical record review from neonatal HSV cases treated at Seattle Children's Hospital between 1993 and 2012. HSV PCR results from plasma (n = 47), cerebrospinal fluid (n = 56), or both (n = 40) at the time of diagnosis were available from 63 infants; 26 with skin-eye-mouth (SEM), 18 with central nervous system (CNS), and 19 with disseminated (DIS) disease. Plasma HSV PCR was positive in 78% of the infants with SEM, 64% with CNS and 100% with DIS disease. Mean plasma viral level was 2.8 log10 copies/mL in SEM, 2.2 log10 copies/mL in CNS, and 7.2 log10 copies/mL in DIS infants. The HSV levels were higher among infants who died compared with surviving infants, 8.1 log10 copies/mL (range 7.7-8.6) vs 3.8 log10 copies/mL (range 0.0-8.6), P = .001, however, level of HSV DNA in the cerebrospinal fluid or in plasma did not correlate with neurologic outcome. Dynamics of HSV clearance from plasma during high-dose acyclovir treatment showed single-phase exponential decay with a median viral half-life of 1.26 days (range: 0.8-1.51). Plasma HSV levels correlate with clinical presentation of neonatal HSV disease and mortality, but not neurologic outcome. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Dec 2014 · Journal of Pediatrics
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    ABSTRACT: Phase 1 preventive HIV vaccine trials are often designed as randomized, double-blind studies with the inclusion of placebo recipients. Careful consideration is needed to determine when the inclusion of placebo recipients is highly advantageous and when it is optional for achieving the study objectives of assessing vaccine safety, tolerability and immunogenicity. The inclusion of placebo recipients is generally important to form a reference group that ensures fair evaluation and interpretation of subjective study endpoints, or endpoints whose levels may change due to exposures besides vaccination. In some settings, however, placebo recipients are less important because other data sources and tools are available to achieve the study objectives. Copyright © 2014 Elsevier Ltd. All rights reserved.
    No preview · Article · Oct 2014 · Vaccine
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    Full-text · Article · Oct 2014 · AIDS Research and Human Retroviruses

  • No preview · Article · Oct 2014
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    ABSTRACT: Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 mu g), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 mu g). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P <= 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452) + LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452) + LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited.
    Full-text · Article · Sep 2014 · Clinical and vaccine Immunology: CVI
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    Glenda E Gray · Lawrence Corey

    Preview · Article · Aug 2014 · The Journal of Infectious Diseases
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    ABSTRACT: Relatively little is known about the human T-cell response to herpes simplex virus type 2 (HSV-2) in the female genital tract, a major site of heterosexual HSV-2 acquisition, transmission, and reactivation. In order to understand the role of local mucosal immunity in HSV-2 infection, T-cell lines were expanded from serial cervical cytobrush samples from 30 HSV-2-infected women and examined for reactivity to HSV-2. Approximately 3% of the CD3+ T cells isolated from the cervix were HSV-2 specific and of these, a median of 91.3% were CD4+, whereas a median of 3.9% were CD8+. HSV-2-specific CD4+ T cells expanded from the cervix were not only more frequent than CD8+ T cells but also exhibited greater breadth in terms of antigenic reactivity. T cells directed at the same HSV-2 protein were often detected in serial cervical cytobrush samples and in blood. Thus, broad and persistent mucosal T-cell responses to HSV-2 were detected in the female genital tract of HSV-2+ women suggesting that these cells are resident at the site of HSV-2 infection. Understanding the role of these T cells at this biologically relevant site will be central to the elucidation of adaptive immune mechanisms involved in controlling HSV-2 disease.Mucosal Immunology advance online publication, 11 June 2014; doi:10.1038/mi.2014.47.
    Full-text · Article · Jun 2014 · Mucosal Immunology
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    ABSTRACT: Background The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data. Methods HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18–35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539. Findings Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31–42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13–2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2–9·5] for vaccine recipients vs 8·8% [7·1–10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients. Interpretation The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines. Funding National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.
    Full-text · Article · May 2014 · The Lancet Infectious Diseases
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    ABSTRACT: Human herpesvirus 8 (HHV8) infection leads to potent activation of nuclear factor kappa B (NFκB) in primary and transformed cells. We used recombinant HHV8 (rKSHV.219) expressing green fluorescent protein under the constitutive cellular promoter elongation factor 2α and red fluorescent protein under an early HHV8 lytic gene promoter T1.1 to monitor replication during infection of human foreskin fibroblasts (HF), noting changes in NFκB activity. In primary HF, NFκB levels do not affect the ability of HHV8 to establish infection or maintain latency. Furthermore, there was no effect on the percent of cells undergoing reactivation from latency, and there were similar numbers of released and cell-associated HHV8 viral particles following reactivation in the presence of inhibitors. Reactivation of HHV8 in latently infected HF in the presence of NFκB inhibitors resulted in production of viral particles that did not efficiently establish infection, due to deficiencies in binding and/or entry into normally permissive cells. Exogenous expression of glycoprotein M, an envelope protein involved in viral binding and entry, was able to partially overcome the deficiency induced by NFκB inhibitors. Our data indicate that in primary cells, NFκB is not required for infection, establishment of latency, or entry into the lytic cycle, but is required for the expression of virion associated genes involved in the initial steps of virion infectivity. These studies suggest that strategies to inhibit NFκB may prevent HHV8 spread and should be considered as a potential therapeutic target for preventing HHV8 associated diseases.
    Full-text · Article · Apr 2014 · Frontiers in Microbiology
  • Lawrence Corey · M Juliana McElrath
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    ABSTRACT: The expression of antibodies to protect against an infectious disease can be achieved by the injection into the host of vectors carrying the gene to the relevant antibodies. Here the authors demonstrate the applicability of this technique to protection from HIV in a humanized mouse model, showing this to be a valid route to pursue in vaccine development for humans (pages 296-300).
    No preview · Article · Mar 2014 · Nature medicine
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    David M Knipe · Lawrence Corey · Jeffrey I Cohen · Carolyn D Deal

    Full-text · Article · Jan 2014 · Vaccine
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    ABSTRACT: Pritelivir, an inhibitor of the viral helicase-primase complex, exhibits antiviral activity in vitro and in animal models of herpes simplex virus (HSV) infection. We tested the efficacy and safety of pritelivir in otherwise healthy persons with genital HSV-2 infection. We randomly assigned 156 HSV-2-positive persons with a history of genital herpes to receive one of four doses of oral pritelivir (5, 25, or 75 mg daily, or 400 mg weekly) or placebo for 28 days. Participants obtained daily swabs from the genital area for HSV-2 testing, which was performed with a polymerase-chain-reaction assay. Participants also maintained a diary of genital signs and symptoms. The primary end point was the rate of genital HSV shedding. HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly. The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose. The percentage of days with genital lesions was also significantly reduced, from 9.0% in the placebo group to 1.2% in both the group receiving 75 mg of pritelivir daily (relative risk, 0.13; 95% CI, 0.02 to 0.70) and the group receiving 400 mg weekly (relative risk, 0.13; 95% CI, 0.03 to 0.52). The rate of adverse events was similar in all groups. Pritelivir reduced the rates of genital HSV shedding and days with lesions in a dose-dependent manner in otherwise healthy men and women with genital herpes. (Funded by AiCuris; ClinicalTrials.gov number, NCT01047540.).
    Preview · Article · Jan 2014 · New England Journal of Medicine

Publication Stats

36k Citations
5,595.89 Total Impact Points

Institutions

  • 1987-2015
    • Fred Hutchinson Cancer Research Center
      • • Division of Vaccine and Infectious Disease
      • • Division of Clinical Research
      Seattle, Washington, United States
  • 1978-2015
    • University of Washington Seattle
      • • Department of Laboratory Medicine
      • • Department of Medicine
      • • Division of Allergy and Infectious Diseases
      • • Department of Microbiology
      • • Department of Obstetrics and Gynecology
      • • Department of Biostatistics
      • • Department of Pediatrics
      Seattle, Washington, United States
  • 2008
    • Seattle University
      Seattle, Washington, United States
  • 2005
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 1988-2002
    • Seattle Children's Hospital
      Seattle, Washington, United States
  • 2001
    • University of Kansas Medical Center
      Kansas City, Kansas, United States
  • 2000
    • University of New South Wales
      • Faculty of Medicine
      Kensington, New South Wales, Australia
  • 1999
    • Texas A&M University - Galveston
      Galveston, Texas, United States
    • University of Ferrara
      Ferrare, Emilia-Romagna, Italy
  • 1997
    • University of California, San Francisco
      San Francisco, California, United States
    • Memorial Hospital, TN
      Chattanooga, Tennessee, United States
    • Duke University Medical Center
      • Department of Obstetrics and Gynecology
      Durham, North Carolina, United States
  • 1992
    • Vanderbilt University
      • Division of Infectious Diseases
      Нашвилл, Michigan, United States
  • 1984
    • University of Alberta
      Edmonton, Alberta, Canada
    • Stanford Medicine
      • Department of Pediatrics
      Stanford, California, United States