COUNTERING EMERGING INFECTIOUS DISEASE THREATS

Transcription

1 COUNTERING EMERGING INFECTIOUS DISEASE THREATS AN ARMY ACCELERATED RESPONSE TO ZIKA KAYVON MODJARRAD, MD, PHD DIRECTOR, EMERGING INFECTIOUS DISEASE THREATS The views expressed in this presentation are those of the author(s) and may not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

2 Building on Decades of Experience to Pivot toward Public Health Emergencies MRMC (WRAIR & USAMRIID) has been able to leverage longstanding capabilities to respond quickly to emerging infectious disease outbreaks: Ø Subject Matter Expertise Ø Basic/Translational Science Ø Manufacturing Ø Broad Network of International Sites Ø Clinical Trial Infrastructure Ø Partnerships Government, Academia, Industry 2

3 MERS- CoV Zika AS Fauci/NIAID/NIH 3

4 # of Virus Species 200 # of Virus Families Year Woolhouse ME

5 Zika Yellow Fever 35 years 70 years Ebola 40 years Polio 45 years Measles 47 years Adapted BS Graham/VRC/NIH 5

6 Introduction of Zika to the West 6

7 Clinical Manifestations Only 20% of infections are symptomatic Also characterized by: Non-purulent conjunctivitis Diffuse myalgia Polyarticular arthralgia Neurologic manifestations Guillan-Barre Syndrome (~1/4000) Encephalitis, Cerebritis Congenital Zika Syndrome 7

8 Zika Threatens Readiness >160 confirmed current Zika virus cases in MHS beneficiary 3 cases in pregnant Service Members 1 in pregnant dependent Ø Ø Devastating Impacts: Sexual transmission impact on military families with potential birth defects Rare occurrence of Guillain-Barre Syndrome 8

9 Zika Vaccine (ZPIV) Rapid Countermeasure Development Early Zika Detection Biosurveillance in South East Asia aided vaccine design Proven Vaccine Platform Successfully developed licensed vaccine for Japanese Encephalitis, another flavivirus In-house Capabilities Developed and produced > 1,500 doses for clinical testing 9

10 Phase I Clinical Trials of ZPIV First vaccination at WRAIR: 09 November 2016 WRAIR Silver Spring, MD Previous flavivirus immunity Saint Louis University (SLU) Center for Vaccine Development Dose optimization Harvard BIDMC Boston, MA Accelerated schedule SLU Center for Vaccine Development Puerto Rico Natural flavivirus immunity NIH Vaccine Research Center Bethesda, MD DNA vaccine prime, ZPIV boost In 9 months, WRAIR went from vaccine concept to clinical testing 10

11 rg 7) s 8): na Infection Rates after Inoculation wit number of plaques. Preexposure serum samples collected from rhesus macaques at 28 DPI and from cynomolgus macaques at 20 DPI showed no neutralization activity for Zika virus, indicating that these animals were not previously exposed to the virus. Postexposure serum samples were screened on 7, 15, 21 and 28 DPI. Animal Model Development Results Intravaginally Inoculated Macaque Viremias and Antibody Responses RESEARCH ARTICLE Impact of prior flavivirus immunity on Zika virus infection in rhesus macaques Michael K. McCracken, Gregory D. Gromowski, Heather L. Friberg, Xiaoxu Lin, Peter Abbink2, Rafael De La Barrera3, Kenneth H. Eckles3, Lindsey S. Garver4, Michael Boyd2, David Jetton2, Dan H. Barouch2, Matthew C. Wise5, Bridget S. Lewis5, Jeffrey R. Currier1, Kayvon Modjarrad6,7, Mark Milazzo6,7, Michelle Liu6,7, Anna B. Mullins5, J. Robert Putnak1, Nelson L. Michael7, Richard G. Jarman1 *, Stephen J. Thomas8 After intravaginal inoculation of Zika virus, 50% (2/4) of rhesus macaques and 50% (2/4) cynomolgus macaques had detectable viremias; mean peak titers were 3.8 log10 PFU/ ml (7.2 log10 copies/ml) for rhesus macaques and 3.5 log10 PFU/mL (6.8 log10 copies/ml) for cynomolgus macaques (Figure 1). We detected viremia at 4 6 DPI (mean duration 3.0 d) for rhesus macaques and 3 7 DPI (mean duration 4.0 d) for cynomolgus macaques and virus RNA in serum at 3 7 DPI for rhesus macaques and 3 9 DPI for cynomolgus macaques. By 15 DPI, only those rhesus and cynomolgus macaques that showed viremia or virus RNA in serum seroconverted (R1, R4, C3, and C4), as shown by PRNT80 titers ranging from 1:640 to 1:1,280 (Table 1). We observed no virus neutralization for macaques R2, R3, C1, and C2 (Table 1). Menstruation was observed in all female macaques during the course of the study, but menstruation was not observed in any of the female macaques at the time of virus inoculation. Intrarectally Inoculated Macaque Viremias and Antibody Responses After intrarectal inoculation of Zika virus, 75 rhesus macaques and 100% (4/4) of cynomolgu had detectable viremias; mean peak titers we PFU/mL (8.0 log10 copies/ml) for rhesus ma 4.8 log10 PFU/mL (8.6 log10 copies/ml) for c macaques (Figure 2). Although we did not det in 1 rhesus macaque (R6), we detected virus rum samples from this macaque at 6 DPI (5.2 ies/ml) and 7 DPI (6.1 log10 copies/ml). Two c macaques (C5, C8) had viremia levels 5.0 log for 2 days. We detected viremia at 3 7 DPI (me 3.0 d) for rhesus macaques and at 2 6 DPI ( tion 2.8 d) for cynomolgus macaques and vir serum at 2 7 DPI for rhesus macaques and 1 cynomolgus macaques. By 15 DPI, all rhesus molgus macaques had seroconverted (R5, R6, C6, C7, C8), as shown by PRNT80 titers ranging to 1:1,280 (Table 2). Clinical Signs and Laboratory Results We observed no overt clinical signs, includi joint swelling, weight loss, or decreased appe of the infected macaques. The telemetry unit C6 failed during the study. Therefore, we also temperatures to determine the absence of pyre Technical Appendix Figure 1, EID/article/23/8/ Techapp1.pdf). No 1 Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of Figure 1. Viremia an Fig 2. ZIKV titers in peripheral blood. ZIKV viral load was determined using RT-qPCR (A, RNAemia) and Vero cell plaque America, 2 Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard detected in serum o assay (B, Viremia). Dotted lines indicate the limit of detection (RNAemia = 2500, Viremia = 25). Serum specimens were used cynomolgus macaqu Medical School, Boston, Massachusetts, United States of America, 3 Pilot Bioproduction Facility, Walter for days 1, 3, 5, 6, 8, and 10. Plasma specimens were used for days 2, 4, 7, and 9. Naïve group days 6 and 7 values represent intravaginal inoculat Reed Army Institute of Research, Silver Spring, Maryland, United States of America, 4 Entomology Branch, two and one positive specimen, respectively. Means with SEM are displayed. Zika virus. A) Rhesu Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America, 5 Veterinary (animals R2 and R3 Services Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of negative results); B) America, 6 Henry M. Jackson Foundation, Bethesda, Maryland, United States of America, 7 Military HIV macaques (animals showed negative res Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of lines indicate virus t America, 8 Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of Pathogens America August 3, 2017 PLOS 6 / 22 RESEARCH RGJ and SJT are co-senior authors. * richard.g.jarman.mil@mail.mil High Infection Rates for Adult Macaques after Intravaginal Abstract or Intrarectal Inoculation with Zika Virus Studies have demonstrated cross-reactivity of anti-dengue virus (DENV) antibodies in Andrew Zika D. Haddow, Aysegul Nalca, Franco D. Rossi, Lynn Miller, Michael R. Wiley, human sera against virus (ZIKV), promoting increased ZIKVJ.infection in vitro. However, Unai Perez-Sautu, Samuel C. Washington, Sarah L. Norris, Suzanne E. Wollen-Roberts, the correlationjoshua between in vitro and in vivo is nota.well characterized. we evalud. Shamblin, Adrienne E. findings Kimmel, Holly Bloomfield, StephanieThus, M. Valdez, Thomas R. Sprague, Lucia M. Principe, Stephanie A. Bellanca, Stephanie S. Cinkovich, ated the impact of Luis heterotypic flavivirus immunity on ZIKV titers in biofluids of rhesus Lugo-Roman, Lisa H. Cazares, William D. Pratt, Gustavo F. Palacios, Sina Bavari, M. Louise Nasar macaques. Animals previously infected ( 420 days)pitt, withfarooq DENV2, DENV4, or yellow fever virus were compared to flavivirus-naïve animals following infection with a Brazilian ZIKV strain.unprotected Sera from DENV-immune macaques demonstrated cross-reactivity with ZIKV sexual intercourse between persons residing Although the primary mechanism of by Zika virus in or traveling from regions with Zika virus transmission is transmission is through the bite of an infective mosquito PFU/mL. Dotted line genome copies in lo ml. The lower limit o was 1.0 log10 PFU/m titers and 3.0 log10 c genome copies. C, c DPI, days postinocu R, rhesus. 11 Emerging Infectious Diseases Vol. 23, No. 8, August 2017

12 Soldier Health. World Health 12