Hantavirus collaborative research and mentorship Gregory Mertz, M.D. University of New Mexico, USA SWMP- Kiev - April 2017

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1 Hantavirus collaborative research and mentorship Gregory Mertz, M.D. University of New Mexico, USA SWMP- Kiev - April 2017

2 Hantaviruses Bunyavirus family Rodent reservoirs Rodent/virus co-evolution Human infection Inhalation of excreta, bites Person-to-person transmission - Andes virus - Chile/Argentina Hemorrhagic fever with renal syndrome (HFRS) Old-world hantaviruses in Europe and Asia Hantavirus cardiopulmonary syndrome (HCPS/HPS) New-world hantaviruses in North, Central and South America Image courtesy of Viral Zone

3 Hemorrhagic fever with renal syndrome, HFRS: Endemic area Case-fatality rate Hantaan virus Asia <15% Seoul virus Asia 1-2% Dobrava virus Balkan 9-12% Puumala virus Europe <0.5% Hantavirus cardiopulmonary syndrome, HCPS: Endemic area Case-fatality rate Sin Nombre virus North America 35% Andes virus, others South America 35% Source:: Schrönich et al. 2008

4 My Background in 1993 Internal Medicine/Infectious Diseases Global health Thailand & Bangladesh Research: herpes virus transmission herpes & rabies vaccine trials antiviral drugs for herpes viruses and HIV Member, NIH Collaborative Antiviral Study Group (CASG)

5 Site of case households in Four Corners area of New Mexico, May 1993

6 Mystery illness New Mexico Spring 1993 A Navajo couple, both elite distance runners, died within days of each other with fulminant respiratory failure & shock. Emergency autopsies excluded pneumonic plague Pulmonary pathology and clinical course were not consistent with ARDS

7 After a febrile prodrome of several days, the cardiplumonary phase begins abruptly with cough, rapidly progressive non-cardiogenic pulmonary edema and respiratory failure, often with cardiogenic shock, followed by a diuretic phase with rapid diuresis in survivors.

8 HCPS/HPS The pathogen, Sin Nombre virus, was identified as previously unrecognized hantavirus US Centers for Disease Control initiated an open trial of intravenous ribavirin in 2013 results were inconclusive I was invited to develop and lead a Collaborative Antiviral Study Group placebo-controlled, multicenter trial of intravenous ribavirin in the United States and Canada

9 % Survivors Survival without ECMO Ribavirin versus Placebo Recipients Ribavirin (N=10) Placebo (N=13) Hours Days Mertz GJ, et al. Clin Infect Dis, 2004 (Nov 1);39:

10 HCPS case home near Coyhaique, Chile 1997

11 Hantavirus Research & Training in Chile and Panama HCPS recognized in Argentina in 1996 and Chile in 1997; I traveled to Chile in 1997 to establish collaborations In 1998, we wrote two grant applications: NIH International Collaborations in ID Research (ICIDR) hantavirus research grant in Chile and Panama, funded NIH Fogarty Global Health Training Grant, funded

12 Participating Institutions USA - University of New Mexico Chile - Pontificia Universidad Católica de Chile, Santiago - Clinica Alemana School of Medicine, Universidad del Desarrollo, Santiago - Universidad de la Frontera, Temuco - Ministry of Health Clinical Centers Hospital Clínico PUC Santiago Clínica Alemana de Santiago Hospital de Curicó Hospital de Chillán Hospital de Concepción Hospital de Los Angeles Hospital de Temuco Clínica Alemana de Temuco Hospital de Valdivia Hospital de Osorno Hospital de Puerto Montt Hospital de Coyhaique

13 Incubation period, Andes virus (ANDV) Infection, Chile 11 patients with hrs of exposure in rural area Days Mean: 18.3 days Range: Vial P, et al. Emerg Infect Dis 2006:12:1271-3

14 Person-to-Person Transmission Person-to-person transmission of ANDV in Argentina was confirmed by molecular epidemiology* We isolated ANDV from a Chilean boy days before he developed symptoms of HCPS** In February 2000 we noted that 30% of the first 105 cases in Chile occurred in household clusters, most suggesting person-to-person transmission. We submitted a grant supplement to prospectively study household contacts of index cases with HCPS in Chile to identify risk factors for person-to-person transmission and determine if viremia preceded onset of symptoms. * Padula P, Virology 1998; **Galeno EID 2004

15 Risk factors in 14 household contacts with hantavirus cardiopulmonary syndrome (HCPS) with definite (n =3), probable (n = 9), or possible (n = 2) acquisition by person-to-person transmission from a household contact with HCPS and 460 household contacts who remained seronegative. Ferrés M et al. J Infect Dis. 2007;195: by the Infectious Diseases Society of America

16 Detection of Andes virus (ANDV) RNA by reverse-transcription polymerase chain reaction (RT-PCR) in peripheral blood cells obtained from household contacts who were asymptomatic and seronegative at study entry. Ferrés M et al. J Infect Dis. 2007;195: by the Infectious Diseases Society of America

17 Methylprednisolone treatment Treatment with intravenous hydrocortisone in Korea appeared to benefit HFRS Mortality was lower with open methylprednisolone treatment of HCPS in Chile compared with historical controls We designed a placebo-controlled trial of intravenous methylprednisolone in Chile

18 Kaplan-Meier survival analysis by treatment arm (methylprednisolone vs placebo) and severity at entry (by sequential organ failure [SOFA] score) Vial P A, et al. Clin Infect Dis. 2013;57:

19 Neutralizing Antibody Titer in HCPS Neutralizing Antibody Titer 1000 Mild Severe * Day of illness (0 = day of hospitalization) 5 2 * P= on Day 0 At hospital admission, patients who have a mild course of HCPS have significantly higher anti-sin Nombre virus (SNV) neutralizing antibody titers when compared to patients who have or progress to severe or fatal disease. (Bharadwaj et al, JID, 2000).

20 Open treatment study with ANDV immune plasma in Chile Plasma was obtained by plasmapheresis of HCPS survivors and frozen at -80C and the neutralizing antibody titer was measured by a BSL-3 focus reduction assay A NAb unit is reciprocal of the titer multiplied by the the volume; a titer of 1:800 has 800 u/ml. Subjects with presumptive diagnosis of HCPS in the cardiopulmonary phase were treated with 5000 u/kg IV with blood type compatible plasma screened for bloodborne pathogens.

21 Survival in the open immune plasma trial versus the placebo-controlled methylprednisolone trial by severity (SOFA) at study entry SOFA <8 immune plasma N=21 SOFA <8 methylprednisolone study N=43 SOFA >8 immune plasma N=8 SOFA >8 methylprednisolone study N=17 SOFA <8 immune plasma vs methylprednisolone study p=0.11 SOFA >8 immune plasma vs methylprednisolone study p=0.15 Vial P et al. Antivir Ther 2015;20(4): PMID:

22 UNM/Chile/Panama Hantavirus Collaboration ~30 peer-reviewed research publications Fogarty Global Health Training Two Chilean PhD trainees Three post-doctoral trainees (1 MD & 2 PhDs) All have academic positions in Chile Ongoing research with Chilean funding Five research grants (4 active, 1 completed) with PIs with prior Fogarty and/or ICIDR support

23 Current Mentoring & Research Activities Ongoing science writing mentorship for: Multiple Chilean collaborators Clinical protocol development, Steven Bradfute, PhD, UNM Research protocol submitted for Phase I evaluation of cell-mediated immune responses to an investigational ANDV DNA vaccine (role: Staff Scientist)

24 UNM Steven Bradfute, Brian Hjelle, Fred Koster Chile Pablo Vial, Marcela Ferres, Francisca Valdivieso, Cecilia Vial NIH-NIAID AI and D43TW FONIS # SA