Hantavirus collaborative research

and mentorship 1993-2017

Gregory Mertz, M.D.

University of New Mexico, USA

SWMP- Kiev - April 2017

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

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 cardio-

pulmonary syndrome,

HCPS:

Endemic area Case-fatality rate

Sin Nombre virus North America 35%

Andes virus, others South America 35% Source:: Schrönich et al. 2008

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)

Site of case households in Four Corners

area of New Mexico, May 1993

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

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.

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

0

20

40

60

80

100

0 8 16 24 32 40 48 56 64 4 8 12 16 20 24 28

Ribavirin

(N=10)

Placebo

(N=13)

Survival without ECMO

Ribavirin versus Placebo Recipients%

Surv

ivors

…

Hours Days

Mertz GJ, et al. Clin Infect Dis, 2004 (Nov 1);39:1307-1313.

HCPS case home near Coyhaique,

Chile 1997

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 1999-2007

– NIH Fogarty Global Health Training Grant,

funded 1999-2011.

Participating

Institutions

USA- University of New

MexicoChile- Pontificia

Universidad Católica de Chile, Santiago

- Clinica Alemana School of Medicine, Universidad del Desarrollo, Santiago

- Universidad de la Frontera, Temuco

- Ministry of Health

Hospital Clínico PUC SantiagoClínica Alemana de Santiago

Hospital de CuricóHospital de ChillánHospital de ConcepciónHospital de Los AngelesHospital de TemucoClínica Alemana de TemucoHospital de ValdiviaHospital de OsornoHospital de Puerto MonttHospital de Coyhaique

Clinical Centers

Incubation period, Andes virus (ANDV) Infection, Chile

11 patients with 24-48 hrs of exposure in rural area

0 5 10 15 20 25 30 35 40

1

2

3

4

5

6

7

8

9

10

11

Days

Mean: 18.3 days

Range: 10-34

Vial P, et al. Emerg Infect Dis 2006:12:1271-3

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

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;195:1563-1571

© 2007 by the Infectious Diseases Society of America

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;195:1563-1571

© 2007 by the Infectious Diseases Society of America

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

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;57:943-951

1000

2000

3000

-2 -1 0* 1 2 3 4 5 6

1

9 8

9 86 1 3

1

1

1110

6

52

2

Neutralizing

Antibody

Titer

Day of illness (0 = day of hospitalization)

Severe

Mild

* P=0.00003 on

Day 0

Neutralizing Antibody Titer in HCPS

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).

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.

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=0.15Vial P et al. Antivir Ther 2015;20(4):377-86. PMID: 25316807

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

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)

UNM – Steven Bradfute, Brian Hjelle, Fred Koster

Chile – Pablo Vial, Marcela Ferres, Francisca

Valdivieso, Cecilia Vial

NIH-NIAID AI045452 and D43TW001133

FONIS # SA07120045