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Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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Page 1: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Zoonoses research at OUCRU Vietnam

Juliet Bryant�Oxford University Clinical Research Center, Vietnam�Thimpu, Bhutan �September 2013 �

Page 2: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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H5N1 Avian influenza�Streptococcus suis�

Page 3: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 4: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

An exclusive focus on zoonoses misses the whole concept of One Health

…and misses the point of why research on animal health is fundamentally important

ONE HEALTH framework

Page 5: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Maudlin, et al 2009 Phil Trans R Soc�

Disease burden of zoonoses

Beyond zoonoses: new ways to conceptualize the interdependence of human and animal health

Although the majority of pathogens may be zoonotic (>60%), the burden of disease from most zoonoses is negligible when compared to human-adapted infectious diseases. �

Why are zoonoses interesting to study?

1)  the emergence potential; 2)  the complexity of control options; 3) associations with poverty and

development.

Page 6: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

The Animal – Human interface

Wellcome Trust Strategic Award 2012-2016

Page 7: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Pathogen discovery

Rule out known pathogens

novel pathogens

Dx Unknown Origin

Next generation seq

Hospital-based syndromic surveillance (3 yrs, N = 12,000 )

Cross-species transmission Community-based cohorts

Vietnam Initiative on Zoonotic Infections (VIZIONS)

sera & swabs

Periodic sampling

Specimen banking

Responsive sampling to clinical episodes

Page 8: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Catchment area

Page 9: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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Page 10: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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Page 11: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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Page 12: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 13: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Baseline sampling at enrollment�

Page 14: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 15: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 16: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 17: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 18: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 19: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 20: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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Page 21: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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Page 22: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 23: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 24: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 25: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 26: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013
Page 27: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Which pathogens will we look for ?

Page 28: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

What we said we would do: �Retrospective serosurveys on 5 most common zoonotic viruses, using baseline and closeout human sera�

Target pathogens�

Specimen banking �� priorities pending results from hospital surveillance�

[Influenza]�Rotavirus�Hepatitis E�Coronavirus�Hantavirus �

What are we currently pursuing: �

Page 29: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Viral zoonoses Rotavirus�•  96% seroconversion by 2 yrs�•  Primary infection usually symptomatic�•  0.5-1% of all human infections may be zoonotic�

Hepatitis E�•  1/3 of the world population is seropositive�•  Primary infection usually asymptomatic�•  Fraction attributable to zoonotic origin UNKNOWN; all one serotype �

Coronavirus�•  4 known human-adapted CoV species account for 10% of hospitalized acute respiratory infections�•  Other than SARS and EMC, no known zoonotic CoV�•  No known human enteric CoVs; no known primate CoV�

Hantavirus �•  1-3% seroprevalence in Vietnam; much higher elsewhere in northern Europe �•  STRICTLY zoonotic; ~10 human cases confirmed in Vietnam in the last decade �

Page 30: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Is the reservoir of rotavirus diversity within domestic animals of epidemiological relevance ?�

Does the advent of pediatric RoV vaccination make the zoonotic reservoir more or less important ?�

Page 31: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Rotavirus prevalence on pig farms, Dong Thap

Ct < 36 167For 454 seq 92

Page 32: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Rotavirus

Hum

an�

Pig�

HCM

C�D

T�

Tra My, et al 2011�

Page 33: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Hepatitis E

Is there a measurable burden of clinical disease associated with HEV in Vietnam ?�

Meng,XJ et al 2010�

…and what fraction of cases might be zoonotic in origin?�

Drexler, JF et al 2012�

Page 34: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Hepatitis E virus prevalence in swine, Dong Thap

5 samples with Ct<27�sent to Sanger for WGS�

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Page 35: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Hepatitis E � Zoonotic transmission through direct contact with swine�

Increased HEV sero prevalence among occupational exposures (vets, butchers, slaughterhouse)�USA � �26% (Meng et al 2002)�Sweden � �13% (Olsen et al 2006)�Moldavia �51% (Drobeniuc et al 2001)�Netherlands �11% (Bouwknegt et al 2007)�

Preliminary results from cohort serology�

Page 36: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Hantavirus Are there food safety risks associated with the rodent trade? �

What is the prevelance and distribution of Hantaviruses circulating in Vietnam?�

Page 37: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Setting up in-house molecular & seroassays� Available ref positive controls [Seoul, Hantaan]� 3 generic pan-hanta assays � Klempa et al, 2004 [L segment]� IFA spotslides [just received pos cntrl sera]�

Market rats (n=150)� Homogenized lungs� pooled (5 rats/pool) � extracted� 11 of 30 pools positive� Individuals re-extracted � � � L and S segment � Seoul virus� R. argentiventer not a known host for any Hantas�

Field-trapped rats (n=136)� IFA results for multiple viruses�

Initial screening�

Hantavirus

Page 38: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

IFA microscopy [collab w/Finland Forest Research Inst, Metla]�

Hantavirus

Page 39: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Coronavirus

Porcine Epidemic Diarrheal virus: potential for zoonotic transmission ? �•  Suspect pig outbreaks within our VIZIONS study province�•  Anecdotal evidence of human diarrheal infections�

1)  Mol screening pediatric diarrhea cases for PEDv�2)  Generate an isolate � set up IFA�3)  Neutralizing antibodies?�

Page 40: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Campylobacter Campylobacter sp.� C. jejuni� C. coli�

> 92% resistant to cephalosporins, erythromycin and nalidixic acid�

Page 41: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Antimicrobial resistance

Page 42: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Antibiotic resistance research: a need for surveillance

Heiman Wertheim Oxford University Clinical Research Unit – Hanoi VINARES WORKSHOP

Page 43: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

A delicate balance

Antibiotic effectiveness is a valuable natural resource, like clean water or forests. �

All antibiotic use, appropriate or not, ‘uses up’ some of the effectiveness. �

But antibiotics are also lifesavers and we need access to them.�

Page 44: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Variable resistance rates of Klebsiella pneumoniae�First report on antibiotic use and resistance in Vietnam 2009, MoH�

Preliminary Resistance Data High resistance rates amongst Gram-negatives�First report on antibiotic use and resistance in Vietnam 2009, MoH�

Page 45: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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GARP National surveillance system at the Ministry of Health Observational study in 15 rural and 15 urban pharmacies of antibiotic sales in

comparision to all drug sales Assessing treatment costs of resistant blood stream and CNS infections (national

WHOnet data)

Klebsiella Characterisation of blood culture isolates / WGS Sanger Cross-sectional population study

Acinetobacter phage therapy C-reactive protein RDT intervention study VINARES

Page 46: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

The three arms of VINARES

ICU: characterise Hospital-Acquired Infections on ICUs

•  Prevalence, aetiology, resistance •  Red flags

Pharmacy: assess antibiotic consumption Appropriateness of prescribing on ICUs

Microbiology: enhance laboratory capacity

•  Quality •  Appropriateness

Page 47: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

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Hospital Number of beds in

2008 Bed occupancy rate

2008,%

Bach Mai Hospital 1500 176.6

National Hospital of Pediatrics 650 180.0

National Hospital of Tropical Diseases 170 101.0

National TB hospital 448 92.5

Saint-Paul Hospital 539 156.2

Thanh Nhan Hospital 673 96.0

Vietnam-Germany Hospital 763 106.0

Vietnam-Sweden Uong Bi Hospital 583 100.8

General Binh Dinh hospital 818 152.0

General Da Nang hospital 852 186.0

Hue Central General 2006 106.6

Cho Ray Hospital 1531 157.0

General Dong Thap hospital 824 99.2

Ho Chi Minh Children Hospital 1 969 139.0

Hospital of Tropical Disease (HTD) 500 107.5

Page 48: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Antibiotic consumption for systemic use (J01) by ATC class in 15 hospitals in 2008�

Page 49: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Treatment guidelines • Most treatment guidelines outdated • Recommendations for AB do not match local current

resistance data A need for good local resistance data!

• Take into account local epidemiology S. suis common cause meningitis K. pneumoniae common in severe pneumonia

Page 50: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Lab issues for resistance testing in Vietnam

Quality control often not place No standard procedures No confirmation of unlikely resistances Errors in CLSI guideline translations Lack of knowledge/training Lack of funding

Page 51: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Transfer of AMR?�Transfer of Salmonella?�

VIBRE: bacterial zoonoses and AMR

Diarrhoea patients (N=500) �

Chickens�• Backyard farms (N=102)�• Medium farms (N=102)�Development of AMR E. coli ? �Presence of Salmonella?�

Chicken farmers�• Backyard farms (N=102)�• Medium farms (N=102)�

• Knowledge and use of antimicrobials:�-Treatment poultry diseases�-Feed additives�

• Bio-security�

• Use of antimicrobials�• Contact with chickens�• Food habits�

Transfer of AMR?�Transfer of Salmonella?�

• Use of antimicrobials�• Food habits�

Non-farmers (N=204)�

• Not involved in poultry farming�• Matched by commune, age/sex to farmer�

• Use of antimicrobials�• Food habits�

Chicken farm�

PROVINCIAL HOSPITAL�

RURAL (3 districts)� URBAN (My Tho)�

Urban inhabitants (N=102)�• Not involved in poultry farming�• Living in urban centre of My Tho�

Page 52: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

VIZIONS: �Established a framework for studying viral zoonoses, risk, and ‘the human-animal interface’�

ANTIMICROBIAL RESISTANCE:�Significant expertise on the clinical side�

CHALLENGE: linking the analysis of hospital-based and community-based data �

Perspectives

Page 53: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013

Many thanks to many many people

Le Nguyen Truc Nhu Nguyet Lam Anh Pham Hong Anh Do Tien Duy Nguyen Van Cuong Ngo Thi Tue Nguyen Thi Diep Ngo Thi Hoa Jim Campbell Juan Carrique-Mas

Page 54: Zoonoses research at OUCRU Vietnam - OIE: Home · Zoonoses research at OUCRU Vietnam Juliet Bryant Oxford University Clinical Research Center, Vietnam Thimpu, Bhutan September 2013