WHO guideline development for CCHF clinical management and ... · WHO guideline development for...

WHO guideline development for CCHF clinical management and the WHO R&D roadmap for

CCHF and other actual aspects

Natalia Pshenichnaya, MD, DSC., Prof.Head of Infectious Diseases Department at the Postgraduate Faculty of Physicians, Rostov State Medical University, Rostov-on-Don, Russia;

Taskforce member of CCHF WHO R&D Blueprint roadmap; Member of WHO CCHF clinical management guideline development group

ESCMID workshop, Bucharest, 23 March

Greece (2008)

Georgia (2009)

India (2011)

Spain (2016)

Country at risk (serological evidence + vector)

Country with low risk (presence of vector)

50 to 200 cases per year

5 to 49 cases per year

Crimean-Congo Haemorrhagic Fever Geographic Distribution

50° North limit for the geographic distribution of genus Hyalomma ticks

Pierre Formenty, et al. In Ergonul & Whitehouse, CCHF, Springer, 2007; modified

Countries where within last 10 years first case of CCHF in human was detected

Karesh WB, Lancet 2012

The Course of Infection in animals

Mild clinical symptoms

Described by Shepherd et al in 1980s.

No striking notes in recent outbreaks, since 2000

Viremia

Lasts for 7-10 days in mammals

Onder Ergonul, Berlin, Germany, 2016

CCHF case fatality rate in different countries

Keshtkar-Jahromi M et al. Antiviral Research 2013;100(1):20-8Shaikh MA et al. J Pak Med Assoc 2015;65(5):576

Nurmakhanov T, et al. IJID 2015;38:19-23Volynkina AS et al. Plague 2015: no.1

Leblebicioglu H et al. Antiviral Research 2016;126:21-34

CFR ≈ 4% - 36%

[2002-2015]

2124 cases

CFR: 4,0%

[1999-2017]

CCHF case definitionPROBLEMS:

1.There is no any standardized case definition for all countries, each country use own case

definition. This circumstance don’t allow to compare studies in different countries;

2. Cases can be missed (mild cases, cases without haemorrhagic symptoms)As example – CCHF case definition in Russia (very close to case definition in Greece and Pakistan)

Suspected case• Acute onset of illnesses with high fever (>38.0°C)• Spring-Summer season• History of tick bite or contact with tick on the endemic area• History of contact with CCHF patient during health care for patient• Occupation (agriculture of field work, cowherd, cattleman, etc.)Probable case• Acute onset of illnesses with high fever (>38.0°C)• Spring-Summer season• At least two of the following haemorrhagic manifestations: petechiae, purpuric rash, rhinorrhagia,

haemorrhage, bloody vomiting, epistaxis, hemoptysis• the absence of any known precipitating factor for haemorrhagic manifestation• absence of any known reasons of haemorrhagic manifestation• leukopenia, thrombocytopenia in bloodConfirmed case• Specific clinical and epidemiological data;• anti-CCHF Ig M titers 1:800 and more, in any IgG titers, detection of RNA of the CCHF virus.Disadvantage of case definition:

include fever only more than 38,0 C.

Mild cases with sub febrile temperature can be missed

Early autumn season is missed

History of contact with possibly infected animals including agriculture animals is missed

0

20

40

60

80

100

120

140

160

180

200

Annual dynamics of CCHF cases by

months in Russia

Number of cases

tick bites60%

unknown24%

Removing of ticks

5%Crushin

g of

ticks10%

Human-to-human

transmission1%

Way of CCHF transmission

in Russia

Volynkina A.S., Kotenev E.S., Lisitskaya Ya.V., Maletskaya O.V., Shaposhnikova L.I., Kulichenko A.N. Epidemiological Situation on Crimean Hemorrhagic Fever in the Russian Federation in 2016, and Prognosis for 2017. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2017; 1:24–28. (In Russ.). DOI: 10.21055/0370-1069-2017-1-24-28;ProMED-mail. Crimean-Congo haemorrhagic fever (Russia, Kazakhstan, preliminary results of 2017) ProMED-mail 2017; 03 Oct: 20180127.5589232. <http://www.promedmail.org>. Accessed 30 Jan July 2018.

Individual farm43%

Collective farm

18%

Field work18%

Outdoor recreation

16%

Pastures5%

Circumstances associated with the

contamination in Russia

Fever

Ergonul O, Lancet ID, 2006

Acute onset, fever, residence in endemic area during season of tick activity

Daily examination of thrombocytes, leucocytes, ALT,

AST

thrombocytes leucocytes

ALT, AST

Testing blood samples for CCHF virus:PCR , ELISA (IgM)

Antivirals (ribavirin) administration before receiving of PCR and ELISA results

Developing of hemorrhage without any other

preconditions

Consultation of hematologist

Acute onset, fever + epidemiological anamnesis for

CCHF (habitation, occupation, visiting nature, tick bite, contact

with tick, contact with probable or confirmed CCHF case, etc.)

Patient refer for medical aidStandard PPE for examination of all patients during first medical aid:

gloves + surgical mask and goggles (if bleeding)

Probable CCHF case;PPE: gloves + goggles + surgical mask or respirator N95 or similar (if patient is

on inhalator or ALV device)

Suspected CCHF case;PPE: gloves + surgical mask

Confirmed CCHF case: PPE and antiviralsis the same as at Probable CCHF case

CCHF in Tajikistan, 2009Cluster of 5 CCHF cases in Tursunzade

Index case

a 50 year old man (day of symptoms onset 18 July 2009,day of death - 26 July 2009) within 18-24 July the

patient was treated from ILI, acute bronchitis in out-patient department, due to

deterioration of clinical picture he was addressed to hospital

- bleeding (vomiting) started in emergency room of regional

hospital(24 July 2009)

Anti CCHF IgM “-”

Secondary case

Physician who

examined patient in

emergency hospital

PPE: tissue mask,

gloves?

(died on 6 Aug)


Secondary case

Wife (alive)Anti CCHF IgM “+”

Secondary case

Relative (alive)Anti CCHF IgM “+”

Secondary case

Relative (died on

5 Aug),He was involved in

bureal


CCHF was not verified,

Body of patient was released to

relatives for burial preparation

CCHF in Kazakhstan 2009 (1)

Index case

a 23 year old woman, who re-admitted in the maternity hospital 3 days after

childbirth with fever and bleeding on 29 June 2009 and died on 4 July 2009

Due to bleeding from uterus she was operated 3 times: first time on 29 June

and twice on 2 July 2009; Anti CCHF IgM “-”

Secondary case

Surgeon in

Turkestan hospital

(died on 10 July)Not tested for CCHF

Secondary case

Vascular surgeon

from Shymkent

(died on 9 July)

CCHF Ag “+”

in corpse

Secondary case

Assistant-

gynecologist

(alive)

Anti CCHF IgM

“+”

Secondary case

Newborn baby

(died on 3 Aug),

Not tested for

CCHF

Tertiary case

Pediatrician,

who took care of

the baby (died

on 12 July)

CCHF Ag “+”

in corpse

Secondary case

old junior

maternity nurse

(alive)

Anti CCHF IgM “+”

Cluster of 7 CCHF cases in Turkestan

Mutabor Shermetova, Turkestan, Kazakhstan, 2007

CCHF in Southern Kazakhstan region, (Turkestan city)


Gulzhan Abuova,, Shimkent, Kazakhstan, 2007

Recent clinical findings

Aerosol way of CCHF transmission

CCHF transmission via sexual

contacts

Severe course of CCHF in pregnancy

Probable CCCHF virus transmission occurred after aerosol-generating medical procedures in Russia:

nosocomial cluster

Index case

A 23-year-old pregnant woman (22 weeks) was admitted to the hospital on 6 May 2011 (2th day of illness) with ILI, died on 11 May 2011 (7th day of illness). She lived in a rural area endemic for CCHF, and denied any tick bites or contacts with ticks within the 2 weeks before onset of the disease. She was on a countryside picnic 2 - 3 days before the debut of symptoms.She developed severe double sided pneumonia (7May), hematemesis, hemoptysis, uterine bleeding, and haemorrhage from the subclaviar catheter (8-9 May). The patient received support therapy and uterine bleedingmucolytics and broncholytics through compression inhaler NEBULFLAEM on May 9-10.Due to a low oxygen saturation the patient was intubated on May 10 and mechanically ventilated until her death.PCR “+” on the 5th day of disease (9 May), ribavirin was not prescribed due to late stage of disease confirmation, pregnancy, anemia.

Secondary caseNurse (ID) assisted in

central venous

catheterization,

performed intravenous

injections through a

catheter, and

monitored inhalation

use hourly ;

PCR “+”, alive

Secondary caseNurse from ICU

department, who

installed the

equipment for

ventilation with 20

min and had no any

direct contact with

patient or her fluids;

PCR “+”, alive

Secondary caseAnesthetist who was in the

ICU ward not more than 10

min, while the patient was in

the ventilator, no any contact

s with patient or her fluids;

PCR “+”, alive

Secondary casewho performed

change of linen,

cleaning room,

and disinfection of

the bedpan;

PCR “+”, alive

Secondary caseClinician from ID

department who attended

the patient, doing rounds

when she was in the

ventilator; PCR “+”, alive

Secondary caseNurse (ID), who

performed i/v

injections through a

catheter, and

monitored inhalation

use hourly ;

PCR “+”, alive

Secondary caseAnesthesiologist

from the ICU who

took care of the

ventilator

treatment;

PCR “+”, alive

Secondary

caseObstetrician who

examined the

patient from the

first day of

admission to the

hospital until

the death;

PCR “+”, alive

Cluster of 9 CCHF cases in the Salsk

district of the Rostov region

• Should be use during certain procedures with an increased risk of infection transmission

– Ingalation via nebulazer

– aspiration or open suctioning of respiratory tract secretions

– intubation

– cardiopulmonary resuscitation

– bronchoscopy

• Appropriate PPE (gown, eye protection, gloves)

• Adequate ventilation (>12 times per 1 hour)

• Avoid unnecessary individuals in the room © WHO

Atkinson J, Chartier Y, Pessoa-Silva CL, Jensen P, Li Y, Seto W-H. Natural ventilation for infection control in health-care settings. In: WHO Publication/Guidelines. Geneva: World Health Organization; 2009 (http://www. who.int/water_sanitation_health/publications/natural_ventilation/en/index. html).

Usually standard, contact and droplet precautionsrecomended during health care for patients with CCHF

Airborne precautions should be add in specific conditions according to WHO recommendations

+

Strict Infection Control

Contact monitoring Lucille Blumberg, Tirana, Albania, 2013

Administrationofribavirin,n=2 Noribavirin,n=4Lethalcasesinpregnancy 0 3Fetusdeath 0 4

Russia – 6 cases

Common mortality rate in pregnancy – 35,7%; before 20th week of pregnancy - 9%; after 20th weeks of pregnancy -48,4%

CCHF and pregnancy: systematic review and case series (42 cases totally)

Administrationofribavirin,n=13

Noribavirin,n=23 p

Lethalcasesinpregnantwomen

5(38,5±13,5%) 10(43,4±10,3%) >0,05

Fetusdeath 5(38,5±13,5%) 15(65,2±9,9%) >0,05

Mild or asymptomatic course of

disease

Subclinical infections with Crimean-Congo hemorrhagic fever virus, Turkey Emerging Infectious Diseases Volume 18, Issue 4, April 2012, Pages 640-642

The screening for IgG to CCHF virus in endemic areas showed the presence of antibodies in 10% of the population. the detection rate of IgG to CCHF increased according to the age.The researchers came to the conclusion that 88% of CCHFCases are mild or asymptomatic

Wife, 45 years old, admitted to the hospital on

the 2th day of disease (22.04.2010), on the 5th

day after tick bite (19.04).

No any hemorrhages at the day of admission,

fever 38-39 C, Hb -119 g/l, WBC - 3,4*109, PLTs -

123*103, on the 3th day of disease hemorrhages at

the places of i/v injections.

ELISA (29.04) anti CCHF IgM 1:800, IgG -negative.

1thcouple

Husband, 47 years old admitted to the hospital on

the 1th day of disease (25.04.2010), there was no

any rick factors in anamnesis, sexual contact with

wife between 20-21.04.

No hemorrhages at the day of admission, fever 39-40 C,

Hb-107 g/l, WBC- 3,2*109, PLTs - 95*103, on the 3th day

of disease gastrointestinal bleeding and massive

hemorrhages in the places of i/v injections.

ELISA (5.05 anti CCHF IgM 1:1600, IgG – negative.

2thcouple

Husband, 27 years old, the slaugther, admitted to the hospital on the 7th day of disease (23.05.2005).No any hemorrhages were detected during whole course of disease, on the first 1-2 days of illness fever was 38,0-39,0 C, next 5 days before hospitalization -32,2-37,3 C, Hb 144 g/L, WBC -3,2*109, PLTs -146*103.ELISA (30.05) anti CCHF IgM 1:800, IgG-negative.

Wife, 29 years old admitted to the hospital on the 2th

day of disease (25.05.2005), unemployed, there was no

any tick bites in anamnesis, sexual contacts with

husband between 19-22.05.

Fever 39,0 C at the day of admission, Hb-118 g/l,

leucocytes - 3,4*109, PLTs - 123*103, on the 3-4th day

of disease small hemorrhages were observed at the

places of i/v injections. CCHF confirmed by ELISA

(06.06) anti CCHF IgM 1:800, IgG – negative.

3thcouple

Husband, 55 years old, store manager,, admitted

to the hospital on the 3th day of disease

(18.06.2014), on the 5th day after tick

bite(13.06).

On the 1th day of disease fever was 37,2 C, on

the 2 and 3th days - 38-39 C, Hb 150 g/l, WBC -

4,3*109, PLTs - 128*103. No any hemorrhages

during whole course of disease were detected.

PCR (20.06) positive, ELISA (24.06) anti CCHF

IgM 1:800, IgG – negative.

Wife, 52 years old, seller, admitted to the hospital on

the 2th day of disease (21.06.2014), she had sexual

contacts with husband between 16-17.06.

Fever was 39,0 C at the day of admission, Hb-118 g/l,

WBC-2,1*109, PLTs-140*103. No any hemorrhages

during whole course of disease were detected.

PCR (22.06) positive, ELISA (30.06) anti CCHF IgM

1:6400, IgG – negative.

Primary case Secondary case

4 days

8 days

5 days

Difference between date of onset of symptoms

Transmission via sexual contacts - close contact way of CCHF transmission? (observation of 3 couples with CCHF in the Salsk district of the Rostov region of Russia, 2004-2015 )

Core factors, which are important for probable transmission via sexual

contacts:

1. All sexual partners of CCHF patient should be under

medical observation with 2-times thermometry within 14

days

1. Ribavirin preventive dose (500 mg qid 7-10 days)

should be administer for partners who had sexual

contacts with CCHF patients during disease or 1-2 days

before it.

High risk exposure

n=146

PEP Ribavirin

n=56 (38%)

Infected

n=7 (12.5%)

symptomatic

n=6 (86%)

Fatal

n=0 (0%)

Not infected

n=49 (87.5%)

no PEP

n=90 (62%)

Infected

n=87 (97%)

symptomatic

n=86 (99%)

Ribavirin <48 hrs after

symptoms

n=12

Fatal

n=0 (0%)

No ribavirin <48 hours after

symptoms

n=74

Fatal

n=32 (43%)

Not infected

n=3 (3%)

Ergonul, in press

Ribavirin in Post-Exposure Prophylaxis for CCHF

Experience from case management• If patients have not a tick bite in anamnesis:

- 30-40% of them at the pre-hemorrhagic stage of disease primary addressed for medical aid into departments of non-communicable disease and had different from CCHF diagnosis (acute diarrhea, ILI, bronchitis, hematological disease, etc.)

- 10-20% of them at hemorrhagic stage addressed to surgical, hematological, oncology, gynecology otorhinolaryngology departments)

• hypodiagnostic of CCHF and late reference for medical aid is lead to delaying of start of specific treatment (ribavirin) and supportive treatment and almost all cases of death in Russia are connected with this options (CFR 4,1%).

• Prescription of ribavirin in pre-hemorrhagic stage of CCHF ( for example, after tick bite or direct contact with confirmed CCHF case) can stop the developing of hemorrhage in 85-90% of cases

Differential diagnosis HFVs

Leptospirosis

Meningococcemia

Rickettsial diseases

Malaria

Sepsis

Influenza

Viral hepatitis

Toxic shock syndrome

Idiopathic or thrombotic thrombocytopenic purpura

Hemolytic uremic syndrome

Acute leukemia

Collagen-vascular diseases

Blumberg L et al. Manson’s Tropical Disease 2014Fisgin NT, et al. Epidemiol Infect 2010;138(1):139-44

Leblebicioglu H. UpToDate.com 2015Consider geographic distribution of diseases

68% of CCHF cases have an initial misdiagnosis of various diseases

42-yr old hunter

Not feeling well on Thursday evening

Collapsed on Friday – hypotensive, confused,

ecchymotic rash, mucosal bleeding

Constant exposure to ticks, skins wild animals

HB 10, WCC 30 000, platelets 67 000

AST 35, ALT 38

Lucille Blumberg, Tirana, Albania, 2013

42-yr old hunter

Not feeling well on Thursday evening

Collapsed on Friday – hypotensive, confused,

ecchymotic rash, mucosal bleeding

Constant exposure to ticks, skins wild animals on game

farm

HB 10, WCC 30 000, platelets 67 000

AST 35, ALT 38

CCHF NEGATIVEBLOOD CULTURE:N MENINGITIDES


36yr old agriculture worker in endemic

area

• Fever, epistaxis

• WCC 18000, platelets 34 000

• AST 34, ALT 45


36yr old agriculture worker in endemic

area

• Fever, epistaxis

• WCC 18000, platelets 34 000

• AST 34, ALT 45

CCHF NEGATIVELEUKEMIA


TreatmentAntiviral treatment

Review 2018 – in press

Comparative studies ofribavirin treatment of CCHF in Iran

Years Route CasesRibavirin/no ribavirin

Study type Result References

1999-2001 PO 139/48 Retrospective observational

Decreased Mardani et al., 2003

1999-2004 PO 236/19 Retrospective observational

Decreased Alavi-Naini et al., 2006

2007 PO 123/0 RestrospectiveCross-sectional

Decreased/early use

Sharifi-Mood et al., 2009

Leblebicioglu H, Berlin, Germany, 2016

150

249 266

438

717

1315 1318

868

1075

796

910967

718

0

20

40

60

80

100

0

200

400

600

800

1000

1200

1400

Cases (n)

Mortality (%)

Ribavirin use (%)

%

Leblebicioglu H et al. Antiviral Research 2016;126:21-34

CCHF in Turkey between 2002-15

Difficult to interpret results of studies

• Most of them observational studies

• All of them except one retrospective studies

• Calculation of an adequate sample size is crucial

• Different study design

• Lack of randomization

• Different case definitions and case groups

• Generally small number of cases who didn’t take ribavirin in control groups

• Differences between the time from the onset of illness to treatment

• Severity of infection varies

• Viral load is not available in most studies

• Most of the studies were performed in tertiary care hospitals with more complicated patients

• Variations in medical practices

• Early diagnosis and supportive treatment may alter the clinical course of the disease

• Genetic differences between CCHFv isolates from different geographic areas

Leblebicioglu H, Berlin, Germany, 2016

Recommendations

The antiviral drug ribavirin has been used in treatment of established

CCHF infection with apparent benefit. Both oral and intravenous formulations seem to be effective

The virus is sensitive in vitro to the antiviral drug ribavirin. It has

been used in the treatment of CCHF patients reportedly with

some benefit

General supportive therapy is the keystone to success of CCHF clinical management

Supportive treatment Standard treatment is supportive therapy

Early aggressive intensive care support (plasma if hypocoagulation, Platelet

transfusion is warranted to maintain platelet count >50,000/mm3 in the setting of

bleeding and for patients with platelet count <20,000/mm3 in the absence of

bleeding).

Support of coagulation system

Careful monitoring

Oxygenation

Fluid & electrolyte balance

Blood pressure

Early use of inotropic agents (dobutamine)

Ventilation support for severe cases

Hemodialysis

Pain management

Parenteral nutrition

British Committee for Standards in Haematology Guideline. British Journal of Haematology, 2003, 122, 10–23 Leblebicioglu H, et al. Vector Borne Zoonotic Dis 2012;12(9):805-11Leblebicioglu H, et al. Vector Borne Zoonotic Dis 2012;12(9):805-11

Discharge of patients

• Relaps and reinfection after discharge were not reported

• The main criteria for discharge are resolving fever and signs and symptoms of CCHF with no longer bleeding

• Laboratory tests taken for decision of discharge in rank of order are– Platelet count (either >100.000/mm3 or 50.000-100.000/ mm3 but in a trend of

increase)– Normal internalization normalization ratio (INR), prothrombin time (PT), activated

partial thromboplastin time (apTT)– Transaminases of lower than 5 times of upper limit of normal

Leblebicioglu H, et al. J Infect 2016;72(4):500-1.

Development of WHO Guideline for Clinical Management of Crimean Congo Haemorrhagic

Fever (2016-2018) (1)

• Guideline is still in progress……

• Guideline is based on PICO questions:• Patient Problem, (or Population)

• Intervention,

• Comparison or Control

• Outcome

It includes:

• Supportive treatment (platelets, fresh frozen plasma, corticosteroids etc.)

• Directed therapeutics (ribavirin (intravenous) OR ribavirin (oral) OR favipiravir OR interferons OR immune globulin (including convalescent plasma)

• Case definition/ laboratory diagnostics (ELISA, PCR) (how case definition for CCHF (sensitivity) compared to laboratory diagnosis with RT-PCR, rapid diagnostic tests for CCHF )

• Transmission/exposure (barrier contraception for sexual contacts, breastfeeding, oral ribavirin as PEP)

• Infection prevention and control (standard PPE for VHFs )

Special attention to high risk populations (age cut-offs, comorbidities, pregnancy, obesity, etc)

Development of WHO Guideline for Clinical Management of Crimean Congo Haemorrhagic

Fever (2016-2018) (1)

EDPLN

Developing & implementing R&Droadmaps

Methodology Synopsis

High level summary of principles and concepts to

provide an overview and to be used for peer-review

publication

Methodology

CoreDocument

Outline of the information and elements to

understand roadmaps and roadmapping

development/process

Appendices

Systematic list of detailed instruction/stepsto

elaborate and to implement R&Droadmaps

CCHF has been identified as a one the WHO priority disease for which accelerated basic and applied research as well as product development would be beneficial.

CCHF R&D Blueprint roadmap (1)Main purpose

• To be able to reduce death and morbidity from CCHF through safe and affordable effective treatments informed by rapid, reliable and easily accessible diagnostics by 2023, and

• To be able to prevent or mitigate CCHF disease through deployment of safe, affordable and effective vaccines and other preventive measures by 2030.

Diagnostic• Development and validation of rapid diagnostic tests for CCHF with high sensitivity and specificity

(simple to use, sample-to-answer nucleic acid tests with high sensitivity and specificity and (ii) rapid point-of-care tests (nucleic acid or antigen detection ) with minimal requirements for biosafety precautions and staff training (2018-2024).

• By 2020, at least 2 WHO-prequalified, accessible commercial IgM and IgG serology tests available for follow-up of suspected CCHF cases, for epidemiological purposes and for pre-screening volunteers for CCHF vaccine trials.

• Investigate utility of alternative sample types (urine, oral fluid, semen etc) for CCHF diagnosis; this will also provide knowledge about CCHFV persistence in body fluids and may support non-invasive diagnostics.

• Developing «fever panel» – diagnostic tests that use a common platform to distinguish CCHF from related illnesses with similar presentation

• Continue to review the utility of next generation sequencing (especially metagenomics) for CCHF diagnostic use (including contact tracing and epidemiological approaches), particularly using portable solutions e.g. MinIon in the field.

EDPLN

CCHFtherapeuticsinterventions

● Ribavirin: systematic reviews regarding the clinical efficacy

of Ribavirin in treatment of CCHF have been published .

Both studies agree that current evidence is insufficient and

call for a large placebo-controlled trial.

● Favipiravir (T-705) good efficacy in transgenic IFNAR mouse

models.

● Intravenous immunoglobulin (IVIG), several studies in

Soviet Union, South Africa, Turkey and Bulgaria reported

but lack of evidence in absence of proper controls.

● Monoclonal antibodies (Mabs) [similar to Ebola]

● New compounds

P i e r r e F o r m e n t y , W H O , 2 n d I n t e r n a t i o n a l C o n f e r e n c e o n C r i m e a n - C o n g o

H e m o r r h a g i c F e v e r , 1 0 - 1 2 S e p t e m b e r 2 0 1 7 , T h e s s a l o n i k i , G r e e c e

Therapeutics

• By 2019, produce protocols in consultation with national regulatory authorities for dose regimen and subsequent randomized controlled trials to assess the efficacy and safety of existing therapeutic products (e.g. favipiravir), alone or in combination therapy against CCHF.

• By 2020, initiate first evaluation of the therapeutic potential of antibody therapy in a relevant preclinical model of CCHFV infection.

• By 2021, start patient enrolment to phase II trials of an existing therapeutic (e.g. favipiravir) in 2 or more countries to evaluate efficacy against CCHF disease and establish pharmacokinetic data.

• By 2023, take successful therapeutics forward to a phase III randomized controlled trial to establish full efficacy against CCHF disease.

• Development of a standardized case definition for CCHF for clinical trials

CCHF R&D Blueprint roadmap (2)

Vaccines and Vector Control

• Working with the appropriate national regulators, take at least one CCHF vaccine candidate that meets the TPP for CCHF vaccines and with proven efficacy in relevant animal models, into human phase 1 safety and early immunogenicity trails by 2019 and phase II trial by 2023.

• Prioritise and progress 5 early-stage developmental human CCHF vaccines through relevant animal models by 2025.

• By 2025, complete a proof-of-concept study of experimental Hyalomma-targeted tick vaccines and/or veterinary anti-CCHF vaccine(s) in relevant animal models.

• By 2025, identify the adaptive immune responses and protective mechanisms in humans and NHPs against CCHF disease and identify the correlates of protection for use in preclinical vaccine studies.

CCHF R&D Blueprint roadmap (3)

CCHFvaccines - candidatesFrom Dowall SD et al., 2017

Vaccine type CCHFVantigen

ImmunityProtection in

preclinical model

Clinical evidence

Antibody Tcell SafetyManufacturin

g

practicalities

Inactivated virus

(mousebrain)Whole virus Y Y ? ? No

Inactivated virus(cell

culture)Whole virus Y NT Y2 ? No

ModifiedVaccinia

Ankara(MVA)M segment Y Y Y3 Y Y

Ssegment Y Y No Y Y

DNAvaccine M segment Y NT NT Y Y

Gc, Gn andNP Y Y Y4 Y Y

Transgenicplant Glycoprotein Y NT NT ? Y

Protein Gn glycoprotein Y NT No ? Y

Gcglycoprotein Y NT No ? Y

Adenovirus M segment Y Y No Y Y

Virus-like particles Gc, Gn andNP Y Y Y5 Y Y

P i e r r e F o r m e n t y , W H O , 2 n d I n t e r n a t i o n a l C o n f e r e n c e o n C r i m e a n - C o n g o

H e m o r r h a g i c F e v e r , 1 0 - 1 2 S e p t e m b e r 2 0 1 7 , T h e s s a l o n i k i , G r e e c e

EDPLN

EDPLNCCHF R&D Blueprint, timelines

2018 2019 2021 2023

Q1-

Q2

Q2-

Q4

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Finalise CCHF R&D Baseline Assessment M1

Develop a CCHF R&D Roadmap M2

Develop CCHF Target Product Profiles M3

Prequalification review of CCHF diagnostic tests M4

CCHF therapeutics clinical trials M5

Only together we can find asolution!

Thank you for attention!

Exposure

Risk assessment

Low risk

Follow up with CBC

Normal Results in 14 days

Stop follow up

Low WBC and PLT

isolation

supportive tx

Tx with Ribavirin

High risk

PEP with ribavirin

watchfull care

Ergonul, in press

Ribavirin in Post-Exposure Prophylaxis for CCHF

42 year prison warder from endemic area

• Fever, abdominal pain

• Lives on farm in endemic area

• 7 days later: Bleeding, ARDS, renal failure

• platelets 34 000, WCC 2

• ALT 8 000, AST 6 000, LDH 30 000

• Hepatitis A and B neg. HIV neg, CCHF neg

• Died


42 year prison warder from endemic

area

• Fever, abdominal pain

• Lives on farm in endemic area

• 7 days later: Bleeding, ARDS, renal failure

• platelets 34 000, WCC 2

• ALT 8 000, AST 6 000, LDH 30 000

• Hepatitis A and B neg. HIV neg, CCHF neg

• Died

HERPES HEPATITISLucille Blumberg, Tirana, Albania, 2013

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