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M. Chudy | 12 June 20071 |
SoGAT XX, Warsaw, Poland12-13 June 2007
Michael Chudy, WHO; Geneva, Switzerland
Development of Biological Reference Preparations for Blood Safety-related IVDs
- WHO Strategic Plan -
Development of Biological Reference Preparations for Blood Safety-related IVDs
- WHO Strategic Plan -
M. Chudy | 12 June 20072 |
Biological StandardizationBiological Standardization
WHO is mandated by it's Member States to "…develop, establish and promote international standards for biological products."
In practice, biological products cover– Vaccines– Blood and blood products– Biological therapeutics– In vitro diagnostic devices
M. Chudy | 12 June 20073 |
Quality Assurance and Safety of Biological ProductsQuality Assurance and Safety of Biological Products
WHO Norms & Standards: Expert Committee on Biological Standardization
Medicines, Policy and StandardsMedicines, Policy and Standards
Department (PSM*);Department (PSM*);
Health Technology and Pharmaceuticals Cluster Health Technology and Pharmaceuticals Cluster (HTP)(HTP)
Medicines, Policy and StandardsMedicines, Policy and Standards
Department (PSM*);Department (PSM*);
Health Technology and Pharmaceuticals Cluster Health Technology and Pharmaceuticals Cluster (HTP)(HTP)
Immunizations, Vaccines & Biologicals Immunizations, Vaccines & Biologicals
Department (IVB);Department (IVB);
Family and Community Health Cluster (FCH)Family and Community Health Cluster (FCH)
Immunizations, Vaccines & Biologicals Immunizations, Vaccines & Biologicals
Department (IVB);Department (IVB);
Family and Community Health Cluster (FCH)Family and Community Health Cluster (FCH)
N SB/IV B/FC H(Vacc ines , cell regula to rs)
Q SD /P SM /H T P(B lood p roduc ts , in v itro d iagnos tic dev ices)
B io log ical P roduc ts(Vacc ines , b lood p roduc ts, o the r bio log ica ls
and in v itro d iagnos tic dev ices)
(*) Expert Committee for Pharmaceutical Preparations(*) Expert Committee for Essential Medicines(*) Expert Committee for Pharmaceutical Preparations(*) Expert Committee for Essential Medicines
M. Chudy | 12 June 20074 |
WHO Biological Reference PreparationsWHO Biological Reference Preparations
Recommendations for the preparation, characterization and establishment of international and other biological reference standards (revised 2004)
Annex 2, WHO TRS, No 932, 2005.
M. Chudy | 12 June 20075 |
WHO Biological Reference PreparationsWHO Biological Reference Preparations
International Standard [expressed in IU] Reference Reagent International Reference Panel
– Endorsed and adopted by Expert Committee on Biological Standardization (decision making body)
– Catalogue on the website
www.who.int/medicineswww.who.int/bloodproducts/ivd/infectious_markers
M. Chudy | 12 June 20076 |
Establishment ofWHO Biological Reference Preparations *
Establishment ofWHO Biological Reference Preparations *
1. Selection of candidate materials
2. Characterization of candidate materials
3. Feasibility studies
4. Inactivation (if needed)
5. Dilution of materials (dilution matrix)
6. Freeze-drying
7. Characterization of final product
8. Stability studies (incl. statistical
analysis)
9. International collaborative study
(incl. statistical analyses)
10. Report to WHO
11. ECBS decision
12. Storage and distribution (maintenance)
*Recommendations for the preparation, characterization and establishmentof international and other biological reference standards (revised 2004); Annex 2, WHO TRS, No 932, 2005.
M. Chudy | 12 June 20077 |
WHO Biological Reference Preparations:IVD Strategic Plan (5 years)
WHO Biological Reference Preparations:IVD Strategic Plan (5 years)
For blood safety-related IVDs:
Serological test platforms
NAT assays
Other tests
Meeting of the WHO Collaborating Centres for Biological Standards and Standardization (NIBSC, CBER, PEI) in Jan 2007 organized by WHO QSD/PSM
M. Chudy | 12 June 20078 |
Meeting of WHO Collaborating Centres forBiological Standards and StandardizationMeeting of WHO Collaborating Centres forBiological Standards and Standardization
WHO Biological Reference Preparations: Review of current situation and new proposals
Role of epidemiological data worldwide
New test platforms and emerging technologies
Define priority projects
Ways forward for collaboration (WHO CC-Network model)– Would strengthen the collaboration between the WHO CCs, and between
WHO CCs and WHO– Respect interests of CCs– Synergize activities
M. Chudy | 12 June 20079 |
Pathogens with impact on blood safety
HIV
HBV , HCV
Other hepatitis viruses
B19V , HTLV1/2, CMV
Bacteria and parasites (causative agents for syphilis, malaria, Chagas disease)
Arthropod-borne agents (WNV, dengue virus)
Prion agents
Other blood-borne agents (bacteria, leishmania, HHV-8)
WHO Biological Reference Preparations: Current Situation and Proposals
WHO Biological Reference Preparations: Current Situation and Proposals
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√NAT; √ Serology; √ Other
M. Chudy | 12 June 200710 |
Testing for Syphilitic InfectionTesting for Syphilitic Infection
Treponema pallidum
Blood screening test in many countries
Anti-syphilitic serum, WHO 1st IS (#HS) nearly exhausted
Proposal for replacement:– IgG preparation (plasma pool of samples from latent syphilis patients)– IgM/IgG preparation (plasma pool of samples from acute syphilis patients)– Collaborative study is completed– Report to ECBS in October 2007
M. Chudy | 12 June 200711 |
Testing for Malarial InfectionTesting for Malarial Infection
1st IS P. falciparum DNA, #04/176 (ECBS 2006)
Antibody Reference Panel (proposal)
Plasmodium falciparum, P. malariae, P. ovale, P. vivax
Endemic in more than 100 countries
Donor testing to reduce the deferral period/loss of donors (non-endemic areas)
Direct parasite detection– Giemsa- or Wright's-stained thick and thin blood film (gold standard method)– Time expensive, need experienced hands
Antigen detection– No sufficient sensitivity
NAT testing– Pro and cons (e. g. DNA vs RNA!)
Antibody testing– Effective indicator of infection– Negative result no guarantee that donor is not infected
M. Chudy | 12 June 200712 |
Chagas DiseaseChagas Disease
American Trypanosomiasis
Protozoan parasite Trypanosoma (T.) cruzi
First described by Carlos Chagas in 1909
Morphologically distinct stages– Insect-stage: epimastigote– Host-stage: Trypomastigote/amastigote
>100 strains classified into two groups (T. cruzi I and T. cruzi II)
Chronic asymptomatic carrier state in infected individuals
Endemic in Latin America
Non-endemic areas: issue due to emigration (e.g. USA, Spain, France)
16–18 million infected cases; >80 million people at risk
T. cruzi DNA detected in mummies from Chile and Peru (7050 BC-1050 AD)
M. Chudy | 12 June 200713 |
T. cruzi InfectionT. cruzi Infection
Main routes of parasite transmission
By bloodfeeding bugs (sub-family Triatominae); the faeces of the insects contain parasites which can enter the wound left after the bloodmeal, usually when it is scratched or rubbed
Transfusion with infected blood (whole blood and components);
Tissue and organ transplantations
Congenital (from infected mother to fetus)
M. Chudy | 12 June 200714 |
Testing for T. cruzi InfectionTesting for T. cruzi Infection
Diagnosis is complex due to low parasitemia in later stages
Microscopic examination of T. cruzi in blood, lymph fluid, cerebrospinal fluid
Xenodiagnosis (uninfected bugs are fed on an individual suspected of having the disease; investigation of blood smear microscopically several weeks later)
PCR (limited sensitivity due to low T.cruzi level in chronic stages)
Serological tests detecting antibodies are well-suited
M. Chudy | 12 June 200715 |
Testing for T. cruzi Infection:Serological Tests for Detecting Antibodies
Testing for T. cruzi Infection:Serological Tests for Detecting Antibodies
Screening tests (initial tests)– Indirect hemagglutination assay (IHA)– Enzyme-linked immunosorbent assay (ELISA)
Confirmatory tests (supplemental tests)– Indirect immunoflourescence assay (IFA)– Radio-immuno-precipitation assay (RIPA)– Immunoblot/Western blot
Rapid tests
Antigens used for ELISA tests– Whole parasite lysates or semipurified antigenic fractions (epimastigote stage)– Trypomastigote excretory-secretory antigens (TESAs; major component trans-sialidase)– Cocktail of recombinant proteins– Synthetic peptides
M. Chudy | 12 June 200716 |
Testing for T. cruzi Infection:Blood Donation Screening
Testing for T. cruzi Infection:Blood Donation Screening
Endemic areas– In most counties for more than 10 years– Prevalence of T. cruzi-infected blood is higher than of HIV, HBV and HCV– Transfusion-transmitted rest-risk differs from country to country
Non-endemic areas– USA
• >12 million immigrants from endemic regions• ARC pilot studies since end of Jan 2007 with ORTHO test
– Spain• Recommendation to test donors from endemic regions (not for excl. source plasma)• To reduce the deferral period/loss of donors
– France• Evaluation of screening tests (blood centre in Tours)
M. Chudy | 12 June 200717 |
Testing for T. cruzi InfectionTesting for T. cruzi Infection
Problems with serological tests– Indeterminate results and false-positive results
• Other T. spec• Other infectious diseases: e.g. leishmaniasis, malaria, syphilis• Autoimmune disorders
– Lack of sensitivity of some assays
No global reference materials for serological tests available
Need for establishing of appropriate BRPs/already ECBS endorsed
WHO Consultation on 2-3 July 2007, WHO/HQ Geneva
Reference Preparations for both screening and clinical diagnostics
M. Chudy | 12 June 200718 |
Epidemiological InformationWHO Collaborating Centres' Meeting (29-30 January 2007)
Epidemiological InformationWHO Collaborating Centres' Meeting (29-30 January 2007)
Points for discussion
Changes of prevalence data of infectious agents (variability, new variants, mutants)
Emerging/re-emerging agents: investigation to assess the relevance on blood and blood product safety
Coordination and information exchange between the WHO CCs and with other groups (e.g. WP-TTID/ISBT)
M. Chudy | 12 June 200719 |
New Tests and Emerging TechnologiesWHO Collaborating Centres' Meeting (29-30 January 2007)
New Tests and Emerging TechnologiesWHO Collaborating Centres' Meeting (29-30 January 2007)
New generations of ELISA systems/platforms
New NAT approaches
Emerging technologies:– Chip technology (microarray)– Nanotechnology-based assays
Suitability of existing WHO Biological Reference Preparations
M. Chudy | 12 June 200720 |
Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007)
Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007)
200720082009ECBS
HCV RNA (3rd)*2007
Anti-syphilitic (2nd)*2007
Anti-HBs (2nd)*2008
Anti-HBc*2008
HIV-1 gt (2nd)**2009
HIV-2 RNA* 2009
HBV gt1**2009
Anti-HCV**2009
Anti-T. cruzi** 2009
Consultation
Feasibility studies
Collaborative study
1two panels for HBsAg- and NAT-tests;
*IS**Panel
M. Chudy | 12 June 200721 |
Future Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007)
Future Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007)
New proposals (ECBS endorsement is needed):– Anti-HTLV-1/2 antibody panel– Anti-Plasmodium species antibody panel
For further discussion:– HIV-2 genotype panel– HCV genotype panel– B19V genotype panel– Anti-CMV antibody standard– WNV RNA preparation/pan panel for arthropod-borne flaviviruses RNA – HCV core antigen preparation– Preparations for anti-HHV-8 antibodies and HHV-8 DNA– TSE blood preparations– Blood-borne bacteria panel– Anti-Leishmania antibody panel
M. Chudy | 12 June 200722 |
Ways Forward for CollaborationWHO Collaborating Centres' Meeting (29-30 January 2007)
Ways Forward for CollaborationWHO Collaborating Centres' Meeting (29-30 January 2007)
To monitor progress– Annual face-to-face meetings– Teleconferences
Need to establish a network of WHO CCs for IVD-related biological standardization representing all the WHO Regions
– To ensure complementary and focused expertise at global level
Master form sheet for future BRP proposals
M. Chudy | 12 June 200723 |
Meeting of WHO Collaborating Centres forBiological Standards and StandardizationMeeting of WHO Collaborating Centres forBiological Standards and Standardization
Meeting Report:
Development of WHO Biological Reference Preparations for blood safety-related in vitro diagnostic tests
Shortly on the website:
www.who.int/bloodproducts/ivd/infectious_markers
M. Chudy | 12 June 200724 |
M. Chudy | 12 June 200725 |
WHO Biological Reference PreparationsWHO Biological Reference Preparations
Validation, quality control and comparability of IVD tests(analytical sensitivity)
Tool for identifying unsuitable diagnostic kits
Tool for global regulation and harmonization in the IVD area
Tool for regulatory bodies, manufacturers, product users
(physicians/scientists) to communicate in a "common language"
Underpin the appropriate diagnoses of the disease
M. Chudy | 12 June 200726 |
WHO Collaborating Centres for Biological Standards and Standardization
WHO Collaborating Centres for Biological Standards and Standardization
WHO CCs: NIBSC, CBER, PEI
WHO CCs represent the greatest know how and experience in establishing global measurement standards
– Characterization of source materials– Freeze-drying procedure– Organizing collaborative studies– Custodian/distribution of reference materials
In collaboration with manufacturers, regulatory bodies, blood transfusion services, WHO CCs involved in diagnostics of blood-borne infections, scientific experts,…
