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Innovation and new Technologies for measles eradication. Dr. David Brown Virus Reference Department HPA Microbiology services Global Measles and Rubella Management Meeting 15 th March 2011. Overview. Current status of measles control Range of research needs already identified

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innovation and new technologies for measles eradication

Innovation and new Technologies for measles eradication

Dr. David Brown

Virus Reference Department

HPA Microbiology services

Global Measles and Rubella Management Meeting

15th March 2011

overview
Overview
  • Current status of measles control
  • Range of research needs already identified
  • PoCT test for measles IgM
  • Molecular epidemiology – Impact of new sequencing technologies
measles r d needs identified
Measles R&D needs Identified
  • Measles elimination:
        • Indicators for elimination/performance of surveillance programme
        • Risk factors for outbreaks
          • Waning Immunity? 2° infections
          • HIV and measles
  • Immunization Strategies
        • Changing patterns of susceptibility
        • Outbreak response immunization
        • Effectiveness of different immunization strategies
  • Laboratory Activities
        • Vaccine development
        • Antivirals
        • Diagnostics/Molecular epidemiology
laboratory tools for surveillance of measles
Laboratory tools for Surveillance of Measles:

IgM assays and RT-PCR for confirmation of acute infections

IgG assays to guide vaccination, serosurveys

IgG avidity to confirm primary infections

RT-PCR/sequencing for Molecular epidemiology

Track epidemiological pathways

Surveillance of virus diversity

Investigation of potential adverse events

slide5
Ideal features of PoCT
  • Highly sensitive and specific
  • Rapid (15 – 30 minutes)
  • No sample preparation
  • Simple, with few operator dependent steps
  • Inexpensive
  • Clear and stable end-point result
  • Storage at room temperature
  • Results improve treatment or public health response
pocts available
PoCTs available

Bacteria

T. pallidum

Viruses

H. pylori

Strep pneumoniae

Influenza

Group A Strep

RSV

HIV

Chlamydia trachomatis

HBsAg

HCV

Biological threats

Protozoa

Anthrax

Botulism

Plague

Malaria

slide7
Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Principle of the IgM capture near patient test

Direction of reagent flow

Oral fluid IgM

Nitrocellulose

membrane

Test line:

anti-human IgM

Control line:

Anti-mouse IgG

rNP

Cotton linter paper wick

Glass fibre

Conjugate release pad

Plastic backing card

Anti-NP gold conjugate

slide9
Serum measles IgM PoCT protocol

Step1 Step 2 Step 3 Step 4 Step 5

Dilute serum

1/100

Add 5µl antigen to reaction tube.

Mix diluted serum and antigen.

Insert test strip.

Incubate room temp.

Read result.

evaluation of measles poct for serum samples
Evaluation of measles PoCT for serum samples:

Sensitivity : 90.8% (95% CI 81.9 – 96.2)

Specificity : 93.6% (95% CI 86.6 – 97.6)

  • Serum Samples:
    • 100 sera collected during measles elimination programme in Malaysia in 2004.
    • 62 sera identified as rubella IgM positive during measles surveillance in Ethiopia 2003-2004.8 cases of rubella IgM positive sera from Russia
    • PoCT vs Siemens IgM on serum samples
        • ppv 92.0 (95% CI 83.4 – 97.0)
        • npv 92.4 (95% CI 85.4 – 96.9)
slide11
Measles IgM PoCT: 10 Sera (# 69 – 78, incubation: 10 minutes)

EIA results - - - - - + + + + + + +T/N ratios: 0.16 0.13 0.24 0.22 0.12 4.06 1.54 1.68 2.93 1.03 PC PC PoCT results - - - - - + + + + + +/- +/-

evaluation of measles poct for of samples
Evaluation of measles PoCT for OF samples:
  • Oral fluid Samples:
    • A total of 282 OF specimens received in the UK during 2008 as part of surveillance programme. 232 received for measles investigation, 39 for rubella investigation, 11 for measles and rubella investigation.
    • PoCT performance vs MicroImmune on OF samples.
    • Sensitivity: 90.0% (95CI 80.5 – 95.8%)
  • Specificity: 96.2% (95% CI 92.6 – 98.3%)
  • ppv 88.7% (95%CI 79.0 – 95.0%)
  • npv 96.6% (95%CI 93.2 – 98.6%)
measles igm poct 10 oral fluid specimens 165 174 incubation 20 minutes
Measles IgM PoCT: 10 Oral fluid specimens (#165 – 174, incubation: 20 minutes)

EIA results - + - - - + + + - + T/N ratios:0.25 19.25 0.18 0.17 0.21 2.66 3.65 1.33 0.13 5.65PoCT results - + - - - + + + - +

measles virus genomic structure
Measles Virus Genomic Structure

Manual for the laboratory diagnosis of measles and rubella virus infection

WHO – EPI, WHO/IVB/07.01: 2nd edition 2007

high throughput sequencing
High-Throughput Sequencing

Amplification methods now available to generate 100,000 clones from single reaction, either multiple or single samples.

Requires high-throughput bioinformatics

Operational Issues:

Cost: £100 – 1000, further reductions in price likely

Turnaround Times >7days

From 454 life sciences website

measles genome sequences
Measles Genome Sequences
  • Increasing the amount of genetic information used in phylogenetic analysis may improve the quality of inferences.
  • There are 63 full-length measles sequences in GenBank
  • Genotype distribution:
    • A 34
    • B3 1
    • C2 2
    • D3 16
    • D5 2
    • D6 4
    • d11 2
    • H1 1
    • H2 1
  • Tree generated using NJ algorithm
  • Based on N 450 only
  • Includes WHO genotype reference sequences
measles virus genomic diversity
N

H

M

P

F

LP

Measles Virus Genomic Diversity

Measles virus diversity along the length of the genome. Gene coding regions are shown in red.

the next steps
The next steps
  • Full-length measles genome sequencing would provide:
    • Greater level of genetic variation
    • Improved lineage stratification of temporally related strains
    • Mutation rate:Measles:1:6x104
    • Polio:1:1x102 Substitutions per site per year.
    • Polio mutation rate 600x measles
    • Robust phylogenies of clusters (D4 Enfield) that are not resolved by 450 nt of nucleocapsid
  • Sequence studies need to be supported by models of:
    • Sampling framework
    • Susceptible population (vaccine uptake)
discussion points
Discussion points

Measles PoCT evaluated for IgM and Virus detection/genotyping on serum and OF samples. IgM PoCT has appropriate sens/spec for field use. RT- PCR on OF extracted strips sensitive and stable (4 weeks at 22C)

Further evaluation of PoCT with WHO AFRO gave similar results using 100 sera and OF collected in Zimbabwe surveillance programme.

. PoCTs have potential to make a significant contribution to Measles surveillance

Challenges-how to make widely available? ( is there a market? what cost)

Acknowledgement: Lennesha Warender, Dhan Samuel

discussion points 2
Discussion points (2)
  • Technological developments have provided a straightforward way to investigate the value of finer characterisation of virus strains.
  • Will it be useful for tracking chains of transmission.
  • Or for discriminating between multiple chains of transmissionwith closely related strains.
  • Acknowledgement: Richard Myers
measles control goals by who region june 2010
Measles Control Goalsby WHO Region, June 2010

Americas, Europe, E. Mediterranean, W. Pacific, Africa have elimination goals

GIVS Goal:

90% reduction in deaths

by 2010 (vs. 2000)

2010

2010

2012

2000

2020

2010 SEAR RC

Endorsed WHA 2015 targets

Target date for elimination TBD

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