Diagnosis of Malaria: Best practices, Issues and way forward€¦ · protein (MSP) antigen coated...

Diagnosis of Malaria:

Best practices, Issues

and way forward

Wellington A. Oyibo

ANDI CENTRE OF EXCELLENCE FOR MALARIA DIAGNOSIS

WHO/TDR Malaria Specimen Bank Site

College of Medicine,University of Lagos

Lagos – Nigeria

[email protected]

7/06/2013 1CME_LagMoH

Overview

• Introduction

• Malaria diagnosis – background – Best practices

• Why parasitological diagnosis?

• Malaria Rapid Diagnostic Tests (RDTs)

implementation

• WHO/FIND’s framework for quality diagnostics

• Conclusions

• Acknowledgement


Introduction

• 216 million clinical cases annually worldwide (WHO,

2012)

• About 650,000 deaths, mostly in children less than 5

yrs old (WHO, 2012)

• Reduction in malaria rates … with massive

interventions ( 37% in children < 5yrs in facilities and 42% in communities nationally; lower prevalence in urban – rural areas/facilities in Lagos State)

• Over-diagnosis of malaria - fever = malaria

• Poor parasite confirmation compared with massive

deployment of ACTs (30 – 40% in Lagos State)

• Current malaria diagnostic realities, challenges and

opportunities7/06/2013 3CME_LagMoH

7/06/2013 CME_LagMoH 4

Objectives

• Highlight current best practices in malaria

diagnosis

• Describe opportunities in parasitological

confirmation of suspected malaria cases in

the context of service delivery and best

practices

• Elucidate misconceptions/beliefs in

performing malaria confirmatory tests

• Describe the Challenges and barriers to

effective malaria testing7/06/2013 CME_LagMoH 5

Outcome

• Knowledge of current best practices in

malaria diagnosis at various levels of care

• Understanding of the opportunities in

malaria testing and how these can be

effectively employed in improving service

delivery

• Recognize misconception/beliefs and

barriers to enhance effective malaria case

management with diagnosis

• Re-orientated to scale-up malaria diagnosis

by providing access to malaria diagnosis

•


Best practices in malaria

diagnosis


Defining malaria

• Malaria is a disease caused by the obligate intracellular protozoa of the genus Plasmodium

• It is important to differentiate clinical malaria from Plasmodium infection

• Clinical malaria emphasizes the concomitant signs and symptoms +malaria parasite

• Plasmodium infection is the presence of the parasite in the blood without symptoms –asymptomatic- some level of immunity

Etiology

• Plasmodium falciparum (>90% of infections and most dangerous)

• Plasmodium malariae (

Invasion Receptors/Ligands

Species Host

Receptor Merozoite

Ligand

P. falciparum glycophorins (sialic acid)

EBA-175

P. vivax, P. knowlesi

Duffy Ag DBP

7/06/2013 CME_LagMoH 12

Plasmodium falciparum

The Machine called Plasmodium

Malaria Case Management Goal

Overall Public health goal: reduction of the infectious reservoir

Specifically

• Early detection and prompt effective treatment to cure the infection and prevent progression to severe disease

• Proper management of severe disease to prevent death

• Prevention of the unset of drug resistance

• Reduction of malaria transmission


Recognizing Malaria may no longer be as easy as “looking and touching”

Hot body and Cold

Hot body and irritabilityHot body, weakness and malaise

Cold and rigorsHot body Hot body, palor and unconsciousness


7/06/2013 CME_LagMoH 15

Malaria Diagnosis

• Prompt, accurate diagnosis of malaria -

integral part of effective disease management

• Good quality tests improves management of

malaria, reduces unnecessary treatment with

antimalarial medicines, and improves

differential diagnosis of febrile illnesses

• Malaria diagnosis –clinical criteria – symptoms

detection of parasites in blood (parasitological or

confirmatory diagnosis – microscopy or RDT)7/06/2013 16CME_LagMoH

WHO Recommendation

• “Prompt parasitologic confirmation by

microscopy or alternatively by rapid diagnostic

tests (RDTs) is recommended for all patients

suspected of malaria before treatment is

started. Treatment solely on the basis of

clinical suspicion should only be considered

when a parasitological diagnosis is not

accessible”

WHO (2010) Malaria Case Management Guide

7/06/2013 CME_LagMoH 17

7/06/2013 CME_LagMoH 18

Test. Treat. Track

WHO, 2012

National Policy Recommendation

National Policy on Diagnosis & Treatment

of Malaria

• Recommends universal parasite-based

confirmation of fevers

• Exemption: Severe malaria

7/06/2013 CME_LagMoH 19

7/06/2013 CME_LagMoH 20

2011 Malaria diagnosis and treatment Guideline (FMoH, 2011)

Rapid diagnosis tests

Avantages :

Rapid and simple,

even in remote areas.

Disadvantages :

Missing low parasites

Microscopy

Avantages :

Simple equipement,

rapid, low cost.

Disadvantages:

Subjective, Training of

microscopists, Difficult

Molecular methods

Avantages :

sensitive, better

species discrimination.

Disadvantages:

High cost,

not field-adapted

Parasite-based Diagnosis of malaria


Malaria Microscopy Quality

Assurance

Provides guidance for

National QA

programme

Development of

national slide banks

Criteria for

accreditation of

microscopists

25/04/2013 Doctors discuss malaria 22

WHO manual on microscopy

QAHierarchical structure•Emphasis on re-training and accreditation standards•Sustainable cross-checking (less slides)•National slide banks

Competency

Selection

Training

Assessment

Equipment/ reagents

Support networkSlide /results delivery

Work environment

Performance

Supervisione.g. cross-checking??

25/04/2013 23Doctors discuss malaria

Malaria Microscopy Quantification

Plus system:• 1-10 parasites per 100 HPF………….

+

• 11-100 parasites per 100 HPF………

++

• 1-10 parasites per

HPF……………….+++

• >10 parasites per

HPF………………..++++

Less accurate

Misinterpretations

• QuantitativeParasite count X est. WBC (8,000) = Parasite/ul

bld

WBC count

Gives approximate density of parasites

per ul of blood

Relies on a predetermined range of WBCs

(200 -500)

Can only be applied on thick films

7/06/2013 CME_LagMoH 24

Semi-quantitative Plus system protocol in semi-quantitative hardly followedQuantification allows accurate follow-up of parasite clearance

Training/re-training, good quality reagents and workload of the microscopists

Highlights on Malaria Microscopy

• In current malaria epidemiological realities, MP

testing useful in patients with continued fever and

+ve malaria HRP-2 RDT – more referrals from

PHCs anticipated

• Permits demonstration (detection & speciation) and

quantification of parasites – esp. in-patients and

children

• High quality consumables, microscopes, and

competency of microscopists critical

• Low competency being addressed with capacity

building

• Quality Assurance frame-work being established7/06/2013 CME_LagMoH 25

Appropriate Malaria Diagnosis for

Developing Countries

• Prompt & timely

• Sensitive & Specific

• Guide therapeutic intervention

• Cost – effective and affordable

• Accessible to rural & urban populations

• Less laboratory sophistication

• Independent of electricity

• Easy-to-perform & interpret

• Non-subjective


State-of-the-arts on Malaria Rapid

Diagnostic Tests

Antigen detected NOT parasites

• Three antigens utilized:

Histidine-Rich Protein 2 (HRPII)

Plasmodium lactate dehydrogenase (pLDH)

Aldolase

Most RDTs are HRP-2 and pLDH

• Immunochromatographic antigen-capture device


Mal. RDTs Contd…

• Antibody detection (IgG, IgM, IgA) specific to

Plasmodium falciparum, P. vivax, P. ovale &

P. malariae

• Recombinant P.f & P.v Merozoite surface

protein (MSP) antigen coated on test band

however not too useful

HRP-2 RDTs RECOMMENDED FOR

PROGRAMMATIC USE IN POLICY


Histidine-Rich Protein II (HRPII)

• Specific to P. falciparum

• Abundant in cytoplasm & membrane of

infected erythrocytes

• Soluble & heat-stable antigen

• Composed largely of histidine & Alanine

• Stable in plasma & circulate for weeks

after clearance of parasitaemia


pLDH & Aldolase

• Rapid antigen clearance from circulation

• P. falciparum specific & pan specific

• Conserved major enzymes in the glycolytic pathway of Plasmodium sp

• Abundant & soluble in parasite’s cytoplasm

• More vulnerable to heat & humidity extremes

• Exhibit little intra-specific polymorphism

• Inter-species antigen variation

• Significant quantities released at time of cell rupture & febrile episodes


Rapid Malaria Tests (RDTs) Use when malaria microscopy is not available:

Health Centers and clinics without microscopy and also at OPDs and off-working hours in hospitals

Health care providers

Community health workers

Private pharmacies

Advantages:

No equipment required

Simplicity, requires minimal training

Rapidity of result

Quality assured mal RDTs available

But: requires some training, follow-up and supervision, need to build confidence in test results


RDT Procedural Steps: Summary

VI. Squeeze out a drop of blood

TEST DESCRIPTION

CONTROL WINDOW

C

TEST WINDOWT

SAMPLE WELL (BLOOD)

A

BUFFER WELL

B

36

ClinicalMicro-

scopyRDT Clinical

Micro-

scopyRDT

Referral Hospitals

District Hospitals

Health Centers

Private Clinics

Aid Posts/Volunteers

Private Pharmacies

Traditional Healers ?

Households ?

Past and FutureExpanding Parasite-based Diagnosis

The Paradigm Shift

WHO/FIND Malaria specimen bank development: Laboratory Network


7/06/2013 CME_LagMoH 38

Global Malaria Specimen Bank

WHO malaria RDT product testing

Round 1-3 results

P. falciparum

Rnd 1 (2008) 41 productsRnd 2 (2009) 29 productsRnd 3 (2010) 50 productsRnd 4 (2011) ~50 products


Positive Control Wells (PCWs) by FIND: Quality control for health workers


Opportunities in

parasitological confirmation of

suspected malaria cases

7/06/2013 CME_LagMoH 41

Why parasitological diagnosis of

malaria is necessary? (1)

• Clinical presentation of malaria least specific

• Causes of fever: non-serious viral infections to serious, life

threatening conditions that require immediate, appropriate

treatment

• Malaria infection can co-exist with other life-threatening

conditions e.g pneumonia

• When managing patients, it is difficult to know if the condition

is due to malaria or another disease solely on the basis of

clinical presentation

• Accurate diagnosis essential for optimal treatment to save

lives

• Dx more vital with successful malaria control where the

likelihood that malaria is the cause of fever is reduced 427/06/2013 CME_LagMoH

Why parasitological diagnosis of

malaria is necessary? (2)• Parasitological testing – only way to diagnose

malaria accurately in febrile patients

• Treatment based on diagnostic testing is good

clinical practice and has many advantages over

presumptive treatment of all fever episodes: Improved care of parasite +ve patients

Identification of parasite –ve patients in whom another diagnosis must be sought and

treated accordingly

Avoidance of antimalarial medicine use in parasite-ve patients, which reduces side

effects, drug interactions and selection pressure for drug resistance, potentially

resulting in financial savings

Better public trust in the efficacy of ACT when it is used only to treat confirmed

malaria cases

Better public trust in diagnosis and treatment of non-malaria causes of febrile illness

7/06/2013 CME_LagMoH 43

Manufacturer Test Company web sites Useable Specimen

ACON Laboratories Malaria P.f. Rapid Test http://www.aconlabs.com/ Whole blood

AmeriTek, Inc. One Step Malaria Test http://www.ameritek.org/ Whole blood

Binax NOW Malaria P.f./P.v. http://www.binax.com/ Whole blood

Bio-Quant, Inc One Step Malaria Test http://www.bio-quant.com/ Whole blood

Core Diagnostics Ltd. CORE Malaria (Pf, Pf/Pv, Pan Pf) http://www.corediag.com/ Whole blood

Cortez Diagnostics, Inc. OneStep RapiCard InstaTest http://www.rapidtest.com/ Whole blood

DiaMed SA OptiMAL Rapid Malaria Test d i amed.com Whole blood

Flow Inc. OptiMAL Rapid Malaria Test http://www.malariatest.com/ Whole blood

Genix Technology Malaria (P. fal.) Ag http://www.genixtech.com/ Whole blood

Genelabls Diagnostics Ltd. ASSURE® Malaria P.f. Rapid Test http://www.genelabs.com.sg/ Whole blood

Global eMed, LLC Smart Strip Malaria Test http://www.globalemed.com/ Whole blood

International Immuno-Diagnostics One-Step Malaria (PF/PV) http://www.intlimmunodiagnostics.com/ Whole blood

Kat-Medical KAT-Quick Malaria test http://www.katmedical.com/ Whole blood

Mega Diagnostics, Inc. MegaKwik Malaria (Pf) Card Test http://www.mega-dx.com/ Whole blood

Orchid Biomedical Systems Paracheck Pf http://www.tulipgroup.com/Orchid/ Plasma, whole blood

Premier Medical Corporation First Response Malaria P.f / P.v Antigen

Strips

http://www.premiermedcorp.com/ Whole blood

Princeton BioMeditech Corporation BioSign Malaria http: //www.pb mc.com Whole blood

SPAN Diagnostics ParaHIT f http://www.span.co.in/ Whole blood

Standard Diagnostics Inc. Malaria P.f/P.v Antigen Test

Malaria P.f/P.v Antibody Test

http://www.standardia.com/eng_product/ Whole blood, serum

Trinity Biotech Rapid Uni-Gold™ Malaria (Pf.) http://www.trinitybiotech.com/ Whole blood

Vencor International Inc. DxStrip Malaria Combo http://www.vencorinternational.com/ Whole blood


http://www.aconlabs.com/http://www.ameritek.org/http://www.binax.com/http://www.bio-quant.com/http://www.bio-quant.com/http://www.bio-quant.com/http://www.corediag.com/http://www.rapidtest.com/http://diamed.com/http://www.malariatest.com/http://www.genixtech.com/http://www.genelabs.com.sg/http://www.globalemed.com/http://www.intlimmunodiagnostics.com/http://www.katmedical.com/http://www.mega-dx.com/http://www.mega-dx.com/http://www.mega-dx.com/http://www.tulipgroup.com/Orchid/http://www.premiermedcorp.com/http://www.pbmc.com/http://www.span.co.in/http://www.standardia.com/eng_product/http://www.trinitybiotech.com/http://www.vencorinternational.com/

Malaria Test and Service delivery

• Opportunity for improving service delivery –

for malaria RDTs and Microscopy

• Improvement of diagnostic system

• Overall health system strengthening

• Dedication to service required: How can I

make things work in my facility? Is RDT

testing additional and undoable work for

me? How do I address the concerns of my

clients and provide satisfactory services?7/06/2013 CME_LagMoH 45

Misconceptions/beliefs and

Challenges in malaria testing

7/06/2013 CME_LagMoH 46

Misconceptions /beliefs

• All fevers are malaria

• Diagnosis not necessary

• 1-2 drops of blood from a patient is not

helpful to do a test considering the total

volume of blood in a patient

• Microscopy for MP test only real tests

• Malaria RDTs are not good (cross-reacts highly with other conditions…)

• Cost of diagnosis/Assumption of patient’s

inability to pay for test7/06/2013 CME_LagMoH 47

Misconception/beliefs

• Malaria RDTs used to test for HIV (among

patients)

• Malaria RDT testing not for Doctors,

Nurses, Chews, etc - ONLY for the Lab

(Healthcare providers says it is not their

job)

• Malaria RDTs not as good as Microscopy

• Too many negative tests – RDTs not good

7/06/2013 CME_LagMoH 48

Challenges in Malaria Diagnosis

• Over diagnosis of malaria – high reliance on clinical diagnosis of febrile illness and poor microscopy skills

• Microscopy: Reliance on high skills, electricity, workload, waiting time for results, unavailable in remote rural areas, subjectivity, lack of QA etc

• Detection of low density parasitaemia: false negatives

• Poor malaria microscopy skills & reporting

• Resistance to change by health workers

• Lack of confidence in malaria tests

• Poor access to diagnosis

7/06/2013 CME_LagMoH 49

Malaria Microscopy Quantification

Plus system:• 1-10 parasites per 100 HPF………….

+

• 11-100 parasites per 100 HPF………

++

• 1-10 parasites per

HPF……………….+++

• >10 parasites per

HPF………………..++++

Less accurate

Misinterpretations

• QuantitativeParasite count X est. WBC (8,000) = Parasite/ul

bld

WBC count

Gives approximate density of parasites

per ul of blood

Relies on a predetermined range of WBCs

(200 -500)

Can only be applied on thick films

7/06/2013 CME_LagMoH 50

Semi-quantitative Plus system protocol in semi-quantitative hardly followedQuantification allows accurate follow-up of parasite clearance

Training/re-training, good quality reagents and workload of the microscopists

Some Issues with Malaria RDTs

• Persistence of HRP II in circulation after parasite

clearance – false positive

• Variation in field trials but high quality RDTs now

available

• HRP II variation: Type A, B, & C sequenced

• Type B is current standards of HRP II

• HRP II deletions in some countries

• Low pLDH stability (shelf life) and performance

• Inability of RDTs to monitor the outcome of

treatment7/06/2013 51CME_LagMoH

Other Factors

a. Inability to read the bands by some health

workers

b. Co-morbidities e.g false +ve with rheumatoid

factor (very, very low and insignificant)

c. Poor knowledge of mechanism of action by

health workers

d. Aberrant use of expired RDTs

e. Poor or lack of illustrative pictorials on RDTs’

use


Field evaluation of Blood transfer devices:Blood transfer devices

– Challenges with blood transfer devices– Improvement of blood transfer devices (accuracy, safety,

and ease-of-use).

UgandaNigeriaPhilippines

Heidi Hopkins et al., (2011). Blood transfer devices for malaria rapid diagnostic tests: evaluation of accuracy, safety and ease of use. Malaria Journal 2011, 10:30 25/04/2013 53Doctors discuss malaria

7/06/2013 CME_LagMoH 54

2011 Malaria diagnosis and treatment Guideline (FMoH, 2011)

7/06/2013 CME_LagMoH 55

Moving forward – Making

progress: Expectations and

deliverables

7/06/2013 CME_LagMoH 56

Current Malaria Realities

Health Workers/Patients

• High malaria negative tests

• More follow-up required for

RDT –ve patients

• Counseling of Patients on

withholding antimalarials

• Low testing in facilities

• Behavioural

modification/reorientation/tr

aining

• Low patient education on

tests

Diagnostic Tools

• Growing improvement in

testing and provision of

tools/commodities

• Quality of tests and

reagents need to be

sustained

• Superior tests – case

management, monitoring

interventions, tracking

resurgence…

• Development of Quality

Assurance in-country at

all levels7/06/2013 CME_LagMoH 57

Global picture

• WHO global policy of universal parasite-based diagnosis before treatment

– Long accepted in Asia and South America

– Now policy in nearly all endemic African countries

• Increased availability of operational funds

• Poor quality global data on malaria transmission

• ACT as first-line therapy: higher cost of treatment, and imperative to preserve efficacy

• Demonstration that RDT use can reduce ACT consumption safely in wide scale use


Picture from the field

• High performing malaria RDTs in field trials (90 -98%

sensitivity and specificity among good RDTs)

• Diagnosis before treatment still poor

• Most RDTs (and microscopy) results are parasite-negative

• Growing capacity of Microscopists to detect malaria

• Rapidly-declining prevalence in many areas: large regions

of low and patchy transmission, with risk of re-emergence

(need to sustain gains, and invest more)

• Drive to Elimination of malaria in low-transmission regions

• Diagnostic commodities yet to match antimalarial medicine

deployment


7/06/2013 CME_LagMoH 60

Diagnostic options in the pipeline

• Magneto-optical biosensors for malaria Test

(MOT) - targets haemozoin in vivo?

• Urine tests?

• Maliva: a malaria-detecting gum that could offer

cheap, new way to diagnose or monitor

diseases?

• Mobile microscopy (hand-held digital

microscopes/cameras)?

• LAMP: Loop mediated isothermal pcr (current

testing shows over 95% sensitivity)• Equivalent capacity with current best-performing RDTs will prove their

usefulness7/06/2013 61CME_LagMoH

http://news.discovery.com/animals/swine-flu-animal-trading.html

62

Population screening and LAMP

Interspecies variability(GC-2) (GC-2) (GC-2) (GC-1) (GC-1) (GC-3)

Primers amplifying Plasmodium mitochondrial DNA

Development underway of Loop-mediated isothermal DNA amplification (LAMP) that detects 1-6 parasites /l with minimal sample processing that requires no sophisticated equipment and can be read with the naked eye (FIND, Eiken).2013 report shows over 98% sensitivity

(+)(-)

In areas with low-transmission, a large proportion of patients with malaria are likely to have less than the 100 p/ml detected by RDTs.

Moving to population screening tests

15/07/201110th NMCP Best Practices Sharing

Workshop 13 - 15 July, 2011

Summary: Parasite-based diagnosis and ACT

If no parasite-based diagnosis:

– Most recipients of ACT will not have malaria

– Patients with non-malarial febrile illness will receive wrong or late treatment

– Malaria incidence rates will be unavailable• (Poor resource allocation, poor planning, no elimination)

However, delaying ACT raises malaria mortality:

– Improving access to ACT is essential, should not be delayed

Diagnosis needs to catch up to treatment.


What facilities should do

• Get acquainted with current guideline & Review

malaria case-management SOPs

• Scale-up prompt and quality assured diagnosis

• Provide access to Testing: Use quality-assured

Diagnosis & ACTs – AVOID STOCK-OUT!!!

• Re-orientation of health workers

• Test request should go beyond etiology given high

rates of non-malarial fevers

• Expand platform to conduct supplementary tests e.g

FBC/differentials in the context of fever diagnosis

7/06/2013 CME_LagMoH 64

In facilities…

• Effectively communicate reasons for malaria testing to

patients at consultation and blood draw

• Organize seamless ways for prompt testing especially

with malaria RDTs at OPDs

• Shorten turn-around time and make results available –

engagement and planning critical

• Procure quality RDTs and consumables for MP testing

• Monitoring/evaluation and review outcomes of fever

management – creating own evidence

• Keep accurate data and frequently analyze for trends

7/06/2013 CME_LagMoH 65

What institutions can do

• Research and innovation on malaria

diagnostics, drugs and vaccines

• Malaria surveillance

• Capacity building for health workers

• Other support for malaria control

7/06/2013 CME_LagMoH 66

67

ClinicalMicro-

scopyRDT Clinical

Micro-

scopyRDT

Referral Hospitals

District Hospitals

Health Centers

Private Clinics

Aid Posts/Volunteers

Private Pharmacies

Traditional Healers ?

Households ?

Past and FutureExpanding Parasite-based Diagnosis

The Paradigm Shift

Closing Messages

• Quality assured RDTs as good as expert microscopists

• RDTs supplied by Government in Nigeria are among the

very best available globally

• Malaria microscopists are being trained for improvement

• Trust your test results and use it to guide antimalarial

prescriptions

• Refer patients to facilities where lab tests can be done

• Malaria testing done in the overall fever context - don’t

close your eyes and insist that it must be malaria – many

other causes of fevers – life threatening ones can be

neglected in the process

• Testing for malaria and withholding antimalarials will

require follow up but do it

• Document evidence – keep accurate records and analyze7/06/2013 CME_LagMoH 68

Conclusion

• Prompt and accurate malaria diagnosis is key to effective malaria case management – reorientation imperative

• High quality RDTs are available for prompt diagnosis

• Parasitological confirmation of malaria still low –scaling up diagnosis to meet national target of 80% is critical

• Dealing with misconceptions and barriers critical to effective and sustainable malaria diagnosis

• Routine monitoring of efficacy of antimalarial medicines dependent on the institutionalization of an effective and efficient malaria diagnostic system

• PCWs by FIND – a useful tool for RDT QA in the field7/06/2013 69CME_LagMoH

Remember, without diagnosis,

medicine is blind!

7/06/2013 CME_LagMoH 70

Malaria diagnostic activities at University of Lagos

Microscopy and RDT Training Certification of MicroscopistsSlide-Banking External QA QA of RDTs (in-country lot testing, field testing, post-purchaseMalaria Indicator Surveys in communities7/06/2013 71CME_LagMoH

Acknowledgement

• WHO/TDR (Geneva)

• WHO/AFRO/Nigeria

• Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland

• NMCP (Nigeria)

• Society for Family Health; SuNMAP

• NIMR

• LagMoH

• EQA programmes in South Africa & Oman

• WHO (Western Pacific) & Philippines MoH

• Dedicated staff

• College of Medicine University of Lagos/LUTH

• Malaria Consortium/DFID, UK

• USAID/MAPS7/06/2013 72CME_LagMoH

Thanks for your attention!

7/06/2013 CME_LagMoH 73

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Diagnosis of Malaria: Best practices, Issues and way forward€¦ · protein (MSP) antigen coated...

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