Gl o ba l M alaria Programme

WHO Malaria Policy Advisory

Committee (MPAC) meeting
SEPTEMBER 2016 MEETING REPORT

SUMMARY

On 14–16 September 2016, the WHO Malaria Policy Advisory Committee (MPAC)
convened to review updates and progress, and provide guidance with respect to
specific thematic areas of work carried out by the Global Malaria Programme
(GMP).

The meeting included nine sessions focused on: (1) an update on the RTS,S
vaccine pilot implementation programme; (2) an update on the malaria
elimination in the Greater Mekong subregion; (3) a review of Malaria
elimination: an operational manual; (4) the results from a multi-country
evaluation of the impact of insecticide resistance on malaria vector control;
(5) an update on the Strategic Advisory Group on malaria eradication; (6) an
update on the development of guidelines for malaria vector control; (7) the
development of the Global Vector Control Response; (8) a proposed evidence
review group to consider the cardiotoxicity of antimalarial medicines; (9) a
report on the WHO technical consultation on detection and surveillance of
HRP2/HRP3 deletions; (10) recommendations for the surveillance, monitoring
and evaluation taskforce; (11) a proposed evidence review group to review
Plasmodium knowlesi; (12) the proposed target product profile for ivermectin;
and (13) proposed plans for the World Malaria Report.

At the closing session, the key outcomes/recommendations of MPAC to GMP

included:

• RTS,S vaccine: MPAC reiterated the urgent need to launch the RTS,S
pilot implementation projects as per the November 2015 joint SAGE-
MPAC recommendation, including an assessment of the impact on
mortality. Neither the design nor the sample size should be changed.
MPAC urged GMP and partners to vigorously pursue ways to cover the
current funding shortfall and agreed on a statement to highlight the
importance of the pilot projects.

WHO/HTM/GMP/MPAC/2016.14
 • Malaria elimination in the Greater Mekong subregion: MPAC noted the
progress that is being made in the region. In response to a comment that there
is new evidence indicating that partner drug resistance is being driven by
artemisinin resistance and that a few multidrug resistant parasite lineages are
outcompeting the other P. falciparum parasites and spreading geographically.
WHO called for the submission of the new evidence, which will be quickly
reviewed. The assessment of the relevance of the information, and the
potential implications will be reported back to MPAC.

• Malaria elimination: an operational manual: MPAC concluded that the

manual is comprehensive, and has incorporates several new elements based
on the growing evidence base is a valuable update to the previous manual;
additional suggestions were provided to improve clarity.

• Results of the Impact of Insecticide Resistance Project: MPAC highlighted

that the study findings reaffirm the key public health role that pyrethroid
impregnated long lasting insecticidal nets continue to play in the
face of emerging insecticide resistance and support the current WHO
recommendations in accordance with GPIRM, and do not indicate a need for
changes to current policy. However, MPAC reiterated the need to re-evaluate
the evidence base periodically and reaffirmed the urgent need to continue
research into, and development, of new classes of insecticides and new tools
for vector control to effectively manage insecticide resistance.

• Strategic Advisory Group on malaria eradication: MPAC supported the two

key decisions of the SAG meeting: 1) to develop a position statement that
clarifies the current terminology and confirms WHO’s commitment to long-
term malaria eradication, and 2) to undertake analyses to provide advice to
WHO on the determinants, expected cost, timeframe, and potential future
strategies for malaria eradication over the ensuing decades.

• Malaria vector control guidelines: MPAC noted that there are a number
of documents for vector control and supported the harmonization and
preparation of an evidence-based document using the formal WHO process
including external review.

• Global Vector Control Response: MPAC commended the progress in the

development of the GVCR over an abbreviated timeframe and highlighted
the need for disease control and vector experts to work more closely together
across diseases and to ensure the meaningful inclusion of non-health sectors.

• Cardiotoxicity of antimalarial medicines: MPAC strongly supported the

convening of the ERG to review the cardiotoxicity of quinoline antimalarial
medicines and the proposed list of experts suggested.

• Detection and surveillance of HRP2/HRP3 deletions: MPAC noted the serious

threat posed by these gene deletions and appreciated the update on the
situation. MPAC broadly agreed with the recommendations from the WHO
consultation, and urged GMP to monitor closely the possible spread of these
parasites given the strong selective pressure that the deletion would impose
and to develop a plan of action for surveillance and response that can be
supported by partners and implemented in countries.

• Surveillance, monitoring and evaluation taskforce recommendations: MPAC

noted that the collection and analysis of the proposed indicators is essential for
country and global monitoring and provided proposed additional indicators,
while noting that only essential data should be collected.

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 • Evidence review group on Plasmodium knowlesi: MPAC strongly supported
the proposed ERG on P. knowlesi and suggested expanding the scope to
include other primate malarias which may naturally infect humans – notably
P. cynomolgi.

• Ivermectin target product profile: MPAC made several suggestions on the

proposed target product profile including the need to define “significant
reduction”, to assess the feasibility of defining a measurement of effect in
vectors as an interim endpoint, to make the target product profile generic
rather than exclusively for ivermectin, to characterize biologically active
metabolites that may explain prolonged endectocidal activity, and that weekly
dosage is not operationally feasible based on current MDA experience. MPAC
will review the revised profile electronically.

• World Malaria Report: MPAC supported keeping a hard copy version of the
World Malaria Report as a useful reference, and making the country profiles
online only. MPAC cautioned that access to Internet remains a barrier in many
parts of the world but agreed that it would be useful to enhance the contents in
the online version.

BACKGROUND

The WHO Global Malaria Programme (GMP) department convened the Malaria
Policy Advisory Committee (MPAC) for its tenth meeting in Geneva, Switzerland
on 14-16 September 2016. MPAC convenes twice annually in Geneva to provide
independent strategic advice to WHO on policy recommendations for malaria control
and elimination. The Committee is supported by technical expert groups and ad
hoc evidence review groups, whose work focuses on thematic areas and specific
research questions in order to generate sufficient evidence to provide guidance.
Over the course of the two-day meeting’s open sessions, 13 MPAC members, four
national malaria control programme managers, the WHO Secretariat and 53
observers discussed the updates and progress in the areas of work presented.
Recommendations were discussed in the final closed session of the committee.

UPDATES FROM THE GLOBAL MALARIA PROGRAMME

The GMP Director opened the meeting by providing general updates on the work
of the WHO-GMP units: Entomology and Vector Control; Prevention, Diagnostics
and Treatment; Strategy, Evidence and Economics; Surveillance, Monitoring and
Evaluation; and Technical Support and Capacity Building. In addition, he presented
key messages from findings from WHO’s Eliminating malaria report, including the
significant increase in the number of countries with very low number of cases reported
annually since 2000 and the identification of 21 countries with the potential to eliminate
local transmission by 2020. The Director highlighted critical areas of work including
the effort to develop a Global Vector Control Response in collaboration with the
Department of Neglected Tropical Diseases and the Special Training Programme for
Research and Training in Tropical Diseases; work to better understand coverage gaps
in diagnostic testing and treatment and how to address them; highlights from the
Greater Mekong subregion; and the work of the newly established Strategic Advisory
Group on malaria eradication.

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 SUMMARY OF THE MPAC SESSIONS

Update on RTS,S/AS01 vaccine pilot implementation programme

Background: The Initiative for Vaccine Research (IVR) and GMP provided an update
on progress with the RTS,S pilot implementation including an update on the country
selection, study design, engagement with PATH and GSK, integration of Phase IV
studies and pilot implementation, and funding commitments. There is currently a
critical funding gap after commitments from GAVI and UNITAID. The consequences
of not proceeding with the pilots after the EMA positive opinion and WHO
recommendation will be serious for the development of malaria and other vaccines
targeted at low income countries in the future to meet public health needs in low-
income countries.

MPAC conclusions: MPAC supported the efforts made by GMP and IVR to move
towards launching the pilot implementation by liaising and planning with the partners
involved. MPAC reiterated the strong support for the WHO recommendation on the
pilot implementation based on a (i) comprehensive, thorough scientific evaluation,
(ii) a WHO recommendation, and (iii) a positive opinion from the European Medicines
Agency (EMA). MPAC strongly opposes any reduction in the scope of the planned
studies, the sample size or in the number of countries in response to resource
limitations as it considers that this would seriously undermine the rationale for, and
scientific integrity of the pilot implementation. MPAC urged GMP and partners to
urgently consider options to cover the funding shortfall as upcoming decision points for
several partners puts the pilot implementation at risk. Finally, MPAC observed that a
failure to move towards the recommended pilot implementation despite the mandate
from SAGE and MPAC, two global health advisory bodies, also reflects a fundamental
gap in the public health funding architecture to support pilot implementation of
new interventions developed exclusively for low-income countries, after obtaining
regulatory and policy approval. MPAC recommended that a communications strategy
be developed to raise public awareness on this issue and suggested a separate
communication from the MPAC to the WHO Director General.

Update on malaria elimination in the Greater Mekong subregion

post Emergency Response to Artemisinin Resistance

Background: Based on the Strategy for malaria elimination in the Greater Mekong
subregion (GMS), with the goal of eliminating malaria by 2030 (P. falciparum malaria
by 2025), the former Emergency Response to Artemisinin Resistance (ERAR) hub
together with the WHO Regional Offices for South-East Asia and the Western Pacific
and other partners have supported countries in the subregion to develop national
strategies for elimination. At the end of 2016, the ERAR hub will transition from
containment to elimination and provide support for capacity building and technical
collaboration, cross border collaboration, monitoring product quality, priority research,
surveillance and monitoring and evaluation, and coordination and governance.
Insecticide resistance monitoring indicates no evidence of resistance in An. dirus
throughout the GMS and no evidence of vector resistance in Myanmar and Thailand.
Resistance to DDT has been identified in Lao People’s Democratic Republic and some
pyrethroid resistance has been identified in Viet Nam and Cambodia. Summary results
from molecular studies with Kelch 13 (K13) have confirmed that artemisinin resistance
has emerged independently in all countries of the GMS; therapeutic efficacy studies
indicate that the majority of cases that have delayed parasite clearance still clear
their infections provided that the artemisinin combination therapy (ACT) partner
drug remains effective, even in areas of high prevalence of K13 mutants; and the
declining number of cases in some study sites requires a longer study period to meet

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the required number of study participants. Monthly monitoring in all countries shows
a trend of declining cases compared to 2015, although key policy and implementation
challenges remain.

MPAC conclusions: MPAC noted the progress that is being made in the region and
asked what more should be done. The current analysis from the regional experts is that
with the Global Fund commitments, lack of funding is not the constraint to accelerating
progress. Insufficient political commitment to action and country leadership were
identified as the limiting factors. Other aspects of the programme which could be
improved are cross-border collaboration, health systems strengthening and the need
for more data to indicate if insecticide resistance is an urgent issue for the region.
Some on the committee called for urgent action, commenting that new evidence
suggests that partner drug resistance is being driven by artemisinin resistance and that
a few multidrug resistant parasite lineages are outcompeting the other P. falciparum
parasites and spreading geographically. WHO called for the submission of the new
evidence, which will be quickly reviewed. The assessment of the relevance of the
information, and the potential implications will be reported back to MPAC.

Review of Malaria elimination: an operational manual

Background: The 13-member Evidence Review Group was first convened in

September 2015 and has met three times to support the development of the revised
Malaria elimination: an operational manual. An advanced draft was shared with
MPAC for input before the document is further circulated to national malaria control
programme managers and finalized for publication. Key new elements in the
manual compared to the 2007 version include: all levels of malaria transmission are
included instead of only moderate and low endemic settings; programme actions are
highlighted across the continuum of transmission from high to no transmission; the
critical role of information systems and surveillance as an intervention is emphasized;
both rapid diagnostic tests (RDTs) and light microscopy are recommended for malaria
diagnosis; focus classification has been simplified to three instead of seven types;
the proposed process for certification is simplified; and a proposed threshold for the
potential for re-establishment of transmission. MPAC was asked to comment on the
overall content, in addition to providing specific inputs on malaria terminology; the
continuum of transmission; diagnostic testing in elimination settings; and the revised
WHO certification process.

MPAC conclusions: MPAC concluded that the manual is comprehensive and has
captured much needed and long awaited updates to the previous manual such as
revisiting the foci classification, including RDTs in the diagnostic tool kit, and others. The
revised manual also addresses countries through the entire range of transmission and
not only those with low or moderate transmission intensity, consistent with the Global
Technical Strategy. However, MPAC cautioned that in its current form, the manual
risks confusing countries by implying that they should abandon their malaria control
strategies and re-plan for a goal of elimination regardless of the current level of
transmission. It was suggested that the document could be more concise by including
a summary in the beginning of every chapter and placing more descriptive material in
annexes. MPAC members will send additional comments on the manual electronically.

Results of the Impact of Insecticide Resistance Project

Background: Major gains have been made against malaria in recent years, largely
through the substantial scale-up of insecticidal interventions targeting Anopheles
mosquitoes including long-lasting insecticidal nets (LLINS) and indoor residual
spraying (IRS). However, their effectiveness is threatened by widespread resistance

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 to insecticides. Efforts to manage this threat, in line with the WHO Global plan for
insecticide resistance management in malaria vectors (GPIRM, 2012), have been
restricted by numerous factors including the dearth of evidence linking resistance to
decreased vector control effectiveness. To address this absence of evidence, a multi-
country evaluation was undertaken in Benin, Cameroon, India, Kenya and Sudan from
2009 to 2016, coordinated by WHO. This represents the first initiative to assemble
a large data set of connected entomological and epidemiological observations to
provide quantitative insights on the implications of insecticide resistance on malaria
vector control effectiveness across different transmission settings. Key conclusions
from the study were that there was: 1) strong evidence that LLINs provide personal
protection against malaria across all the study areas; 2) no detectable evidence
of a difference in LLIN personal protection effectiveness between areas with either
higher or lower pyrethroid resistance; 3) some evidence of loss of community
protection in higher resistance clusters 4) no evidence of an increase in malaria
disease burden associated with higher levels of pyrethroid resistance; and 5) a
possible trend of increasing resistance across some of the evaluation areas. Further
conclusions were that in one area of Sudan with pyrethroid resistance but bendiocarb
susceptibility, 1) adding deltamethrin IRS to LLINs provided no additional protection
whereas adding bendiocarb IRS to LLINs almost halved malaria incidence relative
to LLINs alone and 2) that carbamate IRS in addition to LLINs appeared to slow the
emergence of pyrethroid resistance relative to LLINs only. It was noted that insecticide
resistance was highly labile between years and showed marked heterogeneity on a
relatively fine scale, which indicates the need for improved phenotypic tests and has
implications for sentinel site monitoring. Publication of country-specific results in peer
reviewed journals is ongoing, and final consolidated outcomes will be presented at
a Symposium at the American Society of Tropical Medicine & Hygiene (ASTMH) 65th
annual meeting in November 2016 and followed by a summary publication.

MPAC conclusions: MPAC supported the conclusion that the data indicate that LLINs
are still providing personal protection working across a range of levels of pyrethroid
resistance, although the evaluation areas did not represent areas with of the high
levels of resistance as seen, for example, in West Africa. MPAC cautioned that the
analyses showing some evidence of the loss of community protection could be due
to confounding as the study, by definition, could not be fully randomized. Further
studies may be required to verify this finding. MPAC also noted that limited data are
available on vector behaviour from the evaluation area which may have been useful
in interpreting the study outcomes. MPAC highlighted that the study findings support
the current WHO recommendations in accordance with GPIRM, and do not indicate
a need for changes to current policy. However, MPAC noted that this study was
descriptive rather than a randomized trial and that the results should be treated with
caution. MPAC also reiterated the need to re-evaluate the evidence base periodically
and reaffirmed the urgent need to continue research into, and development of,
new classes of insecticides and new tools for vector control to effectively manage
insecticide resistance.

Strategic Advisory Group on malaria eradication meeting

outputs

Background: GMP convened the inaugural meeting of the Strategic Advisory Group
(SAG) on malaria eradication comprised of 13 leading experts across a variety of
disciplines, supported by WHO Collaborating Centres and other key stakeholders on
29–30 August 2016. Invited speakers addressed the lessons learned from previous
eradication efforts on smallpox and polio and SAG members presented potential
key determinants of malaria eradication including economic development; poverty;
population growth, movement and dynamics; and urbanization. The SAG agreed that
although malaria eradication is epidemiologically feasible, it is likely not technically

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possible with the current tools; that research and innovation must continue and will
drive the effort; and that WHO needs to lead the eradication debate and reaffirm
the commitment to malaria eradication while explicitly NOT launching an eradication
campaign. Two key decision points from the SAG meeting were was that 1) a position
paper on malaria eradication should be presented to the Executive Board in January
that clarifies WHO’s long-term commitment to eradication and 2) in parallel, the SAG
will coordinate and direct a two-year scope of work to analyse future scenarios for
malaria, taking into consideration a broad set of biological, technical, socioeconomic,
political and environmental determinants, including potential products of innovation.
Based on these analyses, the SAG will provide advice to WHO on the timeframe,
expected cost and potential strategies of malaria eradication over the ensuing
decades.

MPAC conclusions: MPAC noted that there is confusion regarding the WHO position
on malaria eradication. While the goal has always been a world free from malaria
as articulated in the Global Technical Strategy, that does not imply a time bound, fully
financed malaria eradication campaign. MPAC supported the two key decisions of the
SAG meeting: 1) to develop a position statement that clarifies the current terminology
and confirms WHO’s commitment to long-term malaria eradication, and 2) to
undertake analyses to provide advice to WHO on the determinants, expected cost,
timeframe, and potential strategies for malaria eradication over the ensuing decades.

Development of malaria vector control guidelines

Background: GMP is in the process of developing consolidated vector control

guidelines to 1) provide global evidence-based recommendations on vector control
strategies and tools for malaria control and elimination, and 2) provide a framework
for the development of specific and more detailed national vector control strategies
and protocols, promoting the use of effective malaria control measures at the
national level based on the best available evidence. Key topics that will be covered
in the guidelines include: core malaria control interventions, complementary vector
control interventions, issues and challenges in implementation, vector control by eco-
epidemiological settings, vector control under special circumstances, and new tools
and methods for malaria vector control. The development is guided by an internal
WHO Steering Group, a Guideline Development Group (Vector Control Technical
Expert Group), and an external review group. The guidelines are anticipated to be
launched by the end of 2017.

MPAC conclusions: MPAC noted that there are a number of documents for vector
control and supported the harmonization and preparation of an evidence-based
document using the formal WHO process including external review. MPAC further
noted that the timelines are ambitious and cautioned that the rate limiting factor may
be the availability of evidence based data and the review process. The guidelines will
need to include aspects related to safety, resistance, quality assurance, pregnancy,
and the combination of interventions. Guidelines for post-elimination settings should
be included without using the term “scaling-back.” MPAC suggested engaging malaria
programme managers and partners to ensure that the guidelines meet their needs.

Development of the Global Vector Control Response

Background: Vector-borne diseases account for 22% of the estimated global burden
of all infectious diseases and the world has recently witnessed a significant re-
emergence of vector-borne diseases. Although impressive global reductions in
malaria have been attributable in large part to the massive scale-up of LLINs and

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 IRS, a critical lack of human, infrastructural and financial capacity has hampered
sustained and successful vector control more broadly. Following support expressed
by Member States at the Sixty-ninth World Health Assembly and the 139th meeting
of the Executive Board, the WHO Secretariat was requested to develop a Global
Vector Control Response (GVCR). This development process is co-led by the Global
Malaria Programme, the Department of Control of Neglected Tropical Diseases,
and the Special Programme for Research and Training in Tropical Diseases, and is
supported by a Steering Committee. An advanced draft of the GVCR will be discussed
by the WHO Executive Board at their 140th meeting. The vision of the draft GVCR is
a world free of vector-borne diseases that affect humans and the goal is to reduce
the burden and threat of vector-borne diseases through sustainable, effective vector
control. The draft objectives of the response are: to strengthen vector control as a key
strategy for vector-borne disease reduction and prevention, including environmental
management in urban and rural development initiatives; to establish and enhance
intersectoral collaboration for integrated action; to develop locally adaptive systems
for efficient vector surveillance and control; to enhance and link entomological and
epidemiological evidence in order to optimize the planning and implementation of
vector control; and to ensure government and partner commitment to vector control
through legislation, policy and planning. The Response currently comprises four pillars:
1) inter-and intra-sectoral action and collaboration; 2) enhanced entomological
surveillance, and vector control monitoring and evaluation; 3) scale-up and integration
of tools/approaches; and 4) community engagement and mobilization. It is based on
a foundation that will enhance human, infrastructural and health systems capacity;
adapt programmatic systems, structure, and policies and improve regulatory and
normative support; increase basic and implementation research and innovation;
and enhanced advocacy, resource mobilization and coordination of partner support.
An electronic version of the Response will be shared with MPAC for comment before
submission to the Executive Board in October 2016.

MPAC conclusions: MPAC commended the progress in the development of the GVCR
over an abbreviated timeframe. Key areas of discussion were that the development
of entomology career avenues are required to inspire young entomologists and that
public health teaching courses should include an entomology component. MPAC
felt that non-entomology leadership should be sensitized and vector control success
stories (e.g. LLINs scale-up to reduce malaria) can be used to raise the visibility of
vector control and the need to strengthen the vector control component of national
programmes for maximum impact. There is a need for disease control and vector
experts to work more closely together across diseases and to ensure the meaningful
inclusion of non-health sectors. MPAC will provide comments on the next draft
electronically.

Proposed evidence review group on cardiotoxicity of

antimalarial medicines

Background: A prolonged QTc interval is a risk factor for ventricular tachyarrhythmias,

such as torsades de points (TdP), which can cause sudden cardiac death,
particularly when the QTc interval is over 500 msec. TdP as a drug side effect has
been a major reason for withdrawal of several medications from the market, in
spite of the unclear relationship between drug-induced prolongation of the QTc
interval and predictors of life-threatening ventricular tachyarrhythmias. Several
quinolone antimalarial medicines are associated with a prolonged QTc interval,
namely chloroquine, quinine, mefloquine, and piperaquine (deployed in fixed dose
combination with dihydroartemisinin). As WHO has now recommended mass drug
administration (MDA) to be considered for use in the elimination of P. falciparum
malaria in areas approaching interruption of transmission and for emergencies/
epidemics, there is a need to better understand these specific risks in relation to the

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benefits of antimalarials. In collaboration with the WHO Department of Essential
Medicines and Health Products, and following the EMA and US Food and Drug
Administration (FDA) recommendations for experts, GMP consulted with a small
group of expert cardiologists and expert cardiologists with particular expertise
related to the physiology of conduction defects related to prolonged QTc intervals
on how best to proceed with a review of the cardiotoxicity of antimalarial medicines.
The specific objectives of the proposed Expert Review Group (ERG) will be the
following: 1) to evaluate the risk of sudden unexplained death following exposure to
quinolone antimalarials; 2) to assess the dose-response effect and risk factors of the
QTc prolongation from pharmacokinetic/pharmacodynamic (PK/PD) studies of the
main artemisinin ACTs used in Africa; 3) to analyse the PK/PD effect of piperaquine
in healthy volunteers and malaria patients, based on comparative clinical trials
of dihydroartemisinin-piperaquine, arterolane-piperaquine and artefenomel-
piperaquine; and 4) to identify evidence gaps and provide recommendations for
additional studies, including meta-analyses of individual patient dose-response effects
and risk factors for QTc prolongation following exposure to different antimalarial
medicines. The conclusions of the ERG and draft recommendations will be presented
to MPAC in April 2017.

MPAC conclusions: MPAC strongly supported the convening of the ERG to review the
cardiotoxicity of quinoline antimalarial medicines and the proposed list of experts
suggested. MPAC suggested that data on pregnant women be included and that
sudden death cases should be investigated. The Committee further noted that data on
cardiotoxicity during misuse/self-medication of antimalarials may be very relevant for
the review but very limited in number.

Report of WHO technical consultation on detection and

surveillance of HRP2/HRP3 deletions

Background: A technical consultation on P. falciparum HRP2/3 gene deletions was

held on 7–8 July 2016 at WHO with seven objectives: 1) Review the currently available
data, and define the scope and scale of pfhrp2/3-deleted parasite populations based
on published or in-press reports and recent unpublished investigations; 2) discuss
options for expanded mapping of pfhrp2/3 deletions; 3) review and update current
recommended procedures for investigating and reporting pfhrp2/3 gene deletions;
4) develop a plan for technical support for countries conducting investigations
into suspected pfhrp2/3 gene deletions; 5) propose alternative RDT-procurement
and case-management strategies for areas affected by pfhrp2-deleted parasites;
6) review the landscape of new tools for non-HRP2 based malaria diagnosis; and
7) update WHO interim guidance on pfhrp2 gene deletions.

Key conclusions from the meeting included: WHO should promote a harmonized
approach to investigating, surveying and reporting pfhrp2/3 gene deletions through
the provision of standard protocols (including sample size calculations) and operating
procedures, and provide a list of reference laboratories; surveillance activities
should first target countries where deletions or concerns have been identified and
neighbouring countries; deletions identified and confirmed by a reference laboratory
should trigger prospective investigations; strengthening complaint reporting
mechanisms and educating supervisors and malaria programme staff about pfhrp2/3
gene deletions is recommended; procedures should be revised to indicate the roles
and responsibilities of stakeholders at each level of the health system; the national
malaria programme coordinates the investigation and response that generates the
initial and confirmatory evidence; WHO should establish a consortium to provide
technical support to investigate suspected false negative RDTs due to pfhrp2/3
deletions, to establish appropriate surveillance systems and to elaborate the factors

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 influencing the emergence and spread of pfhrp2/3 deletions; a nationwide change
to an RDT that detects non-HRP2 target antigens for P. falciparum is recommended
when a prevalence threshold of patients carrying pfhrp2 deleted parasites meets or
exceeds the lower 90% confidence interval for 5% prevalence; if the prevalence is < 5%,
plan for change over a longer timeframe, as it is anticipated that pfhrp2/3 deleted
parasites will persist and spread; acquiring additional surveillance data would help
prioritize roll-out of non-HRP2-based RDTs; in all other cases, if pfhrp2 deletions
are confirmed in samples from any source, establish prevalence through sentinel
site surveillance or surveys; tests with both HRP2 and pLDH antibodies on the same
test line should be prioritized for assessment by WHO prequalification; programmes
should not replace Pf only HRP2-based RDTs with current HRP2/pan-pLDH or aldolase
combination tests for the purpose of detecting non-HRP2 expressing parasites; WHO
should promote new test development and improvements of existing tests as well
as improved manufacturing processes; work with procurers to ensure an adequate
pricing structure; and endeavour to accelerate prequalification/regulatory processes
and conduct field evaluations of new tests and electronic readers for non-HRP2-based
malaria diagnosis.

MPAC conclusions: MPAC highlighted that further research is needed to understand

differences, if any, in the distribution and frequency of pfhrp2/3 gene deletions
between symptomatic and asymptomatic populations, and guidance should be
given about HRP2-based tests for asymptomatic infection in low transmission or
for focal strategies. MPAC noted the geographical heterogeneity in South America
and elsewhere and questioned whether a single prevalence threshold in a focus is
appropriate for switching national policy and whether the concept of “neighbours”
is useful given the current spatial distribution. On microscopy, MPAC highlighted the
need to continue to promote the need for quality assurance in malaria microscopy,
but acknowledged that microscopy cannot be performed in all settings and that the
lack of confidence and use of RDTs may result in a return to presumptive treatment.
MPAC stressed the need to increase the availability of non HRP2-detecting RDTs on
the market noting that the fees for pre-qualification may be a barrier to diagnostics
manufacturers, and questioned how the supply of non-HRP2 tests may increase to
respond to the needs of countries when changing RDTs because of the prevalence of
pfhrp2 gene deletions. MPAC urged GMP to strengthen the direct dialogue with RDT
manufacturers and to urgently develop a plan of action for surveillance and response
that can be supported by partners and implemented in countries.

Recommendations from the surveillance, monitoring and

evaluation (SME) taskforce

Background: The purpose of the taskforce recommendations are to describe how the
Global Technical Strategy (GTS) and Action and Investment to defeat Malaria (AIM)
will be monitored and evaluated, including a list of recommended indicators along
the continuum from high transmission to elimination; milestones for the development
of information systems; the use of information for decision-making and programme
performance; and the definition of institutional responsibilities for monitoring and
evaluation at the different levels. These recommendations are intended for managers
of national malaria programmes and health information systems and are relevant to
other implementing partners and financiers of malaria programmes of information
systems development.

MPAC conclusions: MPAC was asked to comment on the appropriateness of

the proposed indicators and milestones and provided both general and specific
comments. MPAC noted that the collection and analysis of proposed indicators
is essential for the country and global monitoring. Members suggested that GMP
clarify what indicators are minimally essential for global, national and sub-national

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monitoring for the implementation of GTS and AIM. MPAC members submitted
supplementary indicators for entomology and was asked to add indicators for
seasonal malaria chemoprevention and for the prevention of reintroduction as they
may be different from elimination indicators. The MPAC also discussed the roles of
SME taskforce versus the Roll Back Malaria Monitoring and Evaluation Reference
Group (MERG) in an effort to harmonize functions and optimize the work of each
group. MPAC agreed that the SME taskforce will be responsible for setting normative
guidance for malaria surveillance, monitoring and evaluation, and that the primary
responsibility for MERG should be to support countries in the translation and
implementation of WHO normative guidance on surveillance and monitoring and
evaluation while noting the MPAC has no oversight function over the MERG.

Proposed evidence review group on Plasmodium knowlesi

Background: Plasmodium knowlesi is a zoonotic malaria parasite, transmitted

between non-human primate hosts by Anopheles mosquitos (leucosphyrus group),
and causing zoonotic infections in humans where the parasite, vector, primate
host and humans converge. A 2011 WHO informal consultation on the public health
importance of P. knowlesi provided recommendations on determining vector and host
distribution, protocols on diagnostic procedures and disease management. Several
factors have contributed to an increase of P. knowlesi reported cases: improved
diagnostic capacity, a reduction in overall number of human malaria cases and
increased awareness of P. knowlesi, the loss of relative immunity due to decreasing
malaria transmission and a change in land use with closer associations with the
natural reservoir and infected vectors. While the burden of P. knowlesi is still not
fully understood, and may suffer under-reporting, clinical episodes can be severe
and lead to death if undetected and not treated properly. Key knowledge gaps
include: determining whether human-mosquito-human transmission is occurring, the
epidemiological distribution of P. knowlesi infection in humans and common clinical
outcomes, the range and distribution of the primary hosts and vectors, the sensitivity of
available RDTs, the most effective methods of control and prevention and the potential
impact on the success of malaria elimination programmes. Modelling suggests that
human-vector-human transmission is plausible but is likely to be rare and there is a
need to better understand the current and potential future changes that may influence
the levels of exposure to P. knowlesi. Unique enabling technologies may be needed to
limit P. knowlesi transmission to humans and appropriate mitigating and preventive
strategies should be developed. The proposed evidence review group will address
the highlighted gaps in knowledge and advise a path towards malaria elimination,
including P. knowlesi.

MPAC conclusions: The MPAC strongly supported the creation of the proposed ERG
on P. knowlesi and suggested that the scope be expanded to include other primate
malarias which may naturally infect humans – notably P. cynomolgi.

Proposed target product profile for Ivermectin

Background: Ivermectin is a broad-spectrum anti-helminthic drug that also acts as

an endectocide that has been used extensively through a strategy of MDA for the
elimination of onchocerciasis and, in combination with other drugs, lymphatic filariasis.
A WHO technical consultation was held on 30 March–1 April 2016 to define the key
missing data needed to support a policy recommendation on the use of ivermectin,
based on its action as an endectocide in the reduction of malaria transmission and
to develop a target product profile. The technical consultation considered 15 key
topics related to malaria transmission: the mosquitocidal efficacy of ivermectin and
its pharmacokinetic properties; the potential entomological endpoints for assessing

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 the efficacy of ivermectin; potential surrogate markers of the effect of ivermectin;
modelling the potential impact of ivermectin; standardizing assays to assess
the impact of ivermectin transmissibility and mosquito mortality; pharmokinetic
considerations regarding the safety of the use of ivermectin for malaria; evidence
from onchocerciasis elimination programmes and potential mechanisms for mosquito
resistance; safety of ivermectin in mass drug administration campaigns; progress
and challenges of large-scale ivermectin for onchocerciasis and lymphatic filariasis
elimination; potential risks and benefits for neglected tropical diseases from ivermectin
distribution for malaria; ongoing or planned clinical trials on the impact of ivermectin;
the possible regulatory pathway for ivermectin as a vector control tool; possible target
product profile components for ivermectin as a vector control tool; possible trial
design to assess the impact of ivermectin on malaria transmission; and considerations
regarding supply and business model. Key conclusions and a proposed target product
profile are detailed in the meeting report.

MPAC conclusions: It was clarified at the beginning of the discussion that MPAC was
being asked to provide input on the target product profile and the further evidence
needed to consider a policy recommendation, not on whether the intervention would
be an effective tool for malaria programmes. Ivermectin is an active research field
and GMP considered that some shaping and identification of priorities could help
optimize the investments being made to assemble the evidence necessary to consider
its potential role for malaria. MPAC made several suggestions on the proposed target
product profile including the need to define ‘significant reduction’, the omission of a
clinical outcome indicator, but to assess the feasibility of defining a measurement of
effect in vectors as an interim endpoint, to make the target product generic rather
than exclusively for ivermectin, to characterize biologically active metabolites that may
explain prolonged endectocidal activity, and that weekly dosage is not operationally
feasible based on current MDA experience. MPAC also raised the need to consider
ethical issues and the risk benefit considerations for MDA to healthy populations.
MPAC also strongly suggested looking at analyses and approaches used and
validated to develop the case for MDA previously and transmission blocking vaccines
in terms of community benefit, ethical issues and regulatory pathways. The target
product profile will be revised and sent to MPAC for an electronic review.

Proposed plans for the World Malaria Report

Background: World malaria reports were published in 2005, and 2008–2015,

core content has included: financing and expenditures on malaria; commodity
procurement; programme coverage; trends in infection prevalence, cases and deaths;
regional profiles; country profiles and annexes with special analyses or focus each
year. GMP conducted market research including a review of web-hits, an online survey
and consultation with regions to look at what content was most utilized and useful
to its audience, and looked at the future reports planned by partner organizations.
Looking forward to the world malaria reports for 2016-2020, GMP plans to focus the
report on core indicators for the monitoring and evaluation framework for the GTS
and include a theme to provide context for results that include the three pillars of the
GTS and the two supporting elements. The format would be a smaller size hard copy
together with an e-book that would cross-reference more intensive analyses and other
GMP documents. The country profiles would only be contained in the online version,
allowing for more easily updated databases. Thematic reports could be launched
on World Malaria Day rather than included in the World Malaria Report, launched in
December.

MPAC conclusions: MPAC supported keeping a hard copy version of the World
Malaria Report as a useful reference, and making the country profiles, possibly even
extended, online only. MPAC cautioned that access to internet remains a barrier in

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many parts of the world but agreed that it would be useful to enhance the online
version. Suggestions included that a database that can be interrogated would be
useful and the capability to make PowerPoint slides from key graphs and country
profiles would be useful. Additional suggestions included creating a World Malaria
Report application that is easily read on tablets and phones and to increase the
visibility of the burden estimates, which are the most commonly cited numbers. It
would also helpful to clarify what data are reported from countries, what data are
modelled and what data are extrapolated.

All documentation related to this meeting can be found at:

http://www.who.int/malaria/mpac/sep2016/en/

All previous MPAC meeting reports can be found here:

http://www.who.int/malaria/mpac/meeting_reports/en/

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Programme, please visit this page:
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© 2016 World Health Organization

This publication contains the collective views of an international group of experts and does not necessarily
represent the decisions or the policies of the World Health Organization.

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