Acute lower respiratory infections, which broadly include pneumonia and bronchiolitis,
are still the leading cause of childhood mortality. ALRI contributed to 18% of all
deaths in children younger than five years of age in 2008 [1], and the main pathogens
responsible for high mortality were Streptococcus pneumoniae, Haemophilus influenzae
and respiratory syncytial virus [2-4]. In addition, meningitis was estimated to contribute
up to 200 000 deaths each year, and influenza anywhere between 25 000 and 110 000
[1,5]. It is widely acknowledged that a major portion of this mortality should be
avoidable if universal coverage of all known effective interventions could be achieved.
However, some evaluations of the implementation of World Health Organization’s (WHO)
Integrated Management of Childhood Illness (IMCI) strategy, which promotes improved
access to a trained health provider who can administer “standard case management”,
have shown somewhat disappointing results [6-8]. Only a minority of all children with
life-threatening episodes of pneumonia, meningitis and influenza in developing countries
have access to trained health providers and receive appropriate treatment [6-8]. Thus,
novel strategies for control of pneumonia that balance investments in scaling up of
existing interventions and the development of novel approaches, technologies and ideas
are clearly needed.
Emerging interventions against childhood pneumonia, meningitis and influenza
Several recent studies quantified the burden of child mortality due to childhood infections
[1] and sub-divided it further according to the causing infectious pathogens [2-5].
In a series of papers that followed, we systematically reviewed the available information
relevant to the emerging interventions against childhood pneumonia, meningitis and
influenza [9-14]. We defined the list of emerging interventions of interest as follows:
(i) the first set of emerging interventions was suggested by the officers from the
Bill and Melinda Gates Foundation (BMGF) and it was based on strategic priorities
that were being discussed at the Foundation in the year 2009; (ii) additional ideas
were proposed by our team at the University of Edinburgh, after provisionally reviewing
the literature on emerging interventions against childhood infections; (iii) the third
set of emerging interventions was suggested by the 20 international experts invited
to take part in the CHNRI expert panel meeting (see later). We eventually agreed to
evaluate 29 emerging interventions that seemed feasible for reaching the implementation
within a 10-year period (
Table 1
). We aimed to be inclusive and open-minded in their selection because some of them
may still be far from implementation.
Table 1
The consolidated list of 29 emerging interventions against childhood pneumonia, meningitis
and influenza
1
Low-cost polysaccharide conjugate vaccines for Pneumococcus (low-cost: US$ 3.50 per
dose)
2
Low cost, cross-protective common protein vaccines for Pneumococcus
3
Low cost, cross-protective common protein vaccines for seasonal influenza (existing
flu vaccines should be considered as a current intervention)
4
Monoclonal antibodies for passive immunization against RSV
5
Anti-RSV vaccine for use in infants
6
Anti-RSV vaccine for use in pregnant women
7
Meningitis A conjugate vaccine
8
Multivalent meningococcal vaccines
9
Combination vaccines: meningococcal + other vaccines
10
Needle-free versions of current measles vaccines
11
Heat stable versions of current measles vaccines
12
Oxygen delivery systems for low-resource settings
13
Low cost ventilatory support
14
Non-liquid pediatric antibiotic formulations for use in large scale programmes in
appropriate dose
15
Vaccines against S. aureus
16
Passive immunization against S. aureus
17
Combination vaccines against multiple respiratory viruses
18
Maternal vaccination to protect neonates against neonatal sepsis: E coli and Klebsiella
19
Maternal vaccination to protect neonates against neonatal sepsis: Streptococcus B
and S. aureus
20
Rapid diagnostic test for bacterial infections in children
21
Rapid multiplex assay for etiology-specific diagnosis in children
22
Rapid multiplex assay for etiology-specific diagnosis in young infants
23
Rapid diagnostic test to predict severe outcome of pneumonia episode
24
Maternal vaccination for infectious agents relevant in infants (eg, PC, Hib, influenza)
25
Effective mucosal (oral or rectal) antibiotics for neonatal infections
26
Immunomodulating agents to stimulate innate immunity
27
Surfactant replacement therapy
28
Novel interventions to reduce indoor air pollution
29
Water-free solution for hand disinfection to reduce transmission of respiratory pathogens
RSV – respiratory syncytial virus, PC – pneumococcus, Hib – Haemophilus influenzae
Type B
The expert opinion exercise
The CHNRI methodology for priority setting in health research (and technologies) investments
was proposed as a systematic tool that can be used by those who develop research policy
and/or invest in health research [15-18]. It should assist them to understand (i)
the full spectrum of research investment options; (ii) the potential risks and benefits
that can result from investments in different research options; and (iii) the likelihood
of achieving reductions of persisting burden of disease and disability through investments
in health research and health technologies. The CHNRI methodology has 3 stages: input
from investors/policy-makers (who define the context and criteria for priority setting);
input from technical experts (who propose, list in a systematic way, and then score
different research investment options against a pre-defined set of criteria); and
input from other stakeholders (weighing the criteria according to wider societal system
of values). The method has been described in detail elsewhere and many examples of
its implementation are publically available [19-22].
The expert opinion exercise focused only on emerging interventions and a broad, long-term
(downstream) context/vision. We invited 20 leading international experts from international
agencies, industry, basic science and public health research to Dubrovnik, Croatia,
in September 2009. The invited experts provided opinion on how the 29 chosen emerging
interventions satisfy a number of criteria relevant to prioritization of support to
emerging interventions against childhood infections. Based on a modified CHNRI’s conceptual
framework, 12 criteria for prioritization were developed for emerging interventions:
(i) answerability (in an ethical way); (ii) low development cost; (iii) low product
cost; (iv) low implementation cost; (v) likelihood of efficacy and effectiveness;
(vi) likelihood of deliverability; (vii) likelihood of affordability; (viii) likelihood
of sustainability; (ix) maximum potential impact on mortality burden reduction; (x)
likelihood of acceptability to health workers; (xi) likelihood of acceptability to
end users; (xii) predicted impact on equity. Further details about the modified CHNRI
framework with the 12 criteria used for the expert panel meeting in Dubrovnik in 2009,
and the process of the expert opinion exercise, are available from the corresponding
author upon request.
The first task for the experts was to read the background information assembled about
the 29 emerging interventions in a 285-page landscape review, later published as a
series of papers [9-14]. The second task was to participate in the expert panel meeting
where, over the course of 5 days and a total of 10 discussion sessions, the experts
were told why each of the 12 criteria was chosen, and then they discussed how to apply
them to each of the 29 emerging interventions. They were free to challenge all information
provided to them in a background document and to share further personal knowledge
or opinion with the group. Notes of their input were taken and the landscape review
was being continuously amended. After each discussion session the experts were invited
to score, independently of each other, all emerging interventions according to the
12 agreed CHNRI criteria. For each of the 29 emerging interventions and each criterion,
each expert answered questions targeted to assess the likelihood of the proposed emerging
interventions to comply with the priority-setting criterion. A summarized version
of those questions is presented in
Table 2
. The full version of questionnaires that were used is available upon request from
the corresponding author.
Table 2
A summarized version of questions used to assess whether proposed 29 interventions
satisfy the 12 priority-setting criteria
Answerability (“1” for Yes; “0” for No; “0.5” for Undecided)
▪ Do we have a sufficient research and development capacity to make the intervention
available on the market by 2020?
▪ Do we have a sufficient level of funding support to make the intervention available
on the market by 2020?
▪ Would you say that it is likely that the remaining technical hurdles can be overcome
to make the intervention available on the market by 2020?
Cost of Development (In US$) (“1” for Yes; “0” for N; “0.5” for Undecided)
▪ How much will it cost to get from the current stage of development to commercial
availability of each emerging intervention below?
a.<US$1 billion, b.<US$ 500 million, c.<US$ 100 million
Cost of Implementation (In US$) (“1” for Yes; “0” for N; “0.5” for Undecided)
▪ Is it likely to be a low-cost intervention (ie, <3.50 US$ per unit?)
▪ Can we use the existing delivery mechanisms without major modifications (eg, training,
infrastructure)?
▪ Is achievement of a near-universal coverage likely to be affordable to most developing
countries?
Likelihood of Efficacy (0%-100%)
▪ Please assess the likelihood (0%-100%) that adequately powered randomized controlled
trials of the interventions listed below (ROWS), conducted in developing countries,
would consistently show statistically significant reduction in cause-specific mortality
from each of the four causes of death listed below (COLUMNS).
a. Pneumonia, b. Meningitis, c. Neonatal sepsis, d. Influenza
Likelihood of Maximum Potential Impact on Disease Burden
▪ Please predict, for each of the 4 causes of death below (COLUMNS), the proportion
of deaths in children under five years of age due to that cause that could be averted
if the complete coverage with the emerging interventions listed below (ROWS) could
be achieved?
a. Pneumonia, b. Meningitis, c. Neonatal sepsis, d. Influenza
Deliverability and Sustainability (“1” for Yes; “0” for N; “0.5” for Undecided)
▪ Taking into account (i) the infrastructure and resources required to deliver emerging
interventions listed below (eg, human resources, health facilities, communication
and transport infrastructure); (ii) the resources likely to be available to implement
the emerging interventions at the time of introduction; (iii) overall capacity of
the governments (eg, adequacy of government regulation, monitoring and enforcement;
governmental intersectoral coordination), and (iv) internal and external partnership
required for delivery of interventions (eg, partnership with civil society and external
donor agencies), would you say that the emerging interventions would be?
a. Deliverable at the time of introduction, b. Affordable at the time of introduction,
c. Sustainable for at least 10 y after the time of introduction
Assessing Readiness
of Health Systems to take Existing and Emerging Interventions to High Coverage Globally
(90% Urban / 80% Rural) at this Point and at the Time of their Introduction (“1” –
we are ready (or we will be ready); “0.5” – we may be getting closer, but are not
quite ready; “0” – we will not be ready)
▪ Please study the existing and emerging interventions against childhood pneumonia,
meningitis, sepsis and influenza listed below (ROWS) and the 6 “building blocks of
health systems” from the WHO framework (COLUMNS). Please indicate your assessment
of the level of readiness to take each of the interventions below to high coverage
globally (90% urban / 80% rural) at this point in time, and following their introduction
at some future point (the latter is only needed for those interventions that are NOT
already available).
a. Service delivery, b. Health workforce, c. Health information systems, d. Med. products,
e. Vaccines and technologies, f. Health systems financing, g. Leadership and governance
Acceptability and Equity (“1” for Yes; “0” for N; “0.5” for Undecided)
▪ Taking into account the overall context, intervention complexity, health workers’
behavior and the end-user population at the time of introduction,
a. Would health workers be likely to comply with implementation guidelines?, b. Would
end-users be likely to fully accept the intervention?, c. Would you say that the proposed
intervention has the overall potential to improve equity after 10 y following the
introduction?
The process of expert assessment (scoring) of emerging interventions was performed
as follows: all the experts answered the questionnaire related to each criterion by
answering ‘Yes’ (1 point) or ‘No’ (0 points). They were also allowed to declare an
informed but undecided answer (0.5 points) or declare themselves insufficiently informed
to answer the question (missing input). Thus, the proposed research questions got
a score from 20 experts for each of the 12 criteria. This score was “the proportion
of maximum possible points scored when an answer was given” (ie, excluding the missing
input), and it was a number between 0 and 100%. This number represented a direct measure
of “collective optimism” of all the scorers toward each emerging intervention, given
the criterion in question. Each of the 29 proposed emerging interventions received
12 criterion-specific scores, each ranging between 0%-100%. The criterion over which
the experts were most uncertain was the cost of implementation, which was deemed very
difficult to predict by most of them. We agreed that a separate exercise should be
conducted in a low-income setting to improve understanding of the factors that affect
this cost, and this has been done later [23].
The overall research priority score (RPS) for each intervention was computed as the
mean value of 9 intermediate scores for 9 selected criteria. The reason why all 12
criteria weren’t used is because CHNRI exercise requires that the criteria need to
be relatively independent of each other (similar to principal component analysis in
statistics). In this exercise, we were interested in different components of the cost
(development cost, product cost, implementation cost and affordability), but those
4 criteria are in fact a single criterion, and if all 4 were kept in the exercise,
this would give an undue 4-fold ‘weight’ to one criterion at the expense of the others.
The experts agreed that the most important of the 4 cost-related criteria related
to emerging interventions is ‘development cost’, because costs of product and implementation
can be met through other mechanisms (such as GAVI, PEPFAR, Global Fund, etc.). Thus,
the cost of product, cost of implementation and affordability were kept out of the
final score calculation. The exact scores given to all 29 emerging interventions are
presented in
Table 3
. The final report on CHNRI exercise has received the approval of the experts, among
whom some (mainly from the industry) wished to remain anonymous.
Table 3
The results of the CHNRI exercise: 29 emerging interventions with 9 intermediate scores
and an overall research priority score
Rank
Emerging intervention
Answerability
Low development cost
Likelihood of efficacy
Max burden reduction potential
Deliverable
Sustainable
Acceptable to health workers
Acceptable to end users
Impact on equity
RESEARCH INVESTMENT PRIORITY SCORE
1
Low-cost polysaccharide conjugate vaccines for pneumococcus
0.96
0.80
0.81
0.32
0.86
0.86
1.00
0.90
1.00
0.84
2
Non-liquid pediatric antibiotic formulations for use in large-scale programs in appropriate
dose
0.76
0.90
0.78
0.30
0.86
0.95
0.85
1.00
0.95
0.82
3
Low cost, cross-protective common protein vaccines for pneumococcus
0.72
0.50
0.83
0.36
0.86
0.85
1.00
0.90
1.00
0.78
4
New mucosal (oral and rectal) antibiotics for pneumonia and neonatal infections
0.58
0.70
0.60
0.22
0.80
0.90
1.00
0.94
0.89
0.74
5
Meningitis A conjugate vaccine
0.88
0.90
0.18
0.04
0.95
0.77
1.00
0.94
0.95
0.74
6
Multivalent meningococcal vaccines
0.75
0.70
0.17
0.07
0.95
0.77
1.00
1.00
0.95
0.71
7
Heat stable versions of current vaccines targeting pneumonia (eg, measles and others)
0.46
0.50
0.52
0.11
0.91
0.91
0.85
1.00
1.00
0.69
8
Needle-free versions of current vaccines targeting pneumonia (eg, measles and others)
0.57
0.50
0.49
0.10
0.86
0.91
0.85
0.95
0.95
0.69
9
Maternal vaccination for infectious agents relevant in infants (eg, PC, Hib, influenza)
0.66
0.90
0.59
0.22
0.60
0.70
0.94
0.72
0.78
0.68
10
Low cost, cross-protective common protein vaccines for seasonal flu (existing vaccines
excluded)
0.61
0.50
0.52
0.15
0.82
0.75
0.90
0.80
0.90
0.66
11
Water-free solution for hand disinfection to reduce transmission of respiratory pathogens
0.88
1.00
0.69
0.18
0.65
0.50
0.67
0.56
0.67
0.64
12
Oxygen delivery systems for low-resource settings
0.81
1.00
0.77
0.21
0.65
0.55
0.65
0.70
0.44
0.64
13
Combination vaccines: meningococcal + other EPI vaccines
0.36
0.40
0.39
0.12
0.91
0.86
0.95
0.90
0.85
0.64
14
Vaccines against additional pathogens that cause pneumonia – multiple respiratory
viruses
0.48
0.40
0.69
0.24
0.70
0.70
0.85
0.80
0.75
0.62
15
Anti-RSV vaccine for use in infants
0.58
0.50
0.62
0.14
0.56
0.61
0.90
0.67
0.72
0.59
16
Point-of-care diagnostic for bacterial infections in children
0.61
0.60
0.59
0.26
0.55
0.64
0.55
0.65
0.70
0.57
17
Point-of-care diagnostic for etiology-specific pathogen in young infants
0.50
0.60
0.61
0.23
0.50
0.64
0.61
0.65
0.72
0.56
18
Low cost ventilatory support
0.54
0.70
0.73
0.16
0.45
0.45
0.75
0.75
0.44
0.55
19
Anti-RSV vaccine for use in pregnant women
0.43
0.50
0.57
0.11
0.56
0.56
0.85
0.72
0.67
0.55
20
Vaccines against additional pathogens that cause pneumonia – S. aureus
0.47
0.60
0.40
0.12
0.64
0.55
0.85
0.75
0.55
0.55
21
Point-of-care diagnostic to distinguish viral and bacterial infections in young infants
0.36
0.60
0.61
0.20
0.50
0.64
0.61
0.65
0.72
0.54
22
Point-of-care diagnostic to predict severe outcome of pneumonia episode
0.29
0.40
0.63
0.32
0.41
0.59
0.67
0.85
0.72
0.54
23
Novel interventions to reduce indoor air pollution
0.64
0.90
0.54
0.12
0.50
0.40
0.42
0.61
0.56
0.52
24
Immunomodulating agents to stimulate innate immunity
0.51
0.50
0.43
0.10
0.38
0.38
0.75
0.81
0.50
0.48
25
Monoclonal antibodies for passive immunization against RSV
0.71
0.90
0.63
0.09
0.17
0.17
0.65
0.56
0.33
0.47
26
Maternal vaccination to protect neonates against major causes of neonatal sepsis –
Streptococcus B, Staphylocossus
0.25
0.50
0.20
0.07
0.45
0.50
0.85
0.75
0.55
0.46
27
Surfactant replacement therapy
0.62
0.80
0.41
0.08
0.33
0.19
0.63
0.69
0.38
0.46
28
Maternal vaccination to protect neonates against major causes of neonatal sepsis –
E coli, Klebsiela
0.25
0.40
0.25
0.05
0.45
0.50
0.85
0.70
0.50
0.44
29
Passive immunization against Staphylococcus
0.58
0.60
0.32
0.07
0.33
0.33
0.65
0.72
0.28
0.43
RSV – respiratory syncytial virus, PC – pneumococcus, Hib – Haemophilus influenzae
Type B
Photo: Courtesy of Alasdair Campbell, private collection
The main messages
Table 3
shows that the experts declared most of their collective optimism to improvement of
low-cost pneumococcal conjugate vaccines. This was followed by the development of
non-liquid and mucosal antibiotic pediatric formulations with improved deliverability
and acceptability in low resource settings. The development of common-protein pneumococcal
vaccines and multivalent meningococcal vaccines were seen as the third most promising
emerging intervention. Following this cluster at the top, the second level of priority
was assigned to improvements in existing vaccines (eg, measles or H. influenzae type
b) to enable needle-free delivery and heat stability. Similar overall scores were
given to evaluations of maternal immunization, improved use of oxygen systems and
the development of combination vaccines and vaccines against major viral pathogens.
The next level of priority was assigned to various diagnostic tools, the impact of
which is currently limited with sub-optimal levels of access to care, care-seeking
behavior and the availability of 1st and 2nd line antibiotics. Interventions that
proposed passive immunization, action on risk factors such as indoor air pollution
or poor sanitation, or development of vaccines against sepsis-causing bacterial pathogens
such as S. aureus or E coli received the lowest scores (
Table 3
).
An extended version of the results of the CHNRI process with the current status of
each emerging interventions’ development, the key challenges that remain to be addressed,
the visual representation of scores given by the expert panel to each intervention
and the assessment of potential effectiveness of each intervention is available in
the series of papers published elsewhere [9-14]. It should be noted that the assessment
of potential effectiveness (
Table 3
) can also range from 0%-100%, but its interpretation is different than of the other
11 criteria; rather than measuring collective optimism, it actually predicts the proportion
of mortality burden that could be averted through implementation.
Pneumococcal conjugate vaccines, which were treated as emerging interventions back
in 2009 because of a very low uptake in low and middle income countries at the time,
achieved scores over 80% for all criteria apart from “low product cost” – which indeed
ended up being the main point of discussion once they were introduced. In comparison,
common protein pneumococcal vaccines are still held back by concerns over answerability
(although it is getting closer to 80%), and over all criteria related to their future
cost. Other interventions show quite different score profiles. For example, anti-RSV
vaccine for use in infants failed on all criteria apart from “acceptance for health
workers”, whereas monoclonal antibodies for passive immunization against RSV failed
entirely on product cost, affordability and sustainability concerns, although product
development cost was considered feasible. The introduction of oxygen systems was considered
answerable and did not suffer from major cost concerns, but these systems were not
deemed sustainable, sufficiently acceptable and equitable. In comparison, common protein
flu vaccines were considered sustainable, acceptable and equitable, but there were
still concerns about answerability and costs of development and of the final product.
Conclusion
In accordance with other similar exercises with CHNRI methodology the process showed
some clear advantages. The context and the criteria were transparent and the management
of the process was overseen by the funding agency (BMGF) over its entire duration.
This kind of partnership should result in better understanding and promote ownership
and commitment to the main messages of the expert opinion exercise. The scoring process
was highly systematic and structured. It was free from undue influence from prominent
members within the expert group, because all the experts submitted their opinions
and scores independently from each other. The varied mix of the experts from different
backgrounds ensured that the scientific assessment of the research priorities is combined
with a view of the broader community in which the priorities would be implemented.
The entire process from the initial to the final stages was documented and can be
viewed and challenged at any point in time. The final result of the process was a
simple quantitative outcome (“research priority score”), which measured the “value”
of each research option when all the criteria and views were taken into account. This
“value” can be combined with the predicted cost of further research and development
needs in order to derive an optimal mix of emerging interventions to be funded from
a limited budget.