Pneumococcal conjugate vaccine implementation in middle-income countries
Tricarico et al. Pneumonia
Pneumococcal conjugate vaccine implementation in middle-income countries
Serena Tricarico 0 1 2 9
Hannah C. McNeil 0 1 2 9
David W. Cleary 0 1 9
Michael G. Head 0 1 6 9
Victor Lim 5 9
Ivan Kok Seng Yap 5 9
Chong Chun Wie 5 9
Cheng Siang Tan 4 9
Mohd Nor Norazmi 3 9
Ismail Aziah 3 9
Eddy Seong Guan Cheah 7 9
Saul N. Faust 0 1 8 9
Johanna M.C. Jefferies 0 1 9
Paul J. Roderick 1 9
Michael Moore 0 1 9
Ho Ming Yuen 0 1 9
Marie-Louise Newell 1 6 9
Nuala McGrath 0 1 9 11
C. Patrick Doncaster 9 12
Alex R. Kraaijeveld 9 12
Jeremy S. Webb 9 12
Stuart C. Clarke 0 1 2 5 6 9 10
0 Institute for Life Sciences, University of Southampton , Southampton , United Kingdom
1 Faculty of Medicine, University of Southampton , Southampton , United Kingdom
2 University of Southampton Malaysia Campus , Johor , Malaysia
3 Universiti Sains Malaysia Health Campus , Kelantan , Malaysia
4 Faculty of Medicine and Health Sciences , Universiti Malaysia Sarawak, Kota Samarahan, Sarawak , Malaysia
5 International Medical University , Kuala Lumpur , Malaysia
6 Global Health Research Institute, University of Southampton , Southampton , United Kingdom
7 Universiti Tunku Abdul Rahman , Kampar Campus, Kampar, Perak , Malaysia
8 NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust , Southampton , United Kingdom
9 Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust , Southampton , United Kingdom
10 Postal address: Infectious Disease Epidemiology Group, Mailpoint 814, Level C, Sir Henry Wellcome Laboratories , South Block , University Hospital Southampton NHS Foundation Trust , Southampton, UKSO16 6YD
11 Faculty of Social, Human and Mathematical Sciences, University of Southampton , Southampton , United Kingdom
12 Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton , Southampton , United Kingdom
Background: Since 2000, the widespread adoption of pneumococcal conjugate vaccines (PCVs) has had a major impact in the prevention of pneumonia. Limited access to international financial support means some middleincome countries (MICs) are trailing in the widespread use of PCVs. We review the status of PCV implementation, and discuss any needs and gaps related to low levels of PCV implementation in MICs, with analysis of possible solutions to strengthen the PCV implementation process in MICs. Main body: We searched PubMed, PubMed Central, Ovid MEDLINE, and SCOPUS databases using search terms related to pneumococcal immunization, governmental health policy or programmes, and MICs. Two authors independently reviewed the full text of the references, which were assessed for eligibility using pre-defined inclusion and exclusion criteria. The search terms identified 1,165 articles and the full texts of 21 were assessed for suitability, with eight articles included in the systematic review. MICs are implementing PCVs at a slower rate than donor-funded low-income countries and wealthier developed countries. A significant difference in the uptake of PCV in lower middle-income countries (LMICs) (71%) and upper middle-income countries (UMICs) (48%) is largely due to an unsuccessful process of ?graduation? of MICs from GAVI assistance, an issue that arises as countries cross the income eligibility threshold and are no longer eligible to receive the same levels of financial assistance. A lack of country-specific data on disease burden, a lack of local expertise in economic evaluation, and the cost of PCV were identified as the leading causes of the slow uptake of PCVs in MICs. Potential solutions mentioned in the reviewed papers include the use of vaccine cost-effectiveness analysis and the provision of economic evidence to strengthen decision-making, the evaluation of the burden of disease, and post-introduction surveillance to monitor vaccine impact. Conclusion: The global community needs to recognise the impediments to vaccine introduction into MICs. Improving PCV access could help decrease the incidence of pneumonia and reduce the selection pressure for pneumococcal antimicrobial resistance.
Immunization; Streptococcus pneumoniae; Pneumonia; Pneumococcal vaccines; Middle-income countries; GAVI; Health policy
Pneumonia is the leading infectious cause of mortality
among all age groups, especially among children. It
accounts for 15% of all deaths of children under five years
old worldwide, and killed an estimated 922,000 children
in 2015 . Streptococcus pneumoniae is the major cause
of morbidity and mortality associated with childhood
bacterial pneumonia and is responsible for at least
18% of severe episodes and 33% of pneumonia deaths
in children worldwide [1, 2]. It is also responsible for
other invasive infections such as meningitis, sepsis
and peritonitis, as well as non-invasive diseases
including acute otitis media  with a severe burden of
Since 2000, the widespread adoption of pneumococcal
conjugate vaccines (PCVs) has had a major impact on
the prevention of pneumonia. PCVs are projected to
prevent 1 million deaths among children worldwide by
2020, and 7 million by 2030 . Two conjugate vaccines
are currently available: the 10-valent (PCV10) and the
13-valent (PCV13), conferring protection against ten
and 13 of the most prevalent and pathogenic serotypes,
respectively . The most recent estimate of serotypes
implicated in the global burden of pneumococcal disease
in children under five years of age attributed ?70% of
the disease burden to serotypes included in both the
PCV10 and PCV13 vaccines . The worldwide
recommendation that PCVs be included in national
immunization programmes (NIPs) for children aged
less than two years was renewed by the World Health
Organization (WHO) in 2012, with prioritization of
PCV introduction given to countries with high child
mortality rates .
However, five of the world?s 7 billion people live in
middle-income countries (MICs)1 [7, 8], where the
majority of vaccine preventable deaths occur . As of
2014, just 31% of the global target population for PCV
had been immunized, with only 14 more countries
adding PCV to their NIP in 2014, after it was added by 103
countries in 2013 . It is the authors? contention that
in the dynamic and challenging vaccine environment,
MICs may be struggling with PCV implementation
without the international financial and technical support
from which many low-income countries (LICs) benefit
. As a consequence, an opportunity to reduce a
massive burden of mortality and morbidity is potentially
Given the number of countries where infant PCV
immunization is still yet to be widely adopted, the
authors undertook a systematic review into the status of
PCV implementation in MICs. The review identifies
potential impediments to PCV uptake and analyses
possible solutions to improve PCV uptake in MICs that
have yet to include PCVs in their NIP.
Literature on the implementation of the PCV in MICs
was systematically reviewed, with contributions from
peer-reviewed journals and institutional websites. The
following databases were searched: PubMed, PubMed
Central, Ovid MEDLINE 1946, and SCOPUS. The Cochrane
Library (the Cochrane Database of Systematic Reviews
and the Database of Abstracts of Reviews of Effects) and
Zetoc were also scanned using search terms related to
pneumococcal immunization, governmental health policy
or programmes, and MICs. Websites of the World Health
Organization (www.who.int), the United Nations
International Children's Emergency Fund (www.unicef.org),
the World Bank (data.worldbank.org), the Global
Alliance for Vaccines and Immunization Alliance (GAVI;
www.gavi.org), the Pan American Health Organization
(www.paho.org), the Program for Appropriate Technology
in Health (www.path.org), the International Health
Partnership (www. internationalhealthpartnership.net), Centers for
Disease Control and Prevention (www.cdc.gov), the John
Hopkins School of Public Health (www.jhsph.edu) and
Google (www.google.com) were searched for
additional data. This review was conducted according to
the PRISMA statement  with the search filtering
process illustrated in Fig. 1.
The following search terms and structure were used
and modified according to the syntax requirements of
the database concerned: [Streptococcus pneumoniae OR
pneumococcus OR pneumococcal OR pneumococci
OR PCV OR pneumococcal conjugate vaccine] AND
[(vaccin* adj3 policy) OR (vaccin* adj3 policies) OR
(vaccin* adj3 implement*) OR (vaccin* adj3 progra*) OR
(immun* adj3 progra*) OR (immun* adj3 implement*) OR
(immun* adj3 policy) OR (immun* adj3 policies)] AND
[middle income country OR middle income countries OR
developing econom*] (example of Ovid MEDLINE 1946
search syntax), with the search of terms limited to title
and abstract. We found that adding specific words such as
child, childhood and pediatric to the search removed
useful papers, so we kept the search as wide as possible with
regard to age.
Inclusion and exclusion criteria
Two reviewers (ST and HM) performed the database
search, reviewed the literature and extracted data. A
continuous discussion was used as measure at all stages
of the review to minimize bias and error and
disagreements between the two reviewers were resolved by
SCC was regularly consulted to comment on the
literature search, authoring and editorial process. The
full texts of the references finally selected were assessed
for eligibility using pre-defined inclusion and exclusion
Fig. 1 Flowchart of study selection. The following search terms were used: [Streptococcus pneumoniae OR pneumococcus OR pneumococcal OR
pneumococci OR PCV OR pneumococcal conjugate vaccine] AND [(vaccin* adj3 policy) OR (vaccin* adj3 policies) OR (vaccin* adj3 implement*)
OR (vaccin* adj3 progra*) OR (immun* adj3 progra*) OR (immun* adj3 implement*) OR (immun* adj3 policy) OR (immun* adj3 policies)] AND
[middle income country OR middle income countries OR developing econom *]
criteria. The search was limited to papers written in
the English language, and published between 1990
and November 2015. A start date of 1990 was chosen
because pneumococcal vaccines were introduced for
the first time in NIP globally in the 1990s .
Articles reporting on active surveillance in relation to
PCV policy guidance were included. Cross sectional
or cohort studies, and articles relating to burden of
disease, cost-effectiveness and other decision support
tools and research investments (unless related to PCV
policy implementation in MICs) were excluded.
References were managed with the EndNote
bibliographic database (Thomson Reuters, New York,
The search identified 1,165 articles, of which the full
texts of 80 articles were screened. The full texts of 21
were assessed for suitability (Table 1). Finally, eight
papers were included in the systematic review for the
qualitative analysis because they met all of the inclusion
criteria (Table 1). Although the database search was
performed between the years 1990 and 2015, the full-text
articles assessed for eligibility were all published in the
last 11 years. Seven papers were published between 2004
and 2010, and 14 papers between 2011 and 2015.
Out of the 104 MICs, 43 (15/51 [29%] lower
middleincome countries [LMICs] and 28/53 [52%] upper
middle-income countries [UMICs]) had not introduced
Table 1 Summary table of studies reporting PCV implementation in MICs
Blau et al. 
Lack of local expertise in health
economic and economic evaluation.
Lack of available national data on
disease burden and cost of
treatment of disease preventable by
Bonner et al. 
The cost of PCV can be prohibitive,
discouraging countries from
including it in their EPI schedules.
Gordon et al. 
Levine et al. 
Moon et al. 
Philippe et al. 
(list of countries not
Lack of economic expertise and an
explicit desire to include economists
in their NITAGs and interagency
The availability and consistency of
financing was uniformly reported to
be the greatest challenge.
No mechanism is in place ensuring
that poorer countries get the lowest
possible prices. This case
underscores the difficulty in
determining what is a ?fair?
price for MICs.
Limited access to international
support is resulting in LMICs
beginning to lag behind the poorest
countries in protecting their
vaccinepreventable diseases using newer
vaccines and combination vaccines.
Strong disease surveillance and
programme monitoring systems are
to use cost-effectiveness analysis to
strengthen decision making in
immunization policy and to ensure
the sustainability of vaccine
to provide economic evidence to
help decide if introducing new
vaccine should be prioritized along
with other public health programs
to maximise the commitment and
support of existing advisory bodies
in the country: National
Immunization Technical Advisory
Group (NITAG) or Interagency
Coordination Committee (ICC)
to provide scientific
recommendations to support final
decisions of introducing PCV
GAVI and its donors should
respond to WHO recommendations
and countries? needs and expand
the vaccine subsidy window for
vaccination in children up to age
policy should be formulated to
ensure that PCV is used in
emergency contexts, including in
extended age groups, as a rapid
intervention to limit IPD-related
morbidity and mortality
the global immunization
community should address the
obstacles to systematically using
PCV as part of the health service
package in emergencies
the need for post-introduction
surveillance to monitor vaccine
impact and any shifts in the
to seek more suitable formulations
and presentations of new vaccines
surveillance of diseases targeted by
new vaccines including enhanced
laboratory networks and centres of
supporting the establishment/
strengthening of National
Immunization Technical Advisory
to ensure evidence-based decision
at country level, which is particularly
needed in view of the complexity of
Table 1 Summary table of studies reporting PCV implementation in MICs (Continued)
Saxenian et al. 
Shen et al. 
Sri Lanka, Angola,
(list of countries not
Countries had not carried out
detailed financial projections of
vaccine costs by funding source.
(1) policy, standards, and guidelines;
(2) governance, organization and
(3) human resources;
(4) vaccine, cold chain, and logistics
(5) service delivery;
(6) communication and community
(7) data generation and use;
(8) sustainable financing.
An enabling environment, even in
the poorest countries, depends on
the political will of decision-makers.
the immunization programs and
cost of new vaccines
Ministry of Health should ensure
that vaccine procurement methods
result in competitive prices for high
need to build specialised market
knowledge and skills
a well-functioning national regulatory
to maximise the commitment and
support of existing advisory bodies
in the country (NITAG)
a strong routine immunization
platform to benefit the overall
health system by generating policy
and skilled human resources
NITAGs is to guide the
development of national
immunization policies, guidelines,
NRAs are necessary if countries are
to self-procure and ensure a
reliable supply of quality vaccines
to improving governance,
organization, and management of
routine immunization include
to invest to build the capacity and
professional development of an
appropriately trained health care
educating and mobilising the
public to support immunization
and to use immunization services
is central to EPI
the generation of high-quality
immunization data is important to
informing programmatic decisions
PCVs; 46 MICs (24 LMICs and 22 UMICs) introduced
PCVs between 2000 and 2013; 13 MICs (10 LMICs and
3 UMICs) introduced PCVs between 2014 and 2015 and
were supported by GAVI; 3 LMICs were approved for
GAVI support in 2015 (Kyrgyzstan, Uzbekistan, and
Myanmar); one graduating country2 (Mongolia) was
approved for PCV support in 2016 and another six
graduating and graduated2 countries have not yet applied but
are eligible to do so (Bhutan, Cuba, Indonesia, Sri Lanka,
Timor Leste, and Ukraine) (Table 2; Fig. 2).
A lack of country-specific data on disease burden is
considered one of the leading causes of delay in PCV
implementation, particularly in relation to the burden of
pneumonia and other acute respiratory tract infections
[13?15] (Table 1). The prohibitive cost of PCV is
discouraging countries from including it in their NIPs
[13, 15?18] and a lack of local expertise in economic
evaluation [14, 18, 19] was also identified as a recurring
problem (Table 1). Thus, the commonly suggested
solutions to combatting the underuse of PCVs were the
use of cost-effectiveness analysis and the provision of
economic evidence to strengthen decision making in
immunization policy [13?15, 18], the evaluation of the
burden of disease with pre-assessments, and
postintroduction surveillance to monitor vaccine impact and
any shifts in the serotype distribution [13, 15, 18, 20]
(Table 1). Maximizing the commitment and support of
existing advisory bodies in MICs, national immunization
technical advisory groups (NITAGs) or interagency
coordination committees (ICCs) to provide scientific
recommendations to support final decisions of introducing
PCV [13?15, 18, 19] was also recommended, along with
the expansion of the vaccine subsidy window by GAVI
and its donors, in order to respond to WHO
recommendations and countries? needs  (Table 1).
This systematic review provides an update on the status
of, and impediments to, PCV implementation in MICs.
Although PCVs have been available since 2000, the
literature assessing the problems MICs experience in
implementing widespread PCV immunization has only
been published since 2008. This review found that there
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Fig. 2 World map highlighting LMICs that have introduced PCVs in their NIP (dark blue), LMICs that have not yet introduced PCV in their NIP
(light blue), UMICs that introduced PCV in their NIP (dark red), UMICs that have not yet introduced PCV in their NIP (light red). Data source: WHO/
IVB Database and WorldBank, as of February 2016
has been some progress since 2013, but most MICs have
not yet added PCVs to their NIPs for infants.
The significant difference in the uptake of PCV in
LMICs and UMICs, 71% and 48% respectively, is mainly
due to an unsuccessful process of ?graduation?of MICs.
Once a country crosses the income eligibility threshold
for vaccine subsidy support by GAVI, the financial
assistance phases out in a ?graduation? process. GAVI?s
graduation process is designed to ramp up domestic
cofinancing of vaccines; however, once GAVI support ends,
the new UMICs may not be able to fully fund these
Our review has found that a lack of country-specific
data on disease burden is considered one of the leading
causes of delay in PCV implementation in UMICs,
together with a lack of local expertise in economic
evaluation, and the cost of PCV. While WHO recommends
that PCV be used, despite the lack of country-specific
pneumococcal surveillance data , PCV is one of the
most expensive vaccines that WHO recommends for
inclusion in NIP. The cost can be prohibitive,
discouraging many MICs from including it. PCV is sold at
USD$3.30?$7 per dose (when purchased through GAVI);
USD$14.12?$15.68 per dose to the Pan American Health
Organization (PAHO) Revolving Fund [4, 21], and
US$159.58 per dose to the private sector (pediatric
PCV13) . Therefore, in order to fully fund their
immunization programmes, MICs should improve
informed decision-making on vaccine introduction and
other areas of immunization policy and enhance national
funding of immunization through advocacy, technical
assistance, and training.
The two most populated countries in the world, China
and India, require an important mention. China (1.371
billion people) and India (1.311 billion people)  are
still classified as LMICs and have not added PCV to
their NIP. This means that, excluding the unmeasurable
percentage of people who received PCV privately, almost
36.4% of the entire world population has not received
PCV (See Additional file 1). The Indian government
recently announced the possible introduction of PCV in
a phased manner by 2017?18 [24, 25]. Mainland China
has not yet included PCV in its publicly funded
Expanded Program on Immunization (EPI), but it is
available at immunization clinics for a fee . However,
Hong Kong did add PCV to its NIP in 2009. Without
actions in these priority areas, a likely substantial
reduction of child mortality and morbidity from pneumonia
will not be reached.
Although substantial achievements have been made in
preceding decades with other immunization programmes
in MICs (e.g. diphtheria-tetanus-pertussis [DTP3],
Haemophilus influenzae type b [Hib]) , PCV
implementation is still lagging behind in these countries . A
similar delay in implementation has been observed for five
other priority new or underused vaccines, namely
rotavirus, human papilloma virus [HPV], inactivated
poliovirus vaccine [IPV], Japanese encephalitis, and yellow
fever vaccine. According to the latest WHO estimates, this
leaves 20% of MICs unprotected from these important
pathogens, . The main issue is that the majority (73%)
of the world?s poor people (defined as people living at or
below US$1.90 a day ) now reside in MICs, which also
have the highest rates of vaccine preventable deaths .
MICs are home to five of the world?s 7 billion people yet
(with donors focused on assisting LICs) they have been
slow to introduce PCVs. This results in a missed
opportunity to dramatically reduce avoidable morbidity and
mortality [7, 8].
Overview of PCV procurement opportunities
For the period 2010?2015, GAVI committed
approximately US$1.9 billion through the pneumococcal
Advance Market Commitment (AMC) to fund PCVs
that are suitable for developing countries . Those
countries graduating or who have graduated from GAVI
support and who have not yet been approved for PCV
are able to apply for subsidized PCVs, with the terms
and conditions of AMC set at a maximum of US$3.50
per dose . Alongside this, the International Finance
Facility for Immunization (IFFIm) provided US$41.58
million toward GAVI?s PCV programme in 2011, with
the aim to immunize more than 3 million children and
prevent more than 1.5 million deaths by 2020 . Prior
to this, GAVI established the Accelerated Vaccine
Introduction (AVI) initiative in 2008 with the core goal to
broaden and speed up access to PCVs over the period
The WHO has actively developed different programmes
to help MICs with PCV implementation. The WHO
Integrated Global Action Plan for the Prevention and Control
of Pneumonia and Diarrhoea (GAPPD) aims to reduce
deaths from pneumonia to fewer than 3 children per
1,000 live births by 2025 . The WHO Expanded
Programme of Immunization has seen a dramatic increase
in the implementation of new and under-utilized vaccines
providing additional prevention of untimely deaths and
disabilities, including from pneumococcal disease .
The PAHO Revolving Fund, also known as the Regional
Revolving Fund for Strategic Public Health Supplies, helps
Latin American countries negotiate a lower cost of PCV
through bulk procurement, technical assistance on supply
management, and assistance with planning, procurement
systems, warehousing and distribution, and quality
assurance . PAHO?s hospital-based surveillance
network for bacterial pneumonia currently includes 10 MICs
of which five are LMICs (Bolivia, El Salvador, Guatemala,
Honduras, and Nicaragua) and five are UMICs (Brazil,
Ecuador, Panama, Paraguay, and Peru) .
The WHO MIC Task Force has committed to investing
approximately US$20 million per year for the 2016?2020
period to support activities included in the MIC Strategy
. It includes strengthened decision-making for timely
and evidence-based immunization policy, increased
political commitment and financial sustainability of NIPs,
enhanced demand for and equitable delivery of
immunization services, and improved access to affordable and
The WHO Strategic Advisory Group of Experts on
Immunization (SAGE) Global Vaccine Action Plan
(GVAP) aims to make 2011?2020 the ?Decade of
Vaccines? . Its target was to introduce at least one
under-utilized vaccine by 2015 into 90 LICs and MICs.
So far, PCV has been the most frequently introduced
vaccine. An estimated US$42 billion to US$51 billion
will go towards expanding access to routine
immunizations and introducing additional vaccines to routine
The international non-profit organization Program for
Appropriate Technology in Health (PATH) is
collaborating with private- and public-sector partners to advance
the development of PCVs in LICs . In particular,
their vaccine development portfolio includes projects to
advance protein vaccines that can provide broad,
affordable protection across the many varieties of the
pneumococcus, as well as PCVs that are tailored to the health
and cost needs of low-resource countries.
In 2015, Doctors Without Borders/M?decins Sans
Fronti?res (MSF) launched a global campaign??A Fair
Shot?? calling on GlaxoSmithKline (GSK) and Pfizer to
slash the price of PCV in developing countries, including
MICs, to US$5 per child so that more children can be
protected, and to disclose what they currently charge
countries for the vaccine . MSF believes that
governments supporting GAVI must pressure companies to
disclose the price they charge for the PCVs in all countries.
With many initiatives aimed at improving access to
vaccines predominantly being targeted only at LICs, MICs
have a much slower rate of PCV uptake . The
inclusion of PCV in MIC NIPs is also less widespread than in
developed countries. This is due to cost and poor
knowledge of the burden of pneumococcal disease in MICs,
as well as little logistical and technical support for MICs
on how to formulate and implement a coherent policy
on PCV immunization. MICs need assistance in
integrating PCV immunization into their health systems.
Greater political commitment is required towards
commissioning epidemiological studies of pneumococcal
disease and subsequent resource mobilization towards
widespread PCV use at a national policy level. Carriage
studies and disease surveillance of S. pneumoniae,
including disease burden and cost-effectiveness analyses,
will generate the data needed to define the economic
saving of widespread PCV implementation and to
monitor the ongoing impact of widespread PCV
immunization at national level.
The first consequence of PCVs being licensed for use
and yet not being added to the NIP is that there may be
substantial use of PCV in the private sector. This creates
a gap between richer and poorer classes with a
consequent equity issue, especially since the poorest children
tend to experience the highest disease burden.
Disparities in access to vaccines are often poorly understood by
decision makers, particularly in licensure or in
implementation strategies for new vaccines. It is therefore
important to apply pressure at national and regional level
to ensure governments attempt to address these equity
issues to help reduce child morbidity and mortality from
Since the cost per dose for PCVs is among the highest
of the routine childhood immunizations, enhanced
international advocacy on behalf of MICs for greater flexibility
on pricing, and more rational procurement mechanisms
for PCVs are critical actions. In particular, the lack of
competition among manufacturers is a substantial barrier
to reduction of vaccine cost. In fact, only two
manufacturers, Pfizer and GSK, license and produce the two
currently used PCVs?PCV13 and PCV10, respectively.
Moreover, currently 60% of all GAVI-procured vaccines
are manufactured in India. Through a recent partnership,
GAVI and the Government of India will work together to
create a more sustainable vaccine manufacturing base
within India, ensuring valuable supplies for the children
living in all 72 other GAVI-supported countries .
International donors should be encouraged to provide
assistance to developing country manufacturers to produce
vaccine nationally. Also, ?pooled procurement?, which
combines several buyers into a single entity that purchases
vaccines on their behalf (generally at lower price per dose),
would help vaccine procurement for PCV introduction in
MIC . Comprehensive multi-year strategic plans for
immunization including PCV should be developed by all
MICs, and NITAGs (or equivalent committee types)
should be established?their role was found to be key in
LMICs adoption of PCVs . Alongside these, the World
Bank Country Procurement Assessment Report is
intended to be an analytical tool to evaluate the existing
health system of a country, and may be useful in devising
In recent years, the anti-vaccination movement has
become more vocal and even hostile [39, 40]. It is a matter
of concern that some researchers from the anti-vaccine
movements who can influence policy have advocated
against the use of available technology due to perceived
risks, often without scientific evidence. International
organizations (e.g. WHO) and governments, particularly
in LMICs, should ensure the implementation of
evidencebased public practice. Only standard surveillance systems
and research conducted by public health researchers can
provide appropriate evidence for decision-making.
It is in the interests of the international community to
be more aware of the immunization issues faced by
many MICs. Uneven global uptake of PCVs will affect
serotype dynamics and spread of antimicrobial
resistance, which will have an impact beyond the borders
of countries without widespread PCV immunization.
Levels of resistance in S. pneumoniae are of
international concern and were noted in a 2013 ?Threat
report? issued by the US Center for Disease
Prevention and Control (CDC)  and there has been
increasing resistance across Asia . There have also
been observed decreases in prevalence of S.
pneumoniae-related resistance after implementation of PCV
programmes [43, 44].
Donors and non-governmental organizations (NGOs)
can contribute towards building capacity in public health
surveillance by offering technical assistance in strategy
and execution of widespread epidemiological
surveillance towards informing immunization policies. This is
crucial as the dynamics of pneumococcal epidemiology
are complex and studies need to be well designed and
the data properly analysed to optimize the quality of
data that eventually feeds through to informing vaccine
Additionally, MICs should be supported in identifying
and initiating discussions with regional and local
organizations with expertize in the planning, logistics and
training required before implementing PCVs into a NIP.
A successful example of this support model is the PAHO
Revolving Fund (described earlier), which assists Latin
American countries in managing the range of activities
required for the implementation of PCVs.
To address and resolve the issue of poor
implementation of PCVs in MICs, the authors suggest that MICs
need to be considered as a whole group and collectively
undertake a series of steps. MICs should undertake a
mapping exercise of their procurement strategies and
range of practices; build a central headquarters to
collaborate with single countries; understand procurement
challenges and opportunities; develop a structural
framework for MICs to assess their own procurement
systems; explore inter-country and pooled procurement
mechanisms; and improve targeted collaborations
between MICs and international funding organizations.
A number of study constraints exist. First, there are a
limited number of studies examining PCV policy. Second,
the definition of MICs as a category is sometimes
somewhat arbitrary, making analysis of the MIC data difficult.
Gaps also exist in the available literature, which combined
heterogeneous studies. The methodology used and the
article types of the selected papers were also
heterogeneous, so that very few quantitative data can be
extracted from literature. The study examined grey
literature for evidence of unpublished data or studies,
but, given the complexity of grey literature,
publication bias can be present. There are also many
consultations, national and regional meetings and projects
(e.g. The Pneumococcal Awareness Council of Experts
[PACE] ) which are held to discuss new vaccine
introductions, but whose proceedings are often not
The MICs are slowly implementing PCVs. The global
community needs to recognise the barriers to PCV use in many
MICs and respond to the situation by increasing scientific,
financial, procurement and logistical support to broaden
PCV access in MICs. MICs themselves need to strengthen
decision making on pneumococcal immunization policy
and to mobilize national political will and financing to
reduce a significant, largely preventable disease burden, for
the benefit of their populations and in the interests of
wider international public health.
1As of 1 July 2015, middle-income countries (MICs) are
defined as those with a Gross National Income (GNI) per
capita (calculated using the World Bank Atlas method) of
more than US$ 1,045, but less than US$ 12,736 (.
WorldBank. 2015 [Accessed 2015 November]. Available
http://data.worldbank.org/news/new-country-classifications-2015). Of the 104 MICs, 51 are
lower-middleincome (LMICs) and 53 upper-middle-income countries
(UMICs), separated at a GNI per capita of US$ 4,125
(. Ibid.). In the dynamic and challenging vaccine
environment, MICs face increasing technical and economic
issues to maintain levels of vaccine introduction and
implementation comparable with lower-income
countries (LICs) that benefit from international
financial and technical support (. Global Alliance
on Vaccination and Immunization. 2015. Available
2In November 2013, the GAVI Board agreed to
strengthen GAVI?s approach to transition (formerly
referred to as ?graduation?) to support countries in
the accelerated transition phase. Each year, some
countries enter the accelerated transition phase and start
phasing out from GAVI support, as their GNI per capita
on average over the previous three years increases beyond
the eligibility threshold (set at US$1,580 in 2015) .
GAVI. 2016. Available from: http://www.gavi.org/support/
Additional file 1: PCV immunisation coverage in MICs. (XLSX 35 kb)
AMC: Advance market commitment; AVI: Accelerated vaccine introduction;
CDC: Center for Disease Prevention and Control; DTP3:
Diphtheria-tetanuspertussis; GAPPD: Integrated Global Action Plan for the Prevention and
Control of Pneumonia and Diarrhoea; GAVI: Global Alliance for Vaccines and
Immunization Alliance; GSK: GlaxoSmithKline; GVAP: Global Vaccine Action
Plan; Hib: Haemophilus influenzae type B; ICC: Interagency Coordination
Committee; IFFIm: International Finance Facility for Immunization; LIC:
Lowincome country; LMIC: Lower middle-income country; MIC: Middle-income
country; MSF: M?decins Sans Fronti?res/Doctors Without Borders; NGO:
Nongovernmental organization; NIP: National immunization programme;
NITAG: National Immunization Technical Advisory Group; PAHO: Pan
American Health Organization; PATH: Program for Appropriate Technology in
Health; PCV: Pneumococcal conjugate vaccine; SAGE: Strategic Advisory
Group of Experts on Immunization; UMIC: Upper middle-income country;
WHO: World Health Organization
This study was funded, in part, by a Newton Fund Institutional Links grant
(172686537) to Stuart Clarke from the British Council. The funder had no role
in drafting of the manuscript.
Availability of data and materials
The datasets analysed during the current study are available from the
corresponding author on reasonable request.
ST, HCM and SCC planned the systematic review. ST and HCM conducted
the database search, extracted the data, discussed the results and wrote the
main paper. MGH, DWC and SCC edited the manuscript. All authors and
members of the MYCarriage study team (VL, IKSY, CCW, CST, MNN, AI, ESGC,
SNF, JMCJ, PJR, MM, HMY, MLN, NMG, CPD, ARK, JSW) gave their approval of
the final version of the manuscript. ST, HM and MH have nothing to disclose.
DC reports grants from GSK during the conduct of the study. SCC reports
grants from GSK, during the conduct of the study; grants from Pfizer, outside
the submitted work.
ST, HM and MH have nothing to disclose. DC reports grants from GSK during
the conduct of the study. SCC reports a grant from GSK, during the conduct
of the study, and an investigator-led grant from Pfizer, both of which are
outside the submitted work. The authors declare that they have no
Consent for publication
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