The Right Shot:

Extending the reach ofaffordable and adapted
vaccineswww.msfaccess.org

MEDECINS SANS FRONTIERES
Médecins Sans Frontières (MSF, or Doctors Without Borders) is an international,
independent, medical humanitarian organisation that delivers emergency aid
to people affected by armed conflict, epidemics, healthcare exclusion and natural
or man-made disasters.
Each year, MSF teams vaccinate over 10 million people, primarily as outbreak
response to diseases such as measles, meningitis, diptheria, pertussis, andyellow fever. MSF also supports routine immunisation activities in some projects
where we provide healthcare to mothers and children.
In 1999, on the heels of MSF being awarded the Nobel Peace Prize – and largely inresponse to the inequalities surrounding access to HIV treatment between rich andpoor countries – MSF launched the Access Campaign. Its purpose has been to push
for the access to, and development of life-saving and life-prolonging medicines,
diagnostics and vaccines for patients in MSF programmes and beyond.

www.msfaccess.org

Vaccine product, pricing
and schedule resources:
The WHO Vaccine Prequalification site provides detailed product information on all WHO
prequalified vaccines. It can be searched by vaccine type, manufacturer or country of manufacture.
http://www.who.int/immunization_standards/vaccine_quality/PQ_vaccine_list_en/en/index.html
The PAHO Revolving Fund, a mechanism established in 1977 for the procurement of vaccines, syringes
and related health supplies for PAHO Member States, maintains a site with information on the weighted
average cost per dose of vaccine, and injection supplies.
http://www.paho.org/revolvingfund
The UNICEF Vaccine Price Data site provides information on prices contracted with suppliers by
UNICEF per vaccine for the years 2001 – 2011. The site also includes a related link to GAVI-specificprocurement information.
http://www.unicef.org/supply/index_57476.html
The US CDC Vaccine Price List Archives site provides information on CDC contract prices,
as well as private sector vaccine prices, since 1986.
http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list-archives.htm
The WHO Recommendations for Routine Immunization Summary Tables site provides detailed
information on the recommended antigens, vaccination schedule, and protocol for an interrupted
or delayed vaccination series. The tables also include links to the related WHO Position Papers.
http://www.who.int/immunization/policy/immunization_tables/en/

Médecins Sans Frontières | April 2012

Table of Contents
Access to Vaccines – an Overview
		

3

Vaccine prices: Ensuring vaccines are affordable

		

5		

		

7

 accine adaptation: Essential to increasing immunisation coverageVin areas with weak health care systems

		10Conclusions and recommendations

		

11

View from the field: Why we need to simplify vaccination

		

12	Strengthening the Expanded Programme on Immunisation:
Lessons from Chad		13

Procurement and pricing strategies

Methodology

Product Cards
		

14	Diphtheria-Tetanus-Pertussis, Hepatitis B,
Haemophilus influenzae type B and combination vaccines		20	Measles-containing vaccines, with Rubella and Mumps

		

25	Meningococcal Meningitis vaccines		

29

Pneumococcal conjugate vaccines		33

Rotavirus vaccines

Annexes		37		39	Annex 2: The childhood routine
immunisation schedule		

40	References		

44

Annex 1: Vaccine Vial Monitors

Glossary

The Right Shot: Extending the Reach of Affordable and Adapted Vaccines | www.msfaccess.org

Access to Vaccines –an Overview

Access to Vaccines– an Overview
Lack of information on both the price and the different product characteristics of vaccines has been limiting
countries’ ability to operate affordable and effective immunisation programmes. This publication seeks toremedy some of the existing knowledge gaps by raising awareness on existing price differentials, exploring
what factors drive fluctuations in vaccine prices, and discussing where development of better adapted vaccines
could reduce barriers to immunisation and increase coverage levels of traditional and newer vaccines.
This publication serves as a resource for immunisation stakeholders, such as donors, implementing partners,
and developing countries, which are ultimately responsible for their national immunisation programmes.

The positive impact of vaccines on publichealth is well-documented – in the past
century, vaccines have helped eradicate
smallpox and significantly reduced theburden of communicable childhood
diseases such as diphtheria and measles.
Each year, immunisation with eightstandard antigens1 is estimated toavert 2.5 million future deaths.i

This report explores two key challenges
that will need to be overcome if
immunisation coverage is to be
improved and new vaccines are to be
introduced in a sustainable manner.
First, we explore more than ten years
of pricing data for traditional andnewer vaccines to see what factors had
the most influence on bringing down
vaccine prices. Second, considering
the weak Expanded Programme on
Immunisation (EPI) in many developing
countries, we examine the potential
role of vaccine adaptation in increasing
the reach of immunisation services todifficult-to-reach populations.

© Sisay Zerihun

According to the Global Alliance
for Vaccines and Immunisation (GAVI
Alliance), the introduction of new
vaccines against pneumococcal disease
and rotavirus is expected to increasethat number significantly.

Additional attention is being focusedon immunisation with the launch of
the “Decade of Vaccines,” an initiative
designed to re-energise global efforts
toward ensuring access to immunisation
for all. The Decade of Vaccines calls toincrease public and political support
for vaccination, improve delivery of
vaccines, strengthen research anddevelopment for new and improved
vaccines, and address supply security
and affordability.2 The World Health
Assembly first discussed the Decadeof Vaccines in 2011 and is expected
to validate a new Global Vaccine
Action Plan (GVAP) in May 2012.3

Measles vaccination at a transit camp in Ethiopia.
i.

2

Diptheria, tetanus, pertussis, measles, polio, BCG, hepatitus B, haemophilus influenzae type B.

Médecins Sans Frontières | April 2012

Although stakeholders in global
immunisation were generally united
in their support and exceeded GAVI’s
call for funds at a June 2011 pledging
conference, the need for GAVI to be
more effective in bringing prices down
has been emphasised by donors andrecipient countries. This was evidenced
by the adoption of a new Vaccine
Supply and Procurement Strategy
by the GAVI Alliance Board inNovember 2011.
The new Global Vaccine Action Plan
underlines the need to strengthen
national EPI programmes in countries
with low immunisation coverage.

Recently, more attention has been
paid to introducing new vaccines
in national EPI schedules than to
identifying and addressing challenges
in traditional EPI delivery.

through alternative technologies,
such as microneedles, inhalation, ororal administration, is paramount for
ensuring that vaccines reach theirintended recipients.

The focus on expediting introductionof new vaccines also means thatrecent products purchased for
GAVI-eligible countries are often thesame as those used in the U.S. or
Europe, and are not always appropriate
for the epidemiology or operating
conditions in developing countries.
GAVI has yet to use its buying poweror donor influence to drive a researchand development agenda focusedon vaccines relevant for use indeveloping countries.

Although this agenda is being promoted
by Project Optimize, and advisorygroups such as the Immunization
Practices Advisory Committee (IPAC,
founded in 2010) and the Vaccine
Presentation and Packaging Advisory
Group (VPPAG, founded in 2007),there is a need to bring this work toscale. With GAVI’s new Supply andProcurement Strategy there is now astrong mandate to use GAVI’s buying
power to stimulate development of
more adapted vaccines.

In this report we examine one strategy
that could expand the reach of EPI
programmes: vaccine adaptation.
By adaptation, we mean altering
vaccine profiles and presentations tomake the product more suitable fordeveloping country contexts. The
need for vaccine products that areformulated for local epidemiology
to combat the most prevalent strainsof a disease is critical. Additionally,
products that do not require cold
chain and that can be delivered

Based on Médecins Sans Frontières’
field experience, we believe there isa need to put more emphasis on theadaptation agenda to help improvethe efficacy of vaccines considering
disease burden and improve theimpact of programme delivery incountries with weak health system
capacity. Coupled with greater pricetransparency and competition,
vaccines will become more affordable
and accessible to the countries thatstand to benefit from them most.

Vaccine prices: ensuring vaccines are affordable

The prices of vaccines became asignificant issue for immunisation
stakeholders in 2011, when GAVI faced
a US$3.7 billion financial shortfall for its
2011 – 2015 programme implementation.
GAVI’s procurement strategies were an
important contributing factor to thisdeficit, in as much as they had failed
to adequately lower prices for newer
vaccines. At the same time as highvaccine prices are increasingly in the
spotlight, 16 lower-middle income
countries are slated to “graduate” fromGAVI, meaning that they will no longer
benefit from GAVI subsidies.

Vaccine prices:
ensuring vaccines are affordable
In 1974, WHO founded the Expanded
Programme on Immunisation (EPI)
with the goal of providing all children
under one year of age access tovaccines against six key diseases:
diphtheria, tetanus and pertussis(DTP), tuberculosis (TB), measles,and polio. In 2001, in the early daysof GAVI operations, the total costof purchasing a full course of these
EPI vaccines averaged only $1.37
per child.ii
Adding two GAVI priority vaccines
in the early 2000s – Hepatitis B(HepB) and Haemophilus influenza
type B (Hib) – increased the priceof the recommended childhood
immunisation schedule by over$10.iii Prices offered to UNICEF for
pentavalent vaccine – a five-in-one
shot that combines DTP vaccine with
HepB and Hib vaccines, providing thecornerstone of childhood immunisationin developing countries – did notdecrease significantly for most of
the last decade.
In the past five years, WHO has
recommended products thathave higher unit costs such as
pneumococcal conjugate vaccine(PCV) and rotavirus vaccine for
global use in infants, as well as

human papilloma virus (HPV) vaccine
against cervical cancer for use inyoung adolescent girls (other lessexpensive vaccines such as rubella andmeningococcal A conjugate have also
been the subject of recent global andregional WHO recommendations).
The expansion of the EPI programme
has therefore raised the price ofpurchasing a full vaccination course
for a child in a GAVI-eligible country
from $1.37 in the year 2001 to over
$38.80 in 2011 (see Graph 1).
This price does not include otherprogrammatic costs or cost associatedwith vaccine wastage.

ii. Calculated using average of supplier prices offered to UNICEF for 1 BCG ($0.0793) + 3 OPV ($0.2601) + 2 Measles ($0.7952) + 3 DTP ($0.2340).
iii.	In 2001, UNICEF purchased pentavalent for $3.50 a dose, or $10.50 for the three recommended doses. When added together with BCG, OPV and measles vaccines,
the total cost to fully vaccinate a child was $11.63.

The Right Shot: Extending the Reach of Affordable and Adapted Vaccines | www.msfaccess.org

3Timeline: WHOrecommendations &vaccine introduction

Estimated cost to purchase a full course of
vaccines according to WHO Recommended
Routine Immunisation Schedule
40.00
Rotavirus + Rubella added

2001: Baseline vaccine package
includes 1BCG, 3 oral polio vaccine(OPV), 3 DTP and 2 measles.

38.80

35.00
PCV added

30.00

2004: WHO reiterates 1992
recommendation for universal
vaccination against Hepatitis B.

30.45

2006: WHO recommends universal
vaccination against Haemophilus
influenzae type B.

25.00

2010: First GAVI-eligible country
receives pneumoccocal conjugate
vaccine under the Advance Market
Commitment (WHO recommended
vaccination with PCV in 2007).

20.00

US$

Vaccine prices: ensuring vaccines are affordable

GRAPH 1: The Rising Price of Immunising a ChildHib added

15.00

11.23

10.00
Hep B added

5.00

0.00

2.23

1.37

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

Year

2011: First GAVI-eligible countryin Africa receives rotavirus vaccine(WHO recommended vaccination
with rotavirus vaccine in 2009). WHO
recommends universal immunisation
with rubella vaccine and GAVI Board
endorses decision to open a rubellavaccine funding window.

Notes: Price of an individual vaccine is defined as the average price per dose offered by contracted suppliers to UNICEF in a given year, multiplied by the
WHO-recommended number of doses. Where there was a price range for an individual supplier for one product in a given year, the average price was used.
For example, in 2001 the cost included 1 BCG ($0.0793) + 3 OPV ($0.2601) + 3 DTP ($0.2340) + 2 measles ($0.7952).
A vaccine is included in the calculated price once it is recommended by WHO and more generally available in GAVI-eligible countries. For example, although rotavirus
vaccine was introduced in select GAVI-eligible countries in the PAHO region starting in 2006, the graph includes it from 2011. The year in which a new vaccine wasadded to the total price is noted on the right. Measles-rubella combination vaccine was used for the 2011 price, although GAVI had not yet financed its purchase at
the time of publishing. Combination vaccine prices were used, when available, to calculate the total price. The PCV price used is $7.00 per dose for three doses ($21.00
total), i.e. includes the AMC subsidy. The rotavirus price is an average of the two full course products at June 2011-announced prices ($7.75 total). This graph does notinclude the HPV vaccine, as the WHO recommendation is for use in adolescent girls, or the meningitis A conjugate vaccine, as its recommended use is region-specific.
Calculations do not include wastage rates factored into vaccine forecasting and purchasing.

Traditionally, vaccine prices have been
set for wealthy countries based on a
vaccine’s value as it relates to savingsin health care spending (such as daysof hospital stays averted) rather thanthe cost of R&D and production.
Prevnar (PCV-13), for example, isPfizer’s second best selling productgrossing $2.82 billion in the firstnine months of 2011; the majority ofrevenue was earned from industrialised
country sales where the vaccine costs
as much as $97 a dose.4
In the developing world, vaccine
prices are substantially lower. There is,however, a significant price variance
between GAVI-eligible countries andmiddle-income countries. Regardless,the cost of newer vaccines is often
impossible for lower middle-income
and least-developed countries toself-finance. On the other hand,
growing private and public markets
in wealthier middle-income countries

4

Médecins Sans Frontières | April 2012

But even these countries are facing a strain
from the cost of purchasing newer vaccines
and are exploring ways to bring down
prices through more aggressive tendering.

countries is the costs for expanding
national immunisation programmes
to accommodate these new vaccines.
Fixed costs, such as those to expand
cold chain capacity and immunisation
programme infrastructure, as wellas running costs, such as the cost offuel for vaccine transportation, aresignificant elements of the EPI budget.

Prices in least-developed countries
have, for the most part, not gainedmuch attention as GAVI-supported
countries pay a minimal co-payment
toward the total price of new vaccines(up to $0.30 per dose).6 GAVI donors
shoulder the bulk of the financial
burden for purchasing newer vaccines
such as pentavalent, rotavirus,
and pneumococcal vaccine.
The full costs of a national immunisation
programme, however, go well beyond
just that of the vaccine. The more
immediate budgetary impact for GAVI

Some GAVI countries have seen EPI
programme costs double, triple andeven quadruple as they have added
new vaccines to national immunisation
schedules.7 Ethiopia, for example,
which introduced liquid pentavalent in
2007, increased its central refrigeration
volume by 106% and saw a significant
increase in transportation demands.
While GAVI provides one-time grants
for vaccine introduction costs, increased
costs for budget items such as vaccine
transportation continue to be borneby the host government.8

such as Argentina, Brazil andSouth Africa, have become a significant
and fast-growing source of revenue
for multinational pharmaceuticalcompanies.5

High vaccine prices have implications
particularly for countries being
weaned off donor subsidies. In 2011,
the GAVI Board adjusted country
eligibility criteria, resulting in 16
lower-middle-income countries losing
their GAVI-eligible status, with support
to be phased out by the end of 2015.10
Honduras, for example, will graduate
from GAVI support in 2015, though its
2009 average per capita income wasonly $1,800.11 With GAVI’s help, thecountry has introduced immunization
for both rotavirus and PCV, andcurrently pays $1.09 per child for thetwo vaccines.12 Once GAVI support
ends Honduras will have to pay $25.50
per child – assuming it pays the PAHO,
non-GAVI price – for PCV and rotavirus,
to which the cost of other routine
immunisations must be added. In
2015, the country is projected to havea birth cohort of 202,000 children;
at $25.50 per child, vaccinating
against rotavirus and PCV would costan estimated $5.1 million per year.
Honduran authorities are hoping to
get GSK’s approval to continue paying
the GAVI price, even if the country will
no longer be GAVI-eligible.

Procurement and pricing strategies:
Pooled procurement: Lower prices for
vaccines have been consistently achieved
through pooled procurement – wherecountries aggregate their demandand buy vaccines in bulk. As technicaland capital barriers to market entry
are quite high for manufacturers,
most vaccines are initially offeredby only one or two multinational
pharmaceutical companies. Aggregating
demand to guarantee large-volume
purchases over one or multiple years
decreases manufacturer risks, reducestransaction costs, and allows suppliers
to offer prices closer to the costof production.
Both UNICEF and PAHO use pooled
procurement as a means to negotiate
more affordable prices. The two
agencies have different policies andoperating principles for negotiating
contracts, promoting competition,and ensuring supply security.
At UNICEF, the Supply Division
procures for about 40% of the global
demand for children’s vaccines for bothlow- and middle-income countries(as measured in units). Products
must be prequalified by WHO.
UNICEF conducts annual demand
forecasting activities with countries.
While contracts have ranged from
one to five years, UNICEF has foundthrough experience and consultation
with industry that the longer-term
stability of a three-year contract allows
companies to offer better prices.
At the same time, UNICEF proactively
leaves quantities unallocated when
new producers are reaching market.

At PAHO, a Revolving Fund wasestablished in 1977 to purchase vaccinesand related immunisation supplies.
Today most low- and middle-income
countries in the region of the Americas
purchase some or all of their vaccinesfrom the PAHO Revolving Fund. PAHO
also advises governments on productchoices. PAHO conducts procurement
activities on an annual basis,
establishing annual arrangements with
manufacturers for the forthcoming year.

Procurement and pricing strategies

Countries supported by GAVI haveconcerns over their ability to afford
to pay for vaccines in the long run.
A Kenyan Ministry of Health official
equated adding multiple new
vaccines to a national immunisation
programme as “taking out multiple
mortgages”.9 Sustainability of
introducing new life-saving vaccinesrequires that the full cost of national
immunisation programmes, with allof their component parts, be taken
into account. Increased domestic
allocations will be needed as well asinternational support.

Products must be prequalified by
WHO, or registered in a PAHOrecognised national regulatory
authority when products are not in
the WHO prequalification system. PAHO
charges countries the average weighted
price for each vaccine it offers.
Other WHO regions are considering
a similar regional pooled vaccine
procurement system inspired by
the PAHO Revolving Fund model.

The PAHO Revolving fundFor more than 30 years the PAHO Revolving Fund, through its ‘lowest price’clause, has guaranteed access to a single and lowest worldwide price regardlessof territorial size or economic development. The Fund has also created sustained
predictable demand and led to less fluctuation in vaccine prices as well as
contributed to national financial self-sufficiency.
But the clause is disliked by companies which practice tiered pricing. Some areunwilling to offer middle-income countries in the PAHO region – such as Brazil
or Ecuador – the same prices as offered to least-developed countries through
GAVI. Some have side-stepped the lowest price clause by offering different
product presentations to GAVI and other developing countries.
In the case of pneumococcal conjugate vaccines, for example, GSK developed
a two-dose vial for sale to UNICEF ($7.00 per dose, which includes $3.50
AMC subsidy), while offering PAHO a one-dose vial ($14.85).
PAHO’s use of the lowest price clause for an entire region has been a
successful tool in obtaining affordable vaccine prices for both its lowand middle-income member countries. However this mechanism is underpressure as companies move toward prices that are significantly higher
for middle-income countries.

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5Procurement and pricing strategies

Tiered pricing: Many multinational
companies practice tiered pricing– different categories of buyers arecharged different prices for the same
product. The highest prices are charged
in wealthy markets, intermediate prices
in middle-income countries, and lower
prices in the poorer countries, suchas those eligible for GAVI support.
Under the current system, producers
are setting prices and the sharing of
information on prices paid has been
limited (beyond UNICEF and PAHO
prices). Limitations of this system aredemonstrated with the pneumococcal
vaccine. Although the cost of
production has been estimated to bewell below $3.50,13 Pfizer is charging$14.85 to PAHO countries, $26.00
to South Africa, and $7.00 per doseto GAVI.iv As concluded in an analysis
on tiered pricing where the cost of
GSK’s PCV vaccine supplied to PAHO,GAVI and the government of Brazil
was examined, “currently, there is no
straightforward, equitable way to settiered prices to achieve affordability.”14
Price transparency: Until recently,
the only public information available
on how much individual companies
charge for vaccines were the postingsof average weighted prices from
PAHO’s Revolving Fund. But PAHO’s
system does not communicate
individual supplier prices, so it was

impossible to know when prices varied
considerably between similar products.
The lack of pricing information made itdifficult for governments and donors,
as well as other vaccine procuring
stakeholders, to ascertain whether or
not they were receiving a fair deal.
Without a good frame of reference fornegotiation, countries pay too much,particularly those outside of pooled
procurement mechanisms. While somemiddle-income countries in the PAHO
region benefit from prices obtained
through pooled procurement, countries
such as South Africa – despite having
a lower income level – pay nearly fourtimes as much for the same products(See Table 1).

Table 1:
2011 price per dose of new vaccines for South Africa,
compared to PAHO and GAVI / UNICEF prices
Purchaser
VaccineSouth Africa

PAHO

GAVI / UNICEF

Pentavalent

$9.35

$2.95

$1.75

Rotavirus

$7.75

$7.50

$2.50

PCV

$26.00$14.85$7.00

Notes: Prices paid by the government of South Africa are quoted from information obtained fromcorrespondence with the Department of Health. Prices have been converted from South African Rand
using a 26 March 2012 conversion rate.
Price quoted for the South Africa, PAHO and GAVI/UNICEF rotavirus vaccine is the GSK product.
The GAVI/UNICEF rotavirus vaccine price is that announced in June 2011.
Price quoted for the GAVI/UNICEF PCV vaccine includes the AMC subsidy.

In January 2011, UNICEF published anhistorical online database with vaccine
prices, listing prices paid by productand supplier.15 The UNICEF databaserevealed some striking disparities inprice. For example, pentavalent vaccine,the five-in-one shot that is the mainstay
of GAVI purchases, is being offered byIndian manufacturers such as the Serum
Institute at prices almost 40% less than
Crucell, a European company, the mostexpensive competitor (See Table 2).

Table 2:
2011 UNICEF price per dose of DTP-HepB-Hib (pentavalent) vaccines, by supplierSupplier
Crucell
Switzerland AG

GlaxoSmithKline
Biologicals S.A.

Serum Institute of India Ltd.

Presentation

single-dose liquid

two-doselyophilised

single-dose liquid

two-doselyophilised

ten-dose liquid

Country of
Manufacture

Republic of Korea

Belgium

India

India

India

2011 Price perdose$2.80 – 3.20

$2.95

$2.25 – 2.50

$2.25

$1.75 – 2.11

Notes: Prices sourced from: http://www.unicef.org/supply/files/11_05_23_DTP-HepB-Hib.pdf
Country of manufacture information obtained from: http://www.who.int/immunization_standards/vaccine_quality/PQ_vaccine_list_en/en/index.html

Continuing to improve pricetransparency is critical both for donors
supporting GAVI and for countries
that must negotiate with companies

outside of pooled procurement
mechanisms. One of the initiatives thatis exploring the creation of a pricing
and product database is the Vaccine

Product, Price and Procurement
Project (V3P) which began in
September 2011.

iv.	This price is inclusive of the Advance Market Commitment per-dose subsidy of $3.50 per dose. After selling a pre-determined number of doses,
the GAVI price for PCV will drop to $3.50 per dose.

6

Médecins Sans Frontières | April 2012

from several Indian producers in the
pentavalent market, for example, GSK
and Crucell lowered their UNICEF
prices by approximately 15% between
2009 and 2010 (see product card
page 17).

The UNICEF database demonstrates
that vaccine prices are highly
dependent on where a productis produced. Labour and otherproduction inputs can be obtained
at lower prices in emerging markets,
but lower fixed costs for constructing
facilities are also important,particularly as these typically accountfor 60% of vaccine production costs.16
Developed country manufacturers
spend $200 to $400 million per
vaccine on production facilities, while
emerging company manufacturers,
such as in India, typically spend lessthan $100 million.17

Examples such as the development of
the Meningitis A vaccine specificallyfor use in Africa’s Meningitis Belt, showthat lower-cost manufacturers can
produce affordable and appropriate
products that meet developing
countries’ priorities, if adequate
support and incentives are in place.
Of particular note, the Meningitis
Vaccine Project facilitated technology
transfer and utilised the lower costs ofemerging market producers to develop
the vaccine now WHO-prequalified
and sold at $0.525 per dose (2012).19

The UNICEF database illustrates how,as with the price evolution of HIV
medicines,18 the entry of low-costsuppliers into a vaccine market puts
downward pressure on the prices
charged by industrialised country
manufacturers. Following competition

In vaccine markets, however,competition is generally slower toemerge when compared to drug
markets, as “generic” vaccines do
not exist. Vaccine manufacturers
must not only develop or obtain thetechnological know-how but must also
conduct clinical trials on their products
to prove safety and efficacy.

Access to licensing technology for
production of new vaccines has often
proved difficult for emerging market
manufacturers. Working aroundprocess patents, or having delayedaccess to technology, lengthens theamount of time it takes emerging
market producers to get their lowercost vaccines to market.
Competition from emerging market
manufacturers is likely to increasesince March 2011, when China’s
regulatory authority, the State
Food and Drug Administration, wasrecognised to meet international
standards for vaccine regulation by
WHO. Chinese manufacturers are now
eligible to submit their products for
WHO prequalification. When Chinese
products are prequalified, theirproducers will be eligible to sell to
UNICEF and PAHO.20

Vaccine adaptation

Competition from lower-cost
manufacturers: The vaccines market
is evolving quickly, and a growing
number of quality-assured suppliers inemerging markets are able to undercut
the prices of traditional multinationals.

Chinese manufacturers are alreadysupplying vaccines, such as Japanese
encephalitis, to their domestic markets
and have other products against
pneumococcal disease and rotavirus
under development.21

Vaccine adaptation: essential toincreasing immunisation coverage inareas with weak health care systems
The past decade has seen rising global
immunisation coverage but data are
not always reliable. According to WHO,
global coverage with three doses of
DTP vaccine (DTP3) has risen from 66%
since GAVI’s inception in 2000 to 82%
in 2011.8 But household survey results
call official figures into question – while
WHO estimated DTP3 coverage in
Ethiopia at 86% in 2011,22 the 2011
Ethiopia Demographic and Health
Surveys estimated DTP3 coverageat only 37%.23
Additionally, reported progress inglobal immunisation often hides
significant inequities, both across andwithin countries. Many countries arestill failing to raise coverage levels;
Chad's coverage level, for example,
has fluctuated between 19–59% for
DTP3 coverage over the last five years,
one of the lowest levels of coverage ofany country in the world.24 States suchas Bihar in India have coverage levelsof 40%, lagging at least 30 percentage
points behind others such as Tamil
Nadu and Kerala.25
Even though many countries have
improved EPI coverage, vast numbersof infants are still not being reached.
Approximately 20% of babies born
every year – over 19 million infants – do
not receive the cornerstone of basic
immunisation, three doses of DTP
vaccine.26 For this “fifth child”, avaccine’s price is not necessarily themost prohibitive barrier to receiving
immunisations – a measles vaccine,costing under $0.30, may be equallyunlikely to reach a child in an African
village as a $3.50 dose of pneumococcal
vaccine. This failure is primarily due
to weak health systems and vaccine
products which are not appropriately
tailored to the country context.
Adaptation of vaccines and revising
immunisation strategies could havesignificant impact on improving
coverage. Many vaccine presentations
are not practical for use in resourcepoor settings where electricity is nonexistent or erratic. Additionally, unlike
the oral polio vaccine (OPV) which
can be administered by lay volunteers,most other traditional and newer
vaccines require trained health workers
which are often in short supply in theneediest areas.
As with drugs, novel vaccines havepredominantly been brought tomarket to answer developed country
needs. The products are therefore
tailored to wealthy market disease
epidemiology, as well as to be usedin wealthy market health systems.
The research and development (R&D)
that goes into producing a vaccine
does not necessarily take into accountthe resources and conditions ofdeveloping countries.

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7

Vaccine adaptation

GAVI has not thus far created incentives
for adapting vaccines for developing
countries. Instead its principal focus has
been to aggregate demand and reduce
the time lag that developing countries
have to wait before they can accessnew products.
The Bill and Melinda Gates Foundation,
through its Grand Challenges
programme, is addressing the needfor adaptation by funding early stage
research into technologies such as
needle-free vaccines or vaccines that
do not require refrigeration. The Gates
Foundation is also funding several
emerging country supplier products to
help diversify the vaccine market. Until
now, this work has not been coordinatedwith GAVI’s procurement strategy.
Political will and access to resources is
key for expanding the reach of vaccines,
but the availability of adapted products
also plays as essential role as resources.

How ill-adapted vaccines complicatedelivery: There are a number ofchallenges that complicate the deliveryof vaccines.
Many current products have attributes
that make their use difficult in countries
or regions with weak health systems.
Most vaccines must be kept in a cold
chain, at temperatures between two
to eight degrees Celsius. Heat-instablevaccines can only be out of the cold
chain for one week at temperatures
up to 37°C. In areas where electricity
is unreliable and transportationdifficult, these vaccines are notsuitable. Conversely, due to challenges
in maintaining a proper cold chain,vaccines are often accidentally frozen,
which can result in damaged andunusable vaccine, such as in the caseof the tetanus toxoid vaccine. Moreresearch is needed to determine theextent of vaccine wastage due to cold
chain failures, or accidental freezing, but
it is clear that these conditions require amore appropriate vaccine adaptation.
Vaccines that are administered byinjection make it difficult to extend
their reach to locations where healthcare workers visit infrequently.
The Global Polio Eradication Initiative
has relied on lay community healthworkers to vaccinate children in8

Médecins Sans Frontières | April 2012

Table 3:
Vaccine Vial Monitor ratings for select products
VaccineVaccine Vial Monitor (VVM) 37°C

Pentavalent(Serum Institute of India)

14 days

Measles-containing vaccine

14 days

Pneumococcal vaccine

30 days

Rotavirus (GSK Rotarix)

14 days

Rotavirus (Merck Rotateq)

No VVM approved for this product.
Cold chain storage conditions must be
maintained from delivery to administration.

Notes: See annex 1 for information on VVM. A vaccine vial monitor (VVM) is a label containing a heatsensitive material which is placed on a vaccine vial to register cumulative heat exposure over time. There
are four different types of VVMs designed for different types of vaccines depending on their heat stability.
The VVMs above refer to the number of days a vaccine can last in temperatures to endpoint at 37˚C.
Information is included as part of the WHO Prequalification information at
http://www.who.int/immunization_standards/vaccine_quality/PQ_vaccine_list_en/en/index.html

the most remote villages, which has
been possible in part due to oral
administration of the vaccine.27 Most
vaccines however, remain injectables,
which require health workers who
have been trained in proper injection
techniques. Proper disposal of
injection waste is also a challenge
in developing countries where
incinerators are expensive and notreadily available in most communities.
Vaccine administration technologies,
such as products that can be inhaled,administered orally or throughmicroneedle are important for theadaptation agenda.
In countries with limited healthcare
workers and health facilities, morechildren may be vaccinated if there isa mix of vaccine presentations. Despite
WHO’s recommendation to open avaccine vial when any eligible child ispresent, healthcare workers are often
reticent to open multi-dose vials ifthey do not have a quorum of children
present for fear of wasting vaccine.
Although multi-dose vials significantly
reduce the price per dose of vaccine,in areas where healthcare workers
resist opening vials when there are fewer
children than doses, having both single
and multi-dose vials available may
be advantageous.

How dosing schedules hinder
a completed vaccination series:
There is room for improving thevaccine schedule to reduce thenumber of children not completing
their vaccination series.
Dosing schedules should be exploredto maximise the number of children
completing their full vaccination series.
In countries with ongoing measles
transmission, the first dose of measles
vaccine is recommended at ninemonths of age, while children shouldhave already received their threedose DTP series at six, ten, and 14
weeks. Many children do not receive
vaccination against measles due tothe timing of the primary shot, which
is not bundled with other antigens,in most of the developing world. In
some instances, the low coverage ofmeasles vaccine has manifested as
mass measles outbreaks, most acutely
in Africa where 28 countries faced
outbreaks in 2010; in the Democratic
Republic of the Congo (DRC), over
100,000 measles cases were reported
from January to October 2011.28
Further research is needed on the
immunologic response to vaccines ifchildren are vaccinated at ages outsideof the current recommendations.

According to the currently
recommended immunisation schedule,
even if all vaccines are bundled toachieve the minimum number of healthfacility visits, caretakers must still bring
their child to a facility five times for
vaccinations in its first year. Research
into adapting products so as to makethe dosing schedule as convenient
for caretakers as possible, while also
maintaining vaccine efficacy, must
be prioritised.
Some vaccines are not specificallydesigned for developing country
epidemiology: The epidemiology of
diseases in developing countries is not
fully incorporated into vaccines produced
for developed country markets.

In some cases, adapted products may

cost more per dose to manufacture
than traditional products. However,if the vaccine is more efficacious
against the disease, if vaccine wastage
can be minimised by ensuring thatall doses reach their intended
children, or if programme costs canbe reduced by decentralising delivery
to lay community health workers
through non-injectable products,
overall EPI costs may actually
come down.
Investment and additional clinical
trials are needed to further thevaccine adaptation agenda. As
the Decade of Vaccines moves
forward, it will be critical to look atsynergies between Gates Foundationfunded product development and
GAVI’s procurement strategy andseek additional investments bygovernments and companies. There
will need to be a concerted effort todefine desirable products and productprofiles, and to support developmentof these adapted products so as tomeet country needs.

© Pascale Zintzen

The epidemiology of diseases differs
between regions. For example,
meningococcal meningitis has five

serotypes that cause the most disease
worldwide: A, B, C, W135 and Y.
In the United States, the most circulating
serotypes are B, C, and Y, whereas in
the African Meningitis Belt, meningitis
type A is the most prevalent strain,followed by W135. Rotavirus, whichcauses diarrhoeal disease, has a numberof different genotypes. Despite theavailability of two WHO-prequalified
vaccines against rotavirus – Rotarix andRotateq, which are made of one and fiverotavirus genotypes, respectively – there
is a need for further research todetermine the most prevalent genotypesof rotavirus circulating in high-burdencountries. Although each vaccine may
protect against multiple rotavirus
genotypes, it has not been concluded
if the efficacy against other genotypes
is the same. As the body of researchon disease epidemiology in developing
countries grows, it will be importantthat vaccines be modified to be mostefficacious for those contexts and not
only for that of the developed world.

Vaccine adaptation

Changing the dosing schedule toimprove EPI effectiveness will need to
be balanced with the immunologic
issue of ensuring that vaccine
protective efficacy is as high as possible.

In the DRC, MSF measles vaccination teams make their way through the forest to reach isolated villages totally
inaccessible by vehicle.

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9Conclusions and Recommendations

Conclusions andRecommendations
In recent decades, improved vaccine access has averted deaths and serious illness in developing
countries. But there is still a need for increasing the impact of vaccination by increasing the reachof immunisation programmes. In order to fully realise the benefits of immunisation, two key
challenges will need to be overcome.

First, newer vaccines need to bemade affordable. Although GAVIeligible countries are so far spared
the burden of financing most of thecost of newer vaccines, some arebeing weaned off GAVI support andothers will be in the future. High
prices are prohibitive for donors
and unsustainable for the vast
majority of developing countries.
Non-GAVI eligible developing
countries, like South Africa, arealready facing daunting vaccination
bills. Ensuring that vaccine prices
are reduced is therefore essential,
particularly in a context ofdwindling financial resources
for global health.

Second, adapted products must
be designed for local disease
burden, and contexts with few
healthcare workers and weak
health systems. The majorityof currently available vaccine
products have been developed forindustrialised countries and theirdisease epidemiology. Increased
attention and investment todeveloping vaccines that are
more practical to use in resourcelimited settings – such as productsthat are more heat-stable, can beadministered by community healthworkers and with few doses ormore flexible dosing schedules –and more tailored to the specificmedical needs of developing
countries is needed.

Vaccine prices: how to ensure vaccines are affordable• Harnessing the power of greater price transparency: Additional mechanisms
to share pricing data are needed to ensure that purchasers know what is being
paid to each manufacturer for each vaccine. Increased public information
will inform price negotiations so that purchasers can avoid paying
unnecessary premiums.
• Utilising the power of pooled procurement: Additional pooled
procurement mechanisms and/or negotiated reference prices must be
developed so that developing countries outside of PAHO not eligible for
GAVI support do not pay inflated prices. Other WHO regions and countries
should explore opportunities to collectively negotiate reduced prices.
• Supporting the development of lower-cost manufacturers: Companies
with production facilities in emerging countries have proven their capacity to
produce quality-assured products at substantially lower prices. Technical barriers
however remain considerable and will need to be overcome. Major purchasers,
such as GAVI, and agencies subsidising development must better coordinate so
as to speed up development of new products. Concurrently, emerging country
producers must have access to licences and key technology know-how.

Vaccine adaptation: how to increase immunisation coverage inareas with weak health systems and ensure that products match disease burden• Developing the vaccine adaptation agenda: A vaccine adaptation andinnovation agenda that defines products that will extend the reach of
immunisation needs to be developed. As part of this agenda, WHO shouldtake a more proactive and directed approach to determine technical productprofiles that would improve the reach of immunisation programmes.
This work needs to be done in conjunction with the input of countries.
• Putting governments in the lead: Ministries of Health in countries struggling
to raise immunisation coverage must be more involved in setting priorities andfeeding product development information to vaccine developers.
• Innovating delivery strategies: WHO, UNICEF and partners must develop
additional EPI delivery strategies for countries with weak health systems.
There is a need for increased investment in operations research to test
delivery methods for reaching the “last 20 percent”.
• Making vaccines more appropriate for local epidemiology:
The knowledge base on disease epidemiology in developing countries ispoor, while most vaccines are tailored to markets in wealthy countries.
Further research into specific disease burden in developing countries isneeded to inform the development of the most efficacious vaccines.
• Expediting implementation of new products: As new WHO-prequalified
products come to market (inhalation devices, microneedles, etc), strategies
must be developed to expedite their use in developing countries.
• Investing in products and strategies that work: Donors and Ministries of
Health should be willing to pay slightly more for vaccine presentations thatare easier to administer and have the potential to reach more children,
especially since some products might bring down overall progamme costs.

10

Médecins Sans Frontières | April 2012

View From the Field: Why we need to simplify vaccination

View From the Field:
Why we need tosimplify vaccination
Why is it so difficult to achieve and sustain high levels of immunisation coverage in remoteareas, or where health systems are severely limited? Dr. Michel Quéré, MSF medical advisor for
programmes in Niger, Chad and the DRC, explains why the vaccines at our disposal today makereaching remote populations considerably more difficult.

But it’s definitely the case that we getgood results also because we haveconsiderable logistical support at our
disposal. We’ve got the large storage
facilities, the fridges and icepacks to
keep the vaccines under cold chain, thetransportation to get them out to thevillages and the logisticians to make surethat it all runs as smoothly as possible.
With some vaccines, children needto receive several doses, several
months apart to receive full protection.
That means, for instance, to makesure a child is fully protected with thepentavalent vaccine, you have to trace
the child on three separate occasions
so that they can receive three doses ofthe vaccine. And if you’re also giving
additional vaccines, then the ages atwhich you need to vaccinate don’tnecessarily coincide, so for every childunder the age of one, five separate
visits may be needed.
Reaching children scattered across theabsolutely vast and remote areas where
they live is a real challenge – the roads areusually very bad, and some of the healthposts – for instance in the Democratic
Republic of Congo – are so isolated, orpresent such security concerns, they
can only be reached by plane.
Keeping the cold chain when it’s
45˚C outside is a major challenge.
For the national health authorities,
in some rural areas, just maintaining
the fridges in working order is hard

© Anna Surinyach

Our catch-up vaccination programmes
are quite successful – the idea is to
give children the vaccines they havemissed, for example against measlesor the pentavalent vaccine. We getgood results because we put a lot ofeffort into raising awareness in thecommunity, explaining which age
group will get vaccinated when andwhy that’s important, and our locallyrecruited nurses play a vital role.

Social mobilisation before a blanket measles vaccination campaign aimed
at 800,000 children in Eastern DRC.
to guarantee, and then there’s theneed to produce enough ice packs sothat the vaccines are still cold by thetime we get to the children. You canimagine how many icepacks are needed,so even getting the vaccines out to thevillages is a huge logistical effort in itself.

Unless vaccines are simplified so thatthey’re better adapted to real-life
conditions, we will never get on topof these killer diseases and will always
need to respond to outbreaks that wehaven’t managed to prevent througheffective immunisation programmes.

The governments or local authorities
rarely have the means at their disposal
to get all this done – there might be only
one nurse available, expected to provide
services for 10,000 people and that
number can go up to 50,000 people insome parts of Niger and he or she willoften have no means of transportation.

Sadly, there’s been little progress inthis regard over the last 20 or 30 years.
And unless we see some changes,
we’re not likely ever to achieve the goalof good EPI coverage. Adding new
vaccines to the mix isn’t going to bring
us closer to achieving that goal either.

So it’s very clear that we need things
to be made simpler. A vaccine thatcan be taken orally is ideal. It can thus
be administered more simply – even bycommunity health workers – and so canbe made available much more widely,overcoming the shortage of healthstaff. We also need to get around the
problem of needing a cold chain as it’sa huge burden in terms of resources.

It might cost more to develop andprovide better-adapted tools, ofcourse. But responding to epidemics
and disease outbreaks is hugely costly,and children who are ill become
vulnerable to other conditions likemalnutrition, so the extra expense
should quickly be offset with othergains. That’s putting to one side thefundamental question of whether you
can put a price on saving a child’s life.

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“

“

11

MSF has been treating patients for malaria in the Moissala district of Chad for two years, but theteam has also responded to outbreaks of contagious diseases such as measles and meningitis.
These outbreaks continue to occur because in recent years, the national Expanded Programme on
Immunisation (EPI) has suffered from neglect. Florence Fermon, Head of MSF’s Vaccine Working
Group, sets out her concerns about the lack of support for EPI within the country, which has led
to continued outbreaks of disease and unnecessary loss of young lives.
What we are seeing in the country as awhole, and in Moissala in particular, is that
the EPI has not been getting the support
it needs from the Ministry of Health andits partners. There is competition forresources from a growing number of
specific vaccination initiatives – including
polio eradication, maternal and neonatal
tetanus elimination, measles elimination,and the introduction of the newmeningitis A vaccine.
Each of these individual vaccine initiatives
conducts its own self-contained staff
training programmes, funds its own
vaccines and mobilises people to takepart in the vaccination campaigns.
There is limited support in the country
to reinforce EPI as a whole. A basic
strategy to provide routine vaccination is
not in place, by making sure for example
that any eligible child receives their due
vaccines at each contact with a healthpost. Another example in Moissala
district is the absence of systematic
vaccination at birth, when deliveriesoccur in a maternity ward. There
are globally recommended policies tosupport this, but in Chad they havenot been implemented. In fact, the last
national EPI training in Chad took place
as far back as 2004.
Moissala district provides clear illustrationof this: the cold chain storage facilities
are insufficient, and there isn’t evena cold chain officer in place. Should
the cold chain break down, there
is no technical support available inthe district. And only minimal social
mobilisation support is at hand to
inform and encourage people to bring
their children to be vaccinated.
As a result, we see many vulnerable
pockets where people in this area

12

Médecins Sans Frontières | April 2012

© Natacha Buhler“

An MSF meningitis vaccination campaign in collaboration with the Ministryof Health in Chad.
are simply not being reached andimmunised – either at all or fully. That
is why, despite large scale vaccination
campaigns in the country, we are stillencountering persistent outbreaks of
diseases such as measles and pertussis.
In January 2011, a nationwide measles
vaccination campaign was launched.
But although the incidence of measles
has decreased in most districts,
there are still around 300 – 400 new
suspected cases of measles declaredeach week in some places. Clearly the
campaign has failed to reach some ofthose who were targeted. Additionally,
there hasn’t been an investigation
to determine why these outbreaks
continue so that we can implement
an adequate response.
MSF is working with partners on a
strategy to respond to this situation,and reverse this neglect specifically inMoissala district. The proposed strategy
includes catch-up vaccination activities
in the district for all children up to two
years of age for all the basic antigens,and vaccination for all children up to
five years of age for measles and yellow
fever. Altogether, we hope to reach thetarget population in this area of morethan 10,000 children.
Depending on support from ourpartners, we are also interested in
introducing the pneumococcal conjugate
vaccine, at present not included in thenational programme, despite a highnumber of pneumococcal disease casesin the district. In addition, we propose toprovide technical assistance to improveplanning for the EPI system, support the
improved functioning of the cold chain,
as well as offering local training andsuggestions for improved methodsof managing waste.

“

Strengthening the Expanded Programme on Immunisation: Lessons from ChadStrengthening the
Expanded Programmeon Immunisation:
Lessons from Chad

The idea to create this report was stimulated by the May 2011 web publication of ten years ofvaccine prices paid by UNICEF for country procurement. Until these prices became public there
was little knowledge about actual prices paid by donors and governments for vaccines that havebeen used in developing countries.

We have looked at several categories
of vaccine products over the period forwhich data is available and have analysed
movements in prices to pinpoint trends
and better understand factors that impact
price changes over time. In some cases,
UNICEF prices have been presented
alongside other reference prices including
the PAHO Revolving Fund prices for Latin
American countries, and other selected
country public procurement prices.
For each category of products
we outlined:1) general information – WHO
recommendations, products andmanufacturers, dosing schedules
and presentations;2) p rices for each product in the
category; andVaccine categories were selected
because they are either cornerstonesof the WHO-recommended Expanded
Programme on Immunisation (EPI)or because they are newer vaccinesthat have recently been introduced in
at least some developing countries.
The breadth of these products allows
for analysis of vaccines in different
stages of the product life-cycle
and illustrates multiple adaptation
challenges, as well as different
models of development. This analysis,
however, does not include all
antigens recommended in the
WHO vaccination schedule.
All products appearing in thispublication are WHO-prequalified.

Methodology

Methodology

The following vaccine products
are included:• Diphtheria-Tetanus-Pertussis (DTP),
monovalent Hepatitis B (HepB),
monovalent Haemophilus influenzae
type B (Hib) and pentavalent(DTP-HepB-Hib) vaccines• Measles containing vaccines,
including monovalent measles,
measles-rubella (MR), andmeasles-mumps-rubella(MMR) vaccines• Meningococcal meningitis
conjugates vaccines• Pneumococcal conjugate
vaccines (PCV)• Rotavirus vaccines

3) adaptation challenges.

Price data
A retrospective analysis of prices
charged for vaccines purchasedfrom the years 1998 to 2011 was
performed using the following
sources of information:• UNICEF Vaccine Price Data.v
In 2011, UNICEF published retrospective
prices paid for specific products during
the period 2001 – 2010. The database
was last updated in February 2012.
Prices are either Incoterm Free Carrier(named place of delivery) (FCA) to
UNICEF designated freight forwarder orIncoterm Carriage Paid To (named placeof destination) (CPT) to the suppliedcountries. In cases where a range ofprices was provided by UNICEF forthe same product for the same year,
the highest price was taken for the
purposes of the retrospective analysis,
unless otherwise noted.

v.

• PAHO’s Expanded Program of
Immunisation Vaccine Prices.vi
This document provides weighted
average FCA prices for each vaccine
presentation that is offered by PAHO’s
Revolving Fund. The weighted average
price is calculated by summing up thetotal expected purchase value of eachassigned supplier for the same typeof vaccine then dividing the amountby the total of doses expected to bepurchased of the given type of vaccine.
PAHO does not disclose individual
prices of vaccines and charges countries
that participate in its Revolving Fund
this average price – a ‘solidarity’system of paying averages, notactual prices. Participating countries
also contribute a percent of costs tocapital for the Revolving Fund.vii• US CDC Vaccine Price List Archives.viii
The CDC Vaccine Price Lists provide
vaccine contract prices for CDC
contracts that are established
for the purchase of vaccines byimmunisation programmes thatreceive CDC immunisation grant
funds (i.e., state health departments,
certain large city immunisation
projects, and certain current andformer U.S. territories). Prices quoted
include tax and transportation
fees. This would correspond to the
Delivery Duty Paid (named place ofdestination) (DDP) Incoterm.
For the Hepatitis B and measles graphs,
where multiple suppliers with multiple
price points were to be included,
we took the average price across allpresentations for each year for a given
organisation (e.g. UNICEF or PAHO).

http://www.unicef.org/supply/index_57476.html

vi.	http://www.paho.org/revolvingfundvii.	Countries participating in the PAHO Revolving Fund contribute a percentage of costs for the fund’s capital (formerly 3%). Starting in 2011, the contribution will be
3.5% (3% is the capitalization fee of the common capital fund and 0.5% is for strengthening of the procurement mechanism).
viii. http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list-archives.htm

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13© Ton Koene

Diphtheria-Tetanus-Pertussis
Hepatitis B
Haemophilus Influenzae type B
and combination vaccines

 Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus influenzae type B and combination vaccines

WHO recommendations• Diptheria-Tetanus-Pertussis (DTP)
vaccines have constituted thecornerstone of routine immunisation
since the founding of the Expanded
Programme on Immunisation (EPI)in 1974.
• Hepatitis B (HepB) vaccines werefirst prequalified by WHO in 1987,
and first recommended for use in all
national immunisation programmes
in 1992.29 These recommendations

were further strengthened in 200430
and again in 2009.
• Haemophilus influenzae type B (Hib)vaccines were first prequalified andrecommended by WHO in 1998.31
The most recent recommendations
from November 2006 state that
all countries should introduce Hib
into their routine immunisation
programmes, starting the three-doseschedule for infants in line with DTP
vaccination at six weeks of age.32• Scarce data on HepB and Hib disease
burdens in developing countries
contributed to slow uptake of these
relatively expensive vaccines into
national immunisation schedules,
even after WHO recommended theirintroduction.33, 34 After its creation in
1999, one of GAVI’s first priorities
was to help make HepB and
Hib-containing vaccines available
to lower-income countries.35

Products and manufacturers• The first Diphtheria-Tetanus-Pertussis(DTP) trivalent combination vaccine
was developed in the United States in1942.36, 37 DTP vaccines combine threeof the six antigens that constituted
the original Expanded Programmeon Immunisation.38 They are available
in liquid form in one-dose, ten-dose,and 20-dose vials.
• While the U.S. and many European
countries use an acellular pertussis
vaccine (DTaP), UNICEF and PAHO
almost exclusively procure whole cell
pertussis vaccines (DTP). Acellular
pertussis vaccines are associated withfewer adverse events, such as localised
pain and fever.39 Whole cell pertussis
vaccines, however, have been shown
through clinical trials to confer higher
levels of efficacy against pertussis thantheir acellular counterparts with athree-shot schedule, particularly whencombined with other antigens.40, 41• Current WHO-prequalified DTP
manufacturers include Bio Farma,
Sanofi Pasteur, and Serum Institute ofIndia. DTP production has been reduced
as countries have increasingly switchedto pentavalent (DTP-HepB-Hib).
• Monovalent recombinant HepB and
Hib conjugate vaccines came on themarket in industrialised countries
in 198642 and 199143 respectively
and were quickly integrated into
immunisation schedules. There are
11 manufacturers that have beenprequalified for monovalent HepB
and/or Hib production.
• Vaccines against HepB and Hib
were combined with DTP or DTaP
vaccines in the late 1990s, with thegoal of expanding the protection
offered through traditional routine
immunisation, either as tetravalent(DTP-HepB or DTP-Hib) or as pentavalent(DTP-HepB-Hib) vaccines.

• GSK was the first to license a DTP-HepB
combination vaccine in 1996, which
was WHO prequalified in 1998.
• This vaccine was subsequently shown
to be effective when administeredwith GSK’s Hib vaccine44 (which was
also WHO prequalified in 1998),
resulting in the first pentavalentvaccine to provide protection
against all five antigens. GSK helda monopoly over pentavalent sales
to UNICEF until 2006.
• Current WHO-prequalified pentavalentmanufacturers are Berna Biotech
Korea Corporation of Crucell (onedose liquid vial), Biological E Limited(one-dose and ten-dose liquid/lyophilised), GlaxoSmithKline (onedose and two-dose liquid/lyophilised,
one-dose liquid), and Serum Instituteof India (one-dose, two-dose, andten-dose liquid/lyophilised, and onedose, two-dose and ten-dose liquid).

Dosing schedules and presentations• The World Health Organization
recommends that all infants receive
three primary doses of DTP at six,ten, and 14 weeks of age. Hib dosage
is recommended according to thesame schedule as traditional DTP.
• The first dose of Hepatitis B should
be given within 24 hours of birth, but
no real programmatic intervention
has been developed to bring this toscale due to the lack of information
on prevalence of HepB in pregnant

women. Additionally, in many
countries where mothers rarely givebirth in a health facility the HepB birthdose is difficult to implement. After
HepB birth dose, two to three further
infant doses are recommended,
integrated into the DTP schedule, or
administered through pentavalent.45• Monovalent HepB, monovalent Hib
and tetravalent vaccines are available invials containing from one to 20 doses.
Pentavalent vaccines are available inone- and two-dose vials, as well as
recently prequalified ten-dose vials.

 Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus Influenzae type B and combination vaccines

General information• Hib-containing vaccines are available
in liquid or lyophilised formulations,while DTP-HepB or monovalent
HepB are only liquid formulations.
Pentavalent vaccines are available
in both liquid and liquid/lyophilised
combination formulations. Fully liquid
vaccines do not require reconstitution
by a health care worker, and areoften lower-volume.

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15

 Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus influenzae type B and combination vaccines

DTP vaccines
The cost of DTP is relatively low,with UNICEF paying between$0.14 and $0.42 per dose in 2011.46
Vaccines containing whole-cell

pertussis antigens are also much lesscostly – between 1991 and 1997,
while the U.S. was transitioning to
DTaP, the CDC paid approximately

twice as much per dose, for vaccineswith acellular rather than whole cell
pertussis components.47

Hepatitis B vaccines
Early recombinant vaccines against HepB
by GSK and Merck were first sold in
wealthy markets for $40 a dose. Progress
toward lower-cost vaccines was hinderedby originator company patents. In thecase of recombinant HepB vaccines,
originators held dozens of process patents
on development technology, delaying
the efforts of lower-cost producers tocreate similar, lower-cost vaccines.48
Even when lower-cost producers cameon the market at prices as low as$1.00 a dose, developing countries still
considered them expensive comparedto the standard EPI package.48 However,when GAVI started to purchase HepB

vaccines, the price was already low
by industrialised country standards,
and the market was at a stage whenmore suppliers were primed to begin
production and bring prices down
through increased competition.
Once GAVI started supporting thepurchase of new and under-utilised
vaccines, the developing country market
for Hepatitis B vaccines grew – and at
a much faster rate than the market
for Hib. In the early 2000s, most GAVI
countries opted to first introduce only
monovalent Hepatitis B, or a DTP-HepB
combination, and later switched to apentavalent vaccine to include Hib.49

Hepatitis B
5• The market has matured in thepast decade, with lower prices
following the presence of greater
competition from multiple
suppliers.

0.55
PAHO price per dose

0.49

4

0.52

0.50

Average
UNICEF priceper dose

0.45

3

0.35
0.28

US$

0.40

2

0.30

1
0.25
0.23

0

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

UNICEF was able to obtain pricereductions for monovalent HepB early on
in GAVI’s history as more companies had
products prequalified. In 2001, only fourmonovalent product presentations weresold to UNICEF from three producers,
with prices ranging from $0.31 per dose
for a ten-dose vial to $0.68 per dose fora one-dose vial. By 2004, UNICEF wasprocuring monovalent Hep B from five
manufacturers, and more products in
multi-dose vials had entered the market.
By 2007, most multi-dose vials wereselling to UNICEF for between $0.20 and$0.25 per dose. One-dose vials ranged
from $0.23 for PAHO, to $0.27 (Crucell),and $0.40 (LG Life Sciences) for UNICEF.

Hepatitis B prices –the highlights:

Industrialised Manufacturers
Emerging Manufacturers

Number of Manufacturers Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus Influenzae type B and combination vaccines

Prices0.20

Year• Low prices could mean limited
profits for manufacturers,
possibly leading to the market
exit of industrialised country
suppliers.
• There is possible room for asecondary market of specialised
products, such as single-dose
microneedle to be administeredby community health workers.

Note: The number of manufacturers is based upon those from which UNICEF procured Hep B
vaccine in a given year.

Hib vaccines
The Hib vaccine is the newest of the fivevaccines contained in pentavalent, andhas always been the most expensive
component of the five. The conjugate
technology necessary for its production
contributes to its higher cost.

16

Médecins Sans Frontières | April 2012

When PAHO started purchasing
monovalent Hib in 1999, the lowest
price per dose it could obtain was$2.18. In comparison, the PAHO priceper dose for a DTP vaccine the same
year was less than $0.07.

The PAHO price for monovalent
Hib continued to rise during the
2000s, outpacing inflation, possibly
due to low demand for monovalent
Hib in comparison to pentavalentvaccines – most countries in the PAHO

It’s only after the first emerging country
producer, Serum Institute of India, wasprequalified that prices paid by PAHO forthe monovalent lyophilised Hib productbegan to fall. The PAHO average weighted
price per dose (based on purchases ofSerum, GSK and Sanofi products) fell

from $3.45 in 2009 to $2.25 in 2010 andfurther to $2.00 in 2011. On the other
hand, the average price per dose of liquid
Hib rose from $3.20 in 2010 to $3.60
in 2011, despite the 2010 prequalificationof a Cuban manufacturer, Center for
Genetic Engineering and Biotechnology.

Pentavalent vaccines
The high price of Hib has meant that
pentavalent price reductions were neither
as rapid nor as substantial as anticipated.51
In addition, with GSK the only player inthe market until the mid-2000s, there
was no competitive pressure on price.
While GSK held a monopoly, pentavalent
prices offered to UNICEF never dropped
below $3.10 a dose, and in someyears were as high as $3.65. The arrival
in 2006 of products from Crucell, amanufacturer which produces in South
Korea, did not bring down prices – infact, Crucell’s pentavalent prices havebeen typically higher than GSK’s every

year since 2007. GSK’s product is a twodose lyophilised, while Crucell’s productis a single-dose liquid presentation.
It was not until the entrance of
emerging-market suppliers that prices
gradually started to come down, though
in 2008, only one of two new Indian
suppliers – Shantha Biotechnics – offereda lower price of $2.90, while Panacea
Biotec took advantage of the oligopoly
market by offering a $3.60 price similar
to GSK and Crucell. GSK, Crucell, andPanacea only dropped their prices in
response to the Serum Institute of India

Pentavalent prices for UNICEF & PAHO,
1999–2011• The market is still developing as new
suppliers are being prequalified,e.g. Biological E Limited received
prequalification for a pentavalent
product in August 2011 (and pricedata is not yet published).

4.00

Prices Per Dose in US$

3.75

Crucell
1 dose vial
3.63

3.50

3.50
3.50
3.20

3.25

3.00

3.20

GSK
2 dose vial
2.95

2.75
Serum Instituteof India 1 dose vial

2.50

Serum Institute ofIndia 2 dose vial

2.25

2.25

Serum Institute ofIndia 10 dose vial

2.00

2.50

2.25

2.10

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011Year
Notes: UNICEF prices are listed by manufacturer. All product formulations are liquid, with the
exeption of the GSK and Serum two-dose vial (lyophilised).

The number of competing suppliersof pentavalent has in recent
years been reduced as a result ofquality issues. In October 2010,
Crucell, UNICEF’s largest supplierof pentavalent, announced thatbatches of its vaccine may have been
produced using unsterile equipment

Demand for pentavalent vaccine in2010 increased significantly, therefore
some suppliers were willing to offer
additional discounts. Serum announced
further pentavalent price reductions for
UNICEF, to $1.75 a dose for its recently
prequalified liquid ten-dose vial.52
Other manufacturers offer only one- or
two-dose vials. The impact of having
multiple suppliers, particularly thosefrom emerging markets, highlights thesignificant savings that can be achieved
when competition exists.

Pentavalent prices –the highlights:

4.25

PAHO
1 dose liquidcoming on the market in 2010 with apentavalent vaccine priced at $2.25.

following power outages at theirproduction facilities.53 Crucell wasable to restart production following
a WHO investigation. In recent years,
Shantha and Panacea have both had
their pentavalent vaccines de-listedfrom WHO prequalification status.
The Shantha product, Shan5, was• The market first suffered froma lack of competition, followed
by a lack of vaccine security.
• The number of doses per vial
has had an impact on price;
multi-dose vials are less expensive
on a per dose basis.
• Widespread introduction of HepB
and Hib in developing countries
has been a centrepiece of GAVI
success during its first decade ofactivity. However, these productintroductions will be difficult tosustain unless prices of vaccines
containing HepB and Hib reacha level whereby countries
can self-pay.

 Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus Influenzae type B and combination vaccinesregion having introduced pentavalent.50
UNICEF also procures very low volumesof monovalent Hib and DTP-Hib
vaccines in comparison to pentavalentvaccine – in 2010 UNICEF procured
97.5 million doses of pentavalent,and only 3.7 million doses of DTP-Hib.

suspended and subsequently de-listedfrom WHO prequalification in 2010.54
Panacea’s HepB and Hib-containing
vaccines including its pentavalentvaccine, Easyfive, were delisted in2011 following a WHO site audit
that showed inadequate quality
management systems.55

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17

 Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus Influenzae type B and combination vaccines

Adaptation challenges Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus influenzae type B and combination vaccines

Pentavalent introduction reduces
the number of recommended shots
per child that must be administeredfrom nine to three. Fewer doses witha lower volume vaccine presentation
also mean that less transportdeliveries to health facilities are
required, less time spent by healthstaff administering immunisations,

In some countries with limited
health care infrastructure and alack of healthcare workers, in
hard-to-reach districts a stableunidose presentation (with amicroneedle that has a VVM)

would help expand the reach of EPI
programmes. While stable unidose
presentations will cost more, theywould likely be cost-effective
considering reduced logistics andhuman resource costs as well as
reduced disease burden and deathsin the population that has so far
remained unvaccinated.

Cold Chain Logistics
Because pentavalent has limited heatstability and only lasts one to two
weeks outside of the cold chain attemperatures up to 37°C (although
it is recommended that vaccinesremain within the cold chain until
time of administration), a functioning
cold chain is an essential element of
successful vaccine introduction.
Ethiopia, for example, which introduced
liquid pentavalent in 2007, increased
its central refrigeration volume by
106%, and saw the frequency of

vaccine transportation approximately
double at national and regional levels.
While GAVI partners provide one-time
grants to fund the costs of system
expansion, increased costs for budget
items such as vaccine transportation
are and will continue to be borne by
the government.56
The cold chain requirements forpentavalent were one reason that somecountries first introduced a DTP-HepB
combination or monovalent HepB,
and later switched to pentavalent.

Unlike pentavalent, the DTP-HepB
vaccine was available in a multi-dosevial at the time GAVI started to offer
countries support, and required
approximately the same cold chain
capacity as multi-dose DTP vials thatcountries were already using. Some
suppliers now provide pentavalentvaccine in multi-dose presentations,
reducing the need for additional
cold chain space.

Presentations: Liquid vs. Lyophilised and Singlevs. Multi-dose Vials
The slow uptake of pentavalent washindered by a number of factors,
including the lack of supply capacity,lack of a global recommendation for
Hib vaccination, and the lack of a fullyliquid vaccine. The early pentavalentvaccines were liquid-lyophilised
combination vaccines – the freeze-dried
Hib element came in a separate vialfrom the liquid DTP-HepB combination,and needed to be reconstituted

before being administered to a child.
This not only required extra trainingof health staff, but increased theamount of time required for a healthworker to prepare the vaccine foradministration – one study showedthat a liquid vaccine like DTP took an
average of 36 seconds to draw up intoa syringe, while reconstituting thelyophilised pentavalent took over twice
as long.57 Additional preparation time

for health care workers means reducing
the number of children who can be
immunised in a day.

that national DTP coverage
dropped from 64% with the firstdose to 37% with the third dose.58
The development of a pentavalent
combination vaccine that could bedelivered in fewer doses would likely
have a dramatic impact on cost as
well as coverage, as it would increase
convenience for caretakers.

Now that Serum’s liquid vaccine
in a ten-dose vial has been WHO
prequalified, pentavalent is finallyattainable at a similar volume-perdose as a multi-dose vial DTP product,easing the burden on a country’s
cold chain and delivery system.

Dosing Schedules
Finally, a key barrier to increasing
coverage with these vaccines is theneed for three doses over a specified
period of time. A 2011 Demographic& Health Survey in Ethiopia showed

18

less discomfort for children andgreater convenience for caretakers.

Médecins Sans Frontières | April 2012

Infants born to mothers with
Hepatitis B are particularly at riskof acquiring the disease throughperi-natal transmission, and also
more likely to develop chronic
disease related to Hepatitis B
later in life.59, 60 The recommended“birth dose”, administered within
the first 24 hours of a baby’s life, is90% effective in halting this routeof transmission.61 But without astable, easy-to-deliver product, it
will be difficult to reach children
born outside of the healthcare
system, which account for overhalf the world’s births.
Some countries have piloted
innovative strategies. In 2002, theIndonesian government worked
with the Program for Appropriate
Technology in Health (PATH) to train

traditional midwives to administer the
HepB birth dose to babies they deliverin homes, using PATH-developed
Uniject technology. Midwives were
given monthly supplies of single-dose,
ready-to-use vaccines in Uniject
packaging. Because HepB vaccine isheat-stable for up to 30 days outside
cold chain, midwives did not needto refrigerate the vaccines. Unijecttechnology also did not require
midwives to measure the dosage
or prepare the vaccine, simplifying
administration.63
The concept was successfully tested,
increasing birth dose rates from
5% to 52%.64 These results inspired
the Indonesian government toimplement Uniject administrationof the birth dose on a nationwide
scale in 2002,65 producing similar

coverage levels on a national scaleby 2004.63 Positive improvementsfrom similar strategies have also
been reported in other partsof Asia.66
While single-dose microneedle
products are more expensive than
traditional Hepatitis B vaccine vials,
reduced wastage on a programme
level and delivery by community
health workers instead of healthcare professionals offer potential
for programmatic cost savings.67
According to producers, however,
the existing Uniject product isproblematic due to wastage in the
product-filling process. There isneed to build on the potential for
programmatic success by developing
the next generation of single-dose
microneedle products.

Adaptation challenges – the highlights:• More flexibility built into EPI schedules and broader productpresentation would allow countries to create a more customised
approach to their immunisation needs, and improve the reach of
vaccination programmes.
• There is a need to create links between programmatic challenges andnew product adaptation/development, such as the Uniject experiencein Indonesia demonstrates.
• Both governments and donors need to be ready to pay higher
product prices for easier-to-administer products when this will meanreaching children that are currently unreached. Higher prices could beoffset by reduced logistics and human resource costs as well as lower
mortality and morbidity in populations that are so far unreached.

The Right Shot: Extending the Reach of Affordable and Adapted Vaccines | www.msfaccess.org Diphtheria-Tetanus-Pertussis, Hepatitis B, Haemophilus Influenzae type B and combination vaccines

Hepatitis B birth dose19© Mudasiru Ayoola

Measles-containing
vaccines, with Rubella
and Mumps

Measles-containing vaccines, with Rubella and Mumps

WHO recommendations• Vaccination against measles has
been included in the Expanded
Programme on Immunization (EPI)
since its inception in 1974.
• Mumps vaccines have been available
since the 1960s and are only
recommended for use in countries
with effective EPI programmes. Whencountries decide to include mumps
in the schedule, it is recommended
that it be done in combination withmeasles and rubella.

• Measles vaccination gained further
momentum in 2001 with thecreation of the Measles Initiative,
supported by WHO, UNICEF,
American Red Cross, U.S. CDC, andthe United Nations Foundation.
From 2000 to 2010, this initiative
led to an estimated 74% global
reduction in measles-related
mortality.68• In 2011, WHO recommended theinclusion of rubella vaccine in EPI
programmes. In November 2011,GAVI announced it would open awindow of support for countries
introducing rubella vaccination.
Correspondingly, in 2012 theMeasles Initiative integrated rubella
into its strategic plan, refocusing
its efforts on both measles andrubella elimination.

Products and manufacturers• The first measles vaccine waslicensed in the U.S. in 1963 by
Merck. In 1968, Merck introduced
Attenuvax from the Moraten
measles strain. Nine other U.S. andEuropean pharmaceutical companies
subsequenty marketed products.69• Several manufacturers outside of
the U.S. and Europe also produce
measles vaccine. Serum Institute ofIndia introduced a vaccine in 1989
that was prequalified by WHO
in 1993. Biofarma, an Indonesian
pharmaceutical company, wasinjection diluent). Crucell’s MoRuViraten became prequalified in 2004,
although it had been marketed since1986. Crucell, however, recently
decided to exit the market for MR
vaccines, leaving Serum Instituteas the sole supplier.

prequalified in 1997. The Governmental
Pharmaceutical Organization Merieux
Biological Products Company ofThailand gained prequalification
status in 2010. With Sanofi Pasteur’s
product, there are four WHOprequalified measles producers.
• There are currently two WHOprequalified producers of MeaslesRubella (MR) vaccine. The Serum
Institute of India was prequalified
in 2000 and produces one-dose,
two-dose, five-dose, and ten-dosevials (lyophilised and water for

Measles – containing vaccines, with Rubella and Mumps

General information• The first measles, mumps, and rubella(MMR) vaccine was introduced by
Merck in 1971, currently known
as M-M-R II. Currently three othermanufacturers produce MMR.
Products come in one-dose, twodose, five-dose and ten-dose vials.

Dosing schedules and presentations• WHO recommends that all children
receive two doses of measles vaccine.
• In countries with ongoing transmission,
the initial dose should be given assoon as possible after the loss of theprotective maternal antibody, ideallyat the age of nine months, withthe second dose given at least one
month after the first dose, ideallyat 15 to 18 months of age.
• In countries with low measles
transmission, that are near elimination,
and where the first dose of MCV isgiven at age 12 months, the age ofthe second dose of measles vaccine
is left to authorities to determine thebest timing to achieve the highest
coverage possible.
• The efficacy of one dose of measles
vaccine given at nine months of age
is approximately 85 to 90%. The
efficacy increases to 99% when thefirst dose is given at 12 months.70
Children who fail to respond to thefirst dose of vaccine nearly universallyacquire immunity following asecond dose.70• One dose of rubella vaccine isrecommended. Countries including
rubella vaccine in their schedules arerecommended to administer combined
measles-rubella vaccine, at the sameage as the first dose of measles.
• Measles-containing vaccines (MCVs)
come in a variety of multi-dosepresentations; all presentations
are lyophilised with a diluent.

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21

Measles-containing vaccines, with Rubella and Mumps

Measles monovalent vaccine
Despite the number of producers, theprice of measles monovalent vaccine
has gradually trended up over the past
decade, with 2010 prices nearly
double or triple those in 2000, before
adjustment for inflation. This may
be due to decreasing demand formeasles monovalent vaccine, as moreimmunisation programmes shift tousing other MCVs such as MR and
MMR. The PAHO region, for example,
where many countries transitioned
during the late 1990s to MR and MMR
vaccines to meet regional disease
elimination targets, stopped procuring
measles monovalent vaccine after 2006.

Measles prices, UNICEF & PAHO 1998–2011

0.87

0.90
Average
UNICEF
1 dose vial

0.80

0.81

0.90

0.70

0.50

PAHO
1 dose vial

0.40
0.30
0.20

PAHO
10 dose vial

0.13

0.16
0.10

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Year

22

0.24

Average UNICEF
10 dose vial

0.10
0.00

Measles prices –the highlights:• Serum Institute controls bulk of
market which is a concern for
supply security and future pricedevelopment.

0.60
0.60

The price for measles monovalentvaccines is likely to increase as morecountries transition to measlesrubella vaccine, particularly in lightof the 2011 WHO recommendation
to include rubella in all national
immunisation programmes.

• With multiple emerging country
manufacturers, the price of themeasles monovalent vaccine
is relatively low, despite an
upward trend.

1.00

Prices Per Dose in US$

Measles – containing vaccines, with Rubella and Mumps

PricesMédecins Sans Frontières | April 2012

• As demand shifts to combination
vaccines (MR, MMR), prices are likely
to continue on an upward trend.
• There is a significant pricedifferential between monodose
vials and multi-dose vials; singledose vials cost six to nine times
more than ten-dose vials.

While approximately twice the priceof measles monovalent vaccine, MR
is still a relatively inexpensive vaccine
compared to others.
As with the measles monovalent vaccine,
multi-dose vials are significantly more
affordable: single-dose vials cost morethan double that of the ten-dose vials.
Despite the lack of robust competition,

both suppliers have offered ten-dosevials at comparable prices and the pricehas remained relatively stable overthe past decade. Crucell has recently,
however, decided to exit the measles
and measles-rubella market; the impactof this on price is yet to be seen.
With recent WHO recommendations
to include rubella vaccine in EPI

Measles and Rubella prices, UNICEF & PAHO
2002–2011
1.60
1.45

1.50
1.40

Prices Per Dose in US$

1.30
1.20

1.10

PAHO
1 dose

1.10
1.00
0.90
0.80

0.90

PAHO 0.80
2 dose

0.70
0.60
0.50
0.40

Crucell
10 dose 0.50

Serum Instituteof India 10 dose

0.48

0.60 0.56

0.48

PAHO 10 dose

2003

2004

0.49

0.30
0.20

2002

2005

2006

2007

Year

2008

2009

2010

2011

programmes, and GAVI promises offinancial support, the anticipatedincrease in demand may prompt
additional suppliers to enter the
MR market. The low price of thevaccine, however, will likely makeit unattractive to developed countrybased multinational companies.

Measles andRubella prices –the highlights:• The shift to include rubellavaccination in routine
immunisation programs may
drive up prices of MR vaccines
in the short term as demand
increases.

Measles – containing vaccines, with Rubella and Mumps

Measles and Rubella vaccine• The impact on price of a recent
decision by one manufacturer(Crucell) to exit the measles andmeasles-rubella market has yet
to be seen.
• However, over the middle-term,
if more low-cost competitors canbe enticed into the market, pricereductions should be possible.

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23

Measles – containing vaccines, with Rubella and Mumps

Adaptation challenges
Measles-containing vaccines, with Rubella and Mumps

Cold Chain Logistics
Measles-containing vaccines are
relatively heat-stable, although
the vaccine needs to be discarded
within six hours of reconstitution(or if the VVM expires, whichevercomes first). All WHO-prequalified
measles monovalent and measlesrubella vaccines have a VVM of 14,
meaning that they can last up to
14 days outside the cold chain at

a temperature of up to 37°C (although
it is recommended that vaccinesremain within the cold chain until
time of administration).

Unlike DTP, Hib, pneumococcal, andHepatitis B vaccines which are given
during the same timeframe, measles
vaccination occurs separately andindependent of other vaccinations(with the exception of countries
where yellow fever vaccine is in thenational immunisation schedule, andalso administered at nine months). In
countries lacking well-organised routine
immunisation services, the challenge
to deliver MCV can be daunting.

product has shown good efficacy but
requires energy to generate aerosols,
and the liquid vaccine used in thispresentation must be freshly made up
before administration. A dry powder
administration method which uses a
reservoir-mouthpiece filled with vaccine
powder aerosol for inhalation is also
under development. Initial results of thedry powder administration method inanimal studies demonstrate that it can
induce an immune response at least
equivalent to the traditional injection
route. Inhalation products have a highpotential for expanding the reach ofmeasles vaccination.73, 74

Dosing Schedules
As breastfed newborn infants areprotected from measles virus frommaternal antibodies and because
newborn’s immune systems are
not mature enough to mount anappropriate response to measles
vaccination before the age of six
months, the first dose of measles
vaccine is recommended at the ageof nine months.72 As around 15%of children receiving the dose at theage of nine months will not havean adequate response, an additionaldose is recommended for all children
at least one month after the
initial dose.

Two inhalation products are in thepipeline for facilitating measles vaccine
administration. A wet mist inhalation

Adaptation challenges – the highlights:• The unique dosing schedule of measles vaccine requires countries
to recapture children at an age when other vaccinations are notgiven. Adaptation challenges, and not prices, act as the key barrier
to wider coverage.
• Though MCV is relatively heat-stable, vaccine must be quickly used afterreconstitution or otherwise discarded. Additional support is needed to
expedite work on vaccine stability and alternative delivery mechanisms.

24

Médecins Sans Frontières | April 2012© Elisabeth Griot

Meningococcal
Meningitis vaccinesMeningococcal Meningitis Vaccines

General information
Meningococcal Meningitis vaccines

WHO recommendations• The WHO strategy for vaccination
against meningococcal disease varies,
according to the epidemiologicalcontext of a geographical region or
specific outbreak. WHO promotes
epidemic preparedness throughsurveillance, as well as prevention andresponse to epidemics by vaccination,
where appropriate.

• Polysaccharide vaccines can be used
for children over two years of age tocontrol outbreaks in countries whichhave not yet introduced conjugate
vaccines. Meningitis conjugate
vaccines are preferred.
• Conjugate vaccines offer longterm protection, as well as induce
herd immunity, and are therefore
recommended preventatively as
part of routine immunisation insettings where an appropriate vaccine
exists for local serotypes.75, 76• Countries with endemic meningococcal
disease, such as the 25 countries thatmake up the African Meningitis Belt,
are at particular risk of meningitis, andhave recently begun introducing large
scale preventative vaccination campaigns
with MenAfriVac, a conjugate vaccine
against meningitis A.77

Products and manufacturers• The first polysaccharide vaccines
against meningococcal meningitis
groups A and C were developed at
the Walter Reed Military Hospital in
the U.S. in the late 1960s.78 Sanofi
Pasteur was the first manufacturer tolicense a monovalent meningitis A
vaccine in 1974.
• Bivalent A+C polysaccharide
vaccines were developed by
Sanofi Pasteur in 1975,79 andreceived WHO prequalificationin the aftermath of the 1996 and1997 meningococcal epidemics inAfrica. GlaxoSmithKline (GSK) also
produced a bivalent polysaccharide
A+C. Following a Sanofi decision totemporarily suspend production,in 2006 WHO approachedFinlay Institute of Cuba andBio-Manguinhos of Brazil to ensure
an alternative supply. The resulting
Bio-Manguinhos vaccine wassubsequently WHO prequalified
in 2007.80 Sanofi subsequently
resumed sales of their bivalentvaccine to UNICEF.
• Addressing the unreliable supplyof vaccines effective against W135
and with funding provided from
ICG partners, GSK developed atrivalent polysaccharide with A, C,
and W135 serotypes exclusively foruse in Meningitis Belt countries.
Regulatory approval was rapid andthe first products were rolled out
in January 2003, followed by WHO
prequalification in 2005.81 In 2010,
GSK decided to halt production ofthis trivalent vaccine.

• The new meningitis A vaccine(MenAfriVac), prequalified by
WHO in 2010, is the only WHOprequalified conjugate vaccine
against meningococcal disease.
Individual national regulatory
authorities have, however, also
approved conjugate vaccines formeningitis C, and a tetravalentvaccine against A, C,W135 and Y.
• Tetravalent conjugate vaccines against
A, C, W135 and Y meningitis have also
been recently introduced in high-income
markets. Sanofi Pasteur obtained U.S.
FDA approval for a product in 2005,82
and Novartis in 2010.83 Novartis
is awaiting approval for use of thevaccine in a younger age group.
GSK is also awaiting regulatory approvalof a tetravalent conjugate vaccine.

Dosing schedules and presentations• WHO recommends vaccination
against meningococcal disease
in countries with high orintermediate endemic rates
of meningitis, or in epidemicprone areas. Vaccination is also
recommended for definedhigh-risk groups.
• The dosing schedule is dependent
upon the type of vaccine
administered (conjugate orpolysaccharide).

26

Médecins Sans Frontières | April 2012

• Polysaccharide vaccines induce ashort-lived immune response – booster
shots are necessary every three years– and cannot be used in children under
two years. Conjugate vaccines are
preferred to polysaccharide vaccines.
• S ince 2010, meningitis A conjugate
vaccines have been progressively
introduced in the Meningitis Belt
through large scale vaccination
campaigns that target people aged one
to 29 years. The product is available

in a ten-dose vial, and is administeredthrough intramuscular injection.
• WHO-prequalified meningitis
vaccines are available in 10-dosevials and come in lyophilised form.

Meningococcal Meningitis vaccines

Following the largest ever recorded
meningococcal epidemics in Africa
in 1996 and 1997, which resulted in
the deaths of over 25,000 people, in2000 WHO called for development of
meningococcal conjugate vaccines toallow for more preventive responses
to meningitis.84

term immune response, eliminating
the need for recurring booster shots.
The conjugate vaccines could also
be used in children as young as ninemonths – one of the age groups mostvulnerable to the disease. These vaccines
also contribute to “herd immunity” byhalting bacterial transmission from thevaccinated to the unvaccinated, which
is not the case for polysaccharides.

The development of meningococcal
conjugate vaccines significantly
improved the impact of meningitis
vaccination by stimulating a longer-

The development of conjugate vaccines
created the potential to carry out

preventive, rather than reactive
campaigns against meningococcal
meningitis in countries facing recurrent
epidemics. But although tetravalent
conjugate vaccines (A, C, W-135 and Y)
were approved in 2005 and 2010
these products were priced at a levelthat made them impractical for use
in the public sector of Meningitis Belt
countries. There was no tiered price for
GAVI-eligible countries. The CDC lists
the U.S. price as US$68.12 – $82.12
between 2005 – 2011.

Meningococcal Meningitis Vaccines

PricesThe Meningitis Vaccine Project
The Meningitis Vaccine Project (MVP)was established in 2001 by PATH and
WHO and received funding from theBill and Melinda Gates Foundation.85
After negotiating with several
possible industrial partners, the MVP
reached an agreement with Serum
Institute of India to produce a newmonovalent Meningitis A conjugate
vaccine. In exchange for price andsupply commitments, the Serum
Institute benefitted from transfer oftechnology and know-how. Clinical
trials were funded through PATH.
With the cooperation of Synco Bio
Partners in the Netherlands, and theCenter for Biologics Evaluation andResearch of the U.S. Food and Drug

Administration (FDA), the Serum
Institute initiated development of thevaccine in 2003. The total R&D costs
for this vaccine were estimated to beabout $60 million, not including thecost of the manufacturing plant. The
Serum Institute committed about$15 million to the project.86
Following successful clinical trials,
the conjugate A product, called
MenAfriVac, received Indian regulatory
approval and was WHO-prequalified
in 2010. MenAfriVac was initiallyintroduced before the 2010 – 2011
meningitis season in people aged one
to 29 years in Burkina Faso, Mali and
Niger.87 The vaccine has successfully
halted outbreaks in regions where

Meningococcal Conjugate prices for UNICEF,PAHO & CDC 2005–2011
90.00
65.00

Prices Per Dose in US$

68.00

CDC Novartis
79.75 82.12
ACYW 5 dose vial

CDC Sanofi
Pasteur ACWY
5 dose vial

82.12

50.000

15.00
14.00

PAHO C Conjugate
1 dose vial

14.00

0.00002.50
2.00-50.000

1.50
Serum Institute of India
A Conjugate (UNICEF)
10 dose vial

1.00
0.50
0.00

0.43

2005

2006

2007

2008

2009

2010

0.50

2011

-100.00-150.00

it was introduced, and has since
been rolled out in other countries
in the Meningitis Belt, such as Chadand Nigeria, with other countries
planning to follow in coming years.
By one estimate, the advent of ameningococcal conjugate vaccine
for Africa could avert 7,100 deaths
and 14,200 disabilities, and saveover $350 million over 10 years.88
UNICEF purchases the vaccine for$0.50 per dose (2011 price). This isless than half the price of the Sanofi
and Bio-Manguinhos bivalent A+C
polysaccharide products. The productwas almost a decade in the making,and today Serum is the sole supplier.

Meningitis prices –the highlights:• Tetravalent (A, C, W-135 and Y)
vaccines have been developed by
Sanofi Pasteur and Novartis with US
FDA approvals in 2005 and 2010
respectively. The US CDC price in2011 was $82.12 per dose andthere is so far no access programmeor publicly communicated tiered
price for GAVI-eligible or otherdeveloping countries.
• A meningitis conjugate A productwas WHO prequalified in 2010 and
was priced at $0.50 per dose in
2011. This product is being rolled
out in Meningitis Belt countries.

Year

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27

Meningococcal Meningitis Vaccines

Adaptation challenges
Meningococcal Meningitis vaccines

Cold Chain Logistics
MenAfriVac is stable for 30 days
outside the cold chain (VVM 30), attemperatures up to 37°C, although
all vaccines should be kept in thecold chain until administration.
Its heat stability also creates potential

for alternative delivery strategies,
such as leaving back-up supplies
of vaccine at rural health facilities.
MenAfriVac is still, however, an
injectable vaccine. For health centres
unable to administer traditional

Serotypes
One limiting characteristic of the new
MenAfriVac is that it protects against only
one strain of meningitis. While meningitis
A continues to be the predominant
serotype found in the Meningitis Belt,
particularly in hyper-endemic
countries,89 the geographic distributionof serotypes is not static over time.

Outbreaks caused by W135 meningitis
in West Africa in 2001– 2002, andin various countries in 2011– 2012,
demonstrate that serotype prevalenceneeds to be followed carefully. There
will be an ongoing need for new
products as serotype disease
burden is further documented.

Adaptation challenges – the highlights:• Conjugate vaccines offer potential for more predictable and larger
demand from Africa, particularly for potential introduction in EPI.
• Multivalent conjugate vaccines which are needed for Africa are presently
available in developed countries, but are priced prohibitively high andthus inaccessible to developing countries.
• The MenAfriVac project demonstrates the potential of “platforms”
to facilitate transfer of technology and support all aspects of productdevelopment for an adapted, affordable product. The model should
be replicated to harness the development potential and production
capacity of low-cost producers.

28

injections, if single-dose, microneedle
formats were available, community
health workers could deliver thevaccine ensuring a deeper reach
into communities.

Médecins Sans Frontières | April 2012

Although additional products are
currently available for additional
serotypes, prices are prohibitively high.
In order to develop these products at
more affordable prices, partnerships
similar to that of the Meningitis
Vaccine Project collaboration need
to be pursued.

© Bruno de Cock

Pneumococcal
conjugate vaccines Pneumococcal Conjugate Vaccines

General information
Pneumococcal conjugate vaccines

WHO recommendations• In 2007, WHO recommended
pneumococcal conjugate vaccine(PCV) for inclusion in national
immunisation programmes.90
The recommendation particularly
encouraged PCV use in countries

where mortality among children
aged under five years is greaterthan 50 in 1,000 live births, orwhere more than 50,000 children
die annually.

• WHO’s policy setting body, theStrategic Advisory Group of Experts(SAGE), is presently reviewing its
recommendations on the PCV
dosing schedule.

Products and manufacturers• Current WHO-prequalified
pneumococcal conjugate vaccines
include a new ten-valent and13-valent vaccine, as well as
an older seven-valent vaccine.
• The first PCV to gain regulatory
approval in the U.S. and Europe
was Wyeth’s Prevenar 7 (Wyeth
has since been bought by Pfizer).
Offering protection against sevenpneumococcal serotypes common
to industrialised countries, theproduct was designed to meet thepneumococcal disease burden of
higher-income countries, preventing
strains responsible for approximately
65 – 80% of pneumococcal disease in
the U.S. and Europe.90 The vaccine’s
efficacy in developing countries,
however, was uncertain when it
first came on the market.
• In 2003 and 2005, Wyeth conducted
phase III clinical trials on a PCV9candidate vaccine that added two
serotypes prevalent in Africa. Trials
were successfully conductedwith some special conditions.93
Since this product does not containa preservative, which was unique fortwo-dose vial presentation, WHOrecommended that countries using
this presentation take special
precautions, including increased
surveillance. This restriction has
meant that Synflorix has so far
been introduced in very few
GAVI-eligible countries.

in South Africa and the Gambia.91
Despite successful trial results,
Wyeth abandoned PCV9 in favourof developing PCV-13, resulting inseveral years delay of access to a PCV
for developing countries.
• WHO prequalification for Prevenar 7
did not occur until the end of 2009,
almost a decade after the vaccine was
first introduced in the U.S., and two
years after the WHO recommendation.
The delay in prequalifying the
product was due to the presentation
which was a pre-filled syringe
deemed not suitable for developing
countries.
• A new PCV, Synflorix, marketed by
GlaxoSmithKline in a one-dose vial, was
WHO prequalified in 2009. Synflorix
protects against ten pneumococcal
serotypes, and had only been approvedby European regulatory authorities
earlier that year, in April 2009.92 In
March 2010, a new presentationof Synflorix in a two-dose vial also
received a WHO prequalification• A newer iteration of the Pfizer
vaccine, Prevenar 13, protecting
against 13 pneumococcal serotypes
and designed to replace PCV7,
earned U.S. FDA approval in
February 2010.94 Prequalification by
WHO followed in August 2010.
• The first GAVI-eligible countries
to use PCV were the Gambia and
Rwanda. These two countries
received a donation from Pfizer of
PCV7 beginning in 2009. PCV7 did
not meet the set WHO requirements
regarding a minimum number ofserotypes contained in the vaccine.

Dosing schedules and presentations• The recommended WHO dosing
schedule is in the process of being
reviewed by WHO’s policy-setting
body, SAGE.
• According to 2007 WHO guidelines,
there are three acceptable schedules.

30

Médecins Sans Frontières | April 2012

Three doses of PCV at either six, ten
and 14 weeks of age; or at two, fourand six months of age; a booster
shot at 12 – 15 months isrecommended for the latter.90, 95
Or a two dose schedule before

six months of age can beadministered; a booster shot atnine to 15 months is recommended
in this case.
• PCV products all come inliquid form.

Pneumococcal conjugate vaccines

The CDC first approved use of PCV7 in
2000, purchasing the vaccine for $44.25 adose. The CDC price for PCV7 continued
to increase over the next decade – in 2009,
before the CDC switched to purchasing
Prevenar 13, PCV7 was $71.04 a dose,bringing the total cost to vaccinate achild with three doses to $213.12.
The WHO 2007 recommendation for
PCV occurred before any vaccine wasprequalified, and before a vaccine
targeting key serotypes in developing
countries had been developed.
Access to PCV10 and 13 have been
largely supported by a financial
mechanism called an Advance Market
Commitment (AMC), initially imagined
as a tool to stimulate innovation.
Following deliberations in 2007, an
expert working group decided to pilot
the first AMC for pneumococcal vaccines.
But the pilot was not designed tostimulate R&D as the pneumococcal
products were already in late stage
development. The mechanism would
rather be used to stimulate rapid scaleup of production and to speed up
introduction of the vaccine in GAVIeligible countries.
The pneumococcal AMC would only
accept products that met certain
specifications, pre-defined by WHO in a
Target Product Profile (TPP). The TPP set
a minimum standard for serotypes.
While PCV7 did not meet this criteria,
Synflorix and Prevenar 13 did.

The AMC had set an initial target priceof PCV at $2.00 per dose, meaning that
this “tail price” would be the maximum
long-term price paid to a supplier after
the subsidy had been allocated. Finally
the AMC locked in a tail price of $3.50.
By the end of 2011 two firms, Pfizer and
GSK, had agreed to sell the AMC 48% of
the total number of units to be purchased
through the AMC, entitling them eachto receive $360 million in top-up subsidy.
The AMC negotiated a significant
discount from the US price, but this price
was above the price per dose price that
could be achieved by emerging country
producers selling multi-dose vials.
Prevnar 13 is Pfizer’s second best selling
product, grossing $2.82 billion in thefirst nine months of 2011.96
By 2015, 37 GAVI countries are scheduled
to have introduced PCV. Because copayments by governments for new
vaccines are set at $0.10 to $0.30 a dose,
national budgets are not yet unduly
impacted by the AMC procurement
strategy. Countries graduating from GAVI
support, however, will be required toincrease their co-financing payments asthey approach graduation, after which
they will no longer receive GAVI subsidies.
Honduras, for example, will graduate
from GAVI support in 2015, though its
2009 average per capita income was only
$1,800.91 With GAVI’s help, the country
has introduced immunisation for bothrotavirus and PCV, and currently pays

Pneumococcal Conjugate Vaccine prices,
UNICEF, PAHO & CDC 2000–2011
CDC Prevanar 13(Wyeth/Pfizer)

97.21

91.75

Prices Per Dose in US$

80

40

71.04
CDC
Prevanar 7(Wyeth/Pfizer)

53.00

PAHO
1-dose vial

44.25

20

UNICEF Synflorix 10(GSK) 2 dose vial

0

14.85

UNICEF Prevenar 13(Wyeth/Pfizer) 1 dose vial

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009Year
Note: The UNICEF Price of $7.00 includes the AMC subsidy.

7

7
7

7

2010

In addition, the prices GAVI negotiates set
a default lowest global price, so if theseprices are high, middle-income countries
suffer the consequences too. For example,
Brazil and Argentina pay more than $14.00
a dose for PCV (these arrangements
include things like technology transferfrom the manufacturers and cold chain
support). In South Africa, where percapita income is lower than both ofthese Latin American countries, thegovernment pays $25.00 a dose. South
Africa also receives some support from
Pfizer for their EPI programme.
While the AMC is enabling a quick
rollout of PCV in GAVI countries, thecost of the AMC may outstrip both
donors' and countries' ability to pay.
From 2010 – 2025 the cost to GAVI, AMC
donors and countries can be expected
to range from $9 to $11 billion dollars.97

Pneumococcal
conjugate prices –the highlights:

100

60

$1.09 per child for the two vaccines.
Once GAVI support ends (assuming
prices remain stable), Honduras will
have to pay $25.50 per child – assuming
it pays the PAHO, non-GAVI price, of$7.50 per PCV dose – to which the costof other routine immunisations must be
added. In 2015, Honduras the country
is projected to have a birth cohort of
202,000 children; at $25.50 per child,vaccinating against rotavirus and PCV
would cost an estimated $5.1 million per
year. Honduran authorities are hoping to
get GSK’s approval to continue paying
the GAVI price, even if the country will
no longer be GAVI-eligible.

 Pneumococcal Conjugate Vaccines

Prices2011• The current UNICEF price of$7.00 (including AMC top up of$3.50 per dose) is a substantial
reduction from the US CDC price.
However, this price is considerably
higher than the $2.00 target thatcompeting companies have set.
• Because of lack of access to
know-how, licences for production
technology and an AMC
mechanism that has favoured
existing producers, there is not
yet competition from low-cost
producers, and none expecteduntil 2016 at the earliest.

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31

Pneumococcal conjugate vaccines

Dosing schedules
The dosing schedule of PCV aligns
with the pentavalent vaccine, whichallows countries to integrate PCV into
existing programmes. PCV also hashigh heat stability; it can be used in acontrolled temperature cold chain for
30 days at temperatures up to 37°C.
The stability of this product gives
some flexibility to EPI managers.

It is important to note that thepneumococcal AMC did not stimulatecompanies to conduct research ordevelopment to adapt dosing schedules
and/or presentations of the vaccine.
Work is still needed to explore thepossibility of fewer required doses.
The research arm of MSF, Epicentre,
is piloting a novel PCV approach in acluster randomised trial that will look at
the feasibility and impact of vaccinating
a population from birth to 14 years with
one dose of PCV13. This trial is expected
to start by the last quarter of 2012.
Simplified administration methods,
such as through pre-filled microneedles,
should also be developed for contexts
with limited healthcare workers.

© Bruno de Cock Pneumococcal Conjugate Vaccines

Adaptation challenges

32

Médecins Sans Frontières | April 2012

Rotavirus vaccines© GAVI 2011 Doune Porter

Rotavirus Vaccines

General information
Rotavirus vaccines

WHO recommendations• The first rotavirus vaccine wasprequalified by WHO in 2007.
In 2009, following efficacy
studies with rotavirus vaccines indeveloping countries, the WHOStrategic Advisory Group ofExperts on Immunisation (SAGE)
recommended that rotavirus
vaccines be included in all national
immunisation programmes as part ofa comprehensive strategy to control
diarrhoeal diseases.98• Rotavirus vaccines have experienced
mixed uptake in developed countries.
It is widely recommended but notalways integrated into routine
vaccination programmes. The vaccine
first was introduced in PAHO countries
in 2006. Developing countries outside
the Americas have been slow to
introduce the vaccine – Sudan was
the first, with GAVI support, in 201199– but GAVI plans to finance thevaccine’s purchase for over
40 countries by 2015.100• At the April 2012 meeting of WHO’s
policy setting body, SAGE, thedosing schedule for rotavirus vaccine
was revised to remove previously
recommended age restrictions.
At the time of this publication, theofficial WHO recommendation had
not yet been published.

Products and manufacturers• The first rotavirus vaccine,
Rotashield, developed by American
Home Products (formerly WyethAyerst Laboratories), came on themarket in the U.S. in 1998, but
was withdrawn following reportsof vaccine-related intussusceptions.101
The benefits of Rotashield
introduction – in terms of lives
saved – would have outweighed
the effects of adverse events indeveloping countries,102 but the
product was permanently retired.

• Two new rotavirus vaccine
products came on the market in2006 – GlaxoSmithKline’s Rotarix
and Merck, Sharpe and Dohme’s
Rotateq. Rotarix was first WHO
prequalified in 2007 and Rotateq
in 2008. Later versions of Rotarix
were prequalified in 2009.
Available vaccines offer protection
against several, though not all,forms of rotavirus infection.

Dosing schedules and presentations• Two doses of GSK’s Rotarix andthree doses of Merck’s Rotateq arerecommended, with the first dose
administered at six to 15 weeks ofage, and subsequent doses at fourto ten week intervals.
• When WHO first recommended
inclusion of rotavirus vaccine
in all national immunisation
programmes, the recommended
dosing schedule was restricted tocertain age groups to decrease therisk of intussusceptions. For boththe GSK and Merck products,

34

Médecins Sans Frontières | April 2012

the first dose was to be administeredby 15 weeks of age, while the final
dose had to be administered by
32 weeks of age (approximately
eight months). In April 2012, WHO’s
SAGE recommended to remove
the age restrictions based uponevidence which showed that the riskof intussusceptions was outweighedby the additional lives that could besaved with rotavirus vaccination.
The specific SAGE recommendation
was not available at the timeof this publication.

• Rotarix and Rotateq are bothadministered orally. GSK offers
Rotarix in various one-dosepresentations – a liquid doseavailable in an applicator or plastic
tube, and a lyophilised vaccine withdiluent. Merck’s Rotateq is a liquid
vaccine available in a one-dose tube.

Rotavirus vaccines

Rotavirus constitutes a significant
burden of disease among children in
all parts of the world. However, thefirst rotavirus vaccines were developed
for wealthier markets and emerging
markets such as in Latin America.
Global sales in 2010 were over $349
million103 for GSK104 and $519 million for
Merck.105 Merck sold almost exclusively
to wealthy markets, while 43% of GSK
sales came from emerging markets.104
Since the first PAHO introduction in
2006, both products’ prices in the region
have remained at about $15.00 for a fullrotavirus immunisation course – less thanten percent of the price in wealthymarkets. PAHO member states purchasing
the vaccine almost exclusively introduced
GSK’s Rotarix, which requires fewer doses
and is more heat-stable than the Merck
vaccine.106 The only PAHO countries tointroduce the Merck product – Guyana
and Nicaragua – were both GAVI
countries, and in Nicaragua, thevaccine was supplied through a
Merck donation in 2010.
Developing country introduction
outside Latin America began in 2011.
In September 2011, GAVI approved

an additional 16 country applications
for rotavirus vaccine introduction.
In addition to introduction in Sudan,
GAVI has also supported rotavirus
vaccine introduction in Nicaragua,
Bolivia, Guyana and Honduras.
There have been calls for further
research to determine the efficacy
of both rotavirus vaccines against
the dominant circulating rotavirus
genotypes in developing countries,
particularly in Africa.108
In June 2011, both GSK and Merckannounced substantial rotavirus vaccine
price reductions for GAVI-eligible
countries. GSK reduced its price perdose from $7.50 to $2.50 ($5.00 per
course), and Merck reduced its pricefrom $5.00 a dose to $3.50 ($10.50
per course), following sales of 30
million doses. The contractual terms
associated with the GSK rotavirus
agreement include provisions forvolume guarantees, denomination ofcontracts in euro currency and advancepayment. These terms apply to part ofa five year contract. The contracts withboth Merck and GSK cover about 50%
of GAVI demand for rotavirus vaccine forPrice of vaccination course in US$

200$179.28

180
170
160
150

$178.50
CDC
Merck

CDC
GSK

$164.50$156.00
PAHO
Merck

20
PAHO
GSK

15

$16.50$15.75$15.00

10

UNICEF
Merck

0$14.00$10.50

UNICEF
GSK

5

Two vaccine manufacturers inIndia, Serum Institute and Bharat
Biotech, have rotavirus vaccines indevelopment. Clinical trials are being
supported by funding from the Gates
Foundation, and the products are
expected to reach the market within
three years. The introduction of thesenew vaccines should result in lower
prices – Bharat has announced it plans
to price its vaccine at $1.00 a dose,and hopes to bring the product tomarket by 2014.111
While the development of rotavirus
vaccines has followed a traditional
path – widespread introduction atlower prices for developing countries
only after companies earn significant
revenue in wealthy markets – increased
demand from GAVI and a graduallymore competitive market should makethe introduction of rotavirus vaccines
more affordable for GAVI-eligible
countries.

Rotavirus prices –the highlights:

Rotavirus prices, UNICEF, PAHO & CDC
2006 –2012190

the period 2012 – 2016.109 These pricereductions enhanced rotavirus vaccine
affordability for GAVI, which plans topurchase for more than 40 countries
by 2015.110

Rotavirus Vaccines

Prices• In exchange for advancepayments, firm volumecommitments, and a eurodenominated contract,
GSK has offered UNICEF asignificantly lower price thanits competitor Merck.
• Lack of competition,
particularly from emerging
market producers, has so far
meant unrealised potential
for further price reductions.

$5.00

2006

2007

2008

2009

2010

2011

2012

Year
Notes: Price is for a full course of vacination with two doses of GSK’s Rotarix and three doses of Merck’s
Rotateq. UNICEF prices are those announced at the June 2011 GAVI pledging meeting.

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35

Rotavirus Vaccines

Adaptation challenges
Rotavirus vaccines

Cold Chain Logistics
No Vaccine Vial Monitor (VVM)
technology has been approved for
the Merck vaccine – the product insert
reads that the vaccine should bediscarded after 12 hours if exposed totemperatures of 26 – 30˚C; it can be used
for up to 48 hours if at 9 – 25˚C.124 This is
not practical in many GAVI countries,
particularly in more rural areas where
it is difficult to maintain a cold chain.
In an attempt to remedy this limitation,
Merck is exploring the development of aheat-stable, low-volume, less expensive
version of their rotavirus vaccine throughHilleman Laboratories, a joint venture

sponsored by the Wellcome Trust andMerck, based in New Delhi, India.113
Both existing rotavirus vaccine
products are high-volume comparedto other traditional or routine
immunisations – Rotarix and Rotateq
presentations used by GAVI require aminimum of 17.1cm³ and 46.3cm³ perdose, respectively.114, 115 In comparison,
the lowest cold chain volume for a
GAVI pneumococcal vaccine is only
4.8cm³ per dose.116
Bulkiness, combined with the vaccines’
moderate-to-low heat stability, places

a burden on countries to expand
and maintain adequate cold chain
capacity for rotavirus introduction.
WHO estimates that national-level
cold chain capacity is adequate forboth rotavirus and pneumococcal
introduction in only half of all GAVIeligible countries. Only 63 – 67%
of GAVI countries have adequate
capacity to introduce either
pneumococcal or rotavirus vaccine.
This does not account for cold chain
capacity at regional or district level,
where storage space and access toelectricity is more limited.

Disease Epidemiology
Rotavirus has a number of different
genotypes. The two WHO-prequalified
vaccines, Rotarix and Rotateq, are madeof one and five rotavirus genotypes,
respectively; the genotypes included
in both products are the predominantrotavirus strains found in industrialised
countries. Research on rotavirus
genotypes in developing countries
is evolving. Initial research results
indicate that the diversity of genotypes
found in some sub-Saharan countries

Dosing Schedules
Both WHO-prequalified vaccines havea minimum age of primary vaccinationof six weeks, and a maximum ageof first dose at 15 weeks. Rotavirus
vaccine delivery could fit in with aroutine immunisation schedule thatis administered on time, however, achild first seen for immunisation at later
than 15 weeks of age will miss out onreceiving rotavirus vaccines. With thecurrent WHO rotavirus guidelines, themaximum age for administering thelast dose of either rotavirus vaccine
should be 32 weeks. The time window
for achieving a full immunisation course
is especially limited for the Merck
product, which requires three, rather
than two doses.120
A tangible example of this challenge
is Brazil, where WHO lists the national
DTP3 coverage rate at 98%,121 but thepercentage of children receiving a fullcourse of rotavirus vaccines has lagged

36

Médecins Sans Frontières | April 2012

approximately 20% behind otherroutine immunisations every year
since 2007.122
Most rotavirus dosing guidelines are
based on clinical trials that occurredin developed countries, where thereis access to vaccination services.
Preliminary analysis has indicatedthat the additional lives saved bybroadening the age range for rotavirus
vaccination would outweigh the
hypothetical risks of intussusception.123
Further research to explore more
flexible dosing schedules for rotavirus
vaccines would be highly beneficial forcountries planning to introduce thevaccine in the future. At the same time,
it is important to note that the majorityof rotavirus cases are in children under
one year of age, and thus any proposedchange in dosing schedule should
consider the age group which has thegreatest disease burden.

may require a refined rotavirus vaccinethat is more appropriate for local
rotavirus epidemiology.118, 119 As new
data emerges, it will be importantthat vaccines be modified to be mostefficacious for those contexts.

Adaptation
challenges –the highlights:• The Merck product isimpractical in places wherecold chain is weak. There isgreat need for more heatstable rotavirus vaccines.
• Restrictive dosing schedules
have an impact on coverage– research into more flexible
schedules is needed.
• Further research on efficacy
for the predominant rotavirus
serotypes in developing
countries is needed.
• Continued efforts at volume
reduction through novel
presentations and introductionof a multi-dose vial would
help ease introduction indeveloping countries.

A Vaccine Vial Monitor (VVM) is aheat-sensitive and time-sensitive label
affixed to a vaccine vial that indicates
whether a vaccine can be used, or if it
has been damaged through exposure
to excessive heat over time.112 The label

consists of an inner square inside acoloured circle. The square will start
off a lighter colour than the circle,
but gradually darkens over time if
the vaccine is exposed to heat.
The vaccine can be considered safe

VVMs were first introduced in
1996, following almost 20 yearsof development. Today, almost
all vaccines supplied throughUN procurement agencies include
a VVM. The VVM is useful for
vaccine delivery in two very
important capacities:

Interpreting a VVM
Cumulative heat
exposure
VVM start
colour

Discardpoint

VVM start colour of the square is neversnow-white, but always has a bluish-greytinge. From then on, until the temperature
and/or duration of heat reaches a level
known to degrade the vaccine beyond
acceptable limits, the inner square remains
a lighter colour than the outer circle colour.

Beyond discard point.
Square colour is darker
than colour of outer circle.

Do Not use this
vaccine, informyour supervisor

Use this
Vaccinefor use so long as the square remains
a lighter shade than the outer circle.
Once the square is the same shade,or a darker shade than the outercircle, the vaccine is no longer safe
for use, and must be discarded.

Annex 1: Vaccine Vial Monitors (VVM)

Annex 1: Vaccine Vial
Monitors (VVM)(1) VVM give health workers theability to visually and easily assessa vaccine’s appropriateness for use,
without any detailed informationon the vaccine’s cold chain ortransport route.
(2) The ability to assess heat
exposure with a VVM helps prevent
viable vaccines from being thrownaway or wasted if the cold chain
fails for short period of time ata service delivery point.

How does the VVM vary for different vaccines?
Four categories of VVM identify thedifferent levels of heat stability avaccine presentation may fall under.
Vaccines that prevent the same typeof disease but originate with different
manufacturers, or have different
presentations, may have different
VVMs. The chart below illustrates thedifferent VVM categories and the lengthof time vaccines in each category canbe exposed to levels of heat before
reaching their discard point.

Table 1: VVM reaction rates by category ofheat stability
Category (Vaccines)

No. of days to end point at+37˚C

No. of days to end point at+25˚C

Time to end point at+5˚C

VVM 30: High Stability

30

193

> 4 years

VVM 14: Medium Stability

1490> 3 years

VVM 7: Moderate Stability

745> 2 years

VVM 2: Least Stable

2

N/A*

225 days* V VM (Arrhenius) reaction rates determined at two temperature points.

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37Annex 1: Vaccine Vial Monitors (VVM)

What is the VVM for some
important vaccines?
The following chart lists the VVM
for several new vaccines from theirrespective manufacturers in theirdifferent presentations. Countries
and organisations that engage invaccine procurement should consider
the VVM, along with factors likeprice and cold chain volume, when
making procurement decisions andassess whether a vaccine is the proper

stability, given a country’s distribution
system and the typical heat exposurea vaccine will face.

VVM Comparison Chart for Pneumococcal Conjugate, Meningococcal, and Pentavalent Vaccines
Pneumococcal Conjugate Vaccines
Manufacturer

Vaccine Trade Name

Presentation

VVM

Shelf Life

PfizerPrevenar 13

1 dose vial

Type 30

24 months at 2 –  8˚C

GlaxoSmithKline

Synflorix

2 dose vial

Type 736 months at 2 –  8˚C

Meningococcal Vaccines
Manufacturer

Vaccine Trade Name

Vaccine Type

Presentation

VVM

Shelf Life

Serum Institute ofIndia LtdMenAfriVac

Meningococcal A
conjugate

10 dose vial (active)+ 10 dose ampoule(diluent)

Type 30

24 months
at 2 –  8˚C(active); 24
months at
25˚C (diluent)

Pentavalent Vaccines: Diphtheria-Tetanus-Pertussis (whole cell)-Hepatitis B-Haemophilus influenzae type B
Manufacturer

Pharmaceutical Form

Crucell Korea

LiquidGlaxoSmithKline

Presentation

VVM

Shelf Life

1 dose vial

Type 1436 months at
2 –  8˚CLiquid+lyophilised

1 dose vial (DTP-HepB) (liquid) +1 dose vial of Hib (lyophilised)Type 1436 months at
2 –  8˚C

GlaxoSmithKline

Liquid+lyophilised

2 dose vial (DTP-HepB) (liquid) +2 dose vial of Hib (lyophilised)Type 1436 months at
2 –  8˚C

GlaxoSmithKline

Liquid1 dose vial

Type 1436 months at
2 –  8˚C

Panacea Biotec

Liquid1 dose vial

Type 1424 months at
2 –  8˚C

Serum Institute ofIndia Ltd

Liquid+lyophilised

10 dose vial DTPw-HepB (liquid) +10 dose vial Hib (lyophilised)Type 724 months at
2 –  8˚C

Serum Institute ofIndia Ltd

Liquid1 dose vial

Type 724 months at
2 –  8˚C

Serum Institute ofIndia Ltd

Liquid10 dose vial

Type 724 months at
2 –  8˚C

Serum Institute ofIndia Ltd

Liquid+lyophilised

1 dose ampoule DTPw-HepB (liquid) +1 dose vial Hib (lyophilised)Type 724 months at
2 –  8˚C

Serum Institute ofIndia Ltd

Liquid+lyophilised

2 dose ampoule DTPw-HepB (liquid) +2 dose vial Hib (lyophilised)Type 724 months at
2 –  8˚C

Serum Institute ofIndia Ltd

Liquid2 dose vial

Type 724 months at
2 –  8˚C

For more information:
Please consult the following from the WHO for more details on the history and specifics of Vaccine Vial Monitors:
http://www.who.int/immunization_standards/vaccine_quality/vvm_10years_index/en/

38

Médecins Sans Frontières | April 2012

AntigenAge of first dose

Doses inprimary series

BCG (tuberculosis)

As soon as possible after birth1

Hepatitis B (HepB)

As soon as possible after birth (within 24 hours)

3– 4

6 weeks (with DTP1)
10 weeks (with DTP2)
14 weeks (with DTP3)
Oral polio vaccine (OPV)

As soon as possible after birth

3– 4

6 weeks (with DTP1)
10 weeks (with DTP2)
14 weeks (with DTP3)
Diphtheria – Tetanus Pertussis (DTP)

6 weeks

Annex 2: The childhood routine immunisation schedule

Annex 2:The childhood
routine immunisation
schedule

3

10 weeks
14 weeks

Haemophilus influenzae
type B (Hib)

6 weeks (with DTP1)

3

10 weeks (with DTP2)
14 weeks (with DTP3)

Pentavalent (DTP-HepB-Hib)

Same dosing schedule as DTP

3

Pneumococcal
conjugate (PCV)

Option 1

3

6 weeks (with DTP1)
10 weeks (with DTP2)
14 weeks (with DTP3)

Option 2

6 weeks

3

Must wait 4 week minimum
Booster dose at 9 – 15 months
Rotavirus

Option 1(Rotarix)

6 weeks minimum (15 week maximum)

Option 2(Rota Teq)

6 weeks minimum (15 week maximum)2

Must wait 4 week minimum (no later than 32 weeks)
3Must wait 4 week minimum
Must wait 4 week minimum (no later than 32 weeks)

Measles

9 months (4 week minimum to 2nd dose)2

Rubella9 months (with measles)

1

Notes: Based upon the WHO Recommended Routine Immunisations for Children (http://www.who.int/immunization/policy/Immunization_routine_table1.pdf).
See website for more specific technical guidelines. This graph does not include the HPV vaccine, as the WHO recommendation is for use in adolescent girls, nor antigens
which are region or high-risk population specific (such as meningitis A conjugate vaccine, yellow fever, etc).

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39

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GLOSSARYGLOSSARY
Administration – Method of vaccine
delivery. Can be injection, oral,
inhalation/dry powder, microneedle, etc.
Advance Market Commitment (AMC) –The GAVI Alliance advance market
commitment is a financing model thatincentivised pharmaceutical companies tomanufacture pneumococcal vaccines fordeveloping countries by providing a subsidy.
Antigen – A substance that causes theimmune system to produce antibodies.
Birth dose – A dose of vaccine given just after
the birth of a child, or shortly thereafter.
Bivalent – A vaccine which is formulated
against two antigens or two serotypes of a
related group of similar infectious agents.
Booster dose – An additional vaccine dose
given some time after initial immunisation
to re-expose the body to the antigen andincrease immunity.
Cold chain – A temperature-controlled
supply chain where a product needs to be
kept at or below a specified temperatureduring the transport, storage andhandling of the product.
Cold chain volume (per dose) –The volume per dose that a vaccine, with its
packaging, needs for transportation andstorage in a cold chain.
Combination vaccine – Two or moreantigens administered in a single productthat prevent different diseases and reduce
the number of shots that need to beadministered.
Conjugate vaccine – A vaccine that isformulated by linking an antigen derived
from the pathogen to a protein molecule.
Coverage – The percentage of a target
age group who have received particular
vaccines. Different methods are used to
calculate coverage.
CPT – ‘Carriage Paid To (named placeof destination)’. A commercial term(incoterm 2010) meaning the seller pays
for carriage. Risk transfers to buyer uponhanding goods over to the first carrier.
Dosing schedule –see Vaccination schedule.
DDP – ‘Delivered Duty Paid (named place ofdestination)’. A commercial term (incoterm2010) meaning the seller is responsible fordelivering the goods to the named place inthe country of the buyer, and pays all costsin bringing the goods to the destination
including import duties and taxes. This term
places the maximum obligations on the seller
and minimum obligations on the buyer.
Emerging market supplier –A producer and/or innovator of a vaccine
from developing countries, including
India, Brazil and China.
Expanded Programme on Immunisation(EPI) – The World Health Organization
programme, initiated in 1974, that aims
to ensure all children are covered by a listof recommended vaccines.
FCA – ‘Free Carrier (named place of delivery)’.
A commercial term (incoterm 2010) meaning

44

Médecins Sans Frontières | April 2012that the seller hands over the goods, clearedfor export, into the disposal of the first carrier(named by the buyer) at the named place.
The seller pays for carriage to the named pointof delivery, and risk passes when the goods arehanded over to the first carrier.
GAVI-eligible country – A country thatis eligible to receive financial support
from the Global Alliance for Vaccines and
Immunization (GAVI Alliance). Support
covers different forms and eligibility
is restricted to countries with a Gross
National Income per capita of US$1,520
or less; currently 57 countries are classified
as GAVI-eligible.
Herd immunity – A form of immunity that
occurs when the vaccination of a significant
portion of a population (or herd) provides ameasure of protection for individuals who
have not developed immunity.
Immunisation schedule –see Vaccination schedule
Immunisation – Immunisation, or
vaccination, is the administration of
antigenic material (a vaccine) to stimulate
the immune system of an individual todevelop adaptive immunity to a disease.
International Coordinating Group(ICG) – an inter-organizational group,
including WHO, UNICEF, MSF and others,
which supports prevention and epidemic
outbreak response to meningitis. ICG
members help manage meningitis vaccine
stock, following regional epidemiologicaltrends and outbreaks. http://www.who.
int/csr/disease/meningococcal/icg/en/
Liquid Vaccine – A vaccine in liquid form.
Lyophilised vaccine – A vaccine that comes in
the form of a freeze-dried powder that must
be mixed with a liquid (reconstituted) before
it can be administered.
MenAfriVac – The Meningitis A conjugate
vaccine produced through the partnershipof WHO and PATH and the Serum Instituteof India.
Monovalent – A vaccine which isformulated against a single antigen
or a single serotype of a related groupof similar infectious agents.
Multi-dose vial – A vial of vaccine that
contains more than one dose of that vaccine.
Multivalent – A vaccine which isformulated against two or more antigens
or serotypes of a related group of similar
infectious agents.
Pentavalent – A multivalent vaccine which
immunises against five antigens. Usedin this report to refer to the multivalentvaccine immunising against diphtheria,
tetanus, pertussis, hepatitis B, and Hib
disease (DTP+Hep B+Hib).
Presentation – The manner in which a
vaccine is available for use, including
as single or multi-dose vials, pre-filled
syringes, or mono-dose injection devices.
Polysaccharide vaccines –Vaccines that are composed of long chainsof sugar molecules that resemble thesurface of certain types of bacteria; they

are available for pneumococcal disease,meningococcal disease and Haemophilus
influenzae type B.Prequalification – aproduct which meets various quality andsafety standards as certified by WHO.
http://www.who.int/immunization_
standards/vaccine_quality/PQ_vaccine_
list_en/en/index.html
Price per dose – The cost of the vaccine
per single dose.
PAHO Revolving Fund –A cooperation mechanism establishedin 1977 for the joint procurement ofvaccines, syringes and related healthsupplies for PAHO Member States. All
participating Member States have accessto the same products, offered at an average
single price independent of the country’s
size or economic situation. Participants
contribute three and a half percent of the
net purchase price to a common fund thatis used as working capital.
http://www.paho.org/revolvingfund
Routine immunisation – The list of
vaccines that are recommended for all
children according to the country / region.
Serotype – A distinct variation within a
species of bacteria or viruses or among
immune cells of different individuals.
Tail price – A pre-determined maximum
price that manufacturers agree to sella vaccine at or below, after the donor
funds that provided an initial subsidy haverun out. The term is associated with theAdvance Market Commitment.
Technology transfer – The process oftransferring skill, knowledge, technologies,
methods of manufacturing, samples ofmanufacturing and facilities to ensure thatscientific and technological developments
are accessible to a wider range of users
who can then further develop and exploit
the technology into new products,
processes, applications, materials orservices.
Tetravalent – A vaccine which isformulated against four antigens or four
serotypes of a related group of similar
infectious agents.
Trivalent – A vaccine which is formulated
against three antigens or three serotypes ofa related group of similar infectious agents.
Vaccination schedule – A series ofvaccines, including the timing of all
doses, and intervals between doses, thatis recommended. Every immunisation
programme has a vaccination schedule.
WHO has a recommended global
vaccination schedule.
VVM – Vaccine Vial Monitor.
Wastage – The number of vaccine doses
not used and needing to be discarded.
Wastage can be caused by discarding
open vials with remaining vaccine after
an immunisation session has ended, or bydiscarding doses damaged in unopened
vials for other reasons (ex. cold chain
failure, broken vials, expired vaccine, etc).
WHO prequalification –see prequalification.

Acknowledgements:
The editorial team would like to thank Julia Hillfor her skill and dedication in researchand drafting of the initial manuscript.
Front cover photo:
Niger – © Olivier Asselin
Back cover photo:
DRC – © Anna Surinyach
Design/artwork/print:
ACW Ltd+44 (0)20 8392 4330
www.acw.uk.com

Disclaimer:

Cert no. SGS-COC-0620

This report is a review of publicly available prices and although we havestrived to compare prices with similar terms there may be factors beyond
our control which have in some instances distorted comparisons. Purchasers
may not be able to access quoted prices. Médecins Sans Frontières has madeevery effort to ensure the accuracy of information presented in this report,
but MSF makes no representation or warranties, either expressed or implied,
as to their accuracy, completeness or fitness for a particular purpose. Inclusionof a product in this document does not indicate MSF purchases or uses the
product. Clinical decisions should not be made based on this document.

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