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SUPPLEMENT ARTICLE
Considerations for Combination Vaccine
Development and Use in the Developing World
José Luis Di Fabio and Ciro de Quadros
Division of Vaccines and Immunization, Pan American Health Organization, Washington, DC
As more vaccines are developed and become available, combination vaccines will provide a way of delivering
multiple antigens to avoid multiple injections and complications in the regular immunization schedules. The
advantages of combination vaccines are that they decrease the discomfort of vaccine recipients and parents
and also reduce the delivery cost of vaccines. We address some of the issues related to the use of combination
vaccines in the developing world. Which vaccines are needed? Do developing countries have the appropriate
infrastructure to deliver them? Can vaccines become affordable for countries with low incomes? And what is
really needed to achieve the goal of providing developing countries with new vaccines of epidemiologic
significance in a timely fashion?
Vaccines are the most cost-effective public health tool
available for the prevention and control of infectious
disease [1]. Their use has had an enormous impact on
disease, as seen with smallpox eradication, as well as
with polio eradication in the Americas and major advances toward its global elimination. Similarly, measles
is on the verge of eradication in the Americas [2], and
sharp decreases in tetanus, diphtheria, and whooping
cough cases are reported worldwide. However, there is
still disparity with regard to vaccine use and coverage
among regions of the world, associated principally with
access to health care services. In the developing world,
populations with poor access to health care services
either are rural and lack adequate communication systems or are urban and generally are located on the
outskirts of large cities that have a poor sanitary infrastructure. More than 80 million cases of childhood disease (measles, polio, tetanus, diphtheria, and whooping
cough) and 1.5 million deaths due to these diseases are
still reported every year. Inadequacies in vaccine deliv-
Reprints or correspondence: Dr. José Luis Di Fabio, Program of Vaccine
Technology Access, Div. of Vaccines and Immunization, Pan American Health
Organization, 525 23rd St. NW, Washington, DC 20037-2895 ([email protected]).
Clinical Infectious Diseases 2001; 33(Suppl 4):S340–5
2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3312S4-0014$03.00
S340 • CID 2001:33 (Suppl 4) • Di Fabio and de Quadros
ery, communication, and transportation infrastructures
are generally the most relevant problems.
Although new, cost-effective, and sustainable strategies for reaching the unreached are being planned, new
approaches for guaranteeing delivery of most of the
antigens must be also designed. One important approach is combination vaccines [3]. Combination vaccines have the enormous advantage of providing the
ability to administer several antigens in a single shot,
thus decreasing the discomfort for vaccine recipients
and parents and reducing the cost of the delivery process. In addition, because fewer syringes are required,
safer administration with syringes and needles can be
attained [4]. This strategy has been used for many years
to deliver bacterial vaccines (diphtheria-tetanus-pertussis
vaccine [DTP], meningococcal and pneumococcal vaccines) and viral vaccines (measles-mumps-rubella vaccine [MMR]).
ADVANTAGES TO THE USE
OF COMBINATION VACCINES
Most of the vaccines developed and in use to date are
delivered by injection and require several doses to induce complete immunity. Thus, in the typical immunization schedule for children, several injections and
multiple visits to health care clinics, doctors, or vac-
Table 1.
in 1998.
Mortality due to communicable diseases worldwide
No. of deaths
Total
High-income
countries
Middle- and
low-income
countries
Respiratory diseases
3,500,000
310,000
3,190,000
HIV/AIDS
2,285,000
32,000
2,253,000
Diarrheal diseases
2,200,000
7000
2,193,000
Childhood diseases
1,650,000
10,000
1,640,000
Tuberculosis
1,500,000
18,000
1,482,000
Malaria
1,110,000
0
1,110,000
143,000
4000
139,000
Disease
Meningitis
Others
1,000,000
50,000
950,000
Total
13,388,000
431,000
12,957,000
NOTE.
Data are from [7].
cination posts are required. The discomfort that the injection
represents for the child and parent adds to other difficulties in
ensuring compliance with the entire immunization schedule.
One of the key strategies for simplifying immunization has
been the development of combination vaccines. There are several examples, such as DTP and MMR, that have been used
for many years in the immunization programs, and some more
recent ones, such as the combination of Haemophilus influenzae
type b conjugated vaccine (Hib) with DTP [5], of varicella
vaccine with MMR, and of hepatitis B vaccine (Hep B) with
DTP [6].
There are several advantages to the use of combination vaccines in developing countries:
•
•
•
•
Decreases the number of needle sticks and thus the discomfort of child and parent.
Decreases the number of contacts required to administer
multiple antigens and thus increases coverage in areas where
access to health care is limited.
Makes delivery of vaccine more cost-effective.
Increases safety of immunization by decreasing the number
of needles and syringes needed.
have yielded the most significant improvements in child health
in the last few decades, 11.5 million children still die each year
from diseases for which vaccines are available at low cost: measles, polio, neonatal tetanus, diphtheria, and whooping cough.
Hepatitis B, hepatitis C, human papillomavirus, and Helicobacter pylori are pathogens responsible for deaths due to infection-related cancers (liver and cervical cancer) or chronic
diseases (gastric ulcers and cancer), which account for nearly
6 million deaths each year. Table 2 shows the major global
burden of diarrheal and respiratory diseases that occur primarily in the developing world.
Thus, there is a simple answer to the question of which
combination vaccine would be useful or appropriate for the
developing world: any vaccine that can be delivered will have
a major impact. The greatest impact can be obtained with combination vaccines directed against the most common diarrheal
pathogens, such as rotavirus, Salmonella, Shigella, and Vibrio
cholerae, or respiratory pathogens, such as Streptococcus pneumoniae, respiratory syncytial virus, and influenza virus [9].
Many of these important vaccines are in the development
pipeline, and some are close to final clinical trials, licensing,
and availability [10]. But because the most important players
in the development of these vaccines are the commercial manufacturers, vaccines for diseases that represent a burden to the
developed world move faster through the pipeline, because they
represent a higher profit margin. Vaccines directed at respiratory pathogens, for example, are closer to becoming available
than vaccines aimed at diarrheal diseases, in direct association
with the major burden in mortality and morbidity that respiratory diseases place on high-income countries. Nevertheless,
when available, these vaccines will also have a key effect on
mortality and morbidity in the developing world.
INFRASTRUCTURE AND DELIVERY
When safe and effective combination vaccines become available, one of the principal problems will be to deliver the vaccines to those who most need them. By 1999, vaccine coverage
Table 2. Morbidity due to communicable diseases, infectionrelated cancer, or chronic diseases worldwide in 1997.
EPIDEMIOLOGIC CONSIDERATIONS
Although extraordinary medical advances have been made during the 20th century, a significant component of the global
burden of illness still is attributable to infectious diseases, malnutrition, and complications of childbirth. In 1998, nearly 20
million deaths worldwide were linked directly to communicable
diseases, infection-related cancer, or chronic diseases. These
conditions are concentrated in the poorest countries, and they
affect populations within those countries that are living in poverty (table 1). Despite the fact that immunization programs
Disease
No. of cases
Respiratory diseases
Diarrheal diseases
Childhood diseases
Tuberculosis
390,000,000 (new cases)
4,000,000,000 (new cases)
80,000,000 (new cases)
7,400,000 (new cases)
Meningitis
1,500,000 (all cases)
Hepatitis B
350,000,000 (all cases)
Hepatitis C
170,000,000 (all cases)
NOTE.
Data are from [8].
Combination Vaccines for the Developing World • CID 2001:33 (Suppl 4) • S341
with the original 6 Expanded Programme on Immunization
(EPI) vaccines reached a global average of 70%–80% of the
population. However, there are great differences in coverage
between regions, within regions, and within individual countries (table 3). Combination vaccines alone will not solve the
problem, unless major efforts are made to improve the vaccine
delivery infrastructure, such as in transportation, the Cold
Chain, and human resources, which can ensure improvements
in coverage.
The ideal formulation for a combination vaccine would be an
orally administered, multicomponent combination to be given
as a single dose at birth. Other formulations would include combinations to be orally administered at the same time as the other,
standard vaccines. The new generations of combination vaccines
are injectable and are delivered on the same schedule as DTP.
These vaccines are in already-combined formulations (DTP-Hib,
DTP–Hep B) or formulations to be combined at the moment
of administration (DTP ⫹ Hib, DTP–Hep B ⫹ Hib) [12–14].
In general, national immunization programs purchase vaccines through yearly bid solicitations and assign the purchase
to the manufacturers, which can then provide quality vaccines
at the lowest prices. If we consider the use of combination
vaccines in the regular immunization program, this issue becomes critical. Is a country bound to continue the use of the
initial combination vaccine if no other alternatives are possible?
Should the industry reach a consensus on a standardized formulation composed of a group of basic vaccines such as DTP,
Hep B, Hib, and some other priority vaccines (the so-called
universal combination)? Some logistical problems are already
being generated with the use of Hib, which comes in different
formulations—liquid or freeze-dried, in combination with
DTP, or reconstituted with DTP or DTP–Hep B.
COST ISSUES
The US$14 required for the program delivery costs involved in
fully immunizing a child with the original 6 EPI vaccines (BCG,
diphtheria, tetanus, pertussis [DTP], poliovirus, and measles vaccines) also can be applied to the delivery of new vaccines, such
as Hib, pneumococcal and meningococcal conjugated vaccines,
varicella vaccine, and hepatitis A vaccine, that cost 1–3 orders
of magnitude more than the current ones. Thus, the availability
of these new, more expensive vaccines will focus attention increasingly on the relative value of alternative disease-prevention
measures. However, even at higher prices, vaccines will remain
one of the most cost-effective means of preventing diseases and
avoiding treatment costs. Governments are prepared to pay a
higher price for treatment (drugs and tertiary care) than for
prevention. The main challenge is to overcome the perception
that vaccines must be cheap and, at the same time, to promote
S342 • CID 2001:33 (Suppl 4) • Di Fabio and de Quadros
Table 3. Vaccine coverage in countries with the highest and
lowest rates of vaccination, by World Health Organization region,
1998.
Range of vaccine coverage,
% of population
Region
BCG
OPV3
DTP3
Africa
25–99
24–95
23–96
Americas
82–100
72–100
70–97
Eastern Mediterranean
33–100
24–99
24–99
Europe
87–100
88–99
70–99
Southeast Asia
64–94
70–97
37–94
Western Pacific
56–100
64–99
55–98
NOTE. DTP3, diphtheria-tetanus-pertussis vaccine (3 doses); OPV3, oral
poliovirus vaccine (3 doses). Data are from [11].
vaccine affordability. It is necessary to take into account not only
the price of vaccination and the country’s relative wealth but
also the benefit that the use of vaccines can have in protecting
the individual, the group, and, most important, society, in comparison with other health interventions [15].
Introduction of new vaccines will greatly increase the national immunization budgets in countries, and specific actions
will be required to guarantee sustainability of the programs
once they are initiated. To maintain continuous support from
country decision-makers for these improvements in immunization programs, appropriate information has to be generated
from the surveillance systems, initially to evaluate the possible
impact of vaccine introduction and later to monitor the impact.
The responsibility for making the decision to use new vaccines
will go beyond the health sector and will include other sectors,
such as ministries of economy, finance, industry, commerce,
foreign affairs, and international cooperation. Advocacy has to
be directed to these other decision-makers, as well as to multilateral and bilateral agencies, so that they can appreciate the
potential value of vaccines.
EXPERIENCE IN THE REGION
OF THE AMERICAS
After the United States, in 1990, and Canada, in 1991, the next
country in the Americas to introduce Hib was Uruguay, in
1994 [16]. By 1996, Chile had also included Hib in the regular
immunization program [16]. At that time, the Pan American
Health Organization (PAHO) started active promotion of surveillance of H. influenzae type b disease, as well as evaluation
of the possible introduction of the vaccine in the national immunization programs. The decision was reinforced by results
from clinical studies with Hib in The Gambia that indicated
that H. influenzae type b can be responsible for up to 20% of
radiologically confirmed cases of pneumonia [17]. Since then,
dramatic changes have occurred, and, in the year 2000, 190%
of the birth cohort in the Americas had been vaccinated or
had Hib in the vaccination schedule (figure 1). Two major
decisions made by the PAHO led to the current situation. At
the PAHO’s directing council meeting in 1997, member states
were urged to strengthen surveillance in preparation for the
introduction of new vaccines (such as Hib, Hep B, and MMR),
as well as to develop appropriate strategies to introduce these
vaccines. At its 1997 meeting, the PAHO Technical Advisory
Group on Vaccines and Immunization recommended the following: (1) use of Hib in the regular immunization programs;
(2) establishment of well-structured surveillance systems to
monitor illnesses due to H. influenzae type b and measure the
impact of this pathogen; and (3) use of the PAHO Revolving
Fund for joint purchases of vaccine.
It was of great importance that 2 countries in the region,
Uruguay and Chile, had already introduced the vaccine; they
provided examples for the other countries of the use and impact
of the vaccine in reducing disease burden. One of the principal
deterrents for introduction of the vaccine had been the price,
although that had been steadily dropping. With the consolidation of Hib vaccine procurement via the PAHO Revolving
Fund, prices have dropped considerably. These lower prices
have allowed other countries to make the decision to use the
vaccine in standard immunization programs. A combination
vaccine that includes DTP, Hep B, and Hib is now available.
Many countries have rapidly adopted this combination, because
it facilitates the introduction of 2 new vaccines (Hep B and
Hib) simultaneously into the immunization program. This has
been the case for Mexico, Nicaragua, Bolivia, Guyana, and Panama. The combination simplified the delivery of both vaccines
in countries that were already using them, such as Costa Rica,
or facilitated the introduction of Hep B into the standard immunization program of countries that were already using Hib,
such as Uruguay, Honduras, and Peru.
Governments in the Americas have once more demonstrated
a high level of political and financial commitment to vaccines.
Even countries with low incomes, such as Nicaragua, Honduras,
and Guyana (table 4), have considered that the required level
of investment in health care expenditures was worthwhile, considering the benefits and impact of immunization of children
against hepatitis B and H. influenzae type b.
The availability of general information on disease burden
and the incorporation of economic evaluation and opportunity
costs relative to other interventions facilitated the decisionmaking process for vaccine introduction. Advocacy to the Ministry of Health and Ministry of Finance has developed awareness
of and commitment to immunization in society and among
national decision-makers. New strategies and approaches for
vaccine financing were used in the region of the Americas.
Figure 1. Evolution of Haemophilus influenzae type b vaccine (Hib) introduction in the Americas and use of diphtheria-tetanus-pertussis, hepatitis
B, and H. influenzae type b conjugated vaccine (DTP ⫹ Hep B ⫹ Hib) by the year 2000.
Combination Vaccines for the Developing World • CID 2001:33 (Suppl 4) • S343
Table 4.
Country
Financial commitments to vaccination in Latin American countries in 1999.
GNP
per capita,
in US$
Total GNP,
in millions
of US$
Investment in pentavalent
vaccine
Health care
expenditures,
percentage
of GNP
Percentage of
health care
a
expenditures
Percentage of
b
total GNP
Nicaragua
410
2024
5.3
1.71
0.090
Honduras
740
4675
2.8
1.64
0.046
Guyana
800
684
Bolivia
970
7900
3.8
0.93
0.035
Peru
2610
65,850
2.2
0.44
0.010
Costa Rica
2680
10,530
6.0
0.15
0.009
Panama
3080
8660
4.7
0.16
0.007
Mexico
3700
360,025
2.8
0.24
0.007
Uruguay
6130
20,290
1.9
0.16
0.003
0.027
NOTE. The cost of 3 doses of pentavalent vaccine was US$10.50. GNP, gross national product.
Data are from [18].
a
Percentage of the total health expenditures represented by purchase of the 3 doses of pentavalent
vaccine for the birth cohort.
b
Percentage of the total GNP represented by purchase of the 3 doses of pentavalent vaccine for
the birth cohort.
These approaches ranged from allocation of the required resources in the regular immunization budget to consolidation
of resources from different levels (national, provincial, municipal, private, etc.) to negotiation of loans with development
banks, partner agencies, or vaccine manufacturers.
TAKING ADVANTAGE OF OPPORTUNITIES
PROVIDED BY VACCINES
There are 2 main questions related to the availability of combination vaccines for the developing world: How can vaccines
developed specifically for marketing to high-income countries
be made affordable for use in developing countries? And how
can vaccines of special epidemiologic importance for the developing world be developed?
Cost of developing the vaccine. The cost of developing a
vaccine is estimated to be in the tens of millions of US dollars,
and a large percentage of these costs are used to fund clinical
trials. These trials are becoming more complex and thus more
expensive as they address the tighter safety requirements placed
by regulatory agencies [19–21]. These requirements become
even more important in countries where disease burden, medical care, and risk factors are such that the possible risks associated with the vaccine may overrule the intrinsic benefits of
the vaccine. An example has been the licensing of rotavirus
vaccine in the United States [22] and its recent withdrawal
from the market because of associated adverse events [23, 24].
The same issue plays an important role in the decision by
manufacturers not to embark on the development of vaccines
that are a priority for developing countries, even though they
S344 • CID 2001:33 (Suppl 4) • Di Fabio and de Quadros
may also be of some interest in developed countries, for example, for travelers or other risk groups.
International organizations (World Health Organization,
PAHO, United Nations Children’s Fund, foundations, bilateral
agencies, and other institutions) can become involved and subsidize the clinical trials, with the commitment of the industry
to produce the vaccines, but investment is still required for
production facilities, and the manufacturer may not be willing
to take the risk if a market is not ensured.
Private-sector market in the developing countries. It may
be estimated that at least 15% of the population living in developing countries are from middle and higher socioeconomic
strata. Additionally, an average of 40%–50% of the total health
care expenditures in the developing world are private expenditures that cover direct household spending, private insurance,
charitable donations, and direct service payments by private corporations. This indicates the existence of a sizable market in the
developing world that can be targeted for new vaccines developed
initially for the lucrative industrialized markets, thus increasing
the market demand and speeding the filtering down of these
vaccines to developing countries. Similarly, these markets could
be targeted initially for vaccines of regional importance, as long
as epidemiologic studies confirmed the vaccine need in these
populations. This latent demand could motivate industry to
make the investments needed for vaccine production.
Interaction between commercial vaccine manufacturers and
local vaccine producers. Most of the outputs (patents, intellectual property rights) from vaccine research and development technologies are under the control of the major commercial vaccine manufacturers, including manufacturers of
vaccines that are of enormous importance to the developing
world but of no commercial value to developed markets. Under
these conditions, without a major incentive to continue further
development, these new vaccines will not become available.
The international community can promote successful ventures between commercial manufacturers and competent local
vaccine producers [25, 26]. This interaction can lead to the
production and use of “developing market” vaccines by local
manufacturers in direct association with major commercial
manufacturers, who, in turn, can benefit from the technological
experience and results of the corresponding clinical trials and
vaccine use. The commercial manufacturer may use this information to produce the vaccine for the developed-world
market.
Combination vaccines will become fundamental tools in improving public health, preventing millions of deaths and illness
due to devastating diseases. The major task ahead requires the
participation of a multiplicity of partners, including governments, researchers, the vaccine industry, public vaccine manufacturers, regulatory agencies, international organizations, and
the public in general. Notwithstanding the difficulties, one can
look into the future with optimism: the example of the region
of the Americas shows that new vaccines can be introduced
and used by countries regardless of their income. This success
depends on countries’ placing enough value on the benefit of
vaccines to make the vaccines available to their populations.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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