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2000 contents page
The invisible culprit
An avoidable disease continues
to kill more than a thousand children every day. Phyllida Brown
finds out why, and asks what is being done to overcome the problem
IT has been virtually eliminated from
the industrialized countries. Safe, effective vaccines that protect
infants from it have been licensed for about a decade. Yet in
many developing countries, the bacterium Haemophilus influenzae
type b (Hib) goes almost unchecked. Worldwide it is estimated
to kill 400 000 to 500 000 young children each year. Most die
of pneumonia, and a smaller number from meningitis. So far, very
few developing countries use Hib vaccines in routine immunization
programmes (see Map). Why? First, because the
vaccines are relatively expensive. Even though prices have fallen
sharply, the cost of a three-dose schedule is still at least US$6,
compared with just cents for traditional vaccines such as diphtheria,
tetanus and pertussis (DTP). Second, and equally important, many
governments are simply not convinced that the disease is a problem
in their country. Despite being one of two leading causes of pneumonia,
Hib can be difficult to diagnose, so its role often goes unrecognized.
Now, however, years after international
efforts began in earnest to increase childrens access to Hib
vaccines in developing countries (1), some key
gains have been made. First, researchers now have dramatic and solid
evidence of the impact of these vaccines on the incidence of pneumonia
and meningitis in some low-income countries (2).
This evidence has helped to clarify the size of the Hib burden.
Second, cost-effectiveness estimates suggest that, provided Hib
vaccines are delivered within existing immunization programmes,
they can deliver excellent returns. And third, convinced that the
introduction of Hib vaccine is a sound investment for countries
health systems, the GAVI Board has decided that low-income countries
should receive at least initial funding from the Vaccine Fund to do so.
Hib vaccines are safe and effective.
The World Health Organization has published a position paper on
Hib which concludes that, "in view of the demonstrated safety
and efficacy of the Hib conjugate vaccines, Hib vaccine should
be included…. in routine infant immunization programmes" (2).
WHO recognizes that individual nations must take account of their
own capacity and priorities in deciding whether to adopt the vaccine,
but, overall, supports its use.
Yet despite WHOs position, and
even with the prospect of new funding in the short term, many
countries health officials consider Hib to be a relatively low
priority among under-used vaccines, preferring instead to introduce
immunization against hepatitis B, a virus whose prevalence is
relatively well known. In some cases, governments fear that the
addition of Hib vaccine to their immunization programmes will
strain already-overstretched systems.
Still a low priority
For example, in Mozambique, the
national immunization programme is not considering introducing this
vaccine at the moment. "The programme does not have the capacity
for the introduction of a new antigen," says Rose Macauley, technical
adviser to the programme at the Ministry of Health. Even in countries
that are keen in principle to introduce Hib, there is a need for
data to justify the decision. "We would like to introduce Hib vaccine,
but we have no concrete data or statistics on the burden," says
Eva Kabwongera, project officer for UNICEF in Kampala, Uganda. She
contrasts this with the situation for hepatitis B. "For hepatitis
B we have the statistics, we have identified it as a burden, so
it is appropriate to introduce the vaccine." In Sub-Saharan Africa
only Kenya, Malawi and Rwanda have so far requested support for
Hib in their proposals to GAVI and the Vaccine Fund, although a
group of countries in West Africa including Côte dIvoire,
Benin, Burkina Faso, Ghana and Togo is also planning to work with
partners to introduce Hib.
Box 1: Hib: the basics
- Among all strains of Haemophilus
influenzae, type b accounts for about 90 per cent
of the invasive disease. Hib disease kills an estimated
400 000-500 000 children each year
- An estimated 3 million cases of severe
disease are attributed to Hib each year. One in five children
who develop meningitis suffer permanent brain damage
- In industrialized countries before
immunization was widespread, meningitis was the most frequent
manifestation of Hib disease, but worldwide there are
probably about five cases of severe Hib pneumonia for
every case of Hib meningitis
- Hib resistance to antibiotics is
- Since the introduction of conjugate
Hib vaccines from 1990 onwards in industrialized countries,
the incidence of invasive Hib disease in these countries
has fallen by more than 90 per cent
- Outside the industrialized countries,
Hib vaccines have been shown to protect against meningitis
and pneumonia in Chile, Uruguay and The Gambia
For Jay Wenger, coordinator of the
Accelerated Vaccine Introduction Priority Project at WHO, the
invisibility of Hib is a key reason for the lack of demand in
many countries. "People are not going to introduce a vaccine for
a disease they cannot diagnose," he says. Among the diseases that
doctors see regularly, pneumonia is among the most common but
its causes are multiple and the Hib cases look no different from
the others. The bacterium is difficult to isolate without invasive
procedures and special laboratory materials that may not be available
in some developing countries. "If you never isolate the bacterium,
then the clinicians are unlikely to think about the disease,"
And even when samples are obtained,
infection may be masked in children who have been treated indiscriminately
with inappropriate antibiotics. Although a few large city hospitals
in Sub-Saharan Africa do perform laboratory diagnoses of Hib disease,
data on the burden of disease due to the microbe have not been
Measuring the burden
Joel Ward, director of the UCLA Center
for Vaccine Research in Torrance, California, believes that there
is also a problem of perception. In some countries Hib is wrongly
perceived to be a problem only of the industrialised world. "I
have been told that Hib is a Western disease," he told delegates
at the Third Annual Conference on Vaccine Research in Washington,
DC, earlier this year. Yet antibodies to Hib are found in all
populations, as are the diseases it causes.
Since the mid 1990s, however, the evidence
that Hib is a major cause of pneumonia worldwide has strengthened
dramatically. In The Gambia, West Africa, between 1993 and 1995,
researchers assessed the impact of a Hib conjugate vaccine on the
incidence of pneumonia overall in a double-blind trial involving
more than 40 000 infants. They found that in the Hib-vaccinated
group, the incidence of severe pneumonia, diagnosed on chest X-ray,
was reduced by 21 per cent (3). By implication,
the researchers concluded, one in five episodes of severe childhood
pneumonia in the Gambia is Hib-related. This is at least twice as
high as earlier estimates, which had attributed at most 10 per cent
of pneumonia episodes to Hib. Adding weight to these findings, researchers
in Chile have performed similar studies and found very similar results
(4). With the aim of increasing the spread of data
in Asia, a similar Hib vaccine trial, with a measurement of the
impact on pneumonia overall, is under way in Lombok, Indonesia,
coordinated by the Program for Appropriate Technology in Health
and the France-based nongovernmental organization, Association pour
lAide à la Médecine Préventive (AMP).
For English or French briefings, see www.aamp.org
Box 2: Is there an evenly distributed
burden of Hib disease worldwide?
Based on the available estimates, the incidence
of invasive Hib disease varies between regions.
- In the US before widespread immunization,
there were an estimated 40 to 60 cases of Hib meningitis
and an estimated 67-130 cases of all Hib disease per 100
000 children under 5 years of age annually.
- Sub-Saharan Africa appears to have
similar or greater rates for Hib meningitis.
- Asia, by contrast, may have a lower
incidence of the disease with estimates of less than 5
cases of Hib meningitis per 100 000; yet Hib has been
found to be the leading cause of bacterial meningitis
in most hospital-based studies, including in Asia.
- Further studies in China, Korea and
Vietnam are under way to quantify the burden in Asia further.
- Latin American studies at the end
of the 1980s, before the introduction of vaccines, suggest
that, for the region overall, there were 15 to 25 cases
of Hib meningitis per 100 000 children, and 21 to 43 cases
of all Hib disease. However, more population-based studies
are needed to confirm these estimates.
Because of the growing data on the
importance of Hib, the GAVI Board has concluded that there is
justification for introducing the vaccine in Sub-Saharan Africa,
the Americas and the Middle East. Countries in Asia may also be
justified in introducing Hib if epidemiological data confirm the
need. Indeed, one of GAVIs targets is to introduce Hib vaccine
to 50% of high-burden, low-income countries by 2005 (5).
Rapid assessment tool
But many countries prefer to have their
own data on the size of the Hib burden before they go ahead and
introduce the vaccine. "The problem is that, at the moment, countries
still have to take the WHOs word for it," says Wenger. "So
it is still not a definite buy-in." Thus there is also a need
for a tool to enable governments to rapidly assess the burden
of Hib in their own population. To this end, WHO, the US Centers
for Disease Control and Prevention and other partners have been
developing such an assessment tool. Chris Nelson at WHO describes
how it works.
officials scour the records of the main hospital in a district
to identify all logged clinical cases of meningitis over a set
period, usually 12 months. They also check laboratory records
for microbiological records of Hib meningitis and cross-check
lab data with clinical records. The number of Hib meningitis cases,
set against the whole population in the district under age 5,
gives an estimate of the incidence of this condition. Measuring
Hib pneumonia is more difficult, but the trials in The Gambia,
Chile and elsewhere suggested that there are about five pneumonia
cases to each meningitis case in a year.
The rapid assessment tool assumes a
similar ratio and uses the meningitis incidence figure to estimate
the pneumonia figure. Field tests of the tool have begun: six
countries have already either tested it or have planned to test
it over the coming weeks, says Nelson. "We are moving very quickly,"
he says. There will be a meeting in October and a draft by the
end of November, says Nelson.
With better data on disease burden,
says Tore Godal, Executive Secretary of GAVI, many countries will
see the benefit of introducing the vaccine.
But affordability continues to be a
concern to many governments, given that commitments to immunize
children must be sustained well beyond the five years of support
from the Vaccine Fund. Nonetheless,
different strands of evidence suggest that the cost should not
be seen as an insurmountable barrier. First, an increasing number
of studies indicate that Hib vaccines are cost-effective. In January
2000, researchers commissioned by the former Childrens Vaccine
Initiative published estimates of the cost-effectiveness of Hib
in Sub-Saharan Africa which indicated that vaccine could be delivered
for US$21-22 for each year of healthy life gained (6).
That would make the vaccine an excellent "buy", given that, according
to analyses performed for the World Bank, any health intervention
that costs less than $25 per year of healthy life gained would
be regarded as a highly cost-effective investment (7).
Earlier studies by the same researchers had also indicated that
the vaccine could be cost-effective in low-income Asian countries.
There are also some individual national
studies, including some that actually predict cost savings rather than just cost-effectiveness from Hib immunization.
For example, in an analysis published in 1995, researchers in
South Africa measured the costs of the disease against the benefits
of the vaccine there. They calculated that the estimated economic
costs of Hib disease in the 1992 Cape Town cohort ranged from
Rand 10.7 million to R11.8 million. The costs of introducing the
vaccine would have been less, amounting to R8.3 million. They
concluded that the vaccine’s benefits would have exceeded its
costs in Cape Town alone by up to R3.5 million (US$500 000) a substantial return (8). Since 1999, South Africa
has introduced Hib vaccine into its national immunization programme.
Box 3: Hib vaccines
The new generation of "conjugate" Hib vaccines
contain two components - the Hib polysaccharide capsule
and, attached to it, a "carrier" protein antigen such as
tetanus toxoid that stimulates a strong, T-cell related,
immune response. These vaccines are effective in infants
and reduce the number of Hib bacteria carried by healthy
people in their nasopharynx, reducing the spread of Hib
infection not only in vaccinated but also unvaccinated people.
There are several licensed Hib conjugate vaccines, including
combinations with DTP and DTP and hepatitis B.
Impressive as the data on investment
returns may be, some governments nonetheless are still likely
to find $6 or more per immunized child unaffordable for the longer
term. This situation may change, however, as the cost of the vaccine
continues to fall or as resources are freed up for immunization
from other sources.
As for the strain on overstretched
immunization programmes, Wenger argues that the difficulties may
have been overstated. WHO and the other partners in GAVI strongly
advocate the use of combination vaccines where possible, and some
combinations of Hib and DTP are available (see reference
As countries grapple with competing
demands on their highly restricted resources, Hib vaccine may
not appear to be a top priority today. Yet, when in future the
vaccine is introduced, and the crushing burdens of childhood pneumonia
and meningitis begin to lift, health workers and parents may look
back with astonishment at the reasons given for delaying now.
1. The CVI seeks speedy
Third World adoption of Hib vaccine. CVI Forum 12, August 1996,
2. WHO Position Paper
on Haemophilus influenzae type b conjugate vaccines. Undated.
3. Randomised trial
of Haemophilus influenzae type-b tetanus protein conjugate
for prevention of pneumonia and meningitis in Gambian infants.
Mulholland, K. et al., Lancet 349:1997;1191-1197. (Medline
4. Defining the burden
of pneumonia in children preventable by vaccination against Haemophilus
influenzae type b. Levine O.S. et al. Paediatric Infectious
Disease J. 1999. 18:1060-4.
5. Guidelines on Country
Proposals for Support to Immunization Services and New and Under-used
Vaccines. GAVI and The Vaccine Fund. Available
or from the GAVI secretariat.
6. Policy analysis
of the use of hepatitis B, Haemophilus influenzae type
b, Streptococcus pneumoniae-conjugate and rotavirus vaccines
in national immunization schedules. Miller M. and McCann L. Health
Economics, January 2000.
7. Jamison, D. et
al. (Eds). Disease control priorities in developing countries.
Oxford University Press. 1993. New York.
8. The costs and benefits
of a vaccination programme for Haemophilus influenzae type
B disease. Hussey G.D., et al. South African Medical Journal
9. Cost-benefit analysis
for the use of Haemophilus influenzae type b conjugate
vaccine in Santiago, Chile. Levine O.S., et al. American Journal
of Epidemiology. 1993. 137:1221-8.
10. Wenger J.D. et
al. Introduction of Hib conjugate vaccines in the non-industrialized
world: experience in four "newly adopting" countries. Vaccine
Vaccine impact graphs are
adapted from The Jordan Report 1998. NIAID, Bethesda, Maryland,
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