THE LANCET

Vaccines for children in rich and poor countries

Frank Shann, Mark C Steinhoff

Of the 10 million deaths every year in children less than five Panel 2: Approximate annual number of deaths in children
years of age over 99% are in developing countries and 70% less than 5 years of age caused by individual pathogens
are caused by infectious diseases (panel l).l 2 million (millions)
deaths are caused by measles, pertussis, or tetanus despite
Pneumococcus 1.2
the fact that we have had effective vaccines against these dis- 1.1
Measles
eases for many years (panel 2). 1 It is important to develop Haemophilus (a I b I c I d I e t,f nst) 0.9
new vaccines but it is even more important to find ways to Rotavirus 0.8
deliver vaccines to the poorest children, who need them Malaria 0.7
most. The development of new vaccines requires scientific HIV 0.5
work in high-income countries but the provision of vaccines RSV 0.5
to children in developing, low-income countries depends on Pertussis 0.4
financial resources, policy decisions, and other non-scientif- Tetanus 0.4
Tuberculosis 0.1
ic factors.
Hepatitis B GO-1
Many child deaths could be prevented by vaccines avail- Influenza virus co.1
able now or likely to be available soon. Immunisation has Meningococcus co.1
substantially reduced child mortality since WHO began the Parainfluenza virus co.1
Expanded Programme on Immunisation (EPI) in 1974. Varicella co.1
Since 1974 coverage with Total 6.7
Panel 1: Causes of death in the six EPI vaccines has Bold faced type shows that extra lives could be saved with optimal use of existing vaccine.
children less than 5 years of increased from 5% to over Source: adapted from Children’s Vaccine Initiative’s The CVIstrategic plan (CVI/GEN/97.04)
children. (Geneva, 1997).
age, 1995 (millions)1 80% of
Pneumonia 2.1 However, progress has
Diarrhoea 2.0 been hindered by a lack of There are initiatives to improve the research being done
Measles 1.1 vaccines that prevent the on the immunisation of children in developing countries
Prematurity 1.0 two major causes of death (panel 4). These developments are welcome but there is a
Birth asphyxia 0.9 in childhood, childhood worrying tendency to say that research on the older and less
Malaria 0.7 pneumonia and diarrhoea. expensive vaccines is unethical because they are no longer
AIDS 0.5 In high income countries used in developed countries. For example, it seems unwise
Congenital abnormalities 0.5 new vaccines are just being to assume that the expensive new conjugate pneumococcal
Pettussis 0.4
introduced to protect very vaccines will be given routinely to children in developing
Neonatal tetanus 0.4
Other 1.3 young children against countries in the near future, suggesting research on the old
- Haemophilus influenzae, polysaccharide vaccine remains highly desirable.4
Total 10.4 Streptococcus pneumoniae, The development of new vaccines is likely to be accelerat-
and rotavirus, and these ed by the gene-sequencing of pathogens, the ability to use
vaccines could dramatically reduce mortality from pneumo- DNA sequences as vaccines, and improved methods of con-
nia and diarrhoea if they were made universally available. jugating polysaccharides to proteins, but we also need to
Unfortunately, it is likely to be many years before these reduce the number of injections required, to develop safe
new vaccines are delivered to children in the poorest coun- methods of injecting vaccines and alternatives to injection,
tries. Past experience is not encouraging. Many years and to improve cold chains.
elapsed from the time new vaccines were available in the The cost of the vaccines used to prevent nine diseases in
USA until they became generally available to children in the US childhood vaccine schedule has increased ’ Tom
developing countries (panel 3). Also, the new vaccines $US33.7 in 1987 to over $150 in 1997; the increased cost
against pneumococcus, haemophilus, and rotavirus will be included new acellular pertussis, H injl’zunzae type b (Hib)
very expensive. Developing countries have a diminishing conjugate, and hepatitis vaccines5 Vaccines in the pipeline
capacity to buy new vaccines because the proportion of their will also be expensive and will increase costs further.
exports that is needed to service their overseas debt rose Until recently children everywhere received the same six
from 11% in 1970 to 18% in 19962 while industrial coun- basic vaccines (tuberculosis, diphtheria, pertussis, tetanus,
tries have become less willing to help (at 1995 prices, over- poliomyelitis, and measles). However, the gap between vac-
seas aid fell from US$63 billion in 1990 to $49 billion in cines available for children in rich and in poor regions is
19973). widening. For example, infants in the USA receive vaccines
to prevent 11 diseases while children in low-income regions
Lancet 1999; 354 (suppl II): 7-11 receive vaccines against only six or seven (panel 3).
Intensive Care Unit, Royal Children’s Hospital, Flemington Road, In the discussion of selected vaccines that follows we will
Parkville, Victoria 3052, Australia (Prof F Shann FRACP); and discuss the situation both in low income and high income
International Health and Paediatrics, Johns Hopkins University countries. In general, the issues for high-income countries
School of Hygiene and Public Health, Baltimore, MD, USA are elimination of disease and concerns about possible
(Prof M C Steinhoff MD) adverse events of vaccine use, but in poorer parts of the
Correspondence to: Prof Frank Shann world the issues are coverage with vaccines already recom-
(e-mail: shannf@ctyptic.rch.unimelb.cdv.av) mended and the challenge of adding new vaccines to the
-
l’aediatrics - Vol 354 * September - 1999 sr17
THE LANCET

Panel 3: Childhood vaccines recommended for universal infant use in high, middle and low income regions*
Vaccine Doses Year developed or Year 10% children WHO Comment
llcenced (+) in USA* immunised in LIC recommendationcl
BCG 1927 10% in 1981 1977 Many HIC countries use
Diphtheria/pertussis/tetanus 3 1920's 10% In 1981 1977 Acellular in HIC, whole cell in LIC and UK
Yellowfever 1930's 1989 WHO recommended for 31 African countries
Poliot 3 1955+ 10% in 1982 1977 IPV in USA, OPV in UK
Measles l(2) 1963+ 10% in 1983 1977 Many HIC use two-dose schedule
Mumps 1 1967t ~5% in 1998
Rubella 1 1969t ~5% in 1998
Hepatitis B$ 3 1981+ 6% in 1996 1992 Current low usage in LIC
Hib§ 3 1985+ ~5% in 1998 . In nearly all HIC, except Japan
Varicella 1995t ~5% in 1998 Used in Japan since 1970s
Rotavirus 3 1998+ ~5% in 1998 EU licenced in 1999, now suspended
*High inCOme Countries (HI+%3956 GNP/head, low income (LIC)<$725 World Bank, 1996); USA recommendations are an example for HIC while most LlCg use WHO EPI 1977 recommendations.
tPV 1955. OPV1962: +&rum derived vaccine in 1981. recombinant vaccine in 1986. universal childhood use in USA 1992. §Polysaccharide licenced for toddlers in 1985, conjugate for infants
ljcenced in 1989.

schedule, with special emphasis on those in the upper part of immune response sufficient to have a substantial effect on
panel 2. mortality.*

Current vaccines Measles

Pneumococcus Immunisation has substantially reduced mortality from
Pneumococcal infection is estimated to cause 1.2 million measles everywhere. However, measles still kills 1.1 million
deaths a year in children under 5 in developing countries.” children less than 5 years of age every year, despite availabil-
It is an important cause of pneumonia, meningitis, otitis ity of an effective vaccine.’ In high-income countries,
media, and sinusitis. The polysaccharide capsular antigens measles vaccine is usually given at 12-15 months of age
of Spneumoniae do not stimulate a good antibody response because seroconversion rates are higher than in younger chil-
in children less than 2 years old, and this is the age at which dren; many of these countries also use a second dose in older
the pneumococcus causes the greatest morbidity and mor- children to increase seroconversion rates. However, in low-
tality. As with Hib, this problem appears to have been income countries many children die from measles before
solved by conjugating the polysaccharide to a protein anti- they are 12 months old so the vaccine is usually given at 6-9
gen, which increases the antibody response and ensures an months.
anamnestic response to subsquent exposure to the polysac- When standard doses of Schwarz vaccine are given at 4-8
charide.’ Several phase 3 trials of conjugate pneumococcal months, seroconversion rates are lower than after vaccina-
vaccines are in progress, and the vaccines appear to be spec- tion at 9-11 months, and more children get measles.
tacularly successful in preventing invasive disease. A trial of However, case-fatality rates are lower in the excess cases,
the Wyeth-Lederle heptavalent CRM197 conjugate vaccine and the protection against non-measles deaths occurs earli-
in 37 000 Californian children immunised at 2, 4, 6, and er, so total mortality is lower with immunisation at 6 months
12-15 months of age, showed 100% efficacy against bac- despite the lower seroconversion rate.“ There is some con-
teraemia or meningitis8 Preliminary reports also suggest troversial evidence that standard doses of Schwarz vaccine
substantial reduction in radiographic pneumonia cases in reduce mortality from conditions other than measles,‘2~‘3 so it
the vaccine group. This vaccine is likely to be licenced soon might be necessary to continue to give measles vaccine to
in the USA. The conjugate vaccines reduce carriage of the children in poor countries even if we eradicate the disease.
vaccine serotypes: widespread use is therefore likely to Is measles a target for eradication?‘” No animal reservoir is
induce herd immunity to vaccine strains but colonisation known and the vaccine is very effective. On the other hand,
and infection with non-vaccine strains (replacement) is also measles is so infectious that vaccination rates of over 95%
possible. would be rquired over many years, and such high rates ae
The new conjugate vaccines with 7-l 1 different serotypes very difficult to achieve in low-income countries. Despite
are likely to prevent up to 80% of pneumococcal infections this difficulty, some feel that measles is ripe for global eradi-
in children, but the serotype coverage varies by region? The caion. The Pan American Health Organization aims to elim-
next generation of pneumococcal vaccines may be devel- inate this infection in the Americas by the year 2000.
oped from common pneumococcal proteins such as pneu-
molysin and pneumococcal surface protein (PspA), and Panel 4: Selected websites for information on initiatives in
may be effective against all capsular serotypes7 child immunisation
Unfortunately, conjugate pneumococcal vaccines will be Institutions(s) Website
very expensive; attempts are being made to see that these WHO Global Programme on Vaccines www.who.int/gpv/
vaccines can be made available soon to children in develop- Children’s Vaccine Initiative www.vaccines.ch
ing countries but these efforts may not succeed. In the International Vaccine Institute www.ivi.org
meantime, it is prudent to investigate ways of protecting (useful links) wwwvaccinescom
children in low-income countries with the licenced, safe and Jordan report ww.niaid.nih.gov/publications/
inexpensive polysaccharide pneumococcal vaccine. A possi- pdf/jordan.pdf
Gates Children’s Vaccine Program www.childrensvaccine.org
ble strategy would be to immunise mothers in late pregnan-
US Institute of Medicine www.nas.edu/iom
cy, so that antibodies transferred by the placenta could pro- Polio elimination www.whqsabin.who.int:8082
tect infants.‘O When the maternal antibody levels have fallen US Centers for Disease Control www.cdc.gov/nip
at 8-9 months, immunisation of the infant may result in an

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Haemophilus
The Hib conjugate vaccine has been spectacularly success-
ful in high-income countries, but it is still moderately
expensive. Athough it is now beginning to be used by some
countries with transitional economies in South America,
the vaccine is not being used by developing countries in
Africa and Asia.15 Current WHO recommendations are for
use of Hib vaccine “where it is a problem” but many coun-
tries do not have the data to determine if Hib is a problem;
however, disease burden studies are underway in Korea,
Vietnam, China, Indonesia, India, and Thailand.
H inflz~enzae may cause almost as many fatal cases of
pneumonia and meningitis as S pneumoniae does.
However, most cases of haemophilus pneumonia are
probably due to serotypes other than b.16,17In a lung aspi-
rate study of children with pneumonia in Papua New
Guinea,16 18 (56%) of 32 strains isolated were nontypable,
8 were serotypes other than b, and only 6 were type b. In
a controlled trial in the Gambia, conjugated Hib vaccine
reduced severe X-ray proven pneumonia by 20% and total
mortality by 6.1% .I* Vaccines are needed to protect infants
against nonserotypable (unencapsulated) H infuenzae and
types a, c, d, e, and f besides type b.
Rotavirus
Rotavirus is the most important cause of severe diarrhoea
in children, causing 800 000 deaths every year,19 most of
them in early infancy. In high-income countries, severe
rotavirus diarrhoea occurs later than in low-income coun-
tries.
A large trial of Venezuela found that an oral live attenu-
ated vaccine based on rhesus monkey rotavirus was effec-
tive when given at 2, 3, and 4 months of age.2o A tetrava-
lent ressortant vaccine has been produced by,replacing the
RNA encoding the VP7 surface protein in four strains of
rhesus rotavirus. This vaccine had 50-60% efficacy against
severe diarrhoea in children in Peru*’ and Brazil” and the
USA.Z3 The tetravalent rotavirus vaccine was licenced in
the USA in 1998 and in the European Union in 1999 but
routine use has been suspended because it appears to
cause intussusception. Several rotavirus vaccines are in
development and these could reduce diarrhoeal morbidity
and mortality in low-income countries, if they can be made
available.
Pertussis
Whole-cell pertussis vaccines are highly effective and wide-
ly produced in middle-income countries. Their side-effects
are lowest in young children (eg, when given at 2, 3, and 4
months of age).z4 Five acellular pertussis component vac-
cines containing one to five antigens have been licenced in
recent years. Their efficacy correlates poorly with the num-
ber of antigens used and the antibody levels achieved,
although there is a trend to greater efficacy with more anti-
gens. The side-effects are less than with the whole-cell vac-
cine given at 3, 5, and 9 months, but very similar to the
side-effects from whole-cell vaccine given at 2, 3, and 4
months.23 Except for Connaught vaccine whole-cell vac-
cines are at least as effective as the acellular vaccines,** but
many high-income countries have adopted acellular vac-
cines because of the concern about adverse events associ-
ated with whole-cell vaccines. The UK and most low-
income countries continue to use locally produced whole-
cell vaccines. A recent review has described how anti-vac-
cine movements can reduce use of pertussis vaccines, caus-
ing an inevitable rise in pertussis disease.25
Tuberculosis
Tuberculosis kills 2-3 million adults every year and about
100 000 children. BCG was. one of the earliest vaccines
used universally. The efficacy of different BCG vaccines
varies between 0% and 80% in different populationsz6
BCG apparently prevents disseminated tuberculosis in
children better than pulmonary disease in adults. Patients
with HIV infection have a greatly increased risk of tuber-
culosis but BCG should not be given to anyone with
symptomatic HIV infection or AIDS.
A modern tuberculosis vaccine that protects reliably
against tuberculosis is a priority. Subunit vaccines, com-
posed of antigens derived from killed mycobacteria, elicit
only transient, weak protection. However, antigens
derived from cultures of living bacteria may provide long-
lasting protection against both actively multiplying and
dormant bacteria.27 An interesting possibilitiy is that pro-
tection will be afforded by injecting mycobacterial plasmid
DNA; the encoded antigen is expressed for the lifetime of
the recipient. There are concerns about the safety of DNA
vaccines, but no side-effects have been observed so far in
small phase 1 studies.*’
Hepatitis B
Hepatitis B causes about 600 000 deaths every year; most
are adult deaths from hepatic carcinoma caused by hepati-
tis B infection in childhood.’ Deaths from hepatitis B
could be prevented by immunisation, but even SUS1.50
for a course of three injections is more expensive than the
combined cost of the original six El?1 vaccines. WHO has
suggested since 1992 that all countries with a high preva-
lence of hepatitis B include this in their routine immuni-
sation schedule, and about 90 countries have done so.
However, the vaccine is not given routinely in many very
poor countries where th.e incidence of hepatitis B is high.
This situation suggests that adding the new and more
expensive vaccines to EPI will be a challenge and will
require new financing mechanisms. In high-income coun-
tries with good coverage with the genetically engineered
hepatitis B vaccines concerns about adverse events associ-
ated with hepatitis B vaccine have not been borne out.28
Meningococcus
Group A meningococcus causes about 50 000 deaths
every year,’ two-thirds of them in children.‘9 It has been
argued that group A meningococcal polysaccharide vac-
cine given at 3 and 4 months and 2 and 6 years (or as a
single dose in adults) confers long-term protection and
herd immunity, and that this regimen should be used to
eliminate group A meningitis from sub-Saharan Afiica.‘O
Because of the poor antibody response to the type A, C,
Y and W135 polysaccharide vaccine in children, consider-
able work has been done on group A and C conjugate vac-
cines. They are likely to replace the polysaccharide vaccine
in due course. Because group B polysaccharide does not
elicit an adequate antibody response even in adults, a
number of alternative vaccines have been developed in
Cuba, Norway and elsewhere. The most promising
appears to be B polysaccharide conjugated to tetanus tox-
oid alone or with modified polysialic acid from Escherichiu
coli Kl .29
Varicella
An attenuated live varicella vaccine has been used in Japan
for many years$ and the vaccine was licenced in the USA
in 1995, where it is recommended for use in children 12

Paediatrics - Vol354 * September * 1999 SD9

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months to 12 years of age. Its efficacy is approximately VaxGen gp120 subunit vaccine, phase 2 studies of prim-
90%; when clinical disease does occur, it is usually an ing with a live canarypox vaccine with HIV genes inserted
afebrile illness with less than 50 lesions. The role of this and then boosting with a gplO0 subunit vaccine to get
vaccine in low-income countries remains to be deter- both cellular and antibody responses.
mined.
Respiratoty viruses
Poliomyelitis Although pneumococcus and haemophilus cause most fatal
Poliomyelitis has been eliminated from the USA since respiratory infections in children, respiratory syncytial virus
1974 and from the Americas since 1991, and a strategy of (RSV), influenza virus, and parainfluenza virus cause sub-
national immunisation days has been successful in reduc- stantial morbidity and some mortality. The most severe
ing poliomyelitis cases to very low levels in many low- infections occur in children less than 6 months of age, and
income countries. In 1996, WHO reported that two-thirds there are formidable obstacles to successful immunisation in
of children under 5 years of age received oral poliovaccine. this age group.36,37 First, maternal antibodies interfere with
Strategies for elimination of polio from regions in Asia and the response to immunisation, although there is encouraging
Africa where transmission still occurs are being discussed, evidence that this problem can be overcome by the
and WHO’s goal is for elimination of polio by 2000. In the intranasal administration of vaccine. Second, young infants
USA the occurrence of 6-8 vaccine-associated paralytic have a poor antibody response to viral surface glycoproteins,
polio cases per year, in the absence of natural transmis- and the response is predominantly IgG, and IgG, rather than
sion, has prompted a recommendation for use of IgG,. This is very similar to the response to pneumonococ-
injectable vaccine, which does not cause paralytic cus and haemophilus polysaccharides, and suggests that it
poliomyelitis. might be sensible to try conjugating the glycoproteins to a
suitable protein adjuvant. Third, reinfections are common
Rubella throughout life with RSV, influenza, and parainfluenza, sug-
Rubella vaccine has been used for nearly 30 years in high- gesting that it will be very difficult to provide long-term com-
income countries, and congenital rubella seems to be a plete protection. However, reinfection with the same anti-
large enough problem for vaccination to be considered in genie subgroup is usually confined to the upper respiratory
the middle-income countries too.3* In the poorest coun- tract, suggesting that vaccination may be able to protect
tries there are limited data on disease burden. against severe lower-respiratory-tract infection.
There have been several unsuccessful trials of RSV vac-
Vaccine prospects cines. The most promising approaches appear to be cold-
Malaria passaged strains rendered temperature-sensitive by mutation
The morbidity and mortality caused by malaria are (CPTS) and F glycoprotein subunit vaccines.37 CPTS
increasing as the parasite has developed resistance to anti- strains grow at the lower temperatures found in the nose but
malarial drugs and the mosquito has become resistant to not at the higher temperatures of the lower respiratory tract.
insecticides. It has proved very difficult to produce an It may be possible to use genetic techniques to produce a
effective vaccine; every parasite protein exposed to the bivalent vaccine that is immunogenic but highly attenuated
immune system has many polymorphisms, and the para- and genetically stable. RSV F glycoprotein subunit vaccines
site may be able to force a nonprotective immune response adsorbed to alum and purified by ion-exchange chromatog-
or induce apoptosis of immune T cells.33 raphy (PFP-2) have been found to be safe and immunogenic
However, there is reason to hope that it will be possible in children over 12 months of age.3’ Clinical trials are being
to develop an effective vaccine: people living in hyperen- done of PFP-2 adsorbed to a new adjuvant, Quilaja saponar-
demic areas develop a high degree of immunity, humans ia (QS-2 1).
are completely protected against all strains of malaria after With influenza virus, frequent changes in viral antigen
immunisation with irradiated sporozoites (which requires make it difficult to develop a vaccine that protects long-term.
exposure to thousands of infected, irradiated mosquitoes) Inactivated vaccine gives poor antibody responses in young
and monkeys can be protected by injection of blood-stage infants. A live attenuated vaccine has been developed by
parasites (merozoites) in Freund’s complete adjuvant.33 reassortment of the six genes from a cold-adapted H2N2
The optimum strategy will probably be a combination of strain with the genes for the haemagglutinin and neu-
sporozoite (pre-erythrocytic) and merozoite (blood stage) raminidase surface glycoproteins of the circulating wild
vaccines. virus. Doses of lo7 median tissue-culture infective doses
(TCID,,) result in good antibody responses even when the
HIV vaccine is given with routine immunisations at 2 months of
HIV infection killed 500 000 children in 1997 (and 1.8 age? In controlled trials, cold-adapted live attenuated
million adults); 80% of these deaths were in Africa. In influenza vaccine has beeen shown to be as effective as inac-
sub-Saharan Africa, 34 million people have been infected tivated influenza vaccine and the live vaccine is likely to be
since the epidemic began and 1 I.5 million people have licenced soon in the USA.
died, a quarter of them children.34 Developing countries Live attenuated vaccines are also being evaluated for the
have not been able to contain the epidemic by public prevention of parainfluenza virus infections.36 A bovine strain
health education or by treatment. It will be very difficult (BPIV-3) gave good antibody responses in infants older than
todevelop an effective vaccine but it is hard to see the HIV 6 months, but less satisfactory responses in young infants
epidemic being controlled by other means. Encouraging with maternal antibodies. A cold-passaged human strain
results have come from a fusion-component vaccine in (cp-45 PIV-3) produced good antibody responses in infants
which HIV envelope proteins are joined to the HIV recep- older than 6 months.
tor complex (CD4+co-receptor); the blood of mice immu-
nised with this vaccine killed 24 of the 25 HIV isolates Diarrhoeal diseases
tested.35 Phase 3 trials have begun of the controversial Vaccines to prevent Shigella, enterotoxigenic E coli, and

SIIlO Paediatrics * Vol 354 * September * 1999

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lribrio cholerue disease are at an advanced stage of develop- 9 Invasive Bacterial Infection Surveillance Group (IBIS), International
ment, and two Salmonella typhi vaccines have been licenced Clinical Epidemiology Nehvork (INCLEN). Prospective multicentre
hospital surveillance of Streptococcus pneumoniae disease in India.
for high-risk groups in high-income countries. Lancet 1999; 353: 1216-21.
10 World Health Organization. Report on the meeting on maternal and
Vaccine strategy for the future neonatal pneumococcal immunization, Geneva, Jan 26-27, 1998
(WHONRDIGENI98.01). Geneva: WHO, 1998.
The US Institute of Medicine’s 1999 report Vaccines for the
11 Aaby I’, Anderson M, Sodermann M, Jakobsen M, Games J,
21st century: tools for decision making38 uses a cost-effectiveness Fernandes M. Reduced childhood mortality after standard measles
model to develop a priority list of 26 vaccines for infections vaccination at 4-8 months compared with 9-l 1 months of age. EMJ
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12 Aaby P, Samb B, Simon&n F, Co11 Seek AM, Knudsen K, Whittle
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cus, and S pneumoniae. Vaccines with a lower but still
15 Steinhoff MC. Haemophilus inq’luenzae type b infections are pre-
favourable rating were chlamydia, Helicobacter pylorzl hepati- ventable everywhere. Lancet 1997; 349: 1186-87.
tis C virus, Herpes simplex virus, human papillomavirus, 16 Shann F, Genner S, Hazlett D, Gratten M, Linnemann V, Payne R.
Mycobacterium tuberculosis, gonococcus, and RSV. In the Aetiology of pneumonia in children in Goroka Hospital, Papua New
Guinea. Lancet 1984; ii: 537-41.
lower priority groups were parainfluenza virus, rotavirus,
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525-37.
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In high-income countries new vaccine prospects are for rotavirus-based quadrivalent vaccine in infants and young children in
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protective efficacy of one and three doses of the tetravalent rhesus
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vaccine in B&m, Brazil. Bull WHO 1996; 74: 491-500.
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history of vaccine development and the probable high costs National Multicenter Trial. Pediatrics 1996; 97: 7-13.
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