Summary and conclusions
Pneumococcal diseases are a major public health
problem all over the world. The etiological agent, Streptococcus pneumoniae (the
pneumococcus) is surrounded by a polysaccharide capsule. Differences in the composition of
this capsule permit serological differentiation between about 90 capsular types, some of
which are frequently associated with pneumococcal disease, others rarely. Invasive
pneumococcal infections include pneumonia, meningitis and febrile bacteremia; among the
common non-invasive manifestations are otitis media, sinusitis and bronchitis. At least 1
million children die of pneumococcal disease every year, most of these being young
children in developing countries. In the developed world, elderly persons carry the major
disease burden. Conditions associated with increased risk of serious pneumococcal disease
include HIV infection, sickle-cell anaemia and a variety of chronic organ failures.
Vaccination is the only available tool to prevent pneumococcal disease. The recent
development of widespread microbial resistance to essential antibiotics underlines the
urgent need for more efficient pneumococcal vaccines.
Immunity following pneumococcal disease is directed
primarily against the capsular serotype involved. The currently licensed pneumococcal
vaccine is based on the 23 most common serotypes, against which the vaccine has an overall
protective efficacy of about 60%70%. Children under two years of age, and persons
suffering from various states of immunodeficiency, for example HIV infection, do not
consistently develop immunity following vaccination, thus reducing the protective value of
the vaccine in some major target groups for pneumococcal disease. However, in a healthy
elderly population the polysaccharide vaccine provides relatively efficient protection
against invasive pneumococcal disease.
Extensive clinical trials are now under way with a
new generation of pneumococcal vaccines. These protein-polysaccharide combinations, known
as conjugate vaccines, contain 711 selected polysaccharides bound to a protein
carrier, and induce a T-cell dependent immune response. These vaccines are likely to be
protective even in children under two years of age, and may reduce pneumococcal
transmission through a herd effect.
The currently licensed pneumococcal polysaccharide
vaccine has been shown to protect adults and children under two years of age against
invasive pneumococcal infection, and its use is recommended for adults and children at
high risk of pneumococcal disease. Such groups include splenectomized patients and persons
with chronic organ failure or sickle-cell disease, and the elderly population.
HIV-infected persons are at high risk of invasive
pneumococcal disease. The protective efficacy of the vaccine in this population is
currently being evaluated. The use of the vaccine in children under two years of age and
pregnant women remains controversial and requires further study.
Due to reduced immunogenicity and unclear efficacy in
children under two years of age, the current polysaccharide vaccine is not recommended for
routine immunization of children in this age group. Unfortunately, this excludes the most
important target group for pneumococcal vaccines, namely the youngest children in
In view of the potential public health impact of
successful vaccines against pneumococcal disease, WHO considers the development of safe,
efficient and appropriately priced pneumococcal conjugate vaccines a matter of the highest
priority. Detailed planning for their use is possible only when the results of protective
efficacy trials are available. In the meantime, more information on the epidemiology and
burden of pneumococcal disease is urgently required, in particular from developing
Infections caused by pneumococci are a major
cause of morbidity and mortality all over the world. Pneumonia, febrile bacteraemia and
meningitis are the most common manifestations of invasive pneumococcal disease, whereas
bacterial spread within the respiratory tract may result in middle-ear infection,
sinusitis or recurrent bronchitis. Compared with invasive disease, the non-invasive
manifestations are usually less severe, but considerably more common. Thus, in the United
States alone, 7 million cases of otitis media are attributed to pneumococci each year.
Although all age groups may be affected, the highest rate of pneumococcal disease occurs
in young children and in the elderly population. In addition, persons suffering from a
wide range of chronic conditions and immune deficiencies are at increased risk. In
developing countries infants under three months of age are at particularly high risk,
especially for pneumococcal meningitis.
In spite of the importance of pneumococcal disease,
there is a scarcity of information on disease burden, particularly from developing
countries. This is partly due to the inherent problem of obtaining an etiological
diagnosis in cases of pneumonia. However, based on available data, acute respiratory
infections kill an estimated 2.6 million children under five years of age annually. The
pneumococcus causes over 1 million of these deaths, most of which occur in developing
countries, where the pneumococcus is probably the most important pathogen of early
infancy. In Europe and the United States, pneumococcal pneumonia is the most common
community-acquired bacterial pneumonia, estimated to affect approximately 100 per
100 000 adults each year. The corresponding figures for febrile bacteraemia and
meningitis are 1519 per 100 000 and 12 per 100 000, respectively.
The risk for one or more of these manifestations is much higher in infants and elderly
people. Even in economically developed regions, invasive pneumococcal disease carries high
mortality; for adults with pneumococcal pneumonia the mortality rate averages
10%20%, whilst it may exceed 50% in the high-risk groups. Pneumonia is by far the
most common cause of pneumococcal death worldwide.
Streptococcus pneumoniae is a Gram-positive
encapsulated coccus. Based on differences in the composition of the polysaccharide
capsule, about 90 serotypes are identified. This capsule is an essential virulence factor.
The majority of pneumococcal disease in infants is associated with a small number of these
serotypes, which may vary by region. Current data suggest that the 11 most common
serotypes cause at least 75% of invasive disease in all regions. Pneumococci are
transmitted by direct contact with respiratory secretions from patients and healthy
carriers. Although transient nasopharyngeal colonization rather than disease is the normal
outcome of exposure to pneumococci, bacterial spread to the sinuses or the middle ear, or
bacteraemia following penetration of the mucosal layer, may occur in persons susceptible
to the involved serotype. Pneumococcal resistance to essential antimicrobials such as
penicillins, cephalosporins and macrolides is a serious and rapidly increasing problem
worldwide. Facilities for laboratory diagnosis of S. pneumoniae, based on growth in
traditional culture media, are available in laboratories for routine clinical
microbiology, whereas serotyping is performed only in reference laboratories.
Protective immunity is mainly dependent upon
type-specific, anticapsular antibodies, although serological correlates of immunity are
poorly defined. The polysaccharide capsule antigens do not regularly elicit protective
levels of antibodies in children under two years of age, and in individuals with advanced
immunological impairments. Furthermore, the polysaccharides do not induce immunological
memory, which is required for subsequent booster responses. The spectrum of prevailing
capsular types varies with age, time and geographical region, although common serotypes
are consistently identified throughout the world. The currently licensed polyvalent
pneumococcal vaccine contains antigens from 23 of the serotypes that most commonly cause
invasive disease worldwide.
for vaccine control of pneumococcal disease
Pneumococcal disease leads to a wide range of
important human pathologies, from common upper respiratory tract infections to severe
invasive manifestations such as pneumonia, meningitis and septicemia, and is a major
public health problem all over the world. In developed countries this disease burden is
carried mainly by the elderly population; in developing countries mostly by the youngest
children. With increasing sophistication of life-saving medical technology, and with
increasing life expectancy, pneumococcal disease is becoming more common, and more costly
to society. Except for vaccines, no public health measures are likely to have any
significant impact on the incidence of this disease. Increasing pneumococcal resistance to
essential antimicrobial drugs, and the ease with which resistant strains are spread all
over the world, underline the importance of control through vaccination.
The currently available polyvalent pneumococcal
vaccine has an average protective efficacy for the serotypes included of about
60%70%. This vaccine is of documented value for protection against invasive
pneumococcal disease in immunocompetent elderly people living in institutions, as well as
in asplenic and sickle-cell patients. At least in the United States the cost-effectiveness
of a widespread vaccination programme for patients having had pneumonia, at risk of
developing pneumonia, or aged 65 years and above, has been documented. However, the
duration of protection in elderly and immunocompromised target groups is relatively short.
Infants respond poorly to this vaccine. Also, the vaccine has no significant effect on
nasopharyngeal carriage, and hence induces no herd effect. These important shortcomings
underline the need for developing improved pneumococcal vaccines.
Conjugate pneumococcal vaccines are now undergoing
clinical trials in various parts of the world, and the first phase III trial in the United
States with one of these vaccines showed a high degree of efficacy against invasive
pneumococcal disease (defined as blood or CSF culture-positive cases). It is likely that
conjugate vaccines will overcome most of the problems inherent in the polysaccharide
vaccine. As compared with the polysaccharide vaccine, the conjugate vaccines have a
greater potential to control pneumococcal disease, regardless of age, including control of
the serotypes most commonly responsible for resistance against multiple antimicrobials.
(i) The currently licensed vaccine
The polyvalent polysaccharide vaccine contains per
dose (0.5 ml) 25 micrograms of purified capsular polysaccharide from each of the 23
capsular types of S. pneumoniae that together account for most cases (90%) of
serious pneumococcal disease in Western industrialized countries. The marketed versions of
this vaccine are almost identical. Relatively good antibody responses (60%70%) are
elicited in most healthy adults during the two to three weeks following a single
intramuscular or subcutaneous dose of this vaccine. The immune response is unreliable in
children under two years of age, and in immunocompromised individuals. Following the
vaccination of pregnant women, antibodies are transferred both via the placenta and in the
breast milk. However, it is not yet documented that maternal vaccination actually protects
newborn infants against pneumococcal disease.
The polyvalent polysaccharide vaccine is recommended
for selected groups under two years of age with increased risk of pneumococcal disease.
Such groups include healthy elderly people (more than 65 years of age), particularly those
living in institutions, and patients suffering from chronic organ failure, diabetes or
certain immunodeficiencies. The vaccine has little protective efficacy in some important
high-risk groups for pneumococcal disease, such as persons suffering from recurrent otitis
media, haematological malignancies or chronic alcoholism. Revaccination after three to six
years may be considered in certain high-risk groups such as patients with asplenia or
nephrotic syndrome, where immunity following vaccination is known to decline rapidly.
Adverse reactions include some soreness at the site
of injection and, more rarely, low-grade fever. Revaccination within less than three years
may cause these reactions to become more severe, and is therefore not recommended in
(ii) Candidate pneumococcal vaccines
Several manufacturers are in the process of
developing pneumococcal vaccines based on the conjugation of selected capsular
polysaccharides to a protein carrier, such as a bacterial toxoid. The protein carriers
induce a T-cell dependent immune response to the polysaccharides, leading to immunological
memory and boosting upon repeated injection. As the current polysaccharide vaccines may
also be used to boost the response to the conjugates, the combined use of these vaccines
may be a future cost-saving option. The conjugate vaccines that are currently in advanced
stages of development contain 711 capsular serotypes, representing the most common
causes of invasive pneumococcal disease in children. Significant immunological competition
between the antigens included has not been observed. As with polysaccharide vaccines, the
conjugate vaccines induce protection only against the serotypes involved; however, higher
antibody levels are achieved, and the conjugates elicit an immune response more
efficiently in infants and in immunodeficient persons. Several candidate conjugate
vaccines have successfully passed the development phases dealing with safety and
immunogenicity, and results from the first efficacy trial of a conjugate vaccine in
infants show excellent protection against invasive disease. Looked at in comparison with
the Hib vaccines, pneumococcal conjugate vaccines have been shown not only to protect
against invasive disease, but also to suppress nasopharyngeal carriage of the pathogen.
Therefore, these vaccines could possibly prevent even non-invasive pneumococcal disease
and reduce bacterial transmission in the community. Such a herd effect would add
considerable value to the conjugate vaccines.
At least theoretically, there is a possibility that
large-scale use of the conjugate vaccines may result in a shift in prevailing serotypes
from those affected by the vaccines to currently less prevalent serotypes. This
possibility deserves careful observation, and is one of the reasons why alternative
strategies to the development of a pneumococcal vaccine, such as the common protein
antigen approach, should be actively pursued. Theoretically, such common antigens could
induce universal protection against pneumococcal disease, regardless of the serotype
WHO position on
(i) The polysaccharide vaccine
The safety of the current polysaccharide vaccines in
older children and non-pregnant adults is well documented. In developed countries they
have proved effective against serious pneumococcal disease in children under two years of
age, and in some of the adult and elderly populations known to be at particular risk from
this disease. The main indications for use of the polysaccharide vaccines are:
The protection of healthy elderly people,
particularly those living in institutions;
Patients with chronic organ failure;
The prevention of subsequent pneumococcal infection
in patients recovering from proven or assumed pneumococcal pneumonia;
Children at high risk of disease, such as
splenectomized children and those with sickle-cell disease.
There is an almost complete lack of information on
the burden of pneumococcal disease among adults and the elderly population in developing
regions. This illustrates the urgent need for further epidemiological and disease-burden
studies on pneumococcal disease. Properly designed phase III trials may provide
information both on efficacy and disease burden.
The polysaccharide vaccine has not been used in
developing countries where much of the pneumococcal disease burden is found in the
under-two age group. Due to poor immune response in children under two years of age, the
polysaccharide vaccine is not recommended for routine use in national childhood
immunization programmes. The possibility that the vaccine may provide some protection to
newborn infants through systematic immunization of pregnant women is currently being
(ii) Candidate pneumococcal vaccines
Based on immunological considerations and the results
of safety, immunogenicity and efficacy trials, the conjugate vaccines are likely to be
more efficient than the polysaccharide vaccine for the prevention of pneumococcal disease
This chapter was first published as WHO position
paper: Pneumococcal vaccines: WHO position paper. Weekly Epidemiological Record,
1999, 74:177183, and is available on the Internet at http://www.who.int/wer/pdf/1999/wer7423.pdf.
Brichacek B, Swindells S, Janoff EN, Pirrucello S,
Stevenson M. Increased plasma HIV-1 burden following antigenic challenge with pneumococcal
vaccine. Journal of Infectious Diseases, 1996, 174:11911199.
Centers for Disease Control and Prevention.
Prevention of pneumococcal disease. Recommendations of the Advisory Committee on
Immunization (ACIP). Morbidity and Mortality Weekly Report, 1997,
Dagan R, Melamed R, Muallem M, et al. Reduction of
nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent
conjugate pneumococcal vaccine. Journal of Infectious Diseases,
Davidson M, Parkinson AJ, Bulkow LR, Fitzgerald MA,
Peters HV, Parks DJ. The epidemiology of invasive pneumococcal disease in Alaska,
1986-1990 Ethnic differences and opportunities for prevention. Journal of
Infectious Diseases, 1994, 170:368376.
Fedson DS, Musher DM, Eskola J. Pneumococcal vaccine.
In: Plotkin SA, Orenstein WA eds. Vaccines (3rd ed.). Philadelphia: WB Saunders
Company; 1999. pp. 553607.
King JC, Vink PE, Farley JJ, et al. Comparison of the
safety and immunogenicity of a pneumococcal conjugate with a licensed polysaccharide
vaccine in human immunodeficiency virus and non-human immunodeficiency virus-infected
children. Pediatric Infectious Diseases Journal, 1996, 15:192196.
Klein JO. The epidemiology of pneumococcal disease in
infants and children. Review of Infectious Diseases, 1981, 3:246253.
O'Brien KL, Steinhoff MC, Edwards K, Keyserling
H, Thoms ML, Madore D. Immunologic priming of young children by pneumococcal glycoprotein
conjugate, but not polysaccharide, vaccines. Pediatric Infectious Diseases Journal,
O'Dempsey TJD, Mcardle TF, Lloyd-Evans N, Baldeh
I, Lawrence BE, Secka O, Greenwood B. Pneumococcal disease among children in a rural area
of West Africa. Pediatric Infectious Diseases Journal, 1996, 15:431437.
Preventing pneumococcal disease among infants and
young children. Recommendations of the Advisory Committee on Immunization Practices. Morbidity
and Mortality Weekly Report, 2000, 49(RR9);138.
Report of the meeting on maternal and neonatal
pneumococcal immunization. Geneva, 1998 (unpublished document WHO/VRD/GEN/98.01;
available from Vaccines and Biologicals, World Health Organization, 1211 Geneva 27,
Zangwill KM, Vadheim CM, Vannier AM, Hemenway LS,
Greenberg DP, Ward JI. Epidemiology of invasive pneumococcal disease in Southern
California: Implications for the design and conduct of a pneumococcal conjugate vaccine
efficacy trial. Journal of Infectious Diseases, 1996, 174:752759.