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 7–11 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 developing countries.

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 countries.

Background

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 15–19 per 100 000 and 1–2 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.

The pathogen

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 immune response

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.

Justification 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.

Pneumococcal vaccines

(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 immunocompetent persons.

(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 7–11 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 involved.

WHO position on pneumococcal vaccines

(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;

• Particular immunodeficiencies;

• 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 investigated.

(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 in children.

This chapter was first published as WHO position paper: Pneumococcal vaccines: WHO position paper. Weekly Epidemiological Record, 1999, 74:177–183, and is available on the Internet at http://www.who.int/wer/pdf/1999/wer7423.pdf.

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