REVIEW
Pneumococcal conjugate vaccines—a European perspective

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Abstract

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and acute otitis media in children and adults worldwide. In the age group of <2 years the incidence of invasive pneumococcal disease ranges from ∼14 cases per 100,000 in Germany and the Netherlands and more than 90 per 100,000 children in Spain. The vulnerability of children to S. pneumoniae can also be demonstrated by the high rate of sequelae (>20% in Germany) and the high mortality (7.5%) in pneumococcal meningitis. Furthermore, antibiotic resistance of S. pneumoniae is increasing in Europe, particularly in France, Spain, and Eastern European countries, whereas Germany and Northern Europe are only marginally affected. A 7-valent pneumococcal conjugate vaccine (7vPCV) that was shown to be highly efficacious in preventing invasive pneumococcal disease in infants in the USA was licensed in Europe in 2001. It is expected that broad usage of the vaccine would reduce the incidence of invasive pneumococcal disease and the levels of pneumococcal resistance significantly. Important questions have been raised regarding the effectiveness of this vaccine in high-risk populations, serotype replacement, the efficacy of this vaccine in otitis media, and the co-administration of the new vaccine with other standard childhood vaccines used in various European countries. France and Spain currently have the most-wide ranging guidelines recommending pneumococcal vaccination for children. Overall, the development of pneumococcal conjugate vaccines is a significant step in the control of pneumococcal disease in children in Europe. Further progress in pneumococcal vaccine development can be expected from conjugate vaccines including more than seven serotypes (9-valent, 11-valent).

Introduction

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and acute otitis media in children and adults worldwide (Austrian, 1981). According to World Health Organization estimates, at least 1 million children under the age of 5 years of age die each year from pneumococcal pneumonia (WHO, 1999). For more than 100 years S. pneumoniae and pneumococcal infections have occupied a central position in infectious diseases. The organism was first isolated and grown in the laboratory almost simultaneously in 1881 by Sternberg and Pasteur and only three decades later by the early 20th century, the importance of humoral immunity had been recognised and an understanding of the potential protective effects of antisera and vaccines was beginning to develop (Austrian, 1981). The first large-scale clinical trial of a crude whole-cell pneumococcal vaccine was conducted in 1911 and over the next 20 years the experimental foundation was laid for understanding the importance of antibodies to the pneumococcal capsular polysaccharide and for developing an effective polyvalent, type-specific pneumococcal polysaccharide vaccine. Efforts to develop polyvalent pneumococcal capsular polysaccharide vaccines were initiated in the 1960s, and the efficacy of these new vaccines was conclusively demonstrated in clinical trials conducted among gold miners in South Africa (Austrian et al., 1976). This was soon followed by US licensing of a 14-valent capsular polysaccharide vaccine in 1977 and followed by a 23-valent polysaccharide vaccine in 1983. The 23-valent pneumococcal polysaccharide vaccine provides large serotype coverage and is a less expensive option; however, it is efficacious only in adults, not in young infants (Fedson and Musher, 2003). Conjugate vaccines now offer a solution by generating immunological memory at early age. Ninety years after the first trial of a pneumococcal vaccination was conducted, a 7-valent pneumococcal conjugate vaccine (7vPCV) that is immunogenic and efficacious in infants (Black et al., 2000) was licensed in Europe in 2001.

Although post licensure data from the USA indicate a significant decline in invasive pneumococcal disease (IPD) (Whitney et al., 2003) important questions have been raised regarding the effectiveness of this vaccine in high-risk populations, non-vaccine serotype replacement of vaccine serotypes in carriage and disease, and the efficacy of this vaccine in otitis media. Furthermore, the overall benefit of the integration of this vaccine in routine childhood vaccine programmes in Europe has been questioned, as the serotype distribution in European countries differs from those reported from the USA, and clinical efficacy studies on IPD are lacking for Europe to date. Other authorities have raised the question of co-administration of the new vaccine with other standard childhood vaccines and the potential influence on adverse events and immunogenicity (Pelton and Klein, 2002).

The purpose of this report is to review the current data available on pneumococcal conjugate vaccines and to discuss the value of this new vaccine from a European perspective.

Section snippets

Pneumococcal polysaccharides and replacement

The surface of S. pneumoniae is covered by a thick polysaccharide capsule. S. pneumoniae exhibits 90 capsular polysaccharide serotypes/serogroups. The 7vPCV was primarily designed around the serotypes that are predominant in the USA, and there are great variations in the serotype distribution with geographical region, as well as with age or type of pneumococcal disease. In general, IPD is caused by a wider range of serotypes in adults than in young children and in Europe than in the USA (

Burden of pneumococcal disease in Europe

The incidence of IPD in Europe varies considerably both by country and by age group (Table 1). In the age group of children for whom the 7vPCV is currently licensed in Europe (<2 years), the incidence ranges from ∼14 cases per 100,000 children in Germany and The Netherlands to more than 90 cases per 100,000 in Spain. The highest rate of IPD is reported in children of 2 years of age, declining steadily in the years thereafter. These differences between European countries cannot be readily

Serotype coverage

The distribution of pneumococcal serotypes varies between European countries as well as by age and by disease. Data from Germany indicate that the coverage of the 7vPCV is high in the first 2 years of life (81.7% in non-meningitis, 86.8% in meningitis cases) and up to the fifth year of life, coverage of the 7vPCV remains high (>70%). After the age of 5, the diversity of pneumococcal serotypes responsible for IPD increases, and consequently, the serotype coverage declines (Table 4). Hausdorff

Antibiotic resistance of S. pneumoniae in Europe

The epidemiology of antibiotic-resistant S. pneumoniae varies greatly between different countries and continents (Adam, 2002; Appelbaum, 2002; Felmingham et al., 2002). In Europe, high rates of penicillin-resistant pneumococci have been recorded in France (Decousser et al., 2003; Geslin et al., 1998), Spain (Fenoll et al., 1998) and Eastern European countries (Marton et al., 1991; Setchanova and Tomasz, 1999), whereas Germany (Reinert et al., 2001b, Reinert et al., 2002a, Reinert and Appelbaum

Pneumococcal conjugate vaccines

Pneumococcal polysaccharide-protein conjugates are T-cell-dependent antigens. In contrast, native polysaccharides, such as the pneumococcal capsular polysaccharide, are T-cell independent antigens and can activate only mature B cells. As the latter are immature in early infancy, there is a limited immune response to polysaccharides in children of that age group. Priming of naive T cells requires an interaction between dendritic cells and T cells specific for the carrier protein. This

Immunogenicity and correlates for protection

The immunogenicity of pneumococcal conjugate vaccines has been evaluated in many clinical trials, demonstrating them to be immunogenic in all age groups (Ahman et al., 1999; Obaro et al., 2000a, Obaro et al., 2000b; Rennels et al., 1998; Wuorimaa et al., 2001a, Wuorimaa et al., 2001b; Goldblatt et al., 2000b). Generally, up to a 10-fold increase in geometric mean antibody titre (pre- versus postimmune serum) can be demonstrated. After primary immunisation the response is mainly an IgG1, whereas

Efficacy of pneumococcal conjugate vaccines

Colonisation leads to asymptomatic carriage and eventually clearance of bacteria from the nasopharynx. From the nasopharynx, pneumococci may invade the tuba auditiva or the bronchial system leading to acute otitis media or pneumonia, respectively. Pneumococcal carriage and acute otitis media are capable of inducing mucosal antibodies to pneumococcal capsular polysaccharides (Simell et al., 2002). As colonisation of the nasopharynx is the key issue for spread of pneumococcal disease, a

Safety of pneumococcal conjugate vaccines

Pneumococcal conjugate vaccines have been demonstrated to be safe and well tolerated among children and adults (Black et al., 2000; Dagan et al., 2004; Eskola and Anttila, 1999; Wuorimaa et al., 2001a). Adverse effects have been common but are mild and short lived, occurring at the injection site or involving fever. Local adverse effects and fever above 38.5 °C have occurred in up to 38% and 52% of children, and 76% and 4% of adults, respectively. With subsequent doses of conjugate vaccines, no

Co-administration of pneumococcal conjugate vaccines with other routine childhood vaccines

In general, pneumococcal conjugate vaccines are immunogenic when administered together with other routine childhood vaccines, but each vaccine may have an influence on the immunogenicity of the other vaccine antigens. When the pneumococcal conjugate vaccine is given concomitantly with the combination of diphtheria, tetanus and acellular pertussis vaccine, some investigators have demonstrated reduced antibody responses against all the vaccine antigens (Obaro et al., 2000a; Shinefield et al., 1999

Cost-effectiveness studies

The 7vPCV vaccine has been demonstrated to be cost-effective in children in the USA (Le, 2000; Lieu et al., 2000a, Lieu et al., 2000b). In Germany, a cost-effectiveness analysis of a general pneumococcal vaccination programme for infants and children under the age of 2 years was performed by Claes and co-workers using a multiple-period Markov-model (Claes and Graf von der Schulenburg, 2003). From a German healthcare payer perspective a general vaccination recommendation with the 7vPCV would

Current data on recommendations of the 7vPCV in European countries

In contrast to the USA, where a general recommendation for 7vPCV vaccination was put in place very quickly after it was licensed for use, in Europe the integration of the new pneumococcal conjugate vaccine into vaccination programmes was delayed. At the moment, France and Spain have the most-wide ranging guidelines recommending pneumococcal vaccination for children with an increased risk of pneumococcal infections such as those with asplenia, immune deficiency, chronic disease in addition to

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