Review
Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species

https://doi.org/10.1016/j.ijantimicag.2008.01.021Get rights and content

Abstract

Pneumococcal infections elicited by Streptococcus pneumoniae (pneumococcus) (pneumonia, otitis media, sinusitis, meningitis) are frequently occurring diseases that are associated with considerable morbidity and mortality even in developed countries. Pneumococci colonise the nasopharynx of up to 50% of children, and up to 5% of adults are pneumococcal carriers. Two pneumococcal vaccines are currently in clinical use. One of them contains 23 capsular polysaccharides of the as yet known 91 different pneumococcal serotypes. Because polysaccharide vaccines primarily induce a B-cell-dependent immune response, this type of vaccine prevents bacteraemia but does not efficiently protect the host against pneumococcal infection. In 2000, a vaccination programme was launched in the USA making use of a novel pneumococcal conjugate vaccine containing capsular polysaccharides derived from the seven most frequent pneumococcal serotypes causing pneumococcal disease in children <2 years of age. Conjugation of capsular polysaccharides with a highly immunogenic protein, i.e. a non-toxic diphtheria toxoid, induces a B- and T-cell response resulting in mucosal immunity and thus effectively protects against vaccine serotypes that induce invasive pneumococcal disease, thereby at the same time reducing vaccine serotype carrier rates. Pronounced herd immunity resulted in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as reduced antibiotic resistance rates. However, recent studies report that serotypes eradicated by the vaccine are being replaced by non-vaccine pneumococcal serotypes. This so-called ‘replacement’ might soon threaten the success of vaccine use.

Introduction

Although pneumococcal diseases are frequent and vaccine development was started early, the development of an efficacious vaccine was not successful for a long time. The main reason is the low immunogenicity of polysaccharides, which are the target of opsonising antibodies. Two types of vaccines are currently in clinical use: polysaccharide vaccines; and pneumococcal conjugate vaccines.

Polysaccharide vaccines have been available since the mid 1980s. These vaccines contain purified capsular polysaccharides from 23 pneumococcal serotypes (1, 2, 3, 4, 5, 6b, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F). Polysaccharides primarily induce a B-cell-dependent immune response via release of immunoglobulin M (IgM) [1]. Such polysaccharide vaccines are not recommended for use in children <2 years of age, probably due to their immature immune system. Vaccination of adults with polysaccharide vaccines requires re-vaccination after 5–6 years [2]. However, non-responders to immunisation are especially frequent in older patients [3]. It has also been observed that antibodies against bacterial capsular polysaccharides are difficult to induce in response to non-conjugated polysaccharide vaccines for corresponding meningococcal and Haemophilus vaccines [4], [5].

The heptavalent pneumococcal conjugated vaccine (PCV-7) contains capsular polysaccharides from those pneumococci (4, 6B, 9V, 14, 18C, 19F and 23F) that are most frequently involved in paediatric infections. Capsular polysaccharides of PCV-7 are conjugated to highly immunogenic cross-reactive material 197 (CRM197), a non-toxic diphtheria toxoid protein. Employment of this pneumococcal vaccine is particularly successful in the vaccination of young children. Similar to Haemophilus influenzae type B conjugate vaccination, CRM197-specific type 2 helper T (Th2) cells interact with B-cells that have bound and internalised the polysaccharide–CRM197 complex via polysaccharide-specific IgM and subsequently present the processed CRM197 protein along with MHC II to effector T-cells. This type of adaptive immune response is characterised by antibody isotype switching and the generation of memory B-cells.

PCV-7 was approved in the USA in 2000 and since then in several additional countries. Different national schedules are applied. According to the Strategic Advisory Group of Experts (SAGE) of the World Health Organization (WHO), clinical efficacy in children has been demonstrated in two schedules: a 6-week, 10-week, 14-week schedule; and a 2-month, 4-month, 6-month schedule, which was followed by a booster dose at 12–15 months of age.

The 23-valent polysaccharide vaccine is primarily designed for use in older children and adults who are at risk for pneumococcal disease. It is not licensed for use in children <2 years of age. In some countries it is recommended by the public health authorities for all adults at the age of 60 years or older.

Section snippets

Pneumococcal bacteriology and antibiotic resistance

Streptococcus pneumoniae is a Gram-positive encapsulated bacterium (Fig. 1). The bacterial polysaccharide capsule contributes to the overall virulence of the pathogen and protects the bacterium from phagocytosis. Uncapsulated pneumococci such as the laboratory reference strain R6 are considered to be non-pathogenic. Ninety-one different capsular types (i.e. serotypes) have been described so far. Serotypes that are assessed by cross-reacting antibodies are summarised in serogroups.

Increased

Burden of pneumococcal disease

Pneumococci colonise the nasopharynx of ca. 50% of children and ca. 2.5% of adults [11]. Because humans are the only reservoir for these bacteria, it is theoretically possible to eradicate pneumococci by sufficient vaccination, similar to the pox virus.

Pneumococcal diseases primarily affect toddlers and adults [12]. The vaccination recommendations mentioned below reflect age-related incidence maxima. Pneumococci are the most frequent pathogens causing community-acquired pneumonia, otitis media,

Immune responses induced by Streptococcus pneumoniae (Fig. 2)

Besides phagocytosis and intracellular killing by alveolar macrophages and neutrophil granulocytes (innate immunity), acquired humoral immunity is an important part of the host defence against pneumococci. As in other bacterial infections eliciting humoral responses, such a response requires processing and presentation of bacterial antigen in secondary lymphoid tissues. Recent data demonstrate that dendritic cells in particular are involved in this process. Immature dendritic cells process and

Advantages and disadvantages of the currently available pneumococcal vaccines

PCV-7 elicits mucosal immune responses in immunised hosts most probably due to induction of IgA antibodies. Mucosal immunity enables asymptomatic carriers to eradicate colonising pneumococci of vaccine serotypes. Furthermore, PCV-7 is effective in preventing invasive disease progression of vaccine serotypes. A disadvantage of conjugate vaccines is their low coverage of pneumococcal serotypes, which, for example, would result in protection against just 50% of pneumococcal infections occurring in

Is vaccination with pneumococcal polysaccharide vaccines still useful?

Vaccination of adults with the 23-valent polysaccharide vaccine is clinically useful despite its relatively low and timely restricted efficacy. This becomes evident from a Spanish trial [19] where it was shown that out of 524 patients hospitalised with diagnosed pneumococcal pneumonia, the portion of patients (11%) who received the 23-valent pneumococcal vaccine within 5 years before hospitalisation indeed showed significantly less bacteraemia (15% vs. 35%) compared with non-vaccinees. Despite

Direct effects

In the USA, the incidence of invasive pneumococcal diseases in 2004, i.e. after introduction of the vaccine, was reduced by 77% in children <1 year of age, by 83% in children at 1 year and by 73% in 2-year-old children (Fig. 3) [22]. These data demonstrate the rapid reduction of invasive pneumococcal diseases in the target population. Additional data also support a decrease in non-invasive pneumococcal infections such as acute otitis media (−20%) in the US population [23]. Moreover, in a large,

Replacement: threat to vaccination success

Eradication of vaccine serotypes in asymptomatic carriers has created an ecological niche for non-vaccine serotypes (‘replacement’). Data from the CDC (Table 1) show an almost complete reduction of invasive pneumococcal disease in children <2 years of age. This reduction is caused by the almost complete eradication of vaccine serotypes and, to a lesser extent, of vaccine-associated serotypes where a cross-immunity is induced by vaccination [22]. In contrast, diseases caused by non-vaccine

Conjugate vaccine also for adults?

A current German study by de Roux et al. [36] shows that the presently available conjugate vaccine is also effective and safe in older people. This study demonstrated that PCV-7, in comparison with the polysaccharide vaccine, does not only induce a more effective antibody response but also fewer local reactions even after re-vaccination within 1 year. Re-vaccination, which is recommended for the polysaccharide vaccine after 5 years, frequently causes pronounced local reactions in patients.

Open questions

To date, it is unknown whether non-vaccine serotypes exhibit the same fitness and virulence as vaccine serotypes. The much higher frequency of vaccine serotypes in the pre-PCV-7 implementation era among colonising and pathogenic pneumococcal isolates suggests that these serotypes have advantages compared with non-vaccine serotypes. These advantages could hypothetically consist of faster replication, decreased immunogenicity, increased virulence, enhanced airborne spread, resistance to

Conclusions

The pneumococcal conjugate vaccine induces humoral/mucosal immunity and leads to eradication of the serotypes covered by the vaccine. Expansion of non-vaccine serotypes into the ecological niches (replacement) threatens the long-term efficacy of pneumococcal vaccination programmes. Hopefully, the 13-valent conjugate vaccines currently under development will help to overcome these concerns.

Acknowledgement

We thank Bernard Beall, PhD, Chief of the Streptococcus Laboratory, Centers for Disease Control & Prevention, Atlanta, USA for helpful discussions and critical reading.

Funding: Bayer, Pfizer, Wyeth, MSD, sanofi-aventis and Astra Zeneca.

Competing interests: M.W.P. has received lecture fees from Wyeth and MSD. T.W. has received lecture fees from Wyeth, MSD, GSK and sanofi-aventis, and is a member of the Advisory Boards of the aforementioned companies. H.L. participates in clinical studies and is

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