Pneumococcal Vaccine

Infections with Streptococcuspneumoniae are a significant cause for morbidity and mortality in the old and account for 25-35 % of bacterial pneumonias requiring hospitalization [63]. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has been used for many years in the older population. As PPV23 contains plain capsular polysaccharides, it elicits only T cell-independent antibody responses resulting in a lack of immunological memory and booster effects upon repeated vaccination. The efficacy of PPV23 to prevent pneumococcal disease is controversially discussed. A meta-analysis reported efficacy against invasive disease (OR 0.26; 95 % CI 0.150.46), and to a lesser extent all-cause pneumonia (OR 0.71; 95 % CI 0.52-0.97) in adults [64]. However, the clinical efficacy of PPV23 against pneumonia in older persons is frequently doubted. Some individual studies reported efficacy against pneumonia in institutionalized elderly or healthy elderly, respectively [65, 66], but a meta-analysis did not confirm these findings and showed only non-significant vaccine efficacy of 16 % (95 % CI-50-53) [67]. Heterogeneous study populations, such as institutionalized versus community-dwelling elderly, as well as varying read-out parameters (pneumococcal pneumonia, all-cause pneumonia, hospitalization due to pneumonia etc), complicate meta-analyses of pneumococcal vaccine efficacy (reviewed in [68]). Serotype-specific antibody concentrations, which are accepted as correlates of protection, are lower in the elderly and in individuals with underlying disease [63, 69]. Protein-conjugated vaccines (PCV) have been developed for childhood vaccination, as PPV-23 does not elicit immune responses in infants. A 7-valent conjugated vaccine (PCV7) has been successfully used in children and is capable of eliciting memory responses. PCV7 induces higher antibody concentrations in the old compared to PPV23 and shows a booster effect following a second dose of vaccine after 1 year [70]. Routine vaccination of children with PCV7 leads to a decrease of transmission of S.pneumoniae and thereby provides indirect protection of the old against the serotypes included in the vaccine [71]. In the following years conjugated vaccines covering more pneumococcal serotypes have been developed for the pediatric market (PCV10 and PCV13) and replaced PCV7 for childhood vaccination. PCV13 has also been licensed for adults and recent vaccination recommendations for the old include a single vaccination with PCV13 in many countries, with an additional dose of PCV23 12 months later in some countries. Immunogenicity of PCV13 has been demonstrated in adults who had never received PPV23 [72] as well as in individuals who had received PPV23 several years earlier. Clinical efficacy of PCV13 in older adults has been demonstrated in a large randomized, double-blind, placebo-controlled study. More than 84,000 pneumococcal vaccine-naive persons above 65 years of age received one dose of PCV13 or placebo, and were followed up for several years for community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD). Detection of S. pneumoniae and identification of vaccine serotypes was performed by culture and/or urinary antigen test. Vaccine efficacy was 45.6 % (95.2 % CI 21.8-62.5, p < 0.001) for confirmed vaccine-type CAP. Efficacy was also demonstrated for vaccine-type non-bacteraemic and noninvasive CAP (45.0 %, 95.2 % CI 14.2-65.3, p < 0.01) and vaccine-type IPD (75.0 %, 95 % CI 41.490.8, p< 0.001) [73]. In a post-hoc analysis of this study the effect of age on vaccine efficacy was studied and the statistical model showed a decline of vaccine efficacy for vaccine-type CAP and IPD from 65 % (95 % CI 38-81) in 65-year old subjects, to 40 % (95 % CI 17-56) in 75-year old subjects [74]. Recently, safety and immunogenicity of a 15-valent conjugate vaccine, which includes two additional serotypes, has been demonstrated in healthy adults [75].

Polysaccharide and polysaccharide-conjugate vaccines share the limitation of restricted serotype coverage. After the introduction of PCV7, serotype replacement has been observed, i.e. the number of disease cases caused by pneumococcal serotypes not included in the vaccine increased [76]. Similar effects start to emerge for PCV13 [77]. Several approaches aim to develop a universal vaccine, which elicits serotype-independent immune responses and thereby protects from all pneumococcal strains. Several pneumococcal proteins have been identified as vaccine candidates, as they are highly conserved and expressed by all clinical isolates and elicit protective, long-lasting cellular and humoral immunity in animal models. Alternative approaches include combinations of PCV with pneumococcal proteins, whole cell inactivated vaccines and live-attenuated vaccines (summarized in [68]).

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