**2.1 Pneumococcal polysaccharide vaccine**

The currently available PPV-23 was licensed in 1983 and is usually recommended for all elderly people and some at-risk groups including those with chronic respiratory diseases. The vaccine contains capsular polysaccharide antigens from the 23 most dominant serotypes among clinical isolates of *S. pneumoniae*, accounting for approximately 80-90% of overall invasive infections in the adult population. These antigens induce type-specific antibodies (by a T cell-independent mechanism) that enhance opsonization, phagocytosis and killing of pneumococci by phagocytic cells (Fedson 2003).

Antibody response is generally satisfactory after vaccination, but children aged <2 years and immunodeficient persons do not consistently develop immunity, and certain high-risk individuals (including some people with medical co-morbidities and elderly individuals) may respond poorly (Sankilampi 1996, CDC 1997, Fedson 2003). Following vaccination there is a slow but steady decline in serotype-specific antibody titres, and pre-vaccination levels are generally reached within 5-10 years. An anamnestic response does not occur at

Antipneumococcal Vaccination in COPD Patients 427

In 2010, Walters et al uptated the Cochrane review including a total of 7 RCTs in their metaanalysis specifically focused on COPD patients. According this meta-analysis, in six studies involving 1372 people, the reduction in the risk of developing pneumonia among vaccinated compared to control did not achieve statistical significance (OR: 0.72; 95% CI: 0.51-1.01). The reduction in likelihood of acute exacerbations of COPD from two studies involving 216 people neither reached statistical significance (OR: 0.58; 95% CI: 0.30-1.13). Of the secondary outcomes for which data were available there was no statistically significant effect for reduction in hospital admissions (two studies) or emergency department visits (one study). Considering mortality, according to three studies involving 888 people followed during periods up to 48 months postvaccination, there was no significant reductions in the risk of all-cause death (OR: 0.94; 95% CI: 0.67-1.33), or death from cardiorespiratory causes (OR: 1.07; 95% CI: 0.69-1.66). The authors concluded that, while it is posible that PPV may provide some protection against morbidity in persons with COPD, no significant effect on any of the outcomes was shown in the metaanalysis, recomending that further large RCTs in this population would be needed to confirm the effectiveness of the vaccine suggested by results from some individual studies (Walters 2010).

In the present authors opinion, all RCTs on PPV efficacy focused in COPD patients has been largely underpowered considering that the most large RCT (Alfageme 2006) included less than six hundred patients (with only five definitive pneumococcal pneumonias observed during 3-year follow-up). Furthermore, given the effectiveness of the vaccine in protecting individuals against IPD, commencing new RCTs in populations at risk where vaccine effectiveness and disease burden is known would create ethical difficulties. Thus, although nonRCTs have inherent limitations (especially the possibility of selection bias), they can provide interesting data on the effectiveness and impact of the vaccination. In this way, several observational studies have reported benefits using the PPV-23 in patients with chronic

respiratory diseases (Nichol 1999, Ochoa-Gondar 2008, Watanuki 2008, Sumitani 2008).

two last published meta-analyses (Moberley 2008, Huss 2009).

heterogeneity was observed (OR: 0.71; 95% CI: 0.52-0.97) (Moberley 2008).

On other hand, given COPD is not a cause of immunodepression (apart from the impairment of local defences) and the reported antibody response is compatible with a vaccine efficacy despite its relatively rapid decline, data on efficacy in the general population can also be used to establish vaccine recommendations for these persons. Figure 2 shows point estimates of PPV efficacy against IPD, pneumonia and death according to the

The last Cochrane review on PPV efficacy/effectiveness among the general population recommends the use of PPV to prevent IPD in adults (particularly otherwise healthy adults), but it also concluded that the meta-analysis did not provide compelling evidence to support the routine use of PPV to prevent pneumonia or death. This meta-analysis demonstrates strong evidence of protection against IPD, with an efficacy of 74% (95% CI 56% to 85%) in RCTs and an effectiveness of 52% (95% CI 37% to 61%) in observational studies (case-controlled and cohort studies). Vaccine efficacy appears poor amongst the subgroup of adults with chronic diseases, where vaccination efficacy did not reach statistical significance. In relation to all-cause pneumonia (the most reported outcome in the Cochrane review, the meta-analysis showed that the PPV provides an apparent protective efficacy of 29%, although substantial statistical

We note the limited amount of data regarding persons with chronic pulmonary diseases. Considering RCT's data, vaccination of younger patients with COPD appears best supported, while the evidence of a benefit to older patients is weaker. However, given

revaccination, although there is a significant increase in antibody levels (sometimes slightly lower than after the primary dose) (Sankilampi 1996, Artz 2003). Revaccination is only recommended for those persons who received PPV-23 before 65 years of age (CDC 1997) but its clinical effectiveness has not been clearly proved (Artz 2003).

Despite many studies of PPV efficacy in different populations, few randomized-controlled trials (RCTs) to date were focused on COPD patient (Leech 1987, Davis 1987, Alfageme 2006, Steentoft 2006, Ya Tseimakh 2006, Teramoto 2007, Furumoto 2008) and they have reported unconclusive results. Outcome measures in the different trials were very heterogeneous and included pneumonia, acute exacerbations, change in lung function, hospital admissions or visits to the emergency department and mortality (includes mortality from respiratory disease, causes other than respiratory disease and all-cause mortality). The heterogenity of outcomes reported in the distinct trials, together with the low accuracy of the criteria diagnosis for COPD (not verified by spirometric data in some trials), largely limits the comparison of the different results and their interpretation.

In two earlier RCTs published in 1987 evaluating a 14-valent PPV, Davis et al and Leech et al did not observe any efficacy of pneumococcal vaccination, but these negative results were attributed to the small number of patients included in the series and the low rate of pneumococcal bacteremia. Importantly, before vaccination, antibody titers were higher among the COPD patients than among the healthy control subjects in both trial, which suggests previous pneumococcus exposure and largely limits possible conclusions on vaccine efficacy in this population (Leech 1987, Davis 1987).

In the largest RCT on PPV efficacy in COPD patients published to date, Alfageme et al analysed the efficacy of PPV in a RCT including 596 Spanish patients with spirometric diagnosis of COPD (298 receiving PPV-23 and 298 receiving placebo), concluding that the efficacy of vaccination depends on the age and the severity of airflow obstruction. Considering overall study population, in Alfageme's trial, no differences in the risk of all-cause pneumonia was observed in vaccinated as compared with control subjects (OR: 1.03; 95% CI: 0.64-1.67). In subgroup analyses including only cases due to pneumococcus (5 cases) or unknown etiology (53 cases) pneumococcal vaccination appeared effective among subjects under 65 years (OR:0.24; 95% CI: 0.07-0.80), but it did not appear efficacious among COPD patients 65 years or older (OR: 1.14; 95% CI: 0.62-2.07). Among those patients with severe functional obstruction (forced expiratory volume in 1 second <40%) vaccination appeared to be more efficacious (OR: 0.52; 95% CI: 0.20-1.07), with greatest efficacy in younger patients with severe airflow obstruction (OR: 0.09; 95% CI: 0.01-0.65) (Alfageme 2006).

In a short trial including 49 COPD patients, Steentoft et al observed that a rise in antibody levels after PPV-23 occurred among patients with COPD despite the use of systemic steroid treatment, but a statistically significant clinical effect of vaccination was not demonstrated. In fact, no differences between vaccinated and control subjects were observed for the risk of pneumonia (OR: 0.59; 95% CI: 0.15-2.32), acute exacerbations (OR: 1.44; 95% CI: 0.29-7.14) or hospital admission (OR: 0.95; 95% CI: 0.26-3.48) (Steentoft 2006).

In 2006, Granger et al published the first Cochrane systematic review and meta-analysis on PPV efficacy focused on COPD patients, concluding that PPV was not effective in this population to reduce all-cause pneumonia (OR: 0.89; 95% CI: 0.58-1.37) or all-cause mortality (OR: 0.94; 95% CI: 0.67-1.33) (Granger 2006).

revaccination, although there is a significant increase in antibody levels (sometimes slightly lower than after the primary dose) (Sankilampi 1996, Artz 2003). Revaccination is only recommended for those persons who received PPV-23 before 65 years of age (CDC 1997) but

Despite many studies of PPV efficacy in different populations, few randomized-controlled trials (RCTs) to date were focused on COPD patient (Leech 1987, Davis 1987, Alfageme 2006, Steentoft 2006, Ya Tseimakh 2006, Teramoto 2007, Furumoto 2008) and they have reported unconclusive results. Outcome measures in the different trials were very heterogeneous and included pneumonia, acute exacerbations, change in lung function, hospital admissions or visits to the emergency department and mortality (includes mortality from respiratory disease, causes other than respiratory disease and all-cause mortality). The heterogenity of outcomes reported in the distinct trials, together with the low accuracy of the criteria diagnosis for COPD (not verified by spirometric data in some trials), largely limits the

In two earlier RCTs published in 1987 evaluating a 14-valent PPV, Davis et al and Leech et al did not observe any efficacy of pneumococcal vaccination, but these negative results were attributed to the small number of patients included in the series and the low rate of pneumococcal bacteremia. Importantly, before vaccination, antibody titers were higher among the COPD patients than among the healthy control subjects in both trial, which suggests previous pneumococcus exposure and largely limits possible conclusions on

In the largest RCT on PPV efficacy in COPD patients published to date, Alfageme et al analysed the efficacy of PPV in a RCT including 596 Spanish patients with spirometric diagnosis of COPD (298 receiving PPV-23 and 298 receiving placebo), concluding that the efficacy of vaccination depends on the age and the severity of airflow obstruction. Considering overall study population, in Alfageme's trial, no differences in the risk of all-cause pneumonia was observed in vaccinated as compared with control subjects (OR: 1.03; 95% CI: 0.64-1.67). In subgroup analyses including only cases due to pneumococcus (5 cases) or unknown etiology (53 cases) pneumococcal vaccination appeared effective among subjects under 65 years (OR:0.24; 95% CI: 0.07-0.80), but it did not appear efficacious among COPD patients 65 years or older (OR: 1.14; 95% CI: 0.62-2.07). Among those patients with severe functional obstruction (forced expiratory volume in 1 second <40%) vaccination appeared to be more efficacious (OR: 0.52; 95% CI: 0.20-1.07), with greatest efficacy in younger patients with severe airflow

In a short trial including 49 COPD patients, Steentoft et al observed that a rise in antibody levels after PPV-23 occurred among patients with COPD despite the use of systemic steroid treatment, but a statistically significant clinical effect of vaccination was not demonstrated. In fact, no differences between vaccinated and control subjects were observed for the risk of pneumonia (OR: 0.59; 95% CI: 0.15-2.32), acute exacerbations (OR: 1.44; 95% CI: 0.29-7.14) or

In 2006, Granger et al published the first Cochrane systematic review and meta-analysis on PPV efficacy focused on COPD patients, concluding that PPV was not effective in this population to reduce all-cause pneumonia (OR: 0.89; 95% CI: 0.58-1.37) or all-cause

its clinical effectiveness has not been clearly proved (Artz 2003).

comparison of the different results and their interpretation.

vaccine efficacy in this population (Leech 1987, Davis 1987).

obstruction (OR: 0.09; 95% CI: 0.01-0.65) (Alfageme 2006).

mortality (OR: 0.94; 95% CI: 0.67-1.33) (Granger 2006).

hospital admission (OR: 0.95; 95% CI: 0.26-3.48) (Steentoft 2006).

In 2010, Walters et al uptated the Cochrane review including a total of 7 RCTs in their metaanalysis specifically focused on COPD patients. According this meta-analysis, in six studies involving 1372 people, the reduction in the risk of developing pneumonia among vaccinated compared to control did not achieve statistical significance (OR: 0.72; 95% CI: 0.51-1.01). The reduction in likelihood of acute exacerbations of COPD from two studies involving 216 people neither reached statistical significance (OR: 0.58; 95% CI: 0.30-1.13). Of the secondary outcomes for which data were available there was no statistically significant effect for reduction in hospital admissions (two studies) or emergency department visits (one study). Considering mortality, according to three studies involving 888 people followed during periods up to 48 months postvaccination, there was no significant reductions in the risk of all-cause death (OR: 0.94; 95% CI: 0.67-1.33), or death from cardiorespiratory causes (OR: 1.07; 95% CI: 0.69-1.66). The authors concluded that, while it is posible that PPV may provide some protection against morbidity in persons with COPD, no significant effect on any of the outcomes was shown in the metaanalysis, recomending that further large RCTs in this population would be needed to confirm the effectiveness of the vaccine suggested by results from some individual studies (Walters 2010).

In the present authors opinion, all RCTs on PPV efficacy focused in COPD patients has been largely underpowered considering that the most large RCT (Alfageme 2006) included less than six hundred patients (with only five definitive pneumococcal pneumonias observed during 3-year follow-up). Furthermore, given the effectiveness of the vaccine in protecting individuals against IPD, commencing new RCTs in populations at risk where vaccine effectiveness and disease burden is known would create ethical difficulties. Thus, although nonRCTs have inherent limitations (especially the possibility of selection bias), they can provide interesting data on the effectiveness and impact of the vaccination. In this way, several observational studies have reported benefits using the PPV-23 in patients with chronic respiratory diseases (Nichol 1999, Ochoa-Gondar 2008, Watanuki 2008, Sumitani 2008).

On other hand, given COPD is not a cause of immunodepression (apart from the impairment of local defences) and the reported antibody response is compatible with a vaccine efficacy despite its relatively rapid decline, data on efficacy in the general population can also be used to establish vaccine recommendations for these persons. Figure 2 shows point estimates of PPV efficacy against IPD, pneumonia and death according to the two last published meta-analyses (Moberley 2008, Huss 2009).

The last Cochrane review on PPV efficacy/effectiveness among the general population recommends the use of PPV to prevent IPD in adults (particularly otherwise healthy adults), but it also concluded that the meta-analysis did not provide compelling evidence to support the routine use of PPV to prevent pneumonia or death. This meta-analysis demonstrates strong evidence of protection against IPD, with an efficacy of 74% (95% CI 56% to 85%) in RCTs and an effectiveness of 52% (95% CI 37% to 61%) in observational studies (case-controlled and cohort studies). Vaccine efficacy appears poor amongst the subgroup of adults with chronic diseases, where vaccination efficacy did not reach statistical significance. In relation to all-cause pneumonia (the most reported outcome in the Cochrane review, the meta-analysis showed that the PPV provides an apparent protective efficacy of 29%, although substantial statistical heterogeneity was observed (OR: 0.71; 95% CI: 0.52-0.97) (Moberley 2008).

We note the limited amount of data regarding persons with chronic pulmonary diseases. Considering RCT's data, vaccination of younger patients with COPD appears best supported, while the evidence of a benefit to older patients is weaker. However, given

Antipneumococcal Vaccination in COPD Patients 429

(Pilishvili 2010). Nevertheless, it must be noted that for some groups of older adults the reduction was somewhat lower. There was only a very modest reduction in the number of cases in subjects with comorbid conditions, such as chronic renal disease, heart disease and

Considering the good immune response and efficacy shown in children, it has been proposed that the use of the conjugate vaccine could improve antibody responses and clinical efficacy in high-risk adults with poor response to PPV (Fry 2002, Lockhart 2006, Jackson 2008). An important immunological consequence of conjugation of polysaccharide antigen with a carrier protein is that the CD4+ helper T-cell fraction contributes to the immunological response. Thus a T-cell-dependent response is generated, with predominant IgG1 and IgG3 antibodies, instead of the T-cell-independent antibody response that occurs with simple polysaccharide antigens (Wuorimaa 2001). This is an important advantage for the conjugated vaccine, given that the response to polysaccharide antigens is much more varying and age-dependent, and antibody levels therefore more uncertain than with conjugated antigens. Thus, as in young children, adult population groups could obtain

Until now, the low serotype coverage has been a very important shortcoming for the "old" PCV-7, bbut he new PCVs including more serotypes (especially the PCV-13, which has broad serotype coverage for both children and adults) could be a good future alternative for

However, at the moment, there are important factors to consider before PCV could ever be used in adult populations. There are only limited immunogenicity data and no data on clinical efficacy in adults. Furthermore, it is not known how many doses of conjugate vaccine adults would require, what age groups should receive the vaccine, and what would

Although the virulence of Streptococcus pneumoniae is largely dependent on its polysaccharide capsule, it has been demonstrated that numerous protein virulence factors are involved in the pathogenesis of pneumococcal disease (Orihuela 2004), and currently extensive efforts are being made to develop a new generation of pneumococcal vaccines. These vaccines, known as protein-based pneumococcal vaccines (PBPV), are composed of pneumococcal proteins or virulence factors, together with antibodies to them to neutralize

Several formulations of experimental PBPV candidates containing different pneumococcal proteins (eg, PspA, PspC, Ply, or PsaA) have shown protective effects against invasive infections and nasopharyngeal carriage in animal models, and some studies assessing the development of natural antibodies after carriage and invasive disease in humans have reported development of an immune response against some of them (Tai 2006). It has been reported that the combination of various proteins with different protective functions may provide a broader protection (Ogunniyi 2007). Furthermore, other pneumococcal proteins identified very recently by exploiting molecular immunological techniques suggest

be the optimal timing for pneumococcal conjugate vaccination (Abraham Van-Parijs).

their function and reduce the virulence of the infecting bacteria (Tai 2006).

chronic pulmonary disease (Lexau 2005, Lockhart 2006).

benefit from using a conjugate vaccine in the future.

**2.3 Protein-based pneumococcal vaccines** 

interesting new vaccine directions (Giefing 2008).

all age groups (Scott 2008).

Fig. 2. Estimation of PPV efficacy against IPD, pneumonia and death according to the two last published meta-analyses (Moberley 2008, Huss 2009).

observational studies, PPV also appears effective in older patients with COPD. Because the risks of immunization are believed to be very small, public policy at this time continues to support immunization of all patients with chronic lung diseases regardless of age (CDC 1997, CDC 2010). New CDC's recommendations for using the PPV in adults have been publihsed in 2010. The CDC's new recommendations include some changes from 1997 recommendations.the indications for which PPV-23 vaccination is recommended now include smoking and asthma(CDC 2010).
