**2.2 Pneumococcal conjugate vaccines**

Given the poor immunogenicity of PPV in children, extensive efforts have been made to develop a new generation of pneumococcal vaccines with good immunogenicity in infants. The result was a protein-polysaccharide combination, known as pneumococcal conjugate vaccine (PCV), which contains selected polysaccharides bound to a protein carrier. This renders the vaccine T-cell-dependent, and thus capable of stimulating antibody responses and priming for a memory response on rechallenge. The firstly available PCV contained specific antigen for the 7 most common pneumococcal serotypes in children, and was licensed for paediatric use in 2000 (Black 2000).

In contrast to the PPV-23, which only had a limited impact on the overall disease burden, the introduction of the PCV-7 as routine vaccination for infants has provided very encouraging results, even reducing incidences of pneumococcal disease in unvaccinated people (by herd immunity reducing the transmission of PCV-7 strains in the population) (Whitney 2003, Hicks 2007). In addition, an important reduction in drug-resistant Streptococcus pneumoniae isolates has been observed in all-age groups after the introduction of PCV-7 for children (Kyaw 2005).

Among people over 50 years in the United States, IPD declined by 28% (from 40.8 to 29.4 per 100,000 person-year between 1998-2003) (CDC 2005) with further reductions in recent years

**74%**

**OR: 0.62 (IC 95%: 0.05-8.61)** 

**OR: 0.71 (IC 95%: 0.52-0.97) OR: 0.73 (IC 95%: 0.56-0.94)**

**OR: 0.26 (IC 95%: 0.15-0.46)**

**38%**

**OR: 0.87 (IC 95%: 0.69-1.10) OR: 0.88 (IC 95% CI: 0.62-1.25)**

Fig. 2. Estimation of PPV efficacy against IPD, pneumonia and death according to the two

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

Given the poor immunogenicity of PPV in children, extensive efforts have been made to develop a new generation of pneumococcal vaccines with good immunogenicity in infants. The result was a protein-polysaccharide combination, known as pneumococcal conjugate vaccine (PCV), which contains selected polysaccharides bound to a protein carrier. This renders the vaccine T-cell-dependent, and thus capable of stimulating antibody responses and priming for a memory response on rechallenge. The firstly available PCV contained specific antigen for the 7 most common pneumococcal serotypes in children, and was

In contrast to the PPV-23, which only had a limited impact on the overall disease burden, the introduction of the PCV-7 as routine vaccination for infants has provided very encouraging results, even reducing incidences of pneumococcal disease in unvaccinated people (by herd immunity reducing the transmission of PCV-7 strains in the population) (Whitney 2003, Hicks 2007). In addition, an important reduction in drug-resistant Streptococcus pneumoniae isolates has been observed in all-age groups after the

Among people over 50 years in the United States, IPD declined by 28% (from 40.8 to 29.4 per 100,000 person-year between 1998-2003) (CDC 2005) with further reductions in recent years

**27%**

**29%**

**12%**

include smoking and asthma(CDC 2010).

**2.2 Pneumococcal conjugate vaccines** 

licensed for paediatric use in 2000 (Black 2000).

introduction of PCV-7 for children (Kyaw 2005).

**Huss Moberley**

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

**DEATH FROM 13%**

**CAP**

**IPD**

**PNEUMONIA**

(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 chronic pulmonary disease (Lexau 2005, Lockhart 2006).

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 benefit from using a conjugate vaccine in the future.

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 all age groups (Scott 2008).

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

#### **2.3 Protein-based pneumococcal vaccines**

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

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 interesting new vaccine directions (Giefing 2008).

Antipneumococcal Vaccination in COPD Patients 431

technologies, such as protein-based or genomic vaccines, will be greatly needed. Experimental protein-based pneumococcal vaccine candidates offer the potential advantage of serotypeindependent protection and several are in various stages of development in animal models,

Until better options are available, the PPV-23 should continue to be used in high-risk individuals, including younger and older adults with COPD. Although only moderately effective, the burden of pneumococcal disease is greatest in these persons and they can

Abraham-Van Parijs B. Review of pneumococcal conjugate vaccine in adults: implications

Alfageme I, Vazquez R, Reyes N et al. Clinical efficacy of anti-pneumococcal vaccination in

Artz AS, Ershler WB, Longo DL. Pneumococcal vaccination and revaccination of older

Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A, Rello J, Morris AJ, Luna CM,

Black S, Shinefield H, Fireman B et al. The Northern California Kaiser Permanent Vaccine

Centers for Disease Control and Prevention. Direct and indirect effects of routine

Centers for Disease Control and Prevention. Advisory Committee on Immunization

Fedson DS, Musher DM. Pneumococcal polysaccharide vaccine. In: Plotkin SA, Orenstein

Feikin DR, Schuchat A, Kolczak M, Barrett NL, Harrison LH, Lefkowitz L, McGeer A, Farley

WA, eds. Vaccines. 4th ed. Philadelphia: Saunders, 2003: 529-88.

Snydman DR, Ko WC, Chedid MB, Hui DS, Andremont A, Chiou CC; International Pneumococcal Study Group. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care

Study Center Group. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000; 19: 187-95. Black PN, McDonald CF. Interventions to reduce the frequency of exacerbations of chronic obstructivepulmonary disease.Postgrad Med J 2009; 85(1001):141-7. Centers for Disease Control and Prevention. Prevention of pneumococcal disease:

recommendations of the Advisory Committee on Immunization Practice (ACIP).

vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease--United States, 1998-2003. MMWR Morb Mortal

Practices (ACIP). Prevention of pneumococcal disease among infants and children– use of 13valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine. MMWR Recommendations 2010; Reports 59(RR11), 1–18. Davis A, Aranda CP, Schiffman G, Christianson LC. Pneumococcal infection and

immunologic response to pneumococcal vaccine in chronic obstructive pulmonary

MM, Vugia DJ, Lexau C, Stefonek KR, Patterson JE, Jorgensen JH. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997.

but none can be expected to be available in clinical practice for several years at least.

on clinical evelopment. Vaccine 2004; 22: 1362-71.

MMWR Morb Mortal Wkly Rep 1997; 46(RR-8): 1-24.

patients with COPD. Thorax 2006; 61: 189-195.

adults. Clin Microbiol Rev 2003 ; 16: 308-18.

obtain benefit from vaccination.

Med 2004; 170:440-4.

Wkly Rep 2005; 54: 893-7.

disease. Chest 1987; 92(22): 204-212.

Am J Public Health 2000; 90: 223-9.

**4. References** 

Theoretical major advantages for a future PbPV could be the serotype-independent protection, the possibility of oral or intranasal administration, and probably a less complex production process and a lower cost than conjugate vaccines. However, at the moment, information on humans is scarce, and many studies and several years will be needed to elucidate the true potential of PbPV in human prevention. If finally these proteins can not provide sufficient protection as a sole component of the vaccine, it is posssible that they could be used either as a carrier protein for a conjugate vaccine or as a supplement component for the current vaccines to provide additional protection against pneumococcal infections (Wright 2008).
