Efficacy of vaccines against Streptococcus pneumoniae

Introduction

Streptococcus pneumoniae is a pathogenic, gram-positive, α-hemolytic, anaerobic bacterium that causes pneumonia along with other pneumococcal infections some of which include bacterial meningitis, sinusitis, and otitis media (Pletz et. al. 2008; Slonczewski and Foster, 2009; Siemieniuk et. al. 2011). S. pneumoniae has been able to developed antibiotic resistance to traditional β-Lactam drugs such as Penicillin (and its derivatives) by alteration of targeted penicillin binding proteins (PBPs) in the resistant strains that lower its affinity to bind to penicillin (Slonczewski and Foster, 2009). Genome sequencing of the penicillin resistant strains show that point mutations in PBP2x decreases is affinity to bind to penicillin (Laible and Hakenbeck, 1991).

Due to increasing rate of antibiotic resistance it is important to study newer ways in which growth of S. pneumoniae can be inhibited. This is because antibiotics select for growth of rare microorganisms in a population that is otherwise susceptible to the drug (Slonczewski and Foster, 2009). One way of overcoming the problem of antibiotic resistance is by targeting highly conserved surface proteins of S. pneumoniae, thereby disabling the bacteria from becoming virulent (Jedrzejas, 2007). This way the bacteria is not killed however, its ability to infect has finished. Subsequently highly conserved surface proteins that are essentially virulence factors can be used to create vaccines that generate immunogenicity against various serotypes of S. pneumoniae (Jedrzejas, 2007).

Vaccines work by giving the organism immunity against infection by a particular pathogen. Vaccines contain a weakened or dead derivative of the pathogen and in its altered state vaccine pathogens are typically safe and unable to cause disease (WHO, 2013; NIAID, 2011). The non-virulent pathogens in the vaccine stimulate the organisms B-cells to make antibodies for the particular antigens thereby developing immunity to that pathogen (NIAID, 2011). Subsequently, Memory T cells (type of antigen specific T cells) get stimulated upon re-exposure to cognate antigen and rapidly multiply thereby providing “memory” to the body’s immune system (NIAID, 2011). In addition to the weakened or dead form of bacteria or virus, the vaccine also contains antibiotics or preservatives to protect the body against any germs that might get into the vaccine.

Pneumococcal vaccines aim to target the polysaccharide capsule of S. pneumoniae because immunity after pneumococcal disease is directed against the capsular serotype of the S. pneumoniae bacteria involved (WHO, 1999). 91 serotypes of S. pneumoniae have been identified based on the difference in composition of the polysaccharide capsule (Pletz et. al. 2008). The polysaccharide capsule is a virulence factor however; only some of the 91 serotypes cause pneumococcal disease.

Current pneumococcal vaccines

As an alternative to β-lactam antibiotics, vaccines have been created that target cell surface polysaccharide, which aim to develop immunity against the virulent serotypes of S. pneumoniae. The two vaccines that are widely used are polysaccharide vaccine (23-valent polysaccharide vaccine) and pneumococcal conjugate vaccine (heptavalent protein–polysaccharide conjugate vaccine, PCV-7) (Bogaert et. al. 2004). As the name suggests, the polysaccharide vaccine provides immunity against 23 S. pneumoniae serotypes and is effective in older immunocompetent patients (Bogaert et. al. 2004; Pletz et. al. 2008). However, this vaccine cannot be administered to infants below 2 years of age and to immunodeficient patients perhaps due to an immature or a sensitive immune system (Pletz et. al. 2008). The newer conjugate vaccine, PCV-7 is able to provide immunity to this age group (Bogaert et al. 2004; Pletz et. al. 2008).

=23-valent polysaccharide (PS) vaccine=

As the name suggests the 23-valent polysaccharide vaccine contains capsular polysaccharides antigens for 23 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), therefore it provides immunity against these serotypes (Pletz et. al. 2008). To gain immunity the polysaccharides induce B cell dependant response by releasing polysaccharide Immunoglobulin M (IgM), which are a type of antibodies produced by B cells (Pletz et. al. 2008). The PS vaccine does not induce a T cell-dependant immune response. As mentioned above, T cells provide ‘memory’ to the body’s immune system (NIAID, 2011) so antibodies can be made quickly upon re-exposure to cognate antigen. A study done in Mexico evaluating the immune response of this vaccine in children under 5, for 6 serotypes, suggests that the pneumococcal polysaccharide vaccine produced adequate immunogenicity in the given age group (Padilla et. al. 2012). However, this vaccine is not effective in children under 2 years of age (Black et. al. 2000; pedilla et. al. 2012). Therefore, a more comprehensive and a cost effective vaccine is still needed.

Pros for 23-valent PS vaccine

- The vaccine covers a large number of serotypes - Serotypes covered in 23-valent PS vaccine account for 85-90% of invasive pneumococcal diseases in the US(ACIP, 1997) - It is cost effective and widely used in developing countries

Cons for 23-valent PS vaccin

- Cannot be used for children <2 yrs of age and for immunodeficient patients. Immunodeficient patients (HIV infected individuals) show an impaired antibody response to PS vaccination (Kroon et. al. 1999) - No T-cell response means there is absence of memory B cells and therefore the time period of protection is limited (Bogaert, 2004). - Does not affect carrier rate due to no mucosal immunity (Pletz et. al. 2008)

Heptavalent protein–polysaccharide conjugate vaccine (PCV-7)

Unlike the 23-valent polysaccharide vaccine, which can only be used in children >2years the conjugate vaccine can be administered to infants as young as 2months old (Bogaert et. al. 2004; Morsczeck et al. 2007; Pletz et. al. 2008). Polysaccharides of in this vaccine are from seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) that are most frequently involved in infant infections (Pletz et. al. 2008; Johanna et. al. 2011). As the name suggests this vaccine is conjugated to protein (CRM197), which is a non-toxic diphtheria toxoid protein (Pletz et. al. 2008). The protein-specific type 2 T cells associate with B cells, which are bound to the polysaccharide-protein complex via a polysaccharide specific IgM (Pletz et. al. 2008).This association between T and B cells presents the processed protein (CRM197) along with class II MHC (Major Histocompatibility Complex) to the effector T cells (Pletz et. al. 2008). Class II MHCs are cell-surface molecules that mediate interaction between immune cells and body cells. The antigens from Class II peptides come from extracellular proteins instead of from inside the cell. This mechanism leads to adaptive immunity in infants, which is switching of antibody isotype and generation of memory B-cells (Pletz et. al. 2008).

Pros for PCV-7

- More immunogenic than PS vaccine because capsular polysaccharides are covalently bound (or via reactive groups) to proteins carriers, which increases the immunogenicity of the capsular polysacchrides (Poland, 1999). - The bound protein, CRM197 helps in eliciting a T cell dependant response, which induces memory of B cells (Bogaert et. al.2004). - Can be used for <2 years of age because of early maturation of T cell dependant response compared to the late maturation of antipolysaccharide antibodies (Bogaert et. al. 2004). - Affects carrier rate by decreasing nasopharyngeal carriage of vaccine serotype, which suggests that conjugate vaccine provides both, systemic (throughout the body) and mucosal immunity (Spratt and Greenwood, 2000; Bogaert et. al. 2004). Obtaining specific mucosal immunity is important because it allows asymptomatic carriers to eliminate colonizing of vaccine serotypes thereby decreasing carrier rate (Pletz et. al. 2008).

Cons for PCV-7

- There is a limit to the amount of polysaccharide-protein linkages that can be formed. If too many carrier antigens are used antibody response to the antigens can be impaired (Di et. al. 1989). - Not as cost effective because it is expensive to develop and does not cover the major serotypes (1 and 5) that cause pneumococcal diseases in developing countries (Morsczeck et al 2007; Jefferies et. al. 2011)

Combined use of PS and PCV-7

After the newer PCV-7 vaccine was developed, the best form of immunity was seen in patients that took the conjugate vaccine followed by the PS vaccine (Bogaert et. al.2004). A combined vaccination program was recommended for children 2-5 years by the ACIP, which recommended the use of PCV-7 first followed by the use of PS vaccine as a booster (Bogaert et. al.2004). This is perhaps because PCV-7 confers immunity in children from the invasive serotypes and later the PS vaccine provides immunity against additional serotypes not covered by PCV-7.

Replacement Vs. Antibiotic Resistance

As mentioned above antibiotic resistance is a growing concern. However, in using vaccines, eradication of different serotypes by giving vaccines specific for those serotypes also selects for growth of non-vaccine serotypes (Pletz et. al. 2008). This is called ‘replacement’ because pre-existing clones of the non-vaccinated serotypes are able to proliferate. Therefore it is important to target molecules such as proteins that are conserved across different serotypes. Such highly conserved proteins, associated with the cell wall can be used to create vaccines that can protect against a majority of S. pneumoniae serotypes. In a study done, Morsczeck et.al. (2007) used proteomics to identify cell-wall associated proteins, which were screened for vaccine candidates. Further immunization experiments on the 5 selected protein candidates; expressed in E.Coli revealed proteins that were detected in 40 or more different serotypes of S. pneumoniae (Morsczeck et.al. 2007). This study has selected 2 of the 5 candidates that are lipoate protein ligase (Lpl) and the ClpP protease that have shown a decrease in CFU count and should be used for further investigation. This new way of making vaccines that is protein vaccines seems like a likely next step to reduce the likelihood of growth of S. pneumoniae. Although the problem of antibiotic resistance and/or replacement is growing, targeting common denominators across different serotypes will help in eliminating the infectious strains. Elimination of these strains could select for growth of mutated strains however the process of mutation is thought to be slower if highly conserved molecules like proteins are targeted.

References

Black. S. et.al. 2000. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. The Pediatric Infectious Disease Journal.

Chambers H.F. 1999. Penicillin-Binding Protein–Mediated Resistance in Pneumococci and Staphylococci. JID

C. Morsczeck et.al. 2007. Streptococcus pneumoniae: proteomics of surface proteins for vaccine development. European Society of Clinical Microbiology and Infectious Diseases, CMI.

Laible.G and Hakenbeck. R. 1991. Five Independent Combinations of Mutations Can Result in Low Affinity Penicillin-Binding Protein 2x of Streptococcus pneumoniae. Journal of Bacteriology.

M. J. Jedrzejas. 2007. Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies. Cell. Mol. Life Sci.

Mathias W. Pletz et.al. 2008. Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species. International Journal of Antimicrobial Agents

Padilla. S.E.E et.al. 2012. Immunogenicity of A 23-Valent Pneumococcal Polysaccharide Vaccine Among Mexican Children. Archives of Medical Research

Slonczewski, Joan L, and John Foster. Microbiology. 2nd. W.W.Norton and Company, 2009. Print.