Efficacy of Pneumococcal vaccines against Streptococcus pneumoniae

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Introduction

Antibiotic resistance is the decrease in effectiveness of a drug because the sub-population of the microorganism (usually bacteria) being targeted are able to survive exposure to the antibiotic. Antibiotic resistance is a growing concern because antibiotics select for growth of rare microorganisms in a population that is otherwise susceptible to the drug (Slonczewski and Foster, 2009). Bacteria gain antibiotic resistance in various ways, they can pump out the antibiotics through an efflux transmembrane, bypass target pathway, prevent antibiotic from entering the cell and through target mediated Antibacterial Resistance (Slonczewski and Foster, 2009). Streptococcus pneumoniae is a pathogenic, gram-positive, α-hemolytic, anaerobic bacterium that causes pneumonia along with other pneumococcal infections including meningitis, sepsis, cellulitis, bacteremia, septic arthritis, otitis, brain abscess, pericarditis and peritonitis. Mechanisms by which S. pneumoniae develop antibiotic resistance to penicillin (and its derivatives) is essential in the understanding of antibiotic resistance. Such mechanisms can be used to study how newer pathogenic, gram-positive bacteria; similar to S. pneumoniae, might develop antibiotic resistance. Due to increasing rate of antibiotic resistance it is important to study newer ways in which growth of S. pneumoniae can be inhibited. One such way is by targeting highly conserved surface proteins of S. pneumoniae, thereby disabling the bacteria from becoming virulent. This way the bacteria is not killed however, its ability to infect has finished. Subsequently surface proteins that are essentially virulence factors can be used to create vaccines that generate immunogenicity (Jedrzejas, 2007).

Failure of Penicillin antibiotics

Penicillin is a bactericidal drug that functions by inhibiting the formation of peptidoglycan. Peptidolgycan is necessary for cell wall formation; it has two components, glycan and peptide cross-bridges that make up the cell wall. Penicillin blocks cross-bridge formation by targeting transpeptidase that helps in cross-linking the peptides (Slonczewski and Foster, 2009). Penicillin is a β-Lactam antibiotic that consists of a β-Lactam ring in its core structure; the β-Lactam ring is derived by combining cysteine and valine (Slonczewski and Foster, 2009). The molecular structure of Penicillin mimics the D-ala-D-ala cross bridge, which allows it to bind to penicillin binding proteins (transpeptidase and transglycosylase). S. pneumoniae can develop resistance to penicillin via cleavage of penicillin antibiotic by enzyme β-Lactamase or by modifying the penicillin binding proteins (PBPs). β-lactamase works by hydrolyzing and inactivating the drug however, it is exclusively found in staphylococci (Chambers, 1999). Penicillin resistance in S. pneumoniae occurs by alteration of targeted PBPs in the resistant strains. The alterations are caused by mutations in the PBPs, which lower its affinity to bind to penicillin (Slonczewski and Foster, 2009). PBP2x in S. pneumoniae is involved in the development of β-lactam resistance (Laible and Hakenbeck, 1991). Genome sequencing of the penicillin resistant strains shows that point- mutations in PBP2x decreases is affinity to bind to penicillin (Laible and Hakenbeck, 1991). Alteration of PSP target, specifically PBP2x, gives S. pneumoniae resistance to various β-lactam antibiotics like penicillin.

Current pneumococcal vaccines

As outlined above, due to the high β-lactam antibiotic resistance of S. pneumoniae, vaccines have been created that target cell surface polysaccharide and/or proteins. The two vaccines that are widely used are polysaccharide vaccines (23-valent polysaccharide vaccine) and pneumococcal conjugate vaccines (heptavalent protein–polysaccharide conjugate vaccine).

23-valent polysaccharide vaccine.

As the name suggests this vaccine contains capsular polysaccharides 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) (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. However due to an immature immune system polysaccharide vaccines cannot be used on infants <2. 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.

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. 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. 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. 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.

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.