Tuberculosis

Disease Burden
Based on available data, S. pneumoniae is estimated to kill annually close to one million children under five years of age worldwide, especially in developing countries where pneumococcus is one of the most important bacterial pathogens of early infancy.
In developed countries, virtually every child becomes a nasopharyngeal carrier of S. pneumoniae during the first year of life. Many go on to develop one or more episodes of otitis media, whereas a smaller number develop more serious invasive pneumococcal infections. Bacteraemic pneumonia is a...

common form of invasive pneumococcal disease, the next most common being pneumococcal meningitis, with or without bacteraemia. S. pneumoniae is the leading cause of nonepidemic childhood meningitis in Africa and other regions of the developing world. In the USA, most cases of invasive pneumococcal disease are characterized by febrile bacteraemia without specific localization. Less severe but more frequent forms of pneumococcal disease include middle-ear infection, sinusitis or recurrent bronchitis. Thus, in the USA alone, seven million cases of otitis media are attributed to pneumococci each year. Although all age groups may be affected, the highest rate of pneumococcal disease occurs in young children and in the elderly population. In addition, persons suffering from a wide range of chronic conditions and immune deficiencies are at increased risk. In Europe and the USA, pneumococcal pneumonia accounts for at least 30% of all cases of community-acquired pneumonia admitted to the hospital, with a reported annual incidence of 5500 to 9200 per 100 000 persons 65 years of age or older, and a case fatality rate of 10–30%. S. pneumoniae is an under-appreciated cause of nosocomial pneumonia in hospital wards, intensive care units, as well as in nursing homes and long-term care institutions.
Bacteriology

S. pneumoniae is a Gram-positive encapsulated diplococcus. Based on differences in the composition of the polysaccharide (PS) capsule, 90 serotypes have been identified. This capsule is an essential virulence factor. The majority of pneumococcal disease in infants is associated with a small number of these serotypes, which may vary by region. Current data suggest that the 11 most common serotypes cause at least 75% of invasive disease in all regions. Several other virulence factors have been described, including pneumolysin which leads to pore formation and osmotic lysis of epithelial cells, autolysin, and pneumococcal surface protein A (PspA), which interferes with phagocytosis and immune function in the host. Pneumococci are transmitted by direct contact with respiratory secretions from patients and healthy carriers. Although transient nasopharyngeal colonization rather than disease is the normal outcome of exposure to pneumococci, bacterial spread to the sinuses or the middle ear, or bacteraemia following penetration of the mucosal layer, may occur in persons susceptible to the involved serotype. Pneumococcal resistance to essential anti-microbials such as penicillins, cephalosporins and macrolides is a serious and rapidly increasing problem worldwide.
Vaccine

Protective immunity is conferred by type-specific, anticapsular antibodies, although the serological correlates of immunity are poorly defined. Antibodies to pneumococcal surface proteins (PspA) have been demonstrated to confer protection in animal models but the role of these antibodies in humans is yet to be determined.

Currently licensed vaccines are polyvalent PS vaccines containing per dose 25 µg of purified capsular PS from each of the 23 serotypes of S. pneumoniae that together account for most cases (90%) of serious pneumococcal disease in western industrialized countries. Relatively good antibody responses (60–70%) are elicited in most healthy adults within 2–3 weeks following a single intramuscular or subcutaneous immunization. The immune response is however mediocre in children less than two years of age and in immunocompromised individuals (HIV/AIDS). Furthermore, PS vaccines do not induce immunological memory which is required for subsequent booster responses. The polyvalent PS vaccine is recommended for healthy people over 65 years of age, particularly those living in institutions. Randomized controlled trials in healthy elderly people in industrialized countries have, however, failed to show a beneficial effect of the vaccine, so that recommendation for its use in the elderly is based on data from observational studies showing a significant protective effect against invasive (bacteraemic) pneumococcal disease, but not pneumonia.

Following the vaccination of pregnant women with PS vaccines, anti-PS antibodies are transferred both via the placenta and in the breast milk, but formal demonstration that maternal vaccination actually protects newborn infants against pneumococcal disease is still lacking.

Over the past 15 years, several vaccine manufacturers have developed pneumococcal conjugate vaccines in which a number of S. pneumoniae PS are covalently coupled to a protein carrier. Conjugate vaccines elicit higher antibody levels and a more efficient immune response in infants, young children, and immunodeficient persons than the PS vaccines, as well as a significant immunological memory resulting in a booster antibody response on subsequent exposure to the antigen. Moreover, these vaccines suppress nasopharyngeal carriage of the pathogen and reduce bacterial transmission in the community through herd immunity, which adds considerable value to their implementation. Conjugate vaccines immunization followed by PS vaccine boosting might provide a foundation for lifelong protection against pneumococcal disease.

Introduction of the conjugate vaccine in early 2000 in the USA resulted in dramatic decline in the rates of invasive pneumococcal disease, with reductions also seen in unvaccinated individuals as a result of herd immunity. In a double-blind Phase III study of the 7-valent vaccine, Prevnar (Wyeth), conducted at northern California Kaiser Permanente medical centres on 37,868 infants, 40 cases of invasive S. pneumoniae disease were seen in the study population, 39 of which were in the control group, representing a 97% vaccine efficacy. The vaccine was found to be 100% efficacious in the few low birth-weight and preterm infants included in the study. Post-licensure follow-up studies conducted in the same setting have shown an 87% reduction in invasive pneumococcal diseases caused by vaccine serotypes in children less than one year of age, and a 62% reduction in children less than five years of age, with no difference between a two-dose or a three-dose immunization regimen. The vaccine also elicited moderate protection against otitis caused by vaccine serotypes. However, the decrease in cases of vaccine-type otitis media was offset by an increase in those due to non-vaccine-types of S. pneumoniae and by H. influenzae, a phenomenon referred to as "replacement disease". This phenomenon also has recently been observed for invasive pneumococcal disease, although the increase in non-vaccine types was small relative to the decrease in vaccine-type invasive disease caused by vaccination.

The currently licensed 7-valent vaccine, Prevnar, does not contain some of the serotypes that cause severe disease in developing countries, notably serotypes 1 and 5. New conjugate vaccines that provide more optimal serotype coverage in these countries are in clinical development, including a 9-valent Wyeth vaccine, and an 11-valent GSK and Sanofi-Pasteur vaccines. The protein carrier used by Wyeth is CRM197, a genetically detoxified mutant of diphtheria toxin, whereas that used by GSK is the H. influenzae protein D. Merck is using the outer membrane protein complex (OMPC) from N. meningitidis. The 9-valent vaccine has been tested in South Africa with remarkable efficacy results in children less than two years of age, including HIV-positive infants. In addition, an unexpected benefit of vaccination was the decrease of symptomatic pneumonia cases associated with a viral infection, whether influenza virus or one of the paramyxoviruses. The vaccine is now being tested in the Gambia. Sanofi-Pasteur 11-valent vaccine is undergoing an efficacy trial in the Philippines, but it is not clear at this time whether all these conjugate candidate vaccines will be taken to licensure.

Newer vaccine approaches are being developed in order to provide protective immunity against a larger number of S. pneumoniae serotypes, and to circumvent the complexity of manufacture of conjugate vaccines. Several pneumococcal proteins, including pneumolysin, PspA, pneumococcal surface adhesin (PsaA), neuraminidase, and autolysin are at an early clinical stage development. PiaA and PiuA, two newly identified lipoprotein components of S. pneumoniae iron uptake ABC transporters, elicit protective immunity against invasive pneumococcal disease in mice through induction of opsonophagocytosis-promoting antibodies.

Through screening with human convalescent sera of a S. pneumoniae genomic expression library, Shire Biologicals, Canada (now ID BioMedical) has identified what appear to be remarkably conserved bacterial surface proteins (BVH-3 and BVH-11) able to induce protective anti-pneumococcal antibodies in the mouse model. A recombinant 100 kD hybrid protein, BVH3/11V, was engineered by fusion of parts of the two genes and expressed with high yields in E. coli. The fusion protein has successfully been tested in Phase I dose ranging clinical trials in toddlers and elderly volunteers. A 2-dose immunization regimen was able to induce a 50-fold increase in anti-S. pneumoniae antibody levels. Phase II clinical studies in infants and elderly persons have been initiated. This vaccine should be serotype-independent as the BVH3 and BVH11 antigens are common to all 90 serotypes of S. pneumoniae.