Acute Respiratory Infections (Update September 2009)
Streptococcus pneumoniae
Introduction
Streptococcus pneumoniae, or pneumococcus, is a leading cause of morbidity and mortality among children worldwide and particularly in developing countries [259] [260] [261] . It was estimated that 10.6 million children less than 5 years present with pneumococcal disease every year [262] . By far the most common form of the disease is bacteremic pneumococcal pneumonia, whose highest incidence is associated with both extremes of age (children < 2 years of age and adults >65 years of age), the next most common form being pneumococcal meningitis, especially in infants and young children, followed in order of decreasing incidence by blood stream infection (or sepsis) and otitis media. Sinusitis and, more rarely, endocarditis and peritonitis also have been reported. In developing countries, the bacterium is the leading bacterial cause of childhood ARI mortality and the leading cause of nonepidemic childhood meningitis [263] [264].
The capsular polysaccharides (PS) on the surface of S pneumoniae, which are its primary factor of virulence, also are the basis for the serotyping classification of the bacterium among 40 serogroups comprising 90 serotypes [265] , only 20 of which are responsible for 70% of invasive pneumococcal disease. The most common serogroups worldwide are 6, 14, 19 and 23 [266] , but other serogroups such as 1, 5 or 8, contribute much to invasive pneumococcal disease in young children in developing countries. A matter of concern is the increasing antibiotic resistance of S pneumoniae, both in older individuals, where it accounts for an increasing proportion of pneumococcal infections and in children less than 2 years of age, where it has added to the urgency of developing more effective pneumococcal vaccines for this age group [5].
Disease Burden
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.
The only natural reservoir of S pneumoniae is the human nasopharynx, from which it can be transmitted through respiratory droplets to other individuals. Virtually every child in the world is colonized with one or more strains of S pneumoniae and becomes a carrier during his first years of life. In most cases carriage is asymptomatic; disease occurs in only a minority of persons, the bacteria spreading locally from the rhinopharynx into the sinuses and middle ear cavity or to the lungs, or causing systemic infections including bacteremia and meningitis. Infection of the blood stream and subsequent infection of secondary sites is referred to as invasive pneumococcal disease.
In some developing countries, as for example Southern India, 50% of infants have been colonized by S pneumoniae by 2 months of age and 80% are carriers by the age of 6 months [267] . A study in South Africa showed that the prevalence of carriage was 30%, 44%, 51% and 61% in children aged 6 weeks, 10 weeks, 14 weeks and 9 months, respectively [268] . In industrialized countries, carriage occurs on the average at about six months of age.
Pneumococcal disease is estimated to cause more than one third of the 2 million global annual child deaths following ARIs [4] . In industrialized countries, the highest levels of infection occur in children less than 2 years of age, being the highest in the second 6 months of life. Thus, prior to the introduction of the conjugate pneumococcal vaccine, the annual average incidence of invasive pneumococcal disease in the USA was 167 cases per 100,000 population in children less than 12 months of age, with a peak at 235 cases per 100,000 among children 6 to 11 months old, and 203 per 100,000 population among children 12 to 23 months old. Children from minority groups suffered disproportionately, with annual incidence figures in children less than 2 years of age of 400, 642 and 2396 per 100,000 among the black, Alaskan Native and Native American populations, respectively [261] . Reported incidence figures are lower in Europe, ranging from 14 cases per 100,000 in Germany and The Netherlands to more than 90 per 100,000 in Spain. S pneumoniae is recognized as the first cause of infant and young children mortality, the leading cause of meningitis and the first cause of bacteremia in less than 2 years old children in France [269] , where incidence of pneumonia is estimated at 100,000 cases per year, causing 3500-11,000 deaths, essentially in the elderly, and that of otitis media at 200,000 cases per year [270].
The true burden of pneumococcal infections in children less than 5 years old is much less documented in developing countries, where disease surveillance systems and diagnostic facilities are lacking and children with invasive infections are diagnosed only if hospitalized. In several surveys done in sub-Saharan Africa, S pneumoniae was found to account for about 25% to >30% of the cases of meningitis in less than 5 years old children, with a case fatality rate of more than 50% [271] . Conservative estimates have put the incidence of invasive pneumococcal disease in The Gambia at 500 per 100,000 in children in their first year of life and 250 per 100,000 in children less than 5 years of age [272] . A recent study in Kenya reported an annual incidence of presentation to the hospital with pneumococcal bacteremia of 597 per 100,000 children younger than 5 years of age [273] . Case fatality rates for invasive pneumococcal disease range from 5% to 20% for bacteremia and from 40% to >50% for meningitis. From 25% to 56% of children who survive meningitis suffer from long-term neurologic sequelae [274].
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.
Among adults in industrialized countries, pneumococcal pneumonia still accounts for at least 30% of all cases of community-acquired pneumonia admitted to the hospital, with a case fatality rate of 11% to 44%. Annual incidence of commmunity-acquired pneumonia in 2002 in the USA was 18.3 cases per 100,000 elderly persons, and the incidence of pneumococcal pneumonia among the elderly population was at least 5.5 cases per 100,000 population [275] . Again, substantially higher incidence rates were reported in blacks than in whites, and even higher rates in native Americans and Alaskan natives [276] . Similarly, a very high incidence rate was reported in the aboriginal Australian population [277] . S pneumoniae also is an underappreciated cause of nosocomial pneumonia in hospital wards and intensive care units as well as in nursing homes and long-term care institutions. Important risk factors are age, chronic heart and lung disease, cigarette smoking, and asplenia [278].
The burden of invasive pneumococcal infections in adults in developing countries is poorly known, mostly due to failure to obtain blood cultures from patients with pneumonia. S pneumoniae has been the leading nonmycobacterial cause of pneumonia among HIV-infected persons both in developed and developing countries [11] [279] [280] . The impact of HIV infection on pneumococcal disease can clearly be evidenced from the clinical study in HIV-infected young adults in Uganda, which reported an annual incidence of 1700 cases of invasive pneumococcal disease per 100,000 population [281] , as well as from an earlier survey among HIV-positive commercial sex workers in Kenya, where annual incidence of pneumococcal disease was found to be 4250 per 100,000 people [282] . HIV-infected children seem to be 20-40 times more likely to contract pneumococcal disease that uninfected children.
Influenza also increases the risk of secondary pneumococcal infection. Based on evidence from past influenza pandemics, the attack rate for secondary pneumococcal pneumonia in a pandemic setting is anticipated to reach 13% [49].
Bacteriology
S. pneumoniae is a Gram-positive encapsulated diplococcus. The external capsular polysaccharide (PS) of the bacterium is the primary factor of virulence, other virulence factors being 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 or 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.
Capsular PS also are the basis for the serotyping classification of the bacterium among 91 serotypes. The distribution of disease-causing serotypes varies between geographic regions and by age and disease within regions. The most common serogroups worldwide are 6, 14, 19 and 23 but some serogroups, such as 1, 5 or 8, contribute much to invasive pneumococcal disease in young children in developing countries. Approximately 90% of the most frequent isolates belong to 23 serogroups or serotypes and have been included in the 23-valent pneumococcal vaccine.
Vaccines
Current S pneumoniae vaccines are based on the use of the bacterial capsular polysaccharides (PS), which induce type-specific antibodies that activate and fix complement and promote bacterial opsonization and phagocytosis [11] [261] . The two types of currently licensed vaccines [283] are the pneumococcal polysaccharide vaccine (PPV), based on purified capsular PS, and pneumococcal conjugate vaccines (PCV), obtained by chemical conjugation of the capsular PS to a protein carrier [284].
23-valent polysaccharide vaccine (PPV23)
The PPV23 vaccine contains 25 ?g of the purified capsular PS from each of the 23 different S pneumoniae serotypes that together account for 90% of cases of severe pneumococcal disease in industrialized countries. Two vaccines are currently manufactured, Pneumovax 23TM by Merck and Pneumo 23TM by Sanofipasteur. Relatively good antibody responses are elicited following a single IM injection in 60-80% of healthy adults and normal children over two years of age. Pneumococcal vaccination of children 2 to 5 years of age was 62% effective in preventing invasive pneumococcal disease due to vaccine serotypes [285].
In a case control study in Connecticut, the effectiveness of pneumococcal vaccination with PPV23 in immunocompetent adults was estimated to be 61% against pneumococcal bacteremia, but in immunocompromised patients this figure fell to only 21% [286] . In spite of such suboptimal immunogenicity, administration of a single dose of PPV23 continues to be recommended for solid-organ transplant recipients [287] . The PPV23 vaccine also is recommended for people over 65 years of age, particularly those living in institutions. Several studies have shown that PPV23 is effective in preventing invasive pneumococcal disease [288] , but it remains unclear whether it has a significant protective effect against pneumonia [289, 290]. A recent meta-analysis concluded that there actually was little evidence of PS vaccine protection against pneumonia among elderly or adults with chronic illness [291] .
In a case control study in Connecticut, the effectiveness of pneumococcal vaccination with PPV23 in immunocompetent adults was estimated to be 61% against pneumococcal bacteremia, but in immunocompromised patients this figure fell to only 21% [286] . In spite of such suboptimal immunogenicity, administration of a single dose of PPV23 continues to be recommended for solid-organ transplant recipients [287] . The PPV23 vaccine also is recommended for people over 65 years of age, particularly those living in institutions. Several studies have shown that PPV23 is effective in preventing invasive pneumococcal disease [288] , but it remains unclear whether it has a significant protective effect against pneumonia [289] [290] . A recent meta-analysis concluded that there actually was little evidence of PS vaccine protection against pneumonia among elderly or adults with chronic illness [291] . Also, PPV23 is unable to elicit immune memory, so that a second dose of vaccine does not boost antibody levels. PPV23 does not provide protection against mucosal infection, and is thus unable to reduce nasopharyngeal carriage of pneumococci. Moreover, studies of PPV23 in adults and children have shown that a state of immune tolerance, or hyporesponsiveness, can develop to repeated PS vaccine exposures [292] . Last, but not least, PPV is poorly immunogenic in less than 2 years old children and is thus inadapted to infants and young children.
On another hand, a number of studies have confirmed the safety of PPV during pregnancy and documented the use of the vaccine for the vaccination of pregnant or breast-feeding mothers for preventing pneumococcal pneumonia in young infants [293] [294].
Pneumococcal conjugate vaccines
Pneumococcal conjugate vaccines (PCVs) are based on the covalent coupling of the capsular PS from diverse S pneumoniae serotypes to a variety of protein carriers. These vaccines elicit higher antibody levels in infants, young children, the elderly and immunodeficient persons than the PPV23 vaccine, as well as significant immune memory resulting in an anamnestic response on subsequent booster immunizations. Moreover, they suppress nasopharyngeal carriage of the pathogen, thus decreasing bacterial transmission in the community and generating herd immunity. Conjugate vaccines immunization followed by PS vaccine boosting might provide a foundation for lifelong protection against pneumococcal disease and/or maintain high levels opsonophagocytic antibody titers in elderly adults while broadening serotype coverage [295] [296].
The first PCV, PrevnarTM or PrevenarTM (Wyeth), was licensed in the USA in 2000 and recommended for routine use in children younger than 2 years of age, to whom it is administered in a 3 doses schedule, when possible in combination with usual routine vaccination, followed by a booster dose at 15-18 months. Alternatively, the vaccine can be administered in a two-dose immunization schedule at 3 and 5 months of age, followed by a booster immunization at 11-12 months of age [297] [298] . The vaccine contains poly- or oligo-saccharides from seven S pneumoniae serotypes (4, 6B, 9V, 14, 18C, 19F and 23F), each conjugated to genetically detoxified diphtheria toxin CRM 197.
Four large clinical trials of the 7-valent PCV7 and of a closely related, unlicensed 9-valent PCV9 in the USA, South Africa, and The Gambia have reported vaccine efficacy of between 77% and 97% against severe invasive pneumococcal disease caused by vaccine serotypes and of 19% to 37% against radiologically confirmed pneumonia [299] [300] [301] [302] . Efficacy of the vaccine against otitis media was reported to be 57% against vaccine serotypes [303] . Introduction of PCV7 in the USA resulted in a dramatic decline in the rates of invasive pneumococcal disease among children <5 years of age, which dropped from 97 cases per 100,000 population during 1998-1999 to 24 cases per 100,000 in 2005; disease caused by vaccine-type strains fell from 80 cases per 100,000 population to 4.6 [304] . A significantly decreased incidence of pneumococcal otitis media and acute bacterial rhinosinusitis was also noted [305] [306] . In children not at high risk for invasive disease, the effectiveness of the full 4-dose schedule vaccine against vaccine serotypes was estimated to be 91%. Substantial protection against invasive pneumococcal disease and clinical pneumonia was also noted in HIV-infected infants [307].
A significant reduction in S pneumococcus disease incidence also was seen in unvaccinated individuals as a result of herd immunity [308] [309] . Thus, in adults 65 years old and older, invasive disease dropped by about one-third since introduction of the conjugate vaccine for children, and a drop of similar magnitude was seen in hospitalizations for pneumococcal bactaeremia [310] . Paradoxically, after 5 years of wide use of Prevnar for infant immunization in the USA, more cases seem to be prevented through the indirect effects of herd immunity than by vaccine-induced immunity in the vaccinees [311].
Additional Phase III clinical trials also have been performed using 9-valent and 11-valent PCVs that are not expected to reach the market. Trial of PCV9 in South Africa on 40,000 subjects showed 83% and 65% efficacy after 2.3 years of follow-up in HIV-infected and uninfected children, respectively. The figures still were 77.8% and 38.8% after 6.16 years of follow-up [312] . In The Gambia, PCV9 reduced radiologically-confirmed pneumonia by 37% and invasive disease caused by vaccine serotypes by 77% [51] . The Gambian trial of PCV9 also showed a 16% reduction in hospital admissions and deaths from any cause in children 3-29 months of age who received the vaccine compared with those who had not received the vaccine. PCV9 could successfully be administered to infants in a two-dose schedule at 2 and 4 months of age followed by boosting at 12 months of age [313].
In a recent cost-effectiveness analysis of PCV7, it was projected that, in the 72 GAVI-eligible countries, pneumococcal vaccination with a conjugate vaccine would prevent between 262,000 and 407,000 deaths in children aged 3-29 months, depending on the level of vaccine coverage, and not counting herd immunity effects [314] . At a price of $5 per dose, the vaccines would be a highly cost-effective purchase. In more affluent societies, where the cost of the vaccine is definitely higher, studies of cost-benefit ratio of large scale PCV vaccination always have been highly positive [315].
These results speak very favorably in favor of the currently available conjugate vaccine and lead to expect an even greater vaccine effectiveness in infants and young children with the eventual licensing and use of the 10-valent (GSK) and 13-valent (Wyeth) conjugate vaccines which are in Phase III clinical trials at this time and are expected to be licensed in the coming years. The currently licensed 7-valent vaccine, PrevnarTM, does not contain some of the serotypes that cause severe disease in developing countries, notably serotypes 1 and 5 [316] . Serotype 1 is the most common among children over 2 years of age in many countries in Asia and Africa [317] . Serotypes 1 and 5 are predominant In Nepal, whereas serotypes 14 and 19 are predominant in Sri Lanka [318] . The new conjugate vaccines will provide more optimal serotype coverage in these countries. 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 [319] [320].
The success of PCV7 has partly been offset by the observation that introduction of PCV can lead to replacement of the vaccine serotypes by other, nonvaccine S pneumoniae serotypes. Carriage of non-vaccine type strains increased among children receiving the PrevnarTM vaccine such that the overall prevalence of pneumococcal carriage was not different in vaccinated and unvaccinated children, new serotypes taking up the mucosal territory vacated by the pneumococcal serotypes included in the vaccine [268] [321] [322] . So far, strain replacement has only had relatively modest effects on disease, except in certain settings [323] . Replacement disease was nevertheless observed in the otitis media trial in Finland, where the vaccine group had 33% more episodes of otitis media caused by serotypes not included in the vaccine [303] . Of positive note was the significant reduction in the disparity in disease rates between black and white children following PCV introduction in the USA [324] . Serotype replacement makes it essential that there be continued monitoring and surveillance of pneumococcal colonization and invasive disease [325].
Protein vaccines
Newer vaccine approaches are been developed, based on the use of conserved external surface proteins such as PspA and PspC, which have a choline-binding function, pneumococcal surface adhesin A (PsaA), a metal-binding transporter, surface proteins PiaA and PiuA, or virulence factors such as pneumolysin or autolysin. Some of these antigens have been identified by a reverse vaccinology approach, including the pneumococcal pilus, a potent immunogen that elicits cross-protection against various S pneumococcus serotypes [326] [327] . These new vaccines would circumvent the complexity of manufacture of conjugate vaccines and be serotype-independent [328] . Several of these candidate vaccines induced protection against systemic challenge in animal models [329] . PspA and PsaA have been tested in Phase I trials and found to elicit protective anti-S pneumoniae antibodies [330] [331] [332].
Two other surface proteins, BVH 3 and BVH 11, have been identified that can elicit protective anti-pneumococcal antibodies in the mouse model, and a recombinant 100 kD fusion protein, BVH3/11V, was tested by ID BioMedical in a Phase I trial 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. The advantage of this approach is that the BVH proteins seem to be conserved among the 90 serotypes of S pneumoniae and therefore could constitute a universal pneumococcal vaccine [333].