Pneumococcal Vaccines: The Impact of Conjugate Vaccines

This chapter reviews some of the major events in the history of Streptococcus pneumoniae—events that have led to our modern understanding of the pathogenesis, diagnosis, treatment, and prevention of pneumococcal disease. Manifestations of primary infection involved the respiratory tract, including pneumonia, acute purulent tracheobronchitis, otitis media, and acute purulent sinusitis. Pneumococcal pneumonia was a driving force behind clinical and microbiologic research. Until the 1880s and 1890s, pneumonia had been regarded as a respiratory affliction rather than an infectious disease, with no specific therapy other than supportive care and various ineffectual potions and poultices. To provide serum treatment outside the academic medical centers, an ambitious new infrastructure of pneumonia control programs was developed with the intention of providing serum, usually at no cost, to treat the largest number of people possible. The general impression was that penicillin had conquered the pneumococcus: it eliminated the need for serotyping, for serum therapy, and for the further development of vaccines. The reality was that the very young and the very old continued to have high rates of mortality. Capsular type switching, originally observed in experiments with mice, has now been implicated in humans and may play an important role in the expansion of nonvaccine serotypes.

By the year 1800, 200 years ago, the smallpox vaccine had established the principle of preventing serious disease by active immunization. In the 1940s, these whole-cell vaccines were supplanted by the next generation of pneumococcal vaccines, which consisted of the purified capsular polysaccharides (PS) of the bacteria. As early as 1891, animal experiments showed that killed pneumococci elicited protective immunity to subsequent challenge with virulent bacteria. The influenza pandemic of 1918 to 1919, together with the First World War, created a situation conducive to a highly increased incidence of pneumococcal pneumonia. Researchers administered a trivalent vaccine to 12,519 men in training at the United States. The results of the trials with the killed whole-cell vaccines were considered very encouraging at the time. Even a 30% reduction in numbers of cases of lobar pneumonia was welcomed because there were no alternative prevention measures. The experimental research of Avery, Heidelberger, and Goebel in the 1920s formed the essential links between pneumococcal capsules, their serotype specificity, and the identity of the capsules with PS that could be isolated from the bacterial cultures by chemical means. Despite recommendations for routine of pneumococcal immunization at-risk populations, the uptake of the vaccine was relatively slow. Nearly 10 years after the licensure of PS vaccine in the United States, only 10% of persons for whom the vaccine was recommended had ever been immunized. Protection against pneumococcal bacteremia, provided by the 23-valent PS vaccine, wanes over a period of 3 to 5 years, particularly in older people.

The Streptococcus pneumoniae capsules form a diverse group of polymers that are the most important and most recognized virulence factor of the organism. This chapter provides an overview of recent advances regarding the genetics, biosynthesis, and chemistry of pneumococcal capsules. Recently, a new era in differentiating pneumococcal isolates was initiated when, for the first time, preparations of monoclonal antibodies were used to describe the 91st serotype, a “subspecies” of serotype 6A now dubbed 6C. Early work led to the conclusions that genes required for capsule synthesis in S. pneumoniae were closely linked on the chromosome but that genes outside this region were also important. The identification and assignment of cpsABCD (wzg, wzh, wzd, and wze) and any nonhousekeeping sugar biosynthesis genes are fairly straightforward, as their sequences are highly conserved. Capsule synthesis requires the production of nucleotide sugar precursors, the synthesis of which relies on enzymes encoded both within and outside the capsule genetic loci. Polymer synthesis likely initiates on undecaprenyl-P (C55-P or the bactoprenyl-P), the same lipid acceptor used to initiate the synthesis of peptidoglycan and teichoic acids. In S. pneumoniae, the acceptor is a polyprenyl-P whose size and properties are consistent with undecaprenyl-P. A better understanding of the regulation of capsule expression and chain length is critical not only in the isolation of polymers for vaccine preparations but in the development of a full picture of pneumococcal virulence, as reduced capsule levels occur during the colonization of the nasopharynx while elevated levels are essential for systemic disease.

Pneumococcal disease results when colonizing pneumococci in the nasopharynx successfully invade sterile sites. The first half of this chapter focuses on individual disease models and provides general descriptions of the commonly used models. It also discusses considerations important to the application of these models to studies of vaccine antigens and some of the pros and cons of each model. The latter half of the chapter presents experimental considerations that relate to animal models in general: the need for multiple models, inclusion criteria for experiments, and statistics. Bacteremia is a potential outcome in virtually all models of pneumococcal infection and is easily evaluated. The classic mouse model for assessing protective immunity has been the use of otherwise fatal infections following intraperitoneally (i.p.) challenge to detect the effects of active immunization or passive antibodies. As neonates and infants are a major target for pneumococcal vaccination, the murine model of intranasal challenge with aspiration has been adapted to 1-week-old mice, whose immune system corresponds to that of the human neonate, and 3-week-old mice, whose immune system corresponds to that of the human infant. Otitis media models in several animal species have been developed to evaluate vaccine effects. The classic model of otitis media was developed using the chinchilla and has been well reviewed by Giebink. Advantages and limitations of the various animal models of invasive pneumococcal diseases emphasize the importance of a careful selection of animal models to address different scientific questions.

This chapter describes existing animal models of colonization and reviews what these various models have taught us about pneumococcal carriage. The most widely studied model of pneumococcal colonization is the mouse model. Infant rat models of pneumococcal colonization have also been described in several studies. A buccal mucosa model was also developed to evaluate the impact of ambient temperatures on pneumococcal colonization. The major limitation of chinchilla model is the relative lack of chinchilla reagents, as well as the expense. Animal models have provided information about the contribution of specific bacterial components to colonization, the first step in the pathogenesis of all pneumococcal disease. Different laboratories have used different mouse strains, which often vary in susceptibility to pneumococcal colonization and disease. Murine models of pneumococcal colonization have helped enhance the understanding of acquired immunity to pneumococcal colonization. The infant rat model of intralitter spread was used to evaluate the impact of systemic anticapsular antibodies in the prevention of pneumococcal colonization. The administration of bacterial polysaccharide immune globulin (from hyperimmune sera obtained from adults immunized with pneumococcal, Haemophilus influenzae type b, and meningococcal pure-polysaccharide vaccines) to infant rats reduced the likelihood of pneumococcal colonization by about 50%. The development of purified-protein vaccines or whole-cell vaccines, however, faces several challenges, including the inherent difficulty of studying colonization in animals that normally do not carry Streptococcus pneumoniae in their respiratory trees.

Infections with polysaccharide (PS)-encapsulated extracellular bacteria are a major source of global morbidity and mortality among infants, as well as the elderly and immunosuppressed individuals. An understanding of the immunological basis of glycoconjugate interactions is still emerging but is already helping shape strategies to improve conjugate responses. Genetic factors in humans that are known to influence susceptibility to infection with the pneumococcus may also provide a clue to the key factors associated with the immune response to PS antigens. The covalent linkage of PS antigens to immunogenic proteins capable of recruiting CD4+ T-cell help to produce conjugate vaccine, first described in the 1930s, results in the elicitation of protective, high-titer-IgG anti-PS responses and the generation of immunologic memory, as well as immunogenicity in the infant host. Conjugate vaccines used clinically are produced by employing a limited number of carrier proteins (e.g., tetanus toxoid (TT), diphtheria toxin or its genetic mutant form CRM197, the outer membrane protein complex [OMPC] of Neisseria meningitidis, and more recently, protein D derived from Haemophilus influenzae). Alum acts to promote immunity, likely by serving as a depot for antigen, thus enhancing uptake by antigen-presenting cells (APCs) for presentation of the protein component to CD4+ T cells. Effective intranasal immunization appears to require a strong mucosal adjuvant, of which there are several candidates potentially suitable for human use (e.g., CpGODN, LT, and RhinoVax).

This chapter briefly reviews some salient features of complement-mediated opsonophagocytosis. It discusses the inhibitory mechanisms attributed to specific pneumococcal proteins and polysaccharides, and reviews the human immunodeficiencies of particular relevance to complement-mediated killing of Streptococcus pneumoniae. Traditionally, the binding of complement protein C1q to the Fc portion of either pentavalent immunoglobulin M (IgM) or IgG initiates the classical complement pathway. The mannose-binding lectin (MBL) complex, composed of three to six subunits of MBL, preferentially recognizes mannose, mannans, and N-acetylglucosamine (GlcNAc). The integrity of the alternative complement pathway is thought to be critical for those hosts lacking type-specific anticapsular antibodies or proteins required for classical pathway activation (e.g., C2). Comparative studies of pneumococcal bacteremia in C57BL/6 mice genetically deficient in C1q, factor B (encoded by Bf), C3, C4, or natural IgM pointed to the importance of the classical complement pathway in the absence of IgG. Exponentially growing wild-type S. pneumoniae strains of serotypes 3, 4, and 14 are able to degrade both α- and β-chains of purified human C3 in the absence of other serum proteins. The release of pneumolysin (Ply) during autolysis leads to the activation of the classical complement pathway, possibly through the binding of the Fc portion of IgG. At least six pneumococcal proteins—pneumolysin, PhpA, Hic, PspC (CbpA/SpsA/PbcA), PspA, and CppA—are now known to interfere with complement-mediated opsonization and phagocytic killing.

Invasive pneumococcal disease (IPD) in children persists as a major cause of morbidity and mortality throughout the world, despite the introduction of antimicrobial therapy. Following colonization, invasive disease may result from dissemination from a respiratory focus, such as in the case of acute otitis media, sinusitis, or pneumonia, or from dissemination from an unidentified focus to the central nervous system, pleural space, periorbital tissue, bone, or joint. The major clinical syndromes are reflective of the pathogenesis as either (i) bacteremia with or without focal complications or (ii) contiguous spread from the nasopharynx to mucosal surfaces of the lung and middle ear, resulting in pneumonia and acute otitis media, respectively. A temperature greater than 39ºC at follow-up is the best correlate of whether a given child is likely to have persistent bacteremia or a new focus of infection. Complications such as meningitis, pneumonia, cellulitis, or periorbital cellulitis are most common. The role of Streptococcus pneumoniae compared to that of other bacterial pathogens, especially Haemophilus influenzae and Neisseria meningitidis, has been reported in numerous cross-sectional studies globally. Friedland and Klugman observed that 80% of children with penicillin-nonsusceptible strains causing pneumococcal meningitis had an unsatisfactory outcome when treated with chloramphenicol compared to 33% of children with penicillin-susceptible types of pneumococcal disease. Preventative measures such as vaccination will contribute substantially toward attaining the United Nations millennium goal of reducing childhood mortality by two-thirds in 2015 compared to 1990 levels.

Rates of early mortality, within the first week after the onset of illness, have remained high for over 40 years, suggesting that, despite the availability of potent antimicrobials and intensive care support, prevention must be the keystone of the effective control of pneumococcal disease. A multivariate analysis of 129 adults hospitalized with community-acquired pneumococcal pneumonia in Edmonton, Canada, identified a history of smoking, fever, myalgia, chest pain, altered mental state, abdominal pain, and tachycardia as significant predictors of bacteremia. The presence of radiographic findings is key in establishing the diagnosis of pneumonia. Physicians may overdiagnose pneumonia based on patient histories and physical findings alone. With Gram staining and culture of expectorated sputum, rates of pathogen detection in comprehensive epidemiologic studies of CAP are only 30 to 50%, often with paired acute and convalescent serology for atypical organisms. The isolation of Streptococcus pneumoniae from cultures of specimens from normally sterile sites is relatively insensitive. Pneumococcal surface adhesin A (PsaA) is a conserved and highly immunogenic protein of S. pneumoniae expressed at the cell surface in all 90 pneumococcal serotypes. Underlying malignancy (both pulmonary and extrapulmonary) and the absence of fever also predicted lethal infection in most of the studies in which the variables were examined. The goal for clinicians and patients is improved survival, the more rapid resolution of disease and thus decreased need for admission and decreased length of hospital stays, and decreased cost.

This chapter summarizes the relative prevalences of the most common serotypes prior to and following the introduction of the heptavalent pneumococcal capsular polysaccharide vaccine (PCV-7). It provides thoughts about the selection of serotypes for future-generation conjugate vaccines. A remarkable feature of the global epidemiology of pneumococcal carriage is the consistency of the dominant carriage serotypes in very different environments and at different times. Invasive disease potential, or invasiveness, is a measure of the ability of pneumococci to progress from nasopharyngeal carriage to invasive disease in humans. It differs from virulence in that the latter is often used to describe the ability of a pathogen to cause disease in laboratory animals. The 11-valent formulation prevented vaccine-related otitis media and was also shown to elicit antibodies with functional immunogenicity (opsonophagocytic activity) against 6A comparable to that seen with PCV-7. The incidence of invasive pneumococcal disease (IPD) due to vaccine serotypes has decreased substantially since the introduction of PCV-7 in the United States, in vaccinated children as well as all other age groups, indicating that pneumococcal transmission was interrupted as a result of the reduction in carriage in the vaccinated pediatric population. For mucosal disease, otitis media and nonbacteremic pneumonia, it is less clear which serotypes it would be most valuable to add since there appear to be less clearcut differences in invasiveness among serotypes. The only certain way of preventing mucosal disease is to sterilize the nasopharynx with respect to pneumococci.

Most bacteria that cause invasive disease, especially those that cause bacteremia, are protected from innate host immunity because they express polysaccharides (PSs) on their cell surfaces. The bacterial capsular PSs are composed of thousands of carbohydrate repeat units resulting in polydisperse polymers that can have molecular masses into the millions of daltons. Multivalent pneumococcal conjugate vaccines present additional complexities with regard to their syntheses, as each serotype is chemically distinct, effectively requiring the optimization of the manufacture of seven or more individual vaccines. Various proteins and peptide molecules have been demonstrated, in preclinical studies, to be effective carriers for PSs and oligosaccharides, but only a small number of protein carriers have been investigated in humans. Surface-exposed proteins and toxins from human pathogenic bacteria have been used as carriers, as they contain one or more of the T-cell epitopes. In order to convert PSs into T-cell-dependent antigens, the protein must be chemically linked to the carbohydrate; that is, there must be covalent links between the two components. Protein solubility at the required pH, concentration, and temperature is an important determinant of the suitability of a protein for use in a particular conjugation scheme. The conjugation step is generally the slowest chemical step and risks damage to the components. Efforts should be made to improve conjugation efficiencies to levels at which the residual unconjugated components, especially free PSs, do not interfere with inductions of protective immune responses. The use of efficient, mild conjugation chemistry would allow for higher yields of vaccine.

The first industrially produced pneumococcal polysaccharide (PS) vaccine was made under contract from NIAID to Eli Lilly and Company. The source of the strains for this vaccine was the American Type Culture Collection (ATCC), which in essence generated, characterized, and maintained the master seeds. Pneumococcal identity testing should include analyses of colony morphology, Gram staining, and the ability of the organism to ferment insulin and to be lysed in the bile solubility test, as well as its sensitivity to optochin. Personnel involved with production and control should be satisfactorily trained on the standard operating procedures for dealing with emergencies arising from accidental spillage, leakage, or other possible events that may disseminate pneumococcal organisms. All these personnel should maintain records of this training and include records of being vaccinated with a licensed pneumococcal vaccine. PS identification can take the form of a serological method using type-specific antisera. The assay should not only identify the specific type of the PS but also rule out that the PS reacts with any of the other sera, thus demonstrating specificity. Nuclear magnetic resonance is being employed on an ever-increasing scale, not only to identify, characterize, and quantify the particular PS but also to monitor each lot for various impurities, such as the most frequent contaminant, the C-polysaccharide. The efficacy and effectiveness of pneumococcal conjugate vaccines have been difficult to establish with well-controlled clinical trials and will become more complicated in the future.

This chapter provides European Union (EU) and U.S. regulatory perspectives for the licensure of pneumococcal conjugate vaccines indicated for the pediatric and adult populations. In the United States, vaccines are regulated as biological products by the Center for Biologics Evaluation and Research of the U.S. Food and Drug Administration (FDA). For certain new drugs and biological products to prevent or treat serious or life-threatening illnesses, the FDA has published final regulations under which the agency would accelerate the approval of these products. Since the mid-1990s, a new registration system in the EU has governed the granting of marketing authorizations, which manufacturers must obtain for any medicinal product they intend to market, including a vaccine. Potential applicants for new pneumococcal conjugate vaccines indicated for children and adults are expected also to use the EU centralized procedure. The postmarketing evaluation of the safety of Prevnar conducted by the applicant as a postmarketing commitment included an observational study evaluating the safety of Prevnar in approximately 60,000 infants. An assessment of the benefit of a new conjugate vaccine comprising fewer serotypes than the 23vPS vaccine is complicated by the loss of protection afforded by the additional serotypes in the polysaccharides (PSs) vaccine. To facilitate the clinical development of new pneumococcal conjugate vaccines, a series of global and national workshops and meetings were held in consultation with the World Health Organization (WHO) and particular advisory bodies to formulate licensure criteria.

This chapter provides a historical overview of the ligand-binding assays currently recommended by the World Health Organization (WHO) to evaluate immune responses to polysaccharide (PS)-based vaccines against Streptococcus pneumoniae. These assays are designed to quantitatively measure serotype-specific antibody concentrations in the sera of subjects participating in treatment and control groups in clinical trials. The chapter discusses the utility of other types of pneumococcal immunoassays and provides our perspective on critical parameters for maintaining a bridge to previously established serologic correlates associated with the vaccine efficacy. The first pneumococcal vaccines were introduced in the 1940s for adults and included serotype-defining capsular PSs purified from four to six serotypes. The use of highly purified water for injection is recommended for buffers to prevent background noise in the enzyme-linked immunosorbent assays (ELISAs). The accurate measurement of pneumococcal PS (PPS)-specific antibodies is challenging because naturally occurring antibodies in sera can bind to cell wall PS (CPS) as well as to other covalently bound and copurified antigens of S. pneumoniae. While the ELISA is well suited for screening large numbers of specimens against a single analyte, a separate assay is required for each pneumococcal serotype. The current ELISAs provide a solid foundation for the future development, validation, and interlaboratory standardization of new ligand-binding assays for such applications.

This chapter reviews opsonophagocytosis assay (OPA) methods for pneumococcal antibodies and the experience with OPA in clinical trials, stressing the need for further standardization of OPA. In the case of pneumococcal conjugate vaccines (PCV), studies suggest that the vaccine-induced antibodies primarily help phagocytes ingest and kill pneumococci. This mechanism of host protection is described in this chapter. Given that opsonophagocytosis is essential in host defense against pneumococci, pneumococcal vaccines are designed to induce opsonic antibodies. The chapter describes two different types of clinically available vaccines and the various laboratory measures that were used to estimate their protective efficacy. The PCV becomes T cell dependent, induces B-cell memory, and can elicit anti-polysaccharide (PS) antibodies in young children. OPA is the most desirable surrogate assay for measuring pneumococcal vaccine-induced immunity. This chapter uses a historical approach to describe the various OPA methods. However, this classical approach is very tedious to perform, primarily due to the counting of colonies. Consequently, many researchers have developed various alternative OPA methods requiring no colony counting, including a radiolabeled-bacterium uptake assay, a fluorescent-bacterium uptake assay, chemiluminescence, and an oxidative-burst generation assay. Clinical studies have measured opsonophagocytic antibody activity in young children and adults. Due to the past methodological difficulties, these studies tended to be small in size. They are nevertheless informative and are thus discusses in this chapter. Finally, the chapter finally talks about future activities for OPA. OPA will likely become the basis for evaluating the efficacy of protein vaccines.

Several investigational pneumococcal conjugate vaccines (PCVs) have been evaluated in phase II immunogenicity and reactogenicity studies with infants. PCVs prevent mucosal infections (acute otitis media [AOM] and colonization), and thus, some groups have also made efforts to characterize the mucosal immune response after vaccination in the hope of finding serological correlates of mucosal protection. High-avidity antibodies can have greater functional capacity than low-avidity antibodies, and the increase in avidity is regarded as a marker of the development of immunological memory. The South African follow-up study suggests that HIV-infected children would benefit from a booster immunization while non-HIV infected children may have persistent protection due to natural boosting via pneumococcal colonization or cross-reacting antigens. The geometric mean concentrations (GMCs) of antibodies against diphtheria toxoid were generally higher in the group given PCV7-CRM in studies with both wP (15)- and acellular pertussis protein (aP)-containing combinations. In a number of PCV7-CRM trials, the response to a primary series of doses of a diphtheria-tetanus-pertussis combination vaccine (DTP) alone has been compared to the response to DTP coadministered with PCV7-CRM. PCV11-D-T given to infants at 18 weeks of age was able to boost the diphtheria toxoid and TT responses of Filipino infants who had received a DTwP vaccine at 6, 10, and 14 weeks. In a study of PCV11-D-T, a formulation with aluminum hydroxide induced higher GMCs of antibodies, but differences were not statistically significant. In general, there were no significant differences in the avidities of antibodies.

During the past decade, a number of studies have evaluated the immunogenicity and safety of various pneumococcal conjugate vaccine (PCV) formulations in immunocompromised and immunocompetent adults. This chapter summarizes the findings from evaluations of PCVs in immunocompetent adults. Two early studies evaluated the immune response to monovalent PCV formulations by using radioimmunoassays, but since that time, all clinical studies of PCVs in immunocompetent adults have assessed the immunoglobulin G (IgG) antibody response by using enzyme-linked immunosorbent assays (ELISAs) and, in some cases, additional immunologic assays, such as the opsonophagocytic assay (OPA). Two studies were conducted among different populations and used different laboratories for the ELISA, which have been standardized to give similar results in different laboratories. The geometric mean concentrations (GMCs) are strikingly similar, suggesting that the administration of pneumococcal polysaccharide vaccine (PPSV) may induce hyporesponsiveness to PCV which persists for at least 5 years. This chapter defines a booster response simply as one involving significantly higher antibody levels in PCV-primed individuals than in unprimed individuals following the administration of the standard licensed dose of PPSV. PCVs are well tolerated in immunocompetent adults. The experience with PCV in adults as described in published reports is limited, and conclusions about the immunogenicity and safety of PCVs must be viewed as preliminary and subject to confirmation in larger, well controlled studies.

In the developing world, human immunodeficiency virus (HIV) is a major contributor to adult pneumococcal disease, while the contributions of diabetes, chronic cardiopulmonary disease, and the other high-risk conditions are unknown but likely to be significant and increasing. The assessment of vaccine efficacy for many of the less frequent immunocompromising conditions in conventional randomized controlled trials with clinical end points is impractical, and thus, immunogenicity studies combined with case control or postmarketing surveillance studies are the most practical way to assess vaccine effectiveness. Several studies evaluating pneumococcal conjugate vaccine (PCV) in HIV-infected infants and older children have been published, including the only clinical efficacy trial of the nine-valent PCV conjugated to CRM, a nontoxic mutant diphtheria toxin (PCV9-CRM), in South Africa. Children with sickle-cell diseases (SCD) in the United States and Western Europe are particularly susceptible to pneumococcal infection. Several investigators have reported failure to elicit protective responses to pneumococcal polysaccharide vaccine (PPSV) when administered prior to 2 years after the transplant. Chronic obstructive pulmonary disease (COPD) increases the risk of invasive pneumococcal disease (IPD) to up to 10 times that of the age-matched population.

The pneumococcus is one of the most common etiologies of respiratory tract infections like sinusitis, otitis media, and pneumonia, as well as nonrespiratory infections like meningitis, sepsis, and bacteremia. The authors presume the existence of special niches for pneumococcal attachment and the subsequent establishment of colonization, processes in which the newly arriving pneumococcus has to evade the local host defenses and compete with the resident polymicrobial flora, including other strains of pneumococci. Pneumococcal colonization induces a variety of immune responses in humans, including the production of antibodies directed at both surface proteins and the PS capsule. This chapter defines the direct effect of vaccine on carriage as those effects observed among the vaccinated individuals These effects include the impact on vaccine type (VT) carriage, vaccine-associated serotype carriage, nonvaccine type (NVT) carriage, and nonpneumococcal NP carriage. Haemophilus influenzae and Moraxella catarrhalis are common constituents of the microflora of the human nasopharynx and, after pneumococci, are the most common causes of upper respiratory infection; therefore, they could be expected to be affected by changes in pneumococcal colonization. The experience accumulated from the large-scale use of pneumococcal conjugate vaccine (PCV) has also allowed an analysis of the immunization schedule. The direct effect of PCV on pneumococcal carriage is to reduce vaccine serotype and increase nonvaccine serotype colonization among vaccinated children. There are three phases of a nasopharyngeal colonization episode: acquisition, the period of colonization, and clearance of the organism.

Acute otitis media (AOM) is one of the most commonly diagnosed infections of childhood in the industrialized world. The pathophysiology of mucosal pneumococcal infections such as AOM is different from that of invasive pneumococcal diseases (IPD) such as bacteremia and meningitis. A number of studies have evaluated the potential of pneumococcal conjugate vaccines (PCV) to prevent AOM and its complications. When evaluating the results of these studies, it is important to make a distinction between studies in which the subjects were vaccinated in early infancy and studies that enrolled older children with a history of previous attacks of otitis media. In an uncomplicated case of AOM, the signs and symptoms of the acute infection are usually relieved within a few days after the onset of the attack and the potential initiation of antimicrobial therapy, and the middle ear effusion resolves within a few weeks. The reduction of recurrent AOM, tympanostomy tube placements, and otitis media with effusion (OME) demonstrated in the PCV otitis media efficacy studies indicates that PCV may have the strongest impact on complicated AOM. New PCV providing improved efficacy against pneumococcal serotypes included in the current vaccines and broader protection against the most relevant pneumococcal serotypes and nonpneumococcal bacterial pathogens such as Haemophilus influenzae would have a greater impact on AOM and its sequelae than current PCV and may even prevent this microbiological shift.

This chapter reviews the results of four trials to study efficacy of pneumococcal conjugate vaccine against invasive pneumococcal disease (IPD) and explores the protection achieved against aggregate and individual serotypes using the common end point of invasive pneumococcal disease (IPD) in all the four trials. It also discusses these results in terms of the different populations at risk and the schedules of vaccination. Children initially randomized in California received oral polio vaccines and diphtheria-tetanus whole-cell pertussis (DTwP) vaccines, while children randomized later received inactivated polio and diphtheria-tetanus-acellular pertussis (DTaP) vaccines; children in an American Indian trial received inactivated or oral polio and DTaP vaccines. Meta-analyses of results were performed from intent-to-treat analyses, modified to include children who received at least one dose of vaccine or placebo. The demonstration of substantial conjugate pneumococcal vaccine efficacy in large clinical trials in four disparate regions of the world encourages the view that the vaccine is likely to prevent IPD in most countries in which vaccine serotypes are an important cause of IPD among infants. Pneumococcal conjugate vaccine has been considered as a probe to determine the burden of disease due to pneumococci in contexts such as pneumonia, and has greatly reduced the burden of IPD due to vaccine serotypes in the United States. The introduction of vaccine requires well-designed surveillance studies to understand the impact of the vaccine on the range of disease in populations in which it is introduced.

The World Health Organization (WHO) clinical criteria for managing acute respiratory tract infections are sensitive for detecting episodes of severe pneumonia and have been useful in improving the management of childhood pneumonia in developing countries and contributing to the reduction of childhood mortality. The timing of the chest radiograph in relation to the onset of the lung infection, the initiation of antibiotics, and the immune response being mediated by the host may therefore influence the radiological presentation associated with bacterial pneumonia. Comparing the estimates of the efficacy of pneumococcal conjugate vaccine (PCV) from different studies provides insight into the global potential of conjugate vaccines to prevent pneumococcal pneumonia, although the findings of such an undertaking need to be interpreted with caution. A summary of conjugate pneumococcal vaccine efficacy (VE) and burdens of pneumonia prevented in efficacy trials in the United States, South Africa, and The Gambia is provided in this chapter. Despite the variation in estimates of vaccine efficacy against radiologically confirmed pneumonia, the estimates of the efficacy of PCV in reducing the incidence of clinically diagnosed lower respiratory-tract infection (LRTI) were almost identical (efficacy, 6.0 to 7.0%) among the studies for non-HIV-infected low-risk children. The effect that the introduction of PCV would have on the epidemiology of pneumococcal pneumonia in developing countries may be truly appreciated only following the widespread use of the vaccine in such countries.

This chapter discusses the possible immune measurements that could be used to develop a correlative model, the functional forms of statistical models that have been used, and the results of correlative models for invasive pneumococcal disease (IPD), acute otitis media (AOM), pneumonia, and colonization. The most common immune measurement that is used in the development of protective correlates is the enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) class anticapsular polysaccharide antibodies. Generalization to other polysaccharide-based conjugate vaccines regardless of the carrier protein(s) is most likely acceptable, but the models have uncertain validity for nonconjugate pneumococcal vaccines that are protein or polysaccharide based or for populations that differ in important ways from those studied in the clinical efficacy trials, such as infants infected with human immunodeficiency virus. The probability of acquisition as a function of IgG antibody concentration was modeled using logistic regression. Only vaccine serotypes 9V, 14, 19F, and 23F were modeled because of the limited number of acquisition events for the other serotypes. In a separate analysis, serotype 6A was modeled using the immune responses to 6B. The antibody levels needed to protect against IPD, AOM, and colonization apparently differ. Higher levels are required for protection against AOM and colonization than for protection against IPD.

This chapter reviews both the direct and indirect effects of the introduction of pneumococcal conjugate vaccine into routine use. At this time, available data on vaccine impact are primarily from the United States, reflecting the timing of vaccine introduction. Reports from several sources indicate that the routine use of pneumococcal conjugate vaccine had a profound effect on invasive pneumococcal disease (such as bacteremia, bacteremic pneumonia, and meningitis) in children and that the effect occurred quickly following introduction. The shortages of pneumococcal conjugate vaccine that occurred between 2001 and 2004 meant that many children received an abbreviated two-dose series, received the primary three-dose series without the fourth (booster) dose, or experienced delays in the scheduled administration of doses. Pneumococci are generally transmitted from persons carrying pneumococci in the nasopharynx to others who become carriers; a small percentage of the new carriers will go on to develop disease. The reduction in carriage of vaccine serotypes in children who have received pneumococcal conjugate vaccine means that fewer vaccine serotype pneumococci are circulating among families, in day care centers, and in the community. Conjugate vaccines as currently designed can protect against only a limited number of the 90 pneumococcal serotypes. Data on vaccine impact on carriage and disease following routine introduction have added a wealth of information on top of that learned from clinical trials.

The fact that vaccinating infants and young children reduced drug-resistant Streptococcus pneumoniae (DRSP) disease and the carriage of pediatric DRSP serotypes in adults serves as the most compelling and definitive proof that children are responsible in a large part for the transmission of DRSP in the community. In a study to find out the efficacy of the conjugate pneumococcal vaccine against pneumococcal invasive disease caused by DRSP, 19,922 infants received pneumococcal conjugate vaccine (PCV) 9 and 19,914 received a placebo. Another study conducted by the Centers for Disease Control and Prevention (CDC), used laboratory-based active surveillance in multiple representative areas in the United States (the Active Bacterial Core Surveillance) to measure invasive diseases caused by DRSP from 1996 through 2004. The study by Byington and coworkers suggests that invasive pneumococcal infections with nonvaccine serotypes that are nonsusceptible to penicillin are increasing. The changes in proportions of pathogens isolated in cases of severe and refractory AOM before (1992 to 1998) and after (2000 to 2003) the introduction of universal vaccination in rural Kentucky were documented. The proportion of S. pneumoniae isolates decreased from 160 of 336 (48%) to 26 of 83 (31%) and the proportion of H. influenzae isolates increased from 137 of 336 (41%) to 46 of 83 (56%). Since antibiotic use selects for and promotes antibiotic resistance among S. pneumoniae strains, an important question is whether the use of PCVs can reduce antibiotic use.

This chapter reviews key concepts in pharmacoeconomics and the pharmacoeconomic literature pertaining to pneumococcal conjugate vaccine (PCV), with an emphasis on recent work and future advances. A cost minimization analysis assumes that all interventions being analyzed result in equal health outcomes and that the primary consideration is which alternative results in lower net costs. Cost-effectiveness analyses and cost-utility analyses are used predominantly in vaccine-related pharmacoeconomic evaluations. Pharmacoeconomic evaluations of pneumococcal vaccine’s value are built upon models of pneumococcal disease burden. In order to estimate the value for money represented by the introduction of PCV, epidemiologic data on pneumococcal disease incidence need to be integrated with demographic data from the population of interest to develop a proper understanding of the numbers of cases of disease, death, and disability resulting from pneumococcal infection. Most pharmacoeconomic evaluations assumed that PCV prevents invasive pneumococcal disease, pneumonia, and otitis media. One of the greatest challenges in modeling the economic value of PCV lies in developing estimates of pneumonia incidence that are (i) in accord with the vaccine efficacy data available from clinical trials and (ii) appropriate to the population being modeled. The most common direct non-health care cost included in the studies was the value of caregiver time spent tending to sick children.

This chapter reviews some of the specific challenges to the introduction of pneumococcal conjugate vaccines into the developing world and ways in which these challenges may be met. In many developing countries, the epidemiology of pneumococcal disease differs from that in industrialized countries in ways that may influence both the uptake of the vaccine and the overall health impact of its widespread use. Coincidental malaria is likely to be more of a problem for programs that aim to vaccinate older children (e.g., catch-up campaigns). In areas where malaria is seasonal, it would be prudent to conduct any catch-up campaigns outside of the period of maximum malaria transmission to avoid this potential effect. Malnutrition, low birth-weight, and anemia may be anticipated to diminish the immune response to pneumococcal conjugate vaccines. The introduction of new vaccines, such as pneumococcal conjugate vaccine, provides opportunities as well as challenges for the immunization and health systems. Innovative mechanisms of financing like the Advance Market Commitment (AMC) show the ability of vaccines to generate this kind of change. Success will require continued efforts to increase the value assigned to vaccines by donors, developing countries, and individual citizens so that people and governments are prepared for prices of dollars, not pennies, per dose.

The development, manufacture, and administration of pneumococcal polysaccharide vaccine (PPSV) and pneumococcal conjugate vaccine (PCV) have provided significant public health benefit, and these vaccines continue to be important tools in the battle against the pneumococcus. The serotypes that are weak immunogens are also more often associated with antibiotic resistance. If such common-protein vaccines are successfully developed, they could have a number of advantages over the currently available capsular polysaccharide (PS)-based vaccines. The injection of purified pneumolysin (Ply) into rat lungs induces severe lobar pneumonia, indistinguishable histologically from that seen when virulent pneumococci are injected. Pneumococcal surface protein A (PspA) is one of the best-characterized members of the choline-binding protein (CBP) family and has strong credentials as a vaccine antigen. It is found on the surfaces of all pneumococci and has a proven role in the pathogenesis of disease, as evidenced by the significantly reduced virulence of defined PspA-negative pneumococci in animal models. Studies of the vaccine potential of PspA have extended to human trials, and immune sera from volunteers immunized with a family 1 PspA fragment reacted with 37 different Streptococcus pneumoniae strains belonging to diverse capsular and PspA types. The immunization of mice with pneumococcal surface protein C (PspC) is highly protective against intravenous or intraperitoneal challenge with S. pneumoniae. One study has shown that parenteral immunization of mice with purified PsaA in the presence of strong adjuvants elicits significant protection against systemic challenge with S. pneumoniae.