The host immune dynamics of pneumococcal colonization: implications for novel vaccine development.

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The host immune dynamics of pneumococcal colonization: Implications for novel vaccine development a

M Nadeem Khan & Michael E Pichichero

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Center for Infectious Diseases and Immunology; Rochester General Hospital Research Institute; Rochester, NY USA Published online: 10 Feb 2015.

Click for updates To cite this article: M Nadeem Khan & Michael E Pichichero (2014) The host immune dynamics of pneumococcal colonization: Implications for novel vaccine development, Human Vaccines & Immunotherapeutics, 10:12, 3688-3699, DOI: 10.4161/21645515.2014.979631 To link to this article: http://dx.doi.org/10.4161/21645515.2014.979631

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REVIEW Human Vaccines & Immunotherapeutics 10:12, 3688--3699; December 2014; © 2014 Taylor & Francis Group, LLC

The host immune dynamics of pneumococcal colonization: Implications for novel vaccine development M Nadeem Khan and Michael E Pichichero* Center for Infectious Diseases and Immunology; Rochester General Hospital Research Institute; Rochester, NY USA

Keywords: colonization, immunity, Streptococcus pneumoniae, T cells, vaccines

Downloaded by [University of Connecticut] at 15:10 12 April 2015

Abbreviations: IPDs, invasive pneumococcal diseases; MHC, major histocompatibility complex; NP, nasopharynx; OPAs, opsonophagocytic antibodies; PcpA, pneumococcal choline-binding protein A; PPS, pneumococcal polysaccharides; PPVs, pneumococcal polysaccharide vaccines; WCV, whole cell vaccine.

The human nasopharynx (NP) microbiota is complex and diverse and Streptococcus pneumoniae (pneumococcus) is a frequent member. In the first few years of life, children experience maturation of their immune system thereby conferring homeostatic balance in which pneumococci are typically rendered as harmless colonizers in the upper respiratory environment. Pneumococcal carriage declines in many children before they acquire capsular-specific antibodies, suggesting a capsule antibody-independent mechanism of natural protection against pneumococcal carriage in early childhood. A child’s immune system in the first few years of life is Th2-skewed so as to avoid inflammation-induced immunopathology. Understanding Th1/Th2 and Th17 ontogeny in early life and how adjuvant vaccine formulations shift the balance of T helper-cell differentiation, may facilitate the development of new protein-based pneumococcal vaccines. This article will discuss the immune dynamics of pneumococcal colonization in infants. The discussion aims to benefit the design and improvement of protein subunit-based next-generation pneumococcal vaccines.

Pneumococcal Conjugate Vaccines, Shortcomings and Immunology The current conjugate vaccine formulations (PCV 7, 10 and 13) have had a significant impact on the reduction of pneumococcal disease in children since their introduction.1-5 The correlate of protection induced by these vaccines against non-invasive (otitis media, sinusitis and pneumonia) and invasive pneumococcal disease (IPDs) has primarily been described in the context of functional opsonophagocytic antibodies (OPAs) against the vaccine serotypes in these formulations (Table 1).2,6,7 Infants and *Correspondence to: Michael E Pichichero; Email: Michael.Pichichero @rochestergeneral.org Submitted: 06/18/2014; Revised: 08/08/2014; Accepted: 08/25/2014 http://dx.doi.org/10.4161/21645515.2014.979631

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young children are unable to respond adequately to the pneumococcal polysaccharides (PPS), which are T cell-independent antigens.8 The absence of T-cell help is due to the inability of most polysaccharides to associate with major histocompatibility complex (MHC) class II molecules on antigen presenting cells (APCs). This shortcoming predominates among infants and children but was overcome by linking PPS to protein carriers.9 It is broadly hypothesized that being T cell dependent antigens, carrier proteins activate T cells and T cell induced cytokines help in the subsequent generation of serotype-specific B cell memory in the follicles of secondary lymphoid organs.8-10 Although the linkage of a protein carrier with various pneumococcal polysaccharides leads to the generation of serotype-specific functional antibodies and immune memory, there is an age-dependent limiting factor for antibody responses to conjugate vaccines. The carrier-specific T cell response induced by conjugate immunization determines the levels of PPS-specific antibodies and protective efficacy.8 Due to the low immunogenicity of pneumococcal serotypes, even protein carrier linkage requires booster vaccination, and maintaining highly-protective antibody levels in early life is a challenge. In addition, pneumococcal carriage shortly before the first dose of PCV7 in infants resulted in hyporesponsiveness to the capsular polysaccharide of the carried strain. Furthermore, although an additional PCV7 dose administered at 12 months elicited a booster dose response, the response was blunted in children who had carried the specific serotype around the time of the first PCV7 dose, at age 2 or 4 months.11 Therefore, regions where pneumococcal carriage is prevalent, it adds one more layer of complexity vis-a-vis maintaining the serotype specific protective antibody levels. In order to maintain elevated antibody levels in early months of life in children, maternal immunization using pneumococcal polysaccharide vaccines (PPVs) is also being contemplated as an alternative approach.12 Despite the overarching success of conjugate vaccines in combating pneumococcal diseases, their limitations have become evident. Elimination of vaccine-specific pneumococcal serotypes is followed within a few years with the emergence of new strains expressing non-vaccine serotypes13-15, which occur by the

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Table 1. Pneumococcal conjugate vaccines and their protective immunological readout.


Conjugate Vaccines

Serotypes

Immunological Readout and Protection

PCV7

4, 6B, 9V, 14, 18C, 19F, 23F

PCV10

PCV7 C 1, 5, 7F, 23F

PCV13

PCV10 C 3, 6A, 19A 23F

Functional OPA antibodies: Protected against colonization, otitis media, pneumonia and IPD of vaccine serotypes Functional OPA antibodies: Protected against colonization, otitis media, pneumonia and IPD of vaccine serotypes Functional OPA antibodies: Protected against colonization, otitis media, pneumonia and IPD of vaccine serotypes

unmasking of new clones and capsule switching. For instance, a 30% decrease in the incidence of pneumococcal meningitis in the United States from 1998–1999 through 2004–2005 was attributed to direct PCV7 vaccine effects and herd immunity, but the percentage of cases caused by non-PCV7 serotype strains, particularly 19A, increased. Increases in serotype 19A stopped after introduction of 13-valent pneumococcal vaccine (PCV13) in 2010 but data suggest that non vaccine serotype 35B is a major serotype that increased from 2008–2009 to 2010–2011.16-18 Vaccine selection has revealed a greater plasticity among pneumococci than previously anticipated.19 Thus, pneumococcal serotype replacement and the expense of formulating polysaccharide conjugate vaccines for over 90 serotypes has stimulated new investigations into serotype-independent protein subunit vaccines that could elicit protective immune responses in children younger than 3 y old. Although the price of serotype independent protein subunit vaccines is not clear yet, it is anticipated that less complex production of these vaccines could result in lower cost. Whole cell vaccines may cost even less. This article will discuss the dynamics and immunology of natural nasopharyngeal (NP) colonization, immune response in early life, and design and development of next-generation pneumococcal vaccines targeted to protect against pneumococcal colonization in humans.

Advancements in Serotype Independent Pneumococcal Vaccines While emergence of new serotypes has been addressed by expanding the capsular repertoire of PCVs and its widespread success against vaccine serotypes has been reported, there are still multiple concerns that have prompted investigators to look for capsular independent vaccines. Firstly, by continuous addition of newly emerged serotypes to PCVs, manufacturing cost will likely further rise. Although market commitment mechanisms have made the conjugate vaccines available at $3.50 per dose in the developing world, their cost still remains a concern. Secondly, the capsule region of pneumococci has an inherent ability to undergo frequent genetic recombinations and vaccine immune pressure would potentially further select for capsular switching or unmasking.20,21 Thirdly, our group 22,23 and others 17,18 have recently shown number of pneumococcal serotypes emerging in different parts of the world would not be predicted by prior epidemiology studies such as those that led to the selection of the 23 serotypes in the polysaccharide vaccine. On the other hand,

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References 1,90,129–132

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subunit protein based vaccines include antigens that are highly conserved, expressed by all clinically relevant serotypes and therefore are envisaged to provide protection in a serotype independent manner. Although a number of conserved pneumococcal surface proteins are have been investigated for their efficacy in pre-clinical and clinical trials, Pneumococcal choline-binding protein A (PcpA), genetically detoxified pneumolysin (PlyD1, PdA, PdB), chemically detoxified pneumolysin (dPly), and Pneumococcal histidine triad D (PhtD) and E (PhtE) have been most studied recently and included in actively investigated multi-component protein-based vaccine formulations.24-34 In addition, pneumococcal acapsular whole cell vaccine (WCV) that elicits antibody independent CD4C T cell dependent immunity has advanced to clinical trials.35 The S. pneumoniae leucine rich repeat (LRR) protein PcpA is present in all clinically relevant strains of S. pneumonia. Studies in mice showed that PcpA is unlikely to be expressed in the NP due to high manganese levels that suppress expression of PcpA. Those results suggested PcpA expression was not required for optimal NP colonization. However, it was found to be an important virulence determinant in pneumococcal lung infections.36 We have reproduced the results in mice that show PcpA in a high manganese environment does not mediate adherence in the NP; however, we found that the NP of children during a viral upper respiratory infection is changed to a low manganese environment due to dilution of manganese from rhinorrhea [Manuscript under preparation]. We have also shown that PcpA mediates adherence to human nasopharyngeal and lung epithelial cells in-vitro 37 [Kaur et al; Under Review: Infection and Immunity]. Pneumolysin is produced by virtually all clinical isolates and at lower, sublytic concentrations; the toxin may cause a range of effects, including apoptosis, activation of host complement and induction of proinflammatory reactions in immune cells. However, at lytic concentrations, it acts as a toxin and cause pores in cholesterol-containing membranes.38-41 PhtD and PhtE genes (phtD and phtE) are present in 100 and 97% of strains respectively and PhtD is well conserved across pneumococcal strains (94–100% identity).42,43 We have recently shown that PhtD and PhtE are adhesins: pneumococci deficient of PhtD or PhtE have reduced attachment to human epithelial cells.44 Although, a mechanism of PhtD and PhtE mediated adherence to human epithelial cells is not known but genetic link between PhtD and lmb, the latter encoding a putative laminin binding protein has been reported.45 Pneumococcal surface protein A (PspA) was the first pneumococcal antigen to enter the clinical trial stage46 before the


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introduction of PCV7. The overwhelming success of PCV7, PCV10 and PCV13 has decreased interest in evaluating new non-capsular targets momentarily. However, an increase in new clones and serotypes in the post-PCV era has re-emphasized the need of serotype-independent formulations, and new clinical trials have been completed or are in progress. WCV is currently being evaluated in a phase I clinical trial (ClinicalTrials.gov Identifier: NCT01537185). Formulations containing monovalent PhtD, PlyD1, PcpA or bivalent PhtD-PcpA have been tested in phase II clinical trials (ClinicalTrials.gov Identifier: NCT00307528). Results from phase 1 clinical trials have been published by Sanofi Pasteur and Covance clinical research unit.47 All formulations were shown to be safe and immunogenic, and repeated vaccination significantly increased antibody levels. In a phase I/II randomized clinical trial conducted by GSK, formulations containing dPly and PhtD were immunogenic and well tolerated among healthy adults and toddlers.48,49 Therefore, there is tangible evidence that advancement is being made on that front. All antigens described above have been found to contribute to pneumococcal virulence in animal models. Yet, animal models can only provide partial insight to human immune responses. This is especially true considering the remarkable differences in the immune response of infants and young children compared to older children and adults. Our research suggests that infant animal models should be used in preference to adult animals if the target group for vaccination is infants.30 Despite the ability of most pneumococcal serotypes to colonize the mouse nasopharynx, pneumococcus is primarily a human pathogen, and animal models of pneumococcal infections pose important limitations in delineating some of the important mechanistic aspects of hostpneumococcal interactions. Antibody responses generated with recombinant PcpA vaccination have been shown to provide protection against systemic infection36 but not against colonization50 in mice. However, in humans it has been shown that commensal NP colonization of children results in stimulation of serum antibodies.51,52 Although all of these antigens elicit antibody responses in preclinical animal models and are protective in various pneumococcal disease models against a number of serotypes (Table 2), their correlate of protection is not well established. Candidate protein vaccines for pneumococci are T cell-dependent antigens and antibody responses against these antigens require CD4C T cell help. However, there is no comprehensive

account of their ability to elicit antigen-specific CD4C T cell responses. A range of antibody functionalities and their role in protection against pneumococcal disease in animal models will largely depend on the quality of CD4C T cell help to antibody producing B cells. We have recently reported that PhtD can elicit Th1-biased CD4C T cell memory in intranasally immunized mice, although further studies are required to attribute this to correlate of protection against colonization.31 The only pneumococcal non-capsular vaccine that has established a correlate of protection in pre-clinical mouse model is WCV. It has been demonstrated to provide CD4C Th17-dependent protection against pneumococcal NP colonization through potentiation of neutrophil-mediated clearance.35 A number of Th17 antigens have been identified from studies of killed whole cell vaccines that were protective against serotype 6B NP colonization in mice as mucosal vaccines.53 Therefore, in mice, there is evidence to suggest that an antibody-independent Th17 mechanism can provide protection against pneumococcal NP colonization. Given that NP colonization is a precursor to non-invasive and invasive pneumococcal disease54, a robust first line of Th17 defense is envisioned as a new-age protective approach for containing pneumococcal infections.

Determinants of Pneumococcal NP Colonization, NP Co-infection and Immune Response Pneumococci traverse the mucus layer and reach the epithelial surface of the NP. An interaction of pneumococcal adhesins with NP epithelial surface receptors leads to establishment of asymptomatic colonization.55 The human NP mucosal environment is a niche for complex polymicrobial interactions. The most frequent pathogenic upper respiratory mucosal colonizers of children are pneumococci, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus.56 Sequential or simultaneous NP colonization with more than one potentially pathogenic colonizer is common as all 5 of these bacteria can be found colonizing an average of 10–50% of healthy children at some time during the first years of life.56 It is of interest that NP colonization by these organisms occurs with significantly differing frequency as children age. S. pneumoniae and S. aureus colonization occurs in the first months of life, whereas H. influenzae colonization occurs more frequently between the age of 6–24

Table 2. Pneumococcal serotype independent vaccines. Serotype Independent Vaccines Serotype Independent Vaccines

Immunological Readouts and Protection (Pre-clinical)

References

PhtD Trivalent PcpA, PhtD, PlyD1 Detoxified PLY (PdB) Native PspA PspA-Pds CbpA (PspC) PcpA PsaA-Pdt fusion and CWPS WCV

Functional Abs; colonization, survival Functional Abs; pneumonia Anti-PLY antibodies; survival time Anti-PspA IgA, IgG; survival and carriage Cross reactive antibodies; survival Anti-PspC antibodies; survival and colonization Lung infection, survival time IL-17A, antigen specific IgG; Colonization and sepsis IL-17A; colonization and sepsis

31, 32

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months.54,56-59 Moreover, the resident microbiota in the NP ecological niche where infection begins differs greatly in young children compared to adults,60 and therefore a comprehensive understanding of the interaction of the microbiota and the immune response in the child host during pneumococcal pathogenesis is highly warranted. Post PCV-7, we 22 and others 61,62 reported a surge in NP colonization and acute otitis media (AOM) caused by nontypeable H. influenzae. H. influenzae might become a major colonizer of NP and cause of AOM as a result of the depletion of pneumococcal carriage.56 However, the emergence of new pneumococcal serotypes and further changes in co-colonization dynamics occurred resulting in the re-emergence of pneumococci as a predominant NP colonizer and AOM causative pathogen. Co-colonization of pneumococci with other common respiratory bacteria can have consequences on disease progression and invasion. Our group has recently reported that the dynamics of bacterial co-colonization in young child’s upper NP environment differs during health and at the onset of AOM with concurrent viral upper respiratory infections (URI). Among healthy children, S. pneumoniae was synergistically and negatively associated with M. catarrhalis and S. aureus, respectively. However, among children with AOM, negative associations were found between S. pneumoniae and H. influenzae and between H. influenzae and M. catarrhalis. These findings revealed the dynamics of bacterial interactions during nasopharyngeal colonization vis-a-vis child’s health status and vaccine-driven selection of microbiota in the upper respiratory airway.56 Co-colonization studies in mice suggest that the mucosal innate immune response may be subverted to a significant extent in order to favor one colonizer over another.55 For instance, IL-8 is an innate effector chemokine that has been associated with pneumococcal clearance in the NP in a primary co-colonization model with H. influenzae. The mechanism appeared to be stimulation of robust neutrophil recruitment in the NP with consequent clearance of pneumococci.55 In children, our group recently found that co-colonization modulates the adaptive immune response as well. NP colonization with either S. pneumoniae or H. influenzae elicited serum antigen-specific IgA and IgG responses to the homologous species, providing underpinning evidence that carriage is a natural immunizing event and further augments the immunizing potential for subsequent carriage events. Co-colonization with S. pneumoniae and H. influenzae further increased serum antibody responses against pneumococcal protein antigen-specific antibody levels, but not to H. influenzae compared to sole colonization with either S. pneumoniae or H. influenzae. Co-colonization of M. catarrhalis with S. pneumoniae also increased pneumococcal protein specific antibody responses.63 These findings reveal the selective maturation of antigen specific immune responses in the upper airway of healthy children that favor the selection and predominance of one colonizer over another. Therefore, dynamics of complex human NP co-colonization has triggered a new debate as to whether next generation pneumococcal vaccines should be aimed at eliminating NP colonization completely or keeping it below a pathogenic threshold.


The interplay between resident NP microbiota and the immune response during pneumococcal colonization in children is made more complex by the acknowledged near-essential role of upper respiratory viral infections (URIs) to shift the dynamics of pathogenesis in favor of local and systemic invasion.64-66 The most frequently studied viral-bacterial interaction is the synergism between influenza virus and S. pneumoniae.67-70 Animal experiments have shown that death occurs in 35% and 15% of mice infected with either influenza virus or pneumococcus, respectively, whereas 100% of mice infected with both pathogens simultaneously succumb to infection within one day.71 In addition, human rhinovirus, human metapneumovirus, RSV, parainfluenza virus, adenovirus and coronavirus have been associated with different health status of children and have shown different degrees of association with NP bacterial colonizers.65 Viral URIs cause early innate dysfunction ranging from disruption of epithelial defense (viruses replicate intracellularly and resulting cell death may in turn lead to the denudation of the epithelial layer) 72 and up-regulation of bacterial adherence receptors (PAF-r, ICAM-1, CEACAM-1).73-75 Respiratory viruses may also impair neutrophil function, NK cell recruitment, monocyte functions and production of early innate effector cytokine responses (IFNg, TNF-a, IL-10).76-81 Innate immunity not only provides an essential first step in infection control, it is pivotal in shaping the quality and magnitude of pathogen-specific adaptive immunity. Viral URIs facilitate pneumococcal proliferation in the NP thereby pneumococci change from harmless commensals to disease agents. Moreover, since viral URIs subvert the innate and adaptive immune dynamics in the upper respiratory environment, the impact of viral URIs on the longevity and persistence of antigen (vaccine) specific immune memory remains to be understood. The persistence of antigen specific immune memory is a key to the success of vaccine effectiveness and a pre-clinical animal model is required to delineate if viral URIs can temper with existing immune memory in vaccinated animals.

Antibodies and NP Colonization NP colonization studies in mouse models suggest that initial bacterial contact with epithelial cells in the NP induces a TLR2dependent signaling cascade. By day 3, this results in acute inflammation characterized by an influx of neutrophils.55 Gradually, a robust adaptive immune response is mounted to a diversity of pneumococcal antigens, leading to protection against primary and subsequent colonization events.82,83 Serotype-specific opsonophagocytic antibodies (OPAs) in the current pneumococcal conjugate vaccines clearly play a role in reducing pneumococcal NP colonization and overall pneumococcal disease burden in children. In addition to serotype-specific efficacy, limited crossprotection against non-vaccine serotypes has also been reported.84-86 Yet, studies in mice suggest an alternative capsular antibody-independent mechanism of protection against NP colonization because B cell deficient mice are able to clear NP colonization but offer no protection against invasive disease.87,88 Similarly, children start clearing pneumococcal carriage well


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before the acquisition of capsular polysaccharide-specific anti- PhtE, and antibodies directed to PhtD and PhtE partly contribbodies. Data from mouse NP colonization models suggest that ute to protection against secondary pneumococcal NP colonizaprotection against primary pneumococcal carriage is due to anti- tion (re-colonization) in mice.44 Infants and young children start body-independent CD4C Th17-dependent recruitment of developing pneumococcal protein antigen-specific antibodies inflammatory monocytes and macrophages to the NP,82 leading much earlier in their life than antibodies against capsular polysacto clearance of primary.carriage (Fig 1) Though the role of anti- charides.51 Our group has recently shown that IgG levels to bodies appears to be dispensable in protection against primary important pneumococcal vaccine candidates PhtD, PcpA and pneumococcal colonization in mouse models, their role in PlyD1 rise in synchrony in stringently-defined otitis prone (sOP) humans seems to be more essential. For example, PCV7 immuni- and non-otitis prone (NOP) children and appeared equally zation fails to protect against NP colonization in influenzae immunogenic in children at age 6 to 15 months (unpublished infected mice, but has been demonstrated to prevent vaccine serotype-specific colonization in humans.6,89,90 Therefore, although mice provide an important in vivo experimental tool to study dynamics of host-pneumococcal interactions, caution is needed to extrapolate the findings entirely to humans. Unlike laboratory studies of mouse infection, pneumococcal NP colonization events in humans are not controlled and it is difficult to ascertain the frequency of NP colonization events in a child and the varying context of the colonization event, such as the age of the child, coinfection with viruses, cocolonization with other potential respiratory bacterial pathogens, nutrition status, passive smoke exposure, and genetic predisposition. The role of protein antigen-specific antibodies in protection against NP colonization in humans needs further investigation. Some of these antigens are reported to be adhesins, to induce opsonophagocytic antibodies and to enhance complement deposition.44,91-97 We have recently shown that primary pneumococcal carriage is an immunizing Figure 1. Differential innate recruitment and clearance of pneumococcal carriage in primary vs secondary carriage in event in humans for putamouse colonization model: role of antibodies and CD4 T cells in the clearance. tive adhesins PhtD and

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data). IgG titers leveled off at 12 to 25 months. In contrast, the rates of IgG production against PhtE and LytB were significantly slower and titers had not peaked even at 25 months. This is consistent with the fact that PhtE and LytB have lower immunogenicity following natural exposure of children to pneumococci.51,98 These data suggest the predominance of a particular set of antigen specific IgG responses at an early age in life and the ability of certain antigens to evoke robust humoral responses early on. A precise understanding of the age-specific development of immunity against select protein antigens and their role in natural protection against pneumococcal NP colonization will have an important impact on the development of next-generation pneumococcal vaccines and adjuvants. In a first adult human pneumococcal carriage model, antiPspA antibody levels were found to be inversely correlated with NP carriage.99 A more recent experimental human carriage study was reported in healthy adults.100 Carriage resulted in mucosal and systemic immunological responses (immunizing event against a number of protein antigens and capsular polysaccharide). Invasive pneumococcal disease was prevented in mice passively immunized with sera from colonized adults. The IgG responses against a number of protein antigens were boosted following NP colonization in carriage-positive and less so in carriage-negative individuals. This increased and sustained immune response after carriage was reflected in protection against carriage acquisition after rechallenge up to 11 months after clearance of the first carriage episode. However, there was no association of baseline IgG to pneumococcal proteins and carriage.100 We have previously shown that children who suffer multiple ear infections (otitis prone condition) or persistent NP pneumococcal colonization have lower levels of antibodies against pneumococcal protein antigens (PhtD, PhtE, Ply, PcpA, PspA), as compared to non-otitis prone children.98 These were the first comprehensive studies to demonstrate the pivotal role and association of protein antigen-specific antibodies to pneumococcal otitis media susceptibility. If the role of protein antigen-specific antibodies in NP colonization is to be unraveled, important questions ahead include the determination of appropriate experimental models to establish correlates of protection mediated by protein antigen-specific antibodies.

CD4 T Cells and Immunity Against Pneumococcal NP Colonization CD4C T cells are important regulators of immune responses and can be divided into multiple subsets, such as Th1, Th2, Th17 and Tregs; depending on the effector response they mediate.101 The development of a Th1 response is central to the clearance of intracellular pathogens and is characterized by IFN-g release, a potent activator of macrophages.102 The differentiation of Th2 is driven by IL-4 and is important for the production of immunoglobulin (Ig) and subsequent clearance of extracellular organisms.102,103 The Th17 subset of CD4C T cells that produces IL-17A is an important mediator for defense against extracellular pathogens and fungi.104 Evidence from mouse models


suggests an indispensable role of Th17 CD4C T cells in development of natural protective immunity against pneumococcal NP colonization.87 Th17 CD4C cell-mediated protection against NP colonization may occur as a consequence of IL-17A-induced potentiation of pneumococcal killing by innate cells35 (Fig 1). A gradual Th17-dependent recruitment of monocyte/macrophage to the site of colonization over the course of weeks was found to clear primary colonization in adult mice.82 However, the role of IL-17A-dependent potentiation of neutrophil activity was correlated with WCV-induced protection against pneumococcal NP colonization in intranasally immunized mice.35 Murine models have been used to evaluate host and bacterial factors that contribute to defense against NP colonization and also to assess protection induced by new vaccine formulations. These models typically use as mentioned on page 551 mice and evaluate immune responses and protection after successful establishment of carriage. Therefore, decrease in density and duration of carriage is assessed in these models, rather than acquisition. On the other hand, studies in humans have suggested that the low prevalence of carriage in human adults may not be due to their ability to protect against acquisition but instead due to shorter duration of carriage. Some of the clinically important serotypes (serotype 1, 7F and 8) that have low prevalence during carriage have been found to be associated more with invasive diseases.105-107 Therefore, the choice of an accurate model system is pivotal in delineating vaccine efficacy against NP colonization. While antibodies appear to play a limited role to prevent existing primary carriage in na€ıve murine NP colonization models, antibodies provide an important defense against secondary or subsequent colonization events. There is compelling evidence in mice on the role of Th17 cells vis-a-vis protection against NP colonization, but human data on age-specific changes in the immune system and Th17 response in early life is limited. In an adult human experimental carriage model, frequency of cognate IL-17A-secreting CD4C memory T cells was increased in broncho-alveolar lavage (BAL) and blood, and enhanced killing of pneumococci was shown by alveolar macrophages.108 These findings suggest that carriage can even increase the proportion of lung IL-17A CD4C T cells in adults that may significantly enhance lung innate immunity. We and others have previously shown that children and adults have detectable levels of memory CD4C T cells against pneumococcal protein antigens in the blood compartment.109-111 However, active NP colonization sites (adenoids) have more robust antigen-specific CD4C T cell frequency than detectable in the blood.112,113 Antigen-specific memory CD4C T cells in blood are typically central memory cells (TCM). Because of their capacity to renew themselves into effector memory T cells (TEM) upon antigen challenge, these cell subsets have the ability to maintain a stable antigen-specific pool in the blood compartment and therefore are of special interest. TEM cells in secondary lymphoid organs are short-lived. Therefore, the central memory subset of antigen-specific CD4C T cells in circulation could potentially be an important correlate of natural infection or protein vaccine-induced T cell immunity. It is also to be noted that secondary lymphoid organs (adenoids and tonsils) used in previous studies for the detection of IL-17A


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CD4C T cells were derived from the children aged between 3–6 y112,113 While these studies provide important data on age-specific maturation of the Th17 response and its association with reduction in the duration and frequency of carriage, children at this age are not the main target groups for pediatric pneumococcal vaccines. Therefore, even if IL-17AC CD4 T cell response can be demonstrated to be a target for next generation vaccines, understanding of age-specific changes in the pediatric innate and adaptive immune system is of paramount importance that will allow the development of novel formulations to elicit early protective Th17 responses in the first 2 y of life.


Development of the CD4 Th17 Axis: Implications for Vaccines Targeting Colonization Despite that, TLR agonists induced equivalent levels of both IL-6 and IL-23 in APCs of neonates and adults, there is decreased IL-17A secretion by human and murine neonatal cells.114-116 Existing reports suggest that notwithstanding the potent Th17polarizing innate response (IL-6 and IL-23) in mouse neonates, mice slowly and gradually develop CD4 Th17 responses (IL17A), and become protected against pneumococcal NP colonization.117 Unlike overwhelming reports on Th1 defective and Th2 skewed responses in early human life,116,118,119 the data on pneumococcal antigen-specific CD4C Th17 cells in the circulation of neonates or young children is sparse. Our group has consistently tried to detect Th17 responses against pneumococcal antigens in the circulation of healthy, colonized or AOM children between 6 and 24 months of age but have only detected Th17 responses in a few subjects. Therefore, we postulate that, like the Th1 response, neonates and infants are unable to mount a potent Th17 response until around age 3 y old and are therefore more susceptible for the persistence of NP colonization and subsequent disease. Our group has interest in studying whether the decreased IL-17A secretion by neonatal and infant cells can be overcome by augmenting TLR stimulation by use of novel adjuvants. TLR stimulation of human cord blood has been shown to induce potent IL-6 and IL-23 levels that are required for the differentiation of Th17 showing that there is no defect in neonates with regard to their ability to skew na€ıve CD4C T cells in Th17 direction.120 Immune defects or immaturity at an early age is a defined phenomenon (Table 3) ,116,118,119 and despite the immunogenicity of protein antigens in early life, antibody responses are weaker and shorter-lived than responses elicited in adults.9 Repeated vaccine doses are therefore needed to elicit protective antibodies and persistence of protective levels during the first years of life. Since polysaccharides are T cell independent antigens, to generate memory B cells to polysaccharides contact dependent signals from bystander T cells activated by protein carriers are necessary to generate memory as is accomplished with conjugate vaccines. 9,10 Vaccine formulations containing protein subunits or WCV are T cell dependent antigens and therefore will generate immune memory. T cell immunity in

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Table 3. Key Immunological maturation shortcomings in early life: challenges for next generation pneumococcal vaccine formulations Innate Immunity Qualitative dysfunctions in TLR signaling Defective IL-12 (Th1 polarization) Greater IL-10 production Low expression of activation markers CD40, CD80, CD86 and HLA-DR on APCs B cell Immunity Immaturity of marginal zone Low expression of CD21 Delayed and limited germinal center response Inadequate T cell help to B cells Maturation and high affinity antibody generation T cell Immunity Defective TFH CD4CT cells development Th2 skewed Defective Th1 differentiation Antigen specific memory generation and persistence CD4 T cell defects intrinsic or due to poor APC help? Dominant TREG phenotype and overproduction of IL-10

early life of children is skewed toward Th2, an evolutionary measure to prevent infection-induced immunopathology.121 While Th17 cells are an important subset for protection against fungal and bacterial infections, there is an overwhelming evidence of their proinflammatory role in human autoimmunity.122 There is a fine balance between immune-mediated resolution of infection and an immune-mediated pathology. The immune system at an early age tends to be biased more toward containing immunopathology than preventing infections.123 While generation of vaccine-induced, protective IL17A immune responses that prevent NP colonization is highly desirable, caution is needed to ensure that Th17 target vaccines do not breach homeostatic immune equilibrium. Therefore, to achieve this, precise understanding of age-specific acquisition of the IL-17A effector response is highly warranted. Also, at critical points along the time-course of pneumococcal NP colonization, co-colonization or co-infection with other bacterial or viral pathogenic species can have dramatic consequences on disease progression and outcome by subverting the immune response.55,71,124 This is also a matter of intense investigation as to how polymicrobial interaction in early years of life could manipulate the generation of T cell immunity and therefore impact pneumococcal NP colonization and risk for subsequent diseases. Dendritic cell- (DC) induced help to na€ıve CD4C T cells in the lymph node is broadly responsible for CD4C T cell differentiation. Dendritic cells in neonates and infants generally have a selective pattern of low TLR induced immunity125, down-regulation of IL-12 by overproduction of IL-10 that generally skews CD4C T cells toward Th2 bias.126 In addition, homing patterns of DCs in children are different from those of adults and may have a significant impact on the quality of CD4C T cell differentiation.127 A balance between Th17 cells and Tregs is crucial for immune homeostasis, which is maintained by IL-6 and TGF-b. Thus, despite adequate IL-6 and IL-23 levels in early life, the


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levels of TGF-b and other anti-inflammatory cytokines might attenuate Th17 differentiation.128 Tregs overproduce IL-10 which in turn might attenuate APC function and facilitate the persistence of pneumococci further in the NP. Since IL-6 and TGF-b balance is instrumental in determining the fate of T cell polarization, it is not surprising that increased generation or recruitment of Tregs in secondary lymph nodes during early life could be utilized by the host as a mechanism to retain carriage. Therefore, age-specific understanding of this interplay between IL-6 and TGF-b and its relation to the control of inflammation and Th17 differentiation in early age children should significantly enhance our understanding in designing novel vaccines and adjuvants.

and third world countries where cost is a major deterrent. In addition, as the understanding of the immunology of early life is unfolding, the next 5 y would potentially see the rise of new adjuvants and formulations designed to overcome key early-age innate and T cell defects to make neonatal and infant immune cells more responsive to novel formulations. In addition, systems biology has begun to undercover the genetic basis of vaccine failures and key pathways involved in the host immune response to various vaccines. We anticipate that these strategies will have an important effect on not only one set of vaccine designs but also on a systemic scale.

Key Issues Downloaded by [University of Connecticut] at 15:10 12 April 2015

Conclusions: Despite an overwhelming success of pneumococcal conjugate formulations in reducing pneumococcal disease burden globally, the emergence of new serotypes has posed a significant challenge and has encouraged investigators to look for alternative capsularindependent vaccines. Persistent NP colonization may manifest in disease, especially in early life. The immune system of the neonate and the child younger than 2 y old, typically fails to prevent repeated NP colonization events. A shift in focus to develop alternative next generation vaccination strategies requires a critical understanding of key early life changes in innate and adaptive immune responses. The discovery of novel adjuvants and vaccine formulations along with mucosal immunization may overcome the intrinsic defects of early life. This in turn would induce an antigen-specific optimal immune response without deleterious effects on the immune system. In addition, an evolving understanding of complex and selective pattern of NP colonization dynamics in early life may have an important bearing on the design of next-generation pneumococcal vaccines. Establishment and persistence of antigen-specific memory is a key to the longevity and success of vaccination, and there is a need to have the correct animal model systems to study the impact of viral and other co-colonization-induced changes on the dynamics of immune memory vis-a-vis vaccine efficacy. There has been a significant progress on the emergence of new pneumococcal vaccine candidates and formulations in recent past. As explained, some of these candidates have advanced to phase II clinical trials and we highly anticipate that they will qualify for use not only in the developed world but also in developing References 1. Poehling KA, Talbot TR, Griffin MR, Craig AS, Whitney CG, Zell E, Lexau CA, Thomas AR, Harrison LH, Reingold AL, et al. Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine. Jama 2006; 295:1668-74; PMID:16609088; http://dx.doi.org/ 10.1001/jama.295.14.1668 2. Lee H, Choi EH, Lee HJ. Efficacy and effectiveness of extended-valency pneumococcal conjugate vaccines. Korean J Pediatr 2014; 57:55-66; PMID:24678328; http://dx.doi.org/10.3345/kjp.2014.57.2.55 3. Principi N, Esposito S. Use of the 13-valent pneumococcal conjugate vaccine in infants and young


Since the introduction of pneumococcal conjugate vaccines for use in developed countries, pneumococci have shown a great degree of virulence plasticity and has manifested into the emergence of non-vaccine serotypes. Due to the high manufacturing cost of PCVs, their use in developing countries is limited and therefore, if pneumococcal disease burden is to be addressed at global level, an alternate cost-effective and serotype-independent approach is required. Innate and T cell maturation defects in early-life require the need of multiple boosters to keep immune effectors to protective levels. Vaccines and formulations aimed at inducing a stronger and longer-lasting early-life immune response and minimizing immunopathology are being attempted as desirable propositions. Pneumococcal colonization in humans is complex due to polymicrobial interaction in the upper respiratory NP and therefore the use of accurate animal model systems that mimic humans needs to be developed in order to correctly evaluate pneumococcal infection or vaccine-induced immunology and protection.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgment

We thank Dr. Robert Zagursky for his critical reading of the manuscript.

children. Expert Opin Biol Ther 2012; 12:641-8; PMID:22397739; http://dx.doi.org/10.1517/ 14712598.2012.670217 4. Ruckinger S, van der Linden M, Siedler A, von Kries R. Potential benefits from currently available three pneumococcal vaccines for children–population-based evaluation. Klin Padiatr 2011; 223:614; PMID:21271500; http://dx.doi.org/10.1055/s0030-1268465 5. Oosterhuis-Kafeja F, Beutels P, Van Damme P. Immunogenicity, efficacy, safety and effectiveness of pneumococcal conjugate vaccines (1998-2006). Vaccine 2007; 25:2194-212; PMID:17267077; http://dx. doi.org/10.1016/j.vaccine.2006.11.032


6. Goldblatt D, Southern J, Ashton L, Andrews N, Woodgate S, Burbidge P, Waight P, Miller E. Immunogenicity of a reduced schedule of pneumococcal conjugate vaccine in healthy infants and correlates of protection for serotype 6B in the United Kingdom. Pediatr Infect Dis J 2010; 29:401-5; PMID:20010312; http://dx.doi.org/10.1097/INF. 0b013e3181c67f04 7. Ekstrom N, Vakevainen M, Verho J, Kilpi T, Kayhty H. Functional antibodies elicited by two heptavalent pneumococcal conjugate vaccines in the Finnish Otitis Media Vaccine Trial. Infect Immun 2007; 75:1794800; PMID:17261612; http://dx.doi.org/10.1128/ IAI.01673-06

3695


8. Jakobsen H, Hannesdottir S, Bjarnarson SP, Schulz D, Trannoy E, Siegrist CA, Jonsdottir I. Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide-specific antibody response and protective efficacy. Eur J Immunol 2006; 36:287-95; PMID:16385627; http:// dx.doi.org/10.1002/eji.200535102 9. Pichichero ME. Protein carriers of conjugate vaccines: characteristics, development, and clinical trials. Hum Vaccin Immunother 2013; 9:2505-23; PMID:23955057; http://dx.doi.org/10.4161/hv.26109 10. Clarke ET, Williams NA, Findlow J, Borrow R, Heyderman RS, Finn A. Polysaccharide-specific memory B cells generated by conjugate vaccines in humans conform to the CD27CIgGC isotype-switched memory B Cell phenotype and require contact-dependent signals from bystander T cells activated by bacterial proteins to differentiate into plasma cells. J Immunol 2013; 191:6071-83; PMID:24227777; http://dx.doi. org/10.4049/jimmunol.1203254 11. Dagan R, Givon-Lavi N, Greenberg D, Fritzell B, Siegrist CA. Nasopharyngeal carriage of Streptococcus pneumoniae shortly before vaccination with a pneumococcal conjugate vaccine causes serotype-specific hyporesponsiveness in early infancy. J infect dis 2010; 201:1570-9; PMID:20384496; http://dx.doi.org/ 10.1086/652006 12. Holmlund E, Nohynek H, Quiambao B, Ollgren J, Kayhty H. Mother-infant vaccination with pneumococcal polysaccharide vaccine: persistence of maternal antibodies and responses of infants to vaccination. Vaccine 2011; 29:4565-75; PMID:21550374; http:// dx.doi.org/10.1016/j.vaccine.2011.04.068 13. Croucher NJ, Harris SR, Fraser C, Quail MA, Burton J, van der Linden M, McGee L, von Gottberg A, Song JH, Ko KS, et al. Rapid pneumococcal evolution in response to clinical interventions. Science 2011; 331:430-4; PMID:21273480; http://dx.doi. org/10.1126/science.1198545 14. Croucher NJ, Finkelstein JA, Pelton SI, Mitchell PK, Lee GM, Parkhill J, Bentley SD, Hanage WP, Lipsitch M. Population genomics of post-vaccine changes in pneumococcal epidemiology. Nat Genet 2013; 45:656-63; PMID:23644493; http://dx.doi.org/ 10.1038/ng.2625 15. Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. Jama 2007; 298:1772-8; PMID:17940232; http://dx.doi.org/10.1001/jama.298.15.1772 16. Richter SS, Heilmann KP, Dohrn CL, Riahi F, Diekema DJ, Doern GV. Pneumococcal serotypes before and after introduction of conjugate vaccines, United States, 1999-2011(1). Emerg Infect Dis 2013; 19:1074-83; PMID:23763847; http://dx.doi.org/ 10.3201/eid1907.121830 17. Loughlin AM, Hsu K, Silverio AL, Marchant CD, Pelton SI. Direct and indirect effects of PCV13 on nasopharyngeal carriage of PCV13 unique pneumococcal serotypes in Massachusetts’ children. Pediatr Infect Dis J 2014; 33:504-10; PMID:24670957; http://dx.doi.org/10.1097/INF.0000000000000279 18. Ricketson LJ, Wood ML, Vanderkooi OG, MacDonald JC, Martin IE, Demczuk WH, Kellner JD. Trends in asymptomatic nasopharyngeal colonization with streptococcus pneumoniae after introduction of the 13-valent pneumococcal conjugate vaccine in Calgary, Canada. Pediatr Infect Dis J 2014; 33:724-30; PMID:24463806; http://dx.doi.org/10.1097/INF. 0000000000000267 19. Long SS. Capsules, clones, and curious events: pneumococcus under fire from polysaccharide conjugate vaccine. Clin Infect Dis 2005; 41:30-4; PMID:15937759; http://dx.doi.org/10.1086/430608 20. Brueggemann AB, Pai R, Crook DW, Beall B. Vaccine escape recombinants emerge after pneumococcal vaccination in the United States. PLoS Pathogens

3696

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

2007; 3:e168; PMID:18020702; http://dx.doi.org/ 10.1371/journal.ppat.0030168 Donkor ES, Bishop CJ, Gould K, Hinds J, Antonio M, Wren B, Hanage WP. High levels of recombination among Streptococcus pneumoniae isolates from the Gambia. mBio 2011; 2:e00040-11; PMID:21693638; http://dx.doi.org/10.1128/mBio.00222-11 Casey JR, Adlowitz DG, Pichichero ME. New patterns in the otopathogens causing acute otitis media six to eight years after introduction of pneumococcal conjugate vaccine. Pediatr Infect Dis J 2010; 29:3049; PMID:19935445 R. Kaur JRC, S. Dhaliwal, K. Center, D. Scott, M. E. Pichichero. Multiple non-vaccine serotypes of Streptococcus pneumoniae emerge during The 7-Valent (PCV7) and 13-valent (PCV-13) pneumococcal conjugate vaccination - Rochester, NY- 2006-2014. Interscience conference on anti microbial agents and chemotherapy. Washington DC: American Society for Microbiology, 2014 Gosink KK, Mann ER, Guglielmo C, Tuomanen EI, Masure HR. Role of novel choline binding proteins in virulence of Streptococcus pneumoniae. Infect Immun 2000; 68:5690-5; PMID:10992472; http:// dx.doi.org/10.1128/IAI.68.10.5690-5695.2000 Brooks-Walter A, Briles DE, Hollingshead SK. The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein, PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia. Infect Immun 1999; 67:6533-42; PMID:10569772 Frey SE, Lottenbach KR, Hill H, Blevins TP, Yu Y, Zhang Y, Brenneman KE, Kelly-Aehle SM, McDonald C, Jansen A, et al. A Phase I, dose-escalation trial in adults of three recombinant attenuated Salmonella Typhi vaccine vectors producing Streptococcus pneumoniae surface protein antigen PspA. Vaccine 2013; 31:4874-80; PMID:23916987; http://dx.doi.org/ 10.1016/j.vaccine.2013.07.049 Briles DE, Hollingshead SK, Paton JC, Ades EW, Novak L, van Ginkel FW, Benjamin WH Jr. Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae. J Infect Dis 2003; 188:339-48; PMID:12870114; http://dx.doi.org/10.1086/376571 Roche H, Hakansson A, Hollingshead SK, Briles DE. Regions of PspA/EF3296 best able to elicit protection against Streptococcus pneumoniae in a murine infection model. Infect Immun 2003; 71:1033-41; PMID:12595413; http://dx.doi.org/10.1128/IAI.71. 3.1033-1041.2003 Marriott HM, Mitchell TJ, Dockrell DH. Pneumolysin: a double-edged sword during the host-pathogen interaction. Curr Mol Med 2008; 8:497-509; PMID:18781957; http://dx.doi.org/10.2174/ 156652408785747924 Verhoeven D, Xu Q, Pichichero ME. Vaccination with a Streptococcus pneumoniae trivalent recombinant PcpA, PhtD and PlyD1 protein vaccine candidate protects against lethal pneumonia in an infant murine model. Vaccine 2014; 32:3205-10. PMID:24731814 Khan MN, Pichichero ME. CD4 T cell memory and antibody responses directed against the pneumococcal histidine triad proteins PhtD and PhtE following nasopharyngeal colonization and immunization and their role in protection against pneumococcal colonization in mice. Infect Immun 2013; 81:3781-92; PMID:23897609; http://dx.doi.org/ 10.1128/IAI.00313-13 Godfroid F, Hermand P, Verlant V, Denoel P, Poolman JT. Preclinical evaluation of the Pht proteins as potential cross-protective pneumococcal vaccine antigens. Infect Immun 2011; 79:238-45; PMID:20956575; http://dx. doi.org/10.1128/IAI.00378-10 Rajam G, Anderton JM, Carlone GM, Sampson JS, Ades EW. Pneumococcal surface adhesin A


34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

(PsaA): a review. Crit Rev Microbiol 2008; 34:131-42; PMID:18728990; http://dx.doi.org/ 10.1080/10408410802275352 Darrieux M, Goulart C, Briles D, Leite LC. Current status and perspectives on protein-based pneumococcal vaccines. Crit Rev Microbiol 2013; Epub ahead of print. PMID:23895377 Lu YJ, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q, Kolls JK, Srivastava A, Lundgren A, Forte S, et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog 2008; 4: e1000159; PMID:18802458; http://dx.doi.org/ 10.1371/journal.ppat.1000159 Glover DT, Hollingshead SK, Briles DE. Streptococcus pneumoniae surface protein PcpA elicits protection against lung infection and fatal sepsis. Infect immun 2008; 76:2767-76; PMID:18391008; http:// dx.doi.org/10.1128/IAI.01126-07 Khan MN, Sharma SK, Filkins LM, Pichichero ME. PcpA of Streptococcus pneumoniae mediates adherence to nasopharyngeal and lung epithelial cells and elicits functional antibodies in humans. Microbes Infect 2012; 14:1102-10; PMID:22796387; http:// dx.doi.org/10.1016/j.micinf.2012.06.007 Witzenrath M, Pache F, Lorenz D, Koppe U, Gutbier B, Tabeling C, Reppe K, Meixenberger K, Dorhoi A, Ma J, et al. The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol 2011; 187:434-40; PMID:21646297; http://dx.doi.org/10.4049/jimmunol.1003143 McNeela EA, Burke A, Neill DR, Baxter C, Fernandes VE, Ferreira D, Smeaton S, El-Rachkidy R, McLoughlin RM, Mori A, et al. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog 2010; 6:e1001191; PMID:21085613; http:// dx.doi.org/10.1371/journal.ppat.1001191 Srivastava A, Henneke P, Visintin A, Morse SC, Martin V, Watkins C, Paton JC, Wessels MR, Golenbock DT, Malley R. The apoptotic response to pneumolysin is Toll-like receptor 4 dependent and protects against pneumococcal disease. Infect Immun 2005; 73:6479-87; PMID:16177320; http://dx.doi.org/ 10.1128/IAI.73.10.6479-6487.2005 Tilley SJ, Orlova EV, Gilbert RJ, Andrew PW, Saibil HR. Structural basis of pore formation by the bacterial toxin pneumolysin. Cell 2005; 121:247-56; PMID:15851031; http://dx.doi.org/10.1016/j.cell. 2005.02.033 Rioux S, Neyt C, Di Paolo E, Turpin L, Charland N, Labbe S, Mortier MC, Mitchell TJ, Feron C, Martin D, et al. Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae. Microbiology 2011; 157:336-48; PMID:20966093; http://dx.doi.org/10.1099/mic.0. 042184-0 Riboldi-Tunnicliffe A, Isaacs NW, Mitchell TJ. One.2 Angstroms crystal structure of the S. pneumoniae PhtA histidine triad domain a novel zinc binding fold. FEBS letters 2005; 579:5353-60; PMID:16194532; http://dx.doi.org/10.1016/j.febslet. 2005.08.066 Khan MN, Pichichero ME. Vaccine candidates PhtD and PhtE of Streptococcus pneumoniae are adhesins that elicit functional antibodies in humans. Vaccine 2012; 30:2900-7; PMID:22349524; http://dx.doi. org/10.1016/j.vaccine.2012.02.023 Spellerberg B, Rozdzinski E, Martin S, Weber-Heynemann J, Schnitzler N, Lutticken R, Podbielski A. Lmb, a protein with similarities to the LraI adhesin family, mediates attachment of Streptococcus agalactiae to human laminin. Infection and immunity 1999; 67:871-8; PMID:9916102 Nabors GS, Braun PA, Herrmann DJ, Heise ML, Pyle DJ, Gravenstein S, Schilling M, Ferguson LM, Hollingshead SK, Briles DE, et al. Immunization of

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47.

48.


49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules. Vaccine 2000; 18:1743-54; PMID:10699322; http://dx.doi.org/10.1016/S0264-410X(99)00530-7 Bologa M, Kamtchoua T, Hopfer R, Sheng X, Hicks B, Bixler G, Hou V, Pehlic V, Yuan T, Gurunathan S. Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA-pneumococcal histidine triad protein D vaccine. Vaccine 2012; 30:7461-8; PMID:23123106; http://dx.doi. org/10.1016/j.vaccine.2012.10.076 Leroux-Roels G, Maes C, De Boever F, Traskine M, Ruggeberg JU, Borys D. Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: A phase I/II randomized clinical study. Vaccine 2014; 32:6838-46; PMID:24607003; ; http://dx.doi. org/10.1016/j.vaccine.2014.02.052 Prymula R, Pazdiora P, Traskine M, Ruggeberg JU, Borys D. Safety and immunogenicity of an investigational vaccine containing two common pneumococcal proteins in toddlers: a phase II randomized clinical trial. Vaccine 2014; 32:3025-34; PMID:24699466; http://dx.doi.org/10.1016/j.vaccine.2014.03.066 Sanchez-Beato AR, Lopez R, Garcia JL. Molecular characterization of PcpA: a novel choline-binding protein of Streptococcus pneumoniae. FEMS microbiol lett 1998; 164:207-14; PMID:9675866; http://dx. doi.org/10.1016/S0378-1097(98)00206-7 Pichichero ME, Kaur R, Casey JR, Xu Q, Almudevar A, Ochs M. Antibody response to Streptococcus pneumoniae proteins PhtD, LytB, PcpA, PhtE and Ply after nasopharyngeal colonization and acute otitis media in children. Hum Vaccin Immunother 2012; 8:799-805; PMID:22495112; http://dx.doi.org/ 10.4161/hv.19820 Pichichero ME, Kaur R, Casey JR, Sabirov A, Khan MN, Almudevar A. Antibody response to Haemophilus influenzae outer membrane protein D, P6, and OMP26 after nasopharyngeal colonization and acute otitis media in children. Vaccine 2010; 28:7184-92; PMID:20800701; http://dx.doi.org/10.1016/j. vaccine.2010.08.063 Moffitt KL, Malley R, Lu YJ. Identification of protective pneumococcal T(H)17 antigens from the soluble fraction of a killed whole cell vaccine. PLoS One 2012; 7:e43445; PMID:22905267; http://dx.doi.org/ 10.1371/journal.pone.0043445 Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis 2004; 4:144-54; PMID:14998500; http://dx.doi.org/10.1016/S14733099(04)00938-7 Lijek RS, Weiser JN. Co-infection subverts mucosal immunity in the upper respiratory tract. Curr Opin Immunol 2012; 24:417-23; PMID:22658762; http:// dx.doi.org/10.1016/j.coi.2012.05.005 Xu Q, Almudervar A, Casey JR, Pichichero ME. Nasopharyngeal bacterial interactions in children. Emerg Infect Dis 2012; 18:1738-45; PMID:23092680; http://dx.doi.org/10.3201/ eid1811.111904 Jimenez-Truque N, Tedeschi S, Saye EJ, McKenna BD, Langdon W, Wright JP, Alsentzer A, Arnold S, Saville BR, Wang W, et al. Relationship between maternal and neonatal Staphylococcus aureus colonization. Pediatrics 2012; 129:e1252-9; PMID:22473373; http://dx.doi.org/10.1542/peds. 2011-2308 Solorzano-Santos F, Miranda-Novales MG, LeanosMiranda B, Ortiz-Ocampo LA, Echaniz-Aviles G, Palacios-Saucedo G, Guiscafre-Gallardo H. Haemophilus influenzae nasopharyngeal colonization in children. Rev Med Inst Mex Seguro Soc 2011; 49:499502; PMID:22185850 Friedel V, Zilora S, Bogaard D, Casey JR, Pichichero ME. Five-year prospective study of paediatric acute


60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

otitis media in Rochester, NY: modelling analysis of the risk of pneumococcal colonization in the nasopharynx and infection. Epidemiol Infect 2013; 142:2186-94. Garcia-Rodriguez JA, Fresnadillo Martinez MJ. Dynamics of nasopharyngeal colonization by potential respiratory pathogens. J Antimicrob Chemother 2002; 50 Suppl S2:59-73; PMID:12556435; http://dx.doi. org/10.1093/jac/dkf506 Block SL, Hedrick J, Harrison CJ, Tyler R, Smith A, Findlay R, Keegan E. Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr Infect Dis J 2004; 23:829-33; PMID:15361721; http://dx.doi.org/10.1097/01. inf.0000136868.91756.80 Wiertsema SP, Kirkham LA, Corscadden KJ, Mowe EN, Bowman JM, Jacoby P, Francis R, Vijayasekaran S, Coates HL, Riley TV, et al. Predominance of nontypeable Haemophilus influenzae in children with otitis media following introduction of a 3C0 pneumococcal conjugate vaccine schedule. Vaccine 2011; 29:5163-70; PMID:21621576; http://dx.doi. org/10.1016/j.vaccine.2011.05.035 Xu Q, Pichichero ME. Co-colonization by Haemophilus influenzae with Streptococcus pneumoniae enhances pneumococcal-specific antibody response in young children. Vaccine 2014; 32:706-11; PMID:24355091; http://dx.doi.org/10.1016/j. vaccine.2013.11.096 Friedel V, Chang A, Wills J, Vargas R, Xu Q, Pichichero ME. Impact of respiratory viral infections on a-hemolytic streptococci and otopathogens in the nasopharynx of young children. Pediatr Infect Dis J 2013; 32:27-31; PMID:23241988; http://dx.doi.org/ 10.1097/INF.0b013e31826f6144 Bosch AA, Biesbroek G, Trzcinski K, Sanders EA, Bogaert D. Viral and bacterial interactions in the upper respiratory tract. PLoS Pathog 2013; 9: e1003057; PMID:23326226; http://dx.doi.org/ 10.1371/journal.ppat.1003057 Pettigrew MM, Gent JF, Pyles RB, Miller AL, NoksoKoivisto J, Chonmaitree T. Viral-bacterial interactions and risk of acute otitis media complicating upper respiratory tract infection. J Clin Microbiol 2011; 49:3750-5; PMID:21900518; http://dx.doi.org/ 10.1128/JCM.01186-11 Metzger DW, Sun K. Immune dysfunction and bacterial coinfections following influenza. J Immunol 2013; 191:2047-52; PMID:23964104; http://dx.doi. org/10.4049/jimmunol.1301152 Short KR, Habets MN, Hermans PW, Diavatopoulos DA. Interactions between Streptococcus pneumoniae and influenza virus: a mutually beneficial relationship? Future Microbiol 2012; 7:609-24; PMID:22568716; http://dx.doi.org/10.2217/fmb.12.29 Smith AM, Adler FR, Ribeiro RM, Gutenkunst RN, McAuley JL, McCullers JA, Perelson AS. Kinetics of coinfection with influenza A virus and Streptococcus pneumoniae. PLoS Pathog 2013; 9:e1003238; PMID:23555251; http://dx.doi.org/10.1371/journal. ppat.1003238 McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 2006; 19:571-82; PMID:16847087; http://dx. doi.org/10.1128/CMR.00058-05 Diavatopoulos DA, Short KR, Price JT, Wilksch JJ, Brown LE, Briles DE, Strugnell RA, Wijburg OL. Influenza A virus facilitates Streptococcus pneumoniae transmission and disease. Faseb J 2010; 24:1789-98; PMID:20097876; http://dx.doi.org/10.1096/fj.09-146779 Plotkowski MC, Puchelle E, Beck G, Jacquot J, Hannoun C. Adherence of type I Streptococcus pneumoniae to tracheal epithelium of mice infected with influenza A/PR8 virus. Am Rev Respir Dis 1986; 134:1040-4; PMID:3777666 McCullers JA, Rehg JE. Lethal synergism between influenza virus and Streptococcus pneumoniae:


74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

characterization of a mouse model and the role of platelet-activating factor receptor. J Infect Dis 2002; 186:341-50; PMID:12134230; http://dx.doi.org/ 10.1086/341462 Avadhanula V, Rodriguez CA, Devincenzo JP, Wang Y, Webby RJ, Ulett GC, Adderson EE. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner. J Virol 2006; 80:1629-36; PMID:16439519; http://dx.doi.org/10.1128/JVI.80. 4.1629-1636.2006 Jiang Z, Nagata N, Molina E, Bakaletz LO, Hawkins H, Patel JA. Fimbria-mediated enhanced attachment of nontypeable Haemophilus influenzae to respiratory syncytial virus-infected respiratory epithelial cells. Infect Immun 1999; 67:187-92; PMID:9864214 McNamee LA, Harmsen AG. Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection. Infect Immun 2006; 74:6707-21; PMID:16982840; http:// dx.doi.org/10.1128/IAI.00789-06 Colamussi ML, White MR, Crouch E, Hartshorn KL. Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria. Blood 1999; 93:2395-403; PMID:10090951 Small CL, Shaler CR, McCormick S, Jeyanathan M, Damjanovic D, Brown EG, Arck P, Jordana M, Kaushic C, Ashkar AA, et al. Influenza infection leads to increased susceptibility to subsequent bacterial superinfection by impairing NK cell responses in the lung. J Immunol 2010; 184:2048-56; PMID:20083661; http://dx.doi.org/10.4049/ jimmunol.0902772 Raza MW, Blackwell CC, Elton RA, Weir DM. Bactericidal activity of a monocytic cell line (THP-1) against common respiratory tract bacterial pathogens is depressed after infection with respiratory syncytial virus. J Med Microbiol 2000; 49:227-33; PMID:10707942 Sun K, Metzger DW. Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat Med 2008; 14:55864; PMID:18438414; http://dx.doi.org/10.1038/ nm1765 van der Sluijs KF, van Elden LJ, Nijhuis M, Schuurman R, Pater JM, Florquin S, Goldman M, Jansen HM, Lutter R, van der Poll T. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J Immunol 2004; 172:7603-9; PMID:15187140; http://dx. doi.org/10.4049/jimmunol.172.12.7603 Zhang Z, Clarke TB, Weiser JN. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Invest 2009; 119:1899-909; PMID:19509469 Dagan R, Givon-Lavi N, Fraser D, Lipsitch M, Siber GR, Kohberger R. Serum serotype-specific pneumococcal anticapsular immunoglobulin g concentrations after immunization with a 9-valent conjugate pneumococcal vaccine correlate with nasopharyngeal acquisition of pneumococcus. J Infect Dis 2005; 192:36776; PMID:15995949; http://dx.doi.org/10.1086/ 431679 Park SY, Moore MR, Bruden DL, Hyde TB, Reasonover AL, Harker-Jones M, Rudolph KM, Hurlburt DA, Parks DJ, Parkinson AJ, et al. Impact of conjugate vaccine on transmission of antimicrobial-resistant Streptococcus pneumoniae among Alaskan children. Pediatr Infect Dis J 2008; 27:335-40; PMID:18316986; http://dx.doi.org/ 10.1097/INF.0b013e318161434d Whitney CG, Pilishvili T, Farley MM, Schaffner W, Craig AS, Lynfield R, Nyquist AC, Gershman KA, Vazquez M, Bennett NM, et al. Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study. Lancet 2006; 368:1495-502;

3697

86.

87.

88.


89.

90.

91.

92.

93.

94.

95.

96.

97.

3698

PMID:17071283; http://dx.doi.org/10.1016/ S0140-6736(06)69637-2 Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, Takala A, K€ayhty H, Karma P, Kohberger R, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001; 344:403-9; PMID:11172176; http://dx.doi.org/ 10.1056/NEJM200102083440602 Malley R, Trzcinski K, Srivastava A, Thompson CM, Anderson PW, Lipsitch M. CD4C T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc Natl Acad Sci U S A 2005; 102:4848-53; PMID:15781870; http://dx.doi. org/10.1073/pnas.0501254102 Cohen JM, Khandavilli S, Camberlein E, Hyams C, Baxendale HE, Brown JS. Protective contributions against invasive Streptococcus pneumoniae pneumonia of antibody and Th17-cell responses to nasopharyngeal colonisation. PLoS One 2011; 6:e25558; PMID:22003400; http://dx.doi.org/10.1371/journal. pone.0025558 Mina MJ, Klugman KP, McCullers JA. Live attenuated influenza vaccine, but not pneumococcal conjugate vaccine, protects against increased density and duration of pneumococcal carriage after influenza infection in pneumococcal colonized mice. J Infect Dis 2013; 208:1281-5; PMID:23852122; http://dx. doi.org/10.1093/infdis/jit317 Ghaffar F, Barton T, Lozano J, Muniz LS, Hicks P, Gan V, Ahmad N, McCracken GH Jr. Effect of the 7-valent pneumococcal conjugate vaccine on nasopharyngeal colonization by Streptococcus pneumoniae in the first 2 years of life. Clin Infect Dis 2004; 39:9308; PMID:15472842; http://dx.doi.org/10.1086/ 423379 Rosenow C, Ryan P, Weiser JN, Johnson S, Fontan P, Ortqvist A, Masure HR. Contribution of novel choline-binding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae. Mol Microbiol 1997; 25:819-29; PMID:9364908; http:// dx.doi.org/10.1111/j.1365-2958.1997.mmi494.x Pracht D, Elm C, Gerber J, Bergmann S, Rohde M, Seiler M, Kim KS, Jenkinson HF, Nau R, Hammerschmidt S. PavA of Streptococcus pneumoniae modulates adherence, invasion, and meningeal inflammation. Infect Immun 2005; 73:2680-9; PMID:15845469; http://dx.doi.org/10.1128/IAI.73. 5.2680-2689.2005 Anderton JM, Rajam G, Romero-Steiner S, Summer S, Kowalczyk AP, Carlone GM, Sampson JS, Ades EW. E-cadherin is a receptor for the common protein pneumococcal surface adhesin A (PsaA) of Streptococcus pneumoniae. Microb Pathog 2007; 42:225-36; PMID:17412553; http://dx.doi.org/10.1016/j. micpath.2007.02.003 Arulanandam BP, Lynch JM, Briles DE, Hollingshead S, Metzger DW. Intranasal vaccination with pneumococcal surface protein A and interleukin-12 augments antibody-mediated opsonization and protective immunity against Streptococcus pneumoniae infection. Infect Immun 2001; 69:6718-24; PMID:11598043; http://dx.doi.org/10.1128/IAI.69. 11.6718-6724.2001 Harfouche C, Filippini S, Gianfaldoni C, Ruggiero P, Moschioni M, Maccari S, Pancotto L, Arcidiacono L, Galletti B, Censini S, et al. RrgB321, a fusion protein of the three variants of the pneumococcal pilus backbone RrgB, is protective in vivo and elicits opsonic antibodies. Infect Immun 2012; 80:451-60; PMID:22083702; http://dx. doi.org/10.1128/IAI.05780-11 Ren B, Szalai AJ, Hollingshead SK, Briles DE. Effects of PspA and antibodies to PspA on activation and deposition of complement on the pneumococcal surface. Infect Immun 2004; 72:114-22; PMID:14688088; http://dx.doi.org/10.1128/IAI.72. 1.114-122.2004 Melin M, Di Paolo E, Tikkanen L, Jarva H, Neyt C, Kayhty H, Meri S, Poolman J, V€akev€ainen M.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

Interaction of pneumococcal histidine triad proteins with human complement. Infect Immun 2010; 78:2089-98; PMID:20194599; http://dx.doi.org/ 10.1128/IAI.00811-09 Kaur R, Casey JR, Pichichero ME. Serum antibody response to five Streptococcus pneumoniae proteins during acute otitis media in otitis-prone and non-otitis-prone children. Pediatr Infect Dis J 2011; 30:64550; PMID:21487325; http://dx.doi.org/10.1097/ INF.0b013e31821c2d8b McCool TL, Cate TR, Moy G, Weiser JN. The immune response to pneumococcal proteins during experimental human carriage. J Exp Med 2002; 195:359-65; PMID:11828011; http://dx.doi.org/ 10.1084/jem.20011576 Ferreira DM, Neill DR, Bangert M, Gritzfeld JF, Green N, Wright AK, Pennington SH, Bricio-Moreno L, Moreno AT, Miyaji EN, et al. Controlled human infection and rechallenge with Streptococcus pneumoniae reveals the protective efficacy of carriage in healthy adults. Am J Respir Crit Care Med 2013; 187:855-64; PMID:23370916; http://dx.doi.org/ 10.1164/rccm.201212-2277OC Reiner SL. Decision making during the conception and career of CD4C T cells. Nat Rev Immunol 2009; 9:81-2; PMID:19172726; http://dx.doi.org/10.1038/ nri2490 Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis 1999; 5:285-94; PMID:10579123; http://dx.doi.org/ 10.1097/00054725-199911000-00009 Jankovic D, Liu Z, Gause WC. Th1- and Th2-cell commitment during infectious disease: asymmetry in divergent pathways. Trends Immunol 2001; 22:4507; PMID:11473835; http://dx.doi.org/10.1016/ S1471-4906(01)01975-5 Curtis MM, Way SS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology 2009; 126:177-85; PMID:19125888; http://dx.doi.org/10.1111/j.1365-2567.2008.03017.x Harboe ZB, Thomsen RW, Riis A, Valentiner-Branth P, Christensen JJ, Lambertsen L, Krogfelt KA, Konradsen HB, Benfield TL. Pneumococcal serotypes and mortality following invasive pneumococcal disease: a population-based cohort study. PLoS medicine 2009; 6:e1000081; PMID:19468297; http://dx.doi.org/ 10.1371/journal.pmed.1000081 Lujan M, Gallego M, Belmonte Y, Fontanals D, Valles J, Lisboa T, Rello J. Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia. Eur Respir J 2010; 36:1073-9; PMID:20150202; http://dx.doi.org/10.1183/ 09031936.00176309 Sjostrom K, Spindler C, Ortqvist A, Kalin M, Sandgren A, Kuhlmann-Berenzon S, Henriques-Normark B. Clonal and capsular types decide whether pneumococci will act as a primary or opportunistic pathogen. Clin Infect Dis 2006; 42:451-9; PMID:16421787; http://dx.doi.org/10.1086/499242 Wright AK, Bangert M, Gritzfeld JF, Ferreira DM, Jambo KC, Wright AD, Collins AM, Gordon SB. Experimental human pneumococcal carriage augments IL-17A-dependent T-cell defence of the lung. PLoS Pathog 2013; 9:e1003274; PMID:23555269; http://dx.doi.org/10.1371/journal.ppat.1003274 Sharma SK, Casey JR, Pichichero ME. Reduced memory CD4C T-cell generation in the circulation of young children may contribute to the otitis-prone condition. J Infect Dis 2011; 204:645-53; PMID:21791667; http://dx.doi.org/10.1093/infdis/ jir340 Sharma SK, Roumanes D, Almudevar A, Mosmann TR, Pichichero ME. CD4C T-cell responses among adults and young children in response to Streptococcus pneumoniae and Haemophilus influenzae vaccine candidate protein antigens. Vaccine 2013; 31:3090-7; PMID:23632305; http://dx.doi.org/10.1016/j. vaccine.2013.03.060


111. Lundgren A, Bhuiyan TR, Novak D, Kaim J, Reske A, Lu YJ, Qadri F, Malley R. Characterization of Th17 responses to Streptococcus pneumoniae in humans: comparisons between adults and children in a developed and a developing country. Vaccine 2012; 30:3897-907; PMID:22504663; http://dx.doi.org/ 10.1016/j.vaccine.2012.03.082 112. Mureithi MW, Finn A, Ota MO, Zhang Q, Davenport V, Mitchell TJ, Williams NA, Adegbola RA, Heyderman RS. T cell memory response to pneumococcal protein antigens in an area of high pneumococcal carriage and disease. J Infect Dis 2009; 200:783-93; PMID:19642930; http://dx.doi.org/10.1086/605023 113. Gray C, Ahmed MS, Mubarak A, Kasbekar AV, Derbyshire S, McCormick MS, Mughal MK, McNamara PS, Mitchell T, Zhang Q. Activation of memory Th17 cells by domain 4 pneumolysin in human nasopharynx-associated lymphoid tissue and its association with pneumococcal carriage. Mucosal Immunol 2014; 7:705-17; PMID:24220296; http://dx.doi.org/ 10.1038/mi.2013.89 114. Angelone DF, Wessels MR, Coughlin M, Suter EE, Valentini P, Kalish LA, Levy O. Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-a production in vitro and in vivo. Pediatr Res 2006; 60:205-9; PMID:16864705; http://dx.doi.org/10.1203/01.pdr.0000228319. 10481.ea 115. Vanden Eijnden S, Goriely S, De Wit D, Goldman M, Willems F. Preferential production of the IL-12 (p40)/IL-23(p19) heterodimer by dendritic cells from human newborns. Eur J Immunol 2006; 36:21-6; PMID:16342235; http://dx.doi.org/10.1002/ eji.200535467 116. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 2007; 7:379-90; PMID:17457344; http://dx.doi.org/ 10.1038/nri2075 117. Bogaert D, Weinberger D, Thompson C, Lipsitch M, Malley R. Impaired innate and adaptive immunity to Streptococcus pneumoniae and its effect on colonization in an infant mouse model. Infect Immun 2009; 77:1613-22; PMID:19168741; http://dx.doi.org/ 10.1128/IAI.00871-08 118. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol 2004; 4:553-64; PMID:15229474; http://dx.doi.org/ 10.1038/nri1394 119. Schaub B, Liu J, Schleich I, Hoppler S, Sattler C, von Mutius E. Impairment of T helper and T regulatory cell responses at birth. Allergy 2008; 63:1438-47; PMID:18925880; http://dx.doi.org/10.1111/j.13989995.2008.01685.x 120. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, Lavoie PM, Furlong J, Fortuno ES 3rd, Hajjar AM, et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol 2009; 183:7150-60; PMID:19917677; http://dx.doi.org/10.4049/ jimmunol.0901481 121. Szabo SJ, Dighe AS, Gubler U, Murphy KM. Regulation of the interleukin (IL)-12R b 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 1997; 185:817-24; PMID:9120387; http:// dx.doi.org/10.1084/jem.185.5.817 122. Marwaha AK, Leung NJ, McMurchy AN, Levings MK. TH17 Cells in Autoimmunity and Immunodeficiency: Protective or Pathogenic? Frontiers in immunology 2012; 3:129; PMID:22675324; http://dx.doi. org/10.3389/fimmu.2012.00129 123. Pichichero ME. Challenges in vaccination of neonates, infants and young children. Vaccine 2014; 32:3886-94; PMID:24837502; http://dx.doi.org/ 10.1016/j.vaccine.2014.05.008 124. Vu HT, Yoshida LM, Suzuki M, Nguyen HA, Nguyen CD, Nguyen AT, Oishi K, Yamamoto T, Watanabe K, Vu TD. Association between nasopharyngeal load of Streptococcus pneumoniae, viral

Volume 10 Issue 12

125.

126.

127.


128.

129.

130.

131.

132.

coinfection, and radiologically confirmed pneumonia in Vietnamese children. Pediatr Infect Dis J 2011; 30:11-8; PMID:20686433; http://dx.doi.org/ 10.1097/INF.0b013e3181f111a2 Kollmann TR, Levy O, Montgomery RR, Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 2012; 37:771-83; PMID:23159225; http://dx.doi. org/10.1016/j.immuni.2012.10.014 Belderbos ME, van Bleek GM, Levy O, Blanken MO, Houben ML, Schuijff L, Kimpen JL, Bont L. Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life. Clin Immunol 2009; 133:228-37; PMID:19648060; http://dx.doi.org/10.1016/j.clim. 2009.07.003 Chang SY, Ko HJ, Kweon MN. Mucosal dendritic cells shape mucosal immunity. Exp Mol Med 2014; 46:e84; PMID:24626170; http://dx.doi.org/10.1038/ emm.2014.16 Bettelli E, Korn T, Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 2007; 19:652-7; PMID:17766098; http:// dx.doi.org/10.1016/j.coi.2007.07.020 Kim KH, Hong JY, Lee H, Kwak GY, Nam CH, Lee SY, Oh E, Yu J, Nahm MH, Kang JH. Nasopharyngeal pneumococcal carriage of children attending day care centers in Korea: comparison between children immunized with 7-valent pneumococcal conjugate vaccine and non-immunized. J Korean Med Sci 2011; 26:184-90; PMID:21286007; http://dx.doi.org/ 10.3346/jkms.2011.26.2.184 Dagan R, Patterson S, Juergens C, Greenberg D, Givon-Lavi N, Porat N, Gurtman A, Gruber WC, Scott DA. Comparative immunogenicity and efficacy of 13-valent and 7-valent pneumococcal conjugate vaccines in reducing nasopharyngeal colonization: a randomized double-blind trial. Clin Infect Dis 2013; 57:952-62; PMID:23804191; http://dx.doi.org/ 10.1093/cid/cit428 Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, Takala A, K€ayhty H, Karma P, Kohberger R, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001; 344:403-9; PMID:11172176; http://dx.doi.org/ 10.1056/NEJM200102083440602 Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, Elvin L, Ensor KM, Hackell J, Siber G,


133.

134.

135.

136.

137.

138.

et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000; 19:187-95; PMID:10749457; http://dx.doi.org/ 10.1097/00006454-200003000-00003 Prymula R, Hanovcova I, Splino M, Kriz P, Motlova J, Lebedova V, Lommel P, Kaliskova E, Pascal T, Borys D, et al. Impact of the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) on bacterial nasopharyngeal carriage. Vaccine 2011; 29:1959-67; PMID:21215830; http://dx.doi.org/10.1016/j. vaccine.2010.12.086 Hammitt LL, Ojal J, Bashraheil M, Morpeth SC, Karani A, Habib A, Borys D, Goldblatt D, Scott JA. Immunogenicity, impact on carriage and reactogenicity of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in Kenyan children aged 1-4 years: a randomized controlled trial. PloS One 2014; 9:e85459; PMID:24465570; http://dx.doi.org/10.1371/journal. pone.0085459 Scotta MC, Veras TN, Klein PC, Tronco V, Polack FP, Mattiello R, Pitrez PM, Jones MH, Stein RT, Pinto LA. Impact of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on childhood pneumonia hospitalizations in Brazil two years after introduction. Vaccine 2014; 32:4495-9; PMID:24958703; http://dx. doi.org/10.1016/j.vaccine.2014.06.042 Cohen R, Levy C, Bingen E, Koskas M, Nave I, Varon E. Impact of 13-valent pneumococcal conjugate vaccine on pneumococcal nasopharyngeal carriage in children with acute otitis media. Pediatr Infect Dis J 2012; 31:297-301; PMID:22330166; http://dx.doi.org/10.1097/INF.0b013e318247ef84 Harboe ZB, Dalby T, Weinberger D, Benfield T, Molbak K, Slotved HC, Suppli CH, Konradsen HB, Valentiner-Branth P. Impact of 13-valent pneumococcal conjugate vaccination in invasive pneumococcal disease incidence and mortality. Clin Infect Dis 2014; 59(8):1066-73; PMID:25034421; http://dx.doi.org/ 10.1093/cid/ciu524 Becker-Dreps S, Amaya E, Liu L, Moreno G, Rocha J, Briceno R, Aleman J, Hudgens MG, Woods CW, Weber DJ. Changes in childhood pneumonia and infant mortality rates following introduction of the 13-valent pneumococcal conjugate vaccine in


139.

140.

141.

142.

143.

144.

145.

Nicaragua. Pediatr Infect Dis J 2014; 33:637-42; PMID:24445827; http://dx.doi.org/10.1097/INF. 0000000000000269 Verhoeven D, Xu Q, Pichichero ME. Vaccination with a Streptococcus pneumoniae trivalent recombinant PcpA, PhtD and PlyD1 protein vaccine candidate protects against lethal pneumonia in an infant murine model. Vaccine 2014; 32:3205-10; PMID:24731814; http://dx.doi.org/10.1016/j. vaccine.2014.04.004 Ogunniyi AD, Woodrow MC, Poolman JT, Paton JC. Protection against Streptococcus pneumoniae elicited by immunization with pneumolysin and CbpA. Infect immun 2001; 69:5997-6003; PMID:11553536; http:// dx.doi.org/10.1128/IAI.69.10.5997-6003.2001 Briles DE, King JD, Gray MA, McDaniel LS, Swiatlo E, Benton KA. PspA, a protection-eliciting pneumococcal protein: immunogenicity of isolated native PspA in mice. Vaccine 1996; 14:858-67; PMID:8843627; http://dx.doi.org/10.1016/0264410X(96)82948-3 Goulart C, da Silva TR, Rodriguez D, Politano WR, Leite LC, Darrieux M. Characterization of protective immune responses induced by pneumococcal surface protein A in fusion with pneumolysin derivatives. PloS One 2013; 8:e59605; PMID:23533636; http:// dx.doi.org/10.1371/journal.pone.0059605 Badens C, Jassim N, Martini N, Mattei JF, Elion J, Lena-Russo D. Characterization of a new polymorphism, IVS-I-108 (T–>C), and a new b-thalassemia mutation, -27 (A–>T), discovered in the course of a prenatal diagnosis. Hemoglobin 1999; 23:339-44; PMID:10569722; http://dx.doi.org/10.3109/ 03630269909090749 Lu YJ, Forte S, Thompson CM, Anderson PW, Malley R. Protection against Pneumococcal colonization and fatal pneumonia by a trivalent conjugate of a fusion protein with the cell wall polysaccharide. Infect Immun 2009; 77:2076-83; PMID:19255193; http:// dx.doi.org/10.1128/IAI.01554-08 Lu YJ, Leite L, Goncalves VM, Dias Wde O, Liberman C, Fratelli F, Alderson M, Tate A, Maisonneuve JF, Robertson G, et al. GMP-grade pneumococcal wholecell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis. Vaccine 2010; 28:7468-75; PMID:20858450; http:// dx.doi.org/10.1016/j.vaccine.2010.09.031

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Immune modulation by helminth parasites of ruminants: implications for vaccine development and host immune competence.

Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis.

Pneumococcal vaccine: development and prospects.

HIV-Host Interactions: Implications for Vaccine Design.

Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design.

The mucosal immune system for vaccine development.

Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children.

Incidence of Pneumococcal Pneumonia Among Adults in Rural Thailand, 2006-2011: Implications for Pneumococcal Vaccine Considerations.

Antigen delivery systems for analysing host immune responses and for vaccine development.

Immune correlates for dengue vaccine development.

Unveiling Unexpected Immune Activities Induced by Your Pneumococcal Vaccine.

Pneumococcal vaccine for elderly people.

The Pneumococcal Alpha-Glycerophosphate Oxidase Enhances Nasopharyngeal Colonization through Binding to Host Glycoconjugates.

Candida antigens and immune responses: implications for a vaccine.

Pneumococcal vaccine.

Novel immunotherapy vaccine development.

Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau.

Development of Ophiocordyceps sinensis through Plant-Mediated Interkingdom Host Colonization.

Animal models for influenza viruses: implications for universal vaccine development.

Pneumococcal Disease in the Era of Pneumococcal Conjugate Vaccine.

Trial of pneumococcal vaccine for asplenic patients.

Implications of enterotoxigenic Escherichia coli genomics for vaccine development.

Anaphylaxis to pneumococcal vaccine; CRM(197): Novel cause of vaccine allergy.

Pneumococcal Colonization in the Familial Context and Implications for Anti-Pneumococcal Immunization in Adults: Results from the BINOCOLO Project in Sicily.