REVIEW Human Vaccines & Immunotherapeutics 12:2, 383--392; February 2016; © 2016 Taylor & Francis Group, LLC

Rationale and prospects for novel pneumococcal vaccines Kristin Moffitt and Richard Malley* 1

Division of Infectious Diseases; Department of Medicine; Boston Children’s Hospital; Boston, MA USA

Keywords: antibody, pneumococcus, pneumococcal colonization, Streptococcus pneumoniae, serotype-independent vaccines, TH17 cells

Streptococcus pneumoniae remains one of the most frequent bacterial causes of morbidity and mortality worldwide. National immunization programs implementing pneumococcal polysaccharide conjugate vaccines (PCVs) have successfully reduced rates of vaccine-type invasive disease and colonization both via direct effects in immunized children and, in some settings, indirect effects in unimmunized individuals. Limitations of the current PCV approach include the emergence of nonvaccine serotypes contributing to carriage and invasive disease in high-PCV coverage settings and the high cost of goods of PCVs which limits their accessibility in developing countries where the burden of disease remains highest. Furthermore, the distribution of serotypes causing disease varies geographically and includes more serotypes than are currently covered in a single PCV formulation. Researchers have long been exploring the potential of genetically conserved non-capsular pneumococcal antigens as vaccine candidates that might overcome such limitations. To better evaluate the rationale of such approaches, an understanding of the mechanisms of immunity to the various phases of pneumococcal infection is of paramount importance. Herein we will review the evolving understanding of both vaccine-induced and naturally acquired immunity to pneumococcal colonization and infection and discuss how this informs current approaches using serotypeindependent pneumococcal vaccine candidates. We will then review the alternative vaccine candidates that have been or are currently under evaluation in clinical trials.

Introduction Streptococcus pneumoniae causes a range of diseases including invasive infections such as bacteremia with sepsis and meningitis, as well as the more common mucosal site infections such as pneumonia, otitis media and sinusitis. Invasive pneumococcal disease (IPD), including pulmonary infection, impacts those at the extremes of age, with the highest rates of disease in young children and the elderly. S. pneumoniae is the most common cause of severe bacterial pneumonia in children1 and IPD is one of the most common causes of mortality in children worldwide with *Correspondence to: Richard Malley; Email: [email protected]. edu Submitted: 06/08/2015; Revised: 08/07/2015; Accepted: 08/22/2015 http://dx.doi.org/10.1080/21645515.2015.1087625

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the majority of these deaths occurring in low-income countries.2 Countries that have implemented programs to immunize infants with PCVs (PCV 7-, 10- and 13-valent; Prevnar7Ò , SynflorixÒ and Prevnar 13Ò , from Wyeth, GlaxoSmithKline, and Pfizer, respectively) have seen dramatic reduction in rates of IPD and carriage attributable to serotypes included in the PCVs (vaccine types; VT). Importantly, recent nasopharyngeal carriage is required for establishing pneumococcal disease and nasopharyngeal colonization (short or longer term) represents the reservoir from which pneumococci are transmitted human-to-human. A major beneficial indirect effect of PCV immunization programs has been the significant reduction in rates of VT-carriage and also IPD in unvaccinated individuals in areas of high PCV-coverage.3-5 The impact of this indirect effect (also referred to as herd or community protection) has been so significant that some have argued that the clinical trials and licensure of future pneumococcal vaccines should include evaluations of any effect on carriage.6,7 Despite the remarkable successes of PCVs, some limitations have been noted. First, the clinical efficacy of PCVs at preventing the most common manifestations of pneumococcal disease, namely otitis media and pneumonia, are more difficult to ascertain directly given the difficulties in firmly establishing these diagnoses. Secondly, post-licensure surveillance studies of carriage and IPD isolates following the introduction of PCV7 (and, to a lesser extent PCV10 and PCV13) programs have demonstrated a rise in rates of carriage and subsequently IPD attributable to non-vaccine serotypes (non-vaccine types; NVT).8-12 As there are over 90 different pneumococcal serotypes, with humans being the primary hosts of pneumococcus, the emergence of NVT had been predicted before the licensure of the first pneumococcal conjugate vaccine.13 Furthermore, although strategies such as the advance market commitment have now made PCVs available in many countries, the cost of goods of PCVs threatens to limit their availability in the long run. About 40% of the Global Alliance for Vaccine Initiative (GAVI) is currently dedicated to the provision of PCVs to lower income countries at a cost of $3.50 per dose;14 therefore, an effective pneumococcal vaccine that would be 50% less expensive could in theory allow for the introduction for another vaccine in GAVI-eligible countries. For all of these reasons, a serotype-independent pneumococcal vaccine approach is an important global health priority. One of the most practical means of achieving this includes immunization with non-capsular pneumococcal antigens that are

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highly immunogenic and conserved across all serotypes, antigens against which children often naturally develop antibodies within the first 2 years of life.15-17 At present, it is likely that regulatory pathways for such alternative vaccines may require the demonstration of non-inferiority to PCVs in prevention of bacteremia and meningitis, which would likely require over a hundred thousand infants. Instead, evidence of efficacy against pneumococcal carriage, which could be demonstrated in much smaller clinical trials, may be an important element to consider in the licensure of such vaccines.6,7 To facilitate discussion of the non-PCV approaches currently under evaluation, we will first review the mechanisms of immunity to the various phases of pneumococcal pathogenesis, from carriage to invasive disease. Current vaccines and their immune correlates Given the lack of immunogenicity of pure polysaccharides (which are, for the most part, T-cell independent antigens) in infants, PCVs, in which the polysaccharides are each conjugated to a protein carrier, were developed following the remarkable success of the Haemophilus influenzae type B polysaccharide conjugates.18-21 Linkage of the polysaccharide to a protein carrier elicits CD4C T-cell help to elicit durable and boostable memory serotype-specific antibody responses.22,23 Currently available pneumococcal vaccines include the PCVs, administered to infants and children as part of routine vaccination schedules, and PneumovaxÒ (Merck), a 23-valent vaccine comprised of pure polysaccharides used predominantly in adults over the age of 65 (now in conjunction with PCVs). In PCV-immunized individuals, serotype-specific antibody concentrations24 and opsonophagocytic antibody (OPA) levels25 have been measured as correlates of protection against VT invasive and non-invasive pneumococcal disease as well as prevention of carriage with VT pneumococci.26,27 Indeed, the vast experience with anticapsular antibody and OPA levels in the assessment of immunogenicity of polysaccharide-based vaccines has corroborated their utility in predicting serotype-specific protection in immunized individuals. However, acquisition of natural immunity to pneumococcal infections in healthy children and the examples of immunodeficiency in humans with increased susceptibility to pneumococcal infections support the relevance of immune mechanisms other than anticapsular antibody. Immunity to invasive disease The remarkable success of the PCVs in reducing VT IPD validates the concept that anticapsular antibody is sufficient for prevention of IPD. More historical support for the role of anticapsular antibody is suggested by the use of animal antisera raised to polysaccharides for treatment of pneumococcal disease in the early 20th century.26,27 The notion that anticapsular antibody may not represent the only or even main natural mechanism of acquired immunity to IPD was corroborated by several epidemiological findings. Prior to the introduction of PCVs, agerelated decreases in rates of IPD preceded the development of measureable serotype-specific antibody.29 Furthermore, invasive disease incidence peaks at around 10 months of age and then drops by 50% over the following year, at a rate that is similar

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across all serotypes, arguing in favor of a serotype-independent mechanism rather than one which depends on near simultaneous acquisition of immunity to all polysaccharides.29 One possible mechanism of natural immunity may be the acquisition of functional antibodies to non-capsular conserved antigens, following repeated mucosal exposure to pneumococci, although it should be pointed out that conclusive evidence for a role of this type of immunity has not yet been obtained. However, while a protective role of antibodies to conserved pneumococcal proteins has not been conclusively shown in humans, preclinical evaluation of many of these proteins has demonstrated the efficacy of passive transfer of immune sera in preventing sepsis and fatal pneumonia in mice, often against multiple serotypes of pneumococci (reviewed below). The protection conferred by active immunization with protein antigens can be synergistically enhanced by the combination of 2 or more proteins. It has further been proposed that protein-subunit approaches would benefit from the inclusion of several common proteins to minimize the possibility of immune escape, which pneumococci are apt to do.30,31 Pneumococcal vaccine development efforts thus far have focused on the generation of antibodies (capsular or noncapsular) to prevent IPD, a strategy that is supported by the increased susceptibility to IPD in patients with defects in humoral immunity, such as agammaglobulinemia and functional or anatomic asplenia.28,32 However, the finding that the risk of IPD in HIVinfected individuals is inversely correlated with CD4C T-cell count33 suggests a role for non-antibody-mediated mechanisms of acquired immunity to IPD. Indeed, although CD4C T-cells facilitate the generation of memory B cells and their absence could account for defective antibody production, the increased susceptibility of not only pediatric, but also adult AIDS patients with low CD4C cell counts, suggests a potential protective role of CD4 cells independent of antibodies. Immunity to mucosal infection While PCVs have confirmed that anticapsular antibodies are highly effective in the prevention of IPD, their efficacy in preventing mucosal disease, while arguably more difficult to accurately measure, is less clear. Furthermore, the role of mucosal immunoglobulin, comprised of IgG and IgA, in prevention of disease at sites of mucosal infection (middle ear, sinus and respiratory epithelium) is less clearly established than the role of opsonophagocytic IgG in the prevention of IPD. Efforts to evaluate the effect of PCV on acute otitis media (AOM) were undertaken following the introduction of PCV7 in Finland, and showed 57% efficacy against VT AOM,34 significant protection but well below the reported efficacy of this vaccine against IPD (about 94% by intent-to-treat analysis).35 Review of available data using the World Health Organization (WHO) criteria for diagnosing pediatric pneumonia estimated the efficacy of PCVs at reducing radiographically confirmed pneumonia as 27% and clinical pneumonia as 6%.36 The effect of PCV on prevention of radiographically confirmed pneumonia was the primary outcome evaluated in a study in the Philippines; the efficacy of the PCV in preventing pneumonia in children in the first 2 years of life was 23%.37 Most recently, data from the Community-Acquired

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Pneumonia Immunization Trial in Adults (CAPITA) study revealed a reduction in the relative risk of vaccine-strain-related pneumococcal pneumonia of 45.6% and in the relative risk of invasive pneumococcal disease of 75%.38 While these results are encouraging, it has been pointed out that, due to the diversity of serotypes that caused pneumococcal pneumonia in the adults in this trial, there was no demonstrable efficacy against noninvasive pneumococcal community-acquired pneumonia, all-cause pneumonia or death.39-41 Taken together, and recognizing the inherent difficulties in accurately determining the efficacy of PCVs in the control of pneumococcal mucosal disease, these findings do suggest that the current PCVs may not be sufficient for protection against mucosal (primarily pneumonic) pneumococcal infections. Three large clinical trials have evaluated the efficacy of PCVs in the prevention of acute otitis media (AOM):42-44 overall these studies suggested a similar reduction in vaccine-type AOM between 56–67%. Determination of the impact of PCVs on AOM following their implementation is more difficult, however, because the etiology of this disease is varied, the diagnosis is often subjective, and the more definitive diagnostic procedure, tympanocentesis, is rarely performed in practice. Thus while studies have certainly suggested an impact of PCVs on AOM, the magnitude of this impact and the extent to which it may be affected by serotype replacement is difficult to ascertain. Several studies have demonstrated an association between the development of serum antibodies to many of the known pneumococcal virulence factors and episodes of AOM,15,45 but the role of these antibodies in protection against future episodes of AOM and the correlation of serum and mucosal antibody levels remain unclear. More recent evaluation of IgG and IgA directly from nasopharyngeal and middle-ear fluid suggests that acquisition of higher mucosal levels of antibody to several pneumococcal virulence factors was associated with a reduction in pneumococcal AOM episodes in children.46 A role for antibody to non-capsular antigens in immunity to pneumococcal pneumonia has also been suggested from animal studies demonstrating enhanced survival following lung infection in mice treated with sera raised against several pneumococcal proteins (reviewed below). At the same time, a role for TH17-mediated immunity to pneumococcal pneumonia has been suggested by the recent identification of the mutations causing Autosomal Dominant Hyper IgE Syndrome (HIES), also known as Job’s syndrome. In addition to recurrent skin candidal and staphylococcal infections, these patients suffer from recurrent lung infections, with bacterial etiologies split equally between pneumococcus and Staphylococcus aureus.47 Patients with HIES have one of several mutations in the gene encoding the signal transducer and activator of transcription factor 3 (stat3). STAT3, among many other roles, is required for the differentiation of memory TH17 cells.48,49 TH17 cells are CD4C T-cells that secrete IL-17 and other effector cytokines with neutrophil-recruiting function, resulting in enhanced phagocytosis and killing of extracellular organisms. The list of mucosal site pathogens for which a role of IL-17-mediated immunity has been documented is growing.50,51 Studies are needed to evaluate whether pneumococcal protein-specific

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CD4C T-cells can confer immunity to pneumonia and other mucosal forms of pneumococcal disease to more clearly establish the role of cellular immunity in these infections. Immunity to colonization One of the most impressive consequences of universal PCV immunization programs has been the indirect effect of reduced IPD and carriage in unimmunized individuals.5 Reduced rates of carriage of VT pneumococci in post-licensure PCV studies have correlated with serotype-specific OPA and IgG titers26,27 suggesting the role of anticapsular antibody in immunity to carriage. Preclinical evaluation of several protein candidates has included demonstration of reduction of colonization in mice following passive transfer of naturally occurring protein-specific antibody isolated from sera of adults either experimentally or naturally colonized (reviewed below) thereby supporting a role for non-capsular antibody in prevention of carriage. Studies of acquisition of mucosal protein-specific antibody levels in children have been performed but have lacked clear data to associate these levels with pneumococcal carriage (reviewed in ref. 52). Intentional human experimental carriage studies in adults53,54 hold significant potential for further evaluation of the role of non-capsular antibody in clearance of carriage. As will be reviewed below, there should also be carriage data forthcoming from several of the ongoing clinical trials of protein-subunit and whole cell vaccine candidates that may provide further insight on this issue. Several studies in genetically modified mice shed light on the likely role of non-antibody mediated mechanisms of clearance of colonization. Mice lacking mature B-cells (mMT¡/- mice) showed no defect in clearance of primary colonization,55 in contrast to mice with severe combined immunodeficiency (SCID) or lacking major histocompatibility complex-II (required for antigen presentation to CD4C T-cells),56 suggesting little role of antibody in clearance of primary carriage. Further evaluation of adaptive immune responses revealed that the immunity to colonization conferred by either immunization with an unencapsulated killed whole cell vaccine (WCV),57,58 or following a primary colonization event,59 required CD4C T-cells and the cytokine IL17A. Since then, several vaccines tested in mice have elicited protection against colonization in a CD4C T-cell- and IL-17dependent manner, including a vaccine comprised of the zwitterionic cell wall polysaccharide,60 and another containing proteins identified from a screen for TH17 antigens.61 Non-capsular vaccine approaches previously or currently under evaluation in humans Conserved pneumococcal proteins The majority of well-studied protein candidates are pneumococcal virulence factors and well-conserved surface expressed antigens with the additional advantage of potential antibody accessibility. Antigen discovery platforms, using either reverse vaccinology (using genetic sequence signals to predict surface localization) or proteomic screens for B- and T-cell targets have identified an array of pneumococcal proteins for exploration of their potential as immunogens. While there are many promising

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pneumococcal proteins undergoing preclinical evaluation as possible vaccine candidates (reviewed in ref. 62-65), we will focus this discussion on those that have been evaluated or are currently under evaluation as components of protein-subunit vaccines in humans. The reader is also directed to Table 1 for a summary of vaccines for which publically available data indicate previous or current clinical evaluation. Pneumococcal surface protein A One of the best studied antigens to date is pneumococcal surface protein A (PspA), a surface expressed choline-binding protein that contributes to immune evasion by inhibiting the deposition of complement on the bacterial cell surface.66-68 When administered as a recombinant immunogen to mice, PspA provides protection in models of sepsis, pneumonia, and carriage.69 Despite sequence-variability within the immunodominant region of PspA, anti-PspA antibodies elicited during experimental human carriage have been shown to be highly cross-reactive,70 as were antibodies elicited during a phase 1 trial of PspA immunization in adults.71 Sera from PspA-immunized human subjects also protected mice from sepsis following challenge with pneumococci expressing heterologous PspA,72 thus suggesting that a vaccine strategy aimed at generating antibodies to this protein may have protective potential in humans, although more definitive evidence is lacking. Following promising phase 1 trial results, concerns were raised regarding areas of low sequence homology between PspA and human cardiac myosin and the possibility of inducing cardiac auto-immunity.73 While there is neither strong nor conclusive evidence supporting such a concern, further evaluation of PspA as a vaccine candidate was then placed on hold. Pneumolysin Another well-studied pneumococcal protein is pneumolysin (Ply), a cholesterol-dependent pore-forming cytolysin and pneumococcal virulence factor. Many variations of Ply toxoids, or pneumolysoid constructs, have been evaluated in animal models of disease. The majority of these studies have shown some degree of multi-serotype protection against invasive disease (lung infection and sepsis) when pneumolysin is administered either alone74 or more often in combination with other pneumococcal proteins. Immunity to pneumolysin has not traditionally been thought to confer protection against nasopharyngeal colonization, but an association between maternal antibodies against Ply and delayed onset in acquisition of pneumococcal carriage in infants has been shown.16,75 More recently, studies in mice demonstrated that passive transfer of naturally occurring Ply-antibody isolated from human sera conferred a significant reduction in colonization in mice.76 One advantage of immunization studies with pneumolysoid constructs is the ability to use a functional antibody assay to measure the capacity of sera to neutralize pneumolysin-mediated hemolysis.77 A phase 1 trial of a monovalent genetically detoxified pneumolysoid (PlyD1) sponsored by Sanofi Pasteur (ClinicalTrails.gov Identifier: NCT01444352) showed dose-related increases in PlyD1-specific IgG and neutralization capacity in adults.78 The most advanced clinical trials with Ply constructs

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have included co-administration with pneumococcal histidine triad protein D (PhtD) and are described below. Pneumococcal histidine triad proteins This family of surface-expressed proteins (PhtA, PhtB, PhtD, and PhtE) sharing a characteristic histidine triad motif was initially identified based on their genomic signal targeting surfaceexpression.79 Recombinant PhtA, PhtB, and PhtD proteins were subsequently found to confer protection against multi-serotype invasive disease in mice.80 Preclinical evaluation of several of the Pht proteins as immunogens in mice demonstrated efficacy against intranasal colonization and enhanced survival following a pneumonia challenge was observed in mice administered either recombinant PhtD or naturally occurring anti-PhtD antibodies isolated from human sera.81 Further in vitro studies of PhtD antibodies suggest that these proteins contribute to pneumococcal adhesion to epithelial cells.76,82 While immunization of mice with PhtD appears to elicit antigen-specific CD4C T-cell responses, the role of these cells in PhtD-mediated immunity remains to be explored.83 Clinical trials of protein-subunit vaccines including PhtD have been completed or are underway with several sponsors. GlaxoSmithKline, in collaboration with PATH and the Gambian Department of Health, has sponsored a phase 2 trial of PhtD and a chemically detoxified pneumolysin, dPly, co-administered with routine immunizations including PCV10 in Gambian children and infants (ClinicalTrials.gov Identifier: NCT01262872). IgG responses to the 2 proteins were demonstrated in toddlers;84 immunogenicity data in infants and comparison of post-immunization rates of carriage of NVT should be available in the near future. A similar phase 2 GSK-sponsored trial of PhtD and dPly co-administered with PCV10 was completed in Europe; robust IgG responses to the vaccine candidates were demonstrated in infants (ClinicalTrials.gov Identifier: NCT01204658).85 In Bangladesh, Sanofi Pasteur has also sponsored a phase 1 evaluation of a dose-escalated trivalent proteinsubunit vaccine comprised of PhtD, PlyD1, and pneumococcal choline-binding protein A (PcpA) co-administered to infants with routine vaccines (ClinicalTrials.gov Identifier: NCT01764126). At the time of this writing, no published results are yet available from this study. Previously, Sanofi Pasteur sponsored a phase 1 study of the same 3 proteins administered without concurrent vaccines to infants in Bangladesh (ClinicalTrials. gov Identifier: NCT01446926); a three-dose series was well tolerated and elicited robust dose-related antibody responses to the proteins.86 Pneumococcal choline-binding protein A Another pneumococcal virulence factor, PcpA, has been shown to facilitate adherence of pneumococcus to epithelial cells.76,87 Studies of recombinant PcpA immunization of mice demonstrated protective efficacy against pneumonia and sepsis challenge.88 While anti-PcpA antibodies decreased adherence of pneumococci to epithelial cells in vitro, there is no evidence of PcpA efficacy against nasopharyngeal colonization in animal models;76 this may due to the manganese-dependent regulation of PcpA expression and unfavorable manganese concentrations in

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Sepsis and pneumonia (93)

Carriage (61, 97)

Top antibody targets identified from proteomic screens using convalescent human sera (93)

Top TH17 antigens identified from proteomic screens (61, 96)

Killed, unencapsulated whole bacterial cells

Whole cell vaccine; WCV

Sepsis, pneumonia and carriage (102, 103)

Sepsis (90) and carriage (91)

Suggested role of PsaA in adhesion to epithelial cells

Sepsis and pneumonia (88)

Sepsis (80), pneumonia and carriage for PhtD (81)

Pneumococcal surface adhesion A; PsaA Serine/threonine protein kinase; Stk-P and Pneumococcal cell wall separation protein; PcsB SP_2108, SP_0148, and SP_1912

Family of proteins identified by reverse vaccinology as surface expressed (79); suggested role of PhtD in adhesion to epithelial cells (76, 82)

Pneumococcal histidine triad; Pht family (PhtA, PhtB, Pht D and PhtE)

Sepsis and pneumonia (74)

Suggested role of PcpA in adhesion to epithelial cells (76, 87)

Pore-forming cytolysin; genetic (PlyD1) and chemically modified (dPly) toxoids tested in humans

Pneumolysin; Ply

Sepsis, pneumonia and carriage (69)

Protection in preclinical studies

Pneumococcal choline-binding protein A; PcpA

Choline-binding protein; immune evasion by inhibition of complement deposition

Antigen characteristics

Pneumococcal surface protein A; PspA

Antigen

Table 1. Pneumococcal antigens that have been evaluated in clinical trials and selected references

Safe and immunogenic in a phase 1 trial in US adults (104)

Safe and immunogenic in a phase 1 trial of SP_2108, SP_0148, and SP_1912 in adults (98)

Safe and immunogenic in a phase 1 trial of StkP, PcsB and PsaA in adults (95)

Safe and immunogenic in a phase 1 trial of monovalent PcpA and bivalent in combination with PhtD (89). Combined with other antigens in further trials; see PhtD Combined with other antigens in a clinical trial; see StkP and PcsB

Safe and immunogenic as monovalent vaccine in a phase 1 trial in adults (71) and safe but less immunogenic in a phase 1 trial of PspA expressed by an attenuated Salmonella vector administered orally (100) Monovalent PlyD1 was safe and immunogenic in a phase 1 trial in adults (78). Combined with other antigens in further trials; see PhtD Safe and immunogenic in a phase 2 trial of PhtD with dPly in toddlers (84) and infants (85). Safe and immunogenic in a phase 1 trial of PhtD, PlyD1, and PcpA in infants (86)

Clinical trial outcomes with selected references

Ongoing phase 2 trial in adults will evaluate efficacy against colonization in experimental challenge model in adults Ongoing phase 1/2 trials in Kenyan adults and toddlers to evaluate impact on carriage

Post-immunization carriage data from phase 2 trial in Gambian infants forthcoming; ongoing phase 2 study of PCV13 C PhtD/DPly for ear and lung infections in Native American infants

See PhtD

Current status (if publicly known)

nasopharyngeal secretions.88 In addition to evaluation of PcpA as a component of a trivalent vaccine in Bangladeshi infants described above (ClinicalTrials.gov Identifier: NCT01764126 and NCT01446926), a phase 1 trial of monovalent PcpA and bivalent PcpA with PhtD sponsored by Sanofi Pasteur (ClinicalTrials.gov Identifier: NCT 01444339) showed safety and immunogenicity of the vaccine constructs in a dose-dependent fashion as measured by immunogen-specific IgG levels.89 Pneumococcal surface adhesin A Another pneumococcal surface protein that facilitates adhesion to epithelial cells, pneumococcal surface adhesin A (PsaA), has been shown to elicit protection against both invasive disease90 and nasopharyngeal carriage91 when administered as a recombinant immunogen to mice. The protective capacity of PsaA has often been evaluated in combination with other antigens, and in combination with PspA has yielded enhanced reduction of carriage in animal models.92 A clinical trial evaluating the safety and immunogenicity of PsaA in combination with 2 proteins identified from screens of immunodominant antibody targets is described below. Proteins identified from serological screens for antibody targets One of the screening approaches for identification of novel vaccine targets evaluated the pneumococcal proteome for those antigens reactive with antibodies from sera of exposed and convalescing patients and identified a cell wall separation protein (PcsB) and serine/threonine protein kinase (StkP).93 Recombinant PcsB and StkP conferred protection against pneumonia and sepsis challenges with different serotypes in mice. Though identified through antibody screens, the precise mechanism of immunity elicited by these proteins has not been fully evaluated, and studies of antigen-specific cytokine responses from human PBMCs suggested the presence of pre-existing TH17 responses to these proteins as well as PsaA.94 Sponsored by Intercell AG, a phase 1 trial of a trivalent vaccine comprised of PcsB, StkP, and PsaA was completed in adults; the candidate vaccines were safe, well tolerated, and immunogenic as measured by protein-specific IgG responses.95 Proteins identified from TH17 cell screens In collaboration with our group at Boston Children’s Hospital and PATH, Genocea Biosciences (Cambridge, MA) screened a proteomic pneumococcal library for the identification of pneumococcus-specific CD4C IL-17A-secreting T-cells (TH17 cells) from the splenocytes of mice that were rendered immune to colonization by immunization with WCV or from the peripheral blood of healthy adults (presumed immune by virtue of natural exposure).61,96 Combinations of 3 of the identified TH17 antigens (SP_2108, SP_0148, and SP_1912) or fusions of these antigens administered to mice either intranasally with cholera toxin or parenterally with aluminum-hydroxide elicited IL-7A-dependent protection against colonization.61,97 A phase 1 trial of a protein-subunit vaccine comprised of SP_2108, SP_0148, and SP_1912 (ClinicalTrials.gov Identifier: NCT01995617) showed

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safety and immunogenicity of the vaccine. Rises in serum IgG responses were generated to each of the antigens. In the context of relatively high pre-existing IL-17A immunity, antigen-specific IL-17 responses were evaluated from peripheral blood as well, without clear evidence of vaccine-induced increases.98 A phase 2 trial evaluating the efficacy of this vaccine candidate on colonization in an experimental human challenge model was performed recently (ClinicalTrials.gov Identifier: NCT02116998). Formal presentation of the results was not available at the time of this writing; however, a press release describing top-line results was published in October 2015 (http://ir.genocea.com/releasedetail. cfm?ReleaseID=937136), stating that the candidate vaccine “reduced the colonization rate, measured by microbiological culture, by between 22 and 25 percent versus placebo across those measurement time points” and that “when measured by the presence of pneumococcal DNA, the reductions ranged between 18 and 36 percent.” None of the reported differences was statistically significant, but it is important to note that the study was not powered for the detection of differences in this range. Furthermore, since it is not clear how to extrapolate a putative reduction in colonization rates in adults to infants or children, this study does raise the intriguing possibility that a vaccine such as this one, possibly more immunogenic and studied in a younger population, could have an important impact on pneumococcal carriage. Alternative strategies for delivery of recombinant pneumococcal proteins Many strategies evaluating alternative delivery platforms for pneumococcal protein vaccine candidates are being evaluated with the goals of improving the feasibility of administration and/ or enhancing the immunogenicity of vaccine antigens. One such strategy includes orally administered attenuated bacterial vectors engineered to express and secrete chosen vaccine antigens. An example of this is a recombinant attenuated Salmonella enterica serovar Typhi vector producing PspA that demonstrated protection against sepsis in mice.99 A phase 1 trial of this candidate was completed in adults: the vaccine was safe and well tolerated, however a significant increase in anti-PspA antibody titer was not consistently elicited though these may have been affected by high pre-existing titers.100 Killed whole cell vaccine Based on the hypothesis that killed, unencapsulated pneumococcal cells would present a full array of both antibody and T-cell antigens thereby engendering broad non-capsular antibody and T-cell responses, and revisiting an approach to pneumococcal whole cell immunization implemented in the early 20th century,101 a whole cell vaccine (WCV) was developed at Boston Children’s Hospital with support from PATH and in collaboration with Dr. Leite’s group at Instituto Butantan, (Sao Paolo, Brazil). Initial studies with this candidate derived from an autolysin-negative, pneumolysoid-substituted pneumococcal strain demonstrated reproducible, multi-serotype protection against nasopharyngeal colonization and invasive disease in mice immunized subcutaneously with WCV and aluminum-

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hydroxide.102,103 In these models, WCV-elicited protection against colonization is IL-17A dependent and antibody-independent, while protection against invasive disease is transferrable by passive transfer of sera and thus antibody-mediated.57,103 A phase 1 trial in adults of dose-escalated WCV with aluminum-hydroxide (ClinicalTrials.gov Identifier: NCT01537185) demonstrated safety and tolerability of parenteral immunization with WCV. Immunogenicity studies revealed significant IgG responses to multiple pneumococcal proteins, including functional anti-pneumolysin antibody as evidenced by a pneumolysin neutralization assay, as well as increased T-cell cytokine responses including IL-17 in subjects immunized with the highest tested dose.104 Passive transfer of sera from WCV-immunized adults also protected mice against sepsis challenge with type 3 pneumococci administered intravenously.105 Phase 1/2 trials of the WCV are ongoing in Kenyan adults and toddlers who are also receiving PCV immunization (ClinicalTrials.gov Identifier: NCT02097472). Results of this trial, which will include evaluations of safety, tolerability and impact on pneumococcal carriage, are expected mid 2016. The future of pneumococcal vaccine development and unresolved issues While there are thus several trials ongoing that will inform the future of pneumococcal vaccine development, many issues regarding non-PCV approaches remain to be addressed. Given the remarkable success of PCVs at reducing VT IPD, the bar for a non-PCV vaccine to meet non-inferiority criteria with respect to IPD prevention is very high. The approach of combining one or several conserved pneumococcal proteins with PCVs to broaden the serotype coverage (either as soluble proteins, or proteins used as carriers for the polysaccharides) or to enhance the protection against mucosal phases of pneumococcal infection is under evaluation currently, and assessing the effect of co-administration of these proteins with PCVs will be critical. The effect References 1. Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O’Brien KL, Campbell H, Black RE. Global burden of childhood pneumonia and diarrhoea. Lancet 2013; 381(9875):1405-16; PMID:23582727; http://dx.doi.org/10.1016/S01406736(13)60222-6 2. O’Brien KL, Wolfson LJ, Watt JP, Henkle E, DeloriaKnoll M, McCall N, Lee E, Mulholland K, Levine OS, Cherian T. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009; 374(9693):893-902; PMID:19748398; http://dx.doi.org/10.1016/S01406736(09)61204-6 3. Davis SM, Deloria-Knoll M, Kassa HT, O’Brien KL. Impact of pneumococcal conjugate vaccines on nasopharyngeal carriage and invasive disease among unvaccinated people: review of evidence on indirect effects. Vaccine 2013; 32(1):133-45; PMID:23684824; http://dx.doi.org/10.1016/j. vaccine.2013.05.005 4. Loo JD, Conklin L, Fleming-Dutra KE, Knoll MD, Park DE, Kirk J, Goldblatt D, O’Brien KL, Whitney CG. Systematic review of the indirect effect of pneumococcal conjugate vaccine dosing schedules on pneumococcal disease and colonization. Pediatr Infect Dis J 2014; 33 Suppl 2:S16171; PMID:24336058; http://dx.doi.org/10.1097/ INF.0000000000000084

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of any investigational vaccine on prevention of carriage should be considered a major factor to estimate the impact such a candidate may have on a population of both immunized and unimmunized individuals. Many other issues will need to be addressed for nonPCVs including the number of doses required and durability of elicited responses, whether an adjuvant is required and if so which one, and whether or not pneumococcal colonization at the time of immunization of infants (which is likely in most developing world settings) will impact the response to vaccination. For any vaccine that is licensed, as has been critical to our understanding of pneumococcal epidemiology in the post-PCV era, post-licensure surveillance of disease and carriage isolates will be of utmost importance. This may be especially true to assess whether vaccine-escape variants emerge through recombinational evolution in response to vaccine-elicited immunity to a well-conserved antigen or antigens. Additionally, a potential impact of universal pneumococcal vaccines that target colonization on the nasopharyngeal microbiome should be evaluated as well, although the implications of any effect may be difficult to evaluate. In summary, while there remain many unanswered questions in the development of a serotype-independent pneumococcal vaccine approach, progress is being made, and such advances are made possible by the evolving elucidation of how Streptococcus pneumoniae causes infection, carriage and transmission, and how the host immune responses interfere with these processes.

Disclosure of Potential Conflicts of Interest

RM serves as a scientific advisor to Merck Vaccines, is a consultant to Genocea Biosciences and is on the scientific advisory board of Arsanis Biosciences. He is the scientific founder, consultant and member of the board of directors of Affinivax. KM discloses no potential conflicts of interest.

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