Post Doctoral Researcher, Liverpool School of Tropical Medicine
Developing a new vaccine to protect against pneumonia
Pneumonia is a terrifying and painful infection; patient’s lungs fill with fluid and they desperately struggle to breathe. According to the World Health Organisation, in 2015 pneumonia killed almost one million children under 5 years old. Pneumonia is primarily caused by a highly infectious encapsulated bacterium, Streptococcus pneumoniae (aka “the pneumococcus”). Based on the capsule, it is classified in serotypes. There are more than 90 serotypes and current vaccines, based on capsular components, only protect against 13 of them. Pneumococcus is commonly found in the microflora that colonises the nose and throat of heathy adults (5-10%) and children (20-40%).
Pneumococcus can also cause middle ear infections, meningitis and bacteraemia. Current vaccines licensed for use with children have succeeded in reducing the nasal presence of this bacterium (termed “carriage”). Carriage can often lead to disease. A major drawback to these vaccines is that protection is limited to serotypes found in industrialised nations and not necessarily strains circulating in low-income countries. Moreover, they are expensive to produce, which drastically limits their worldwide availability.
Researchers (including my team) are trying to develop a wide-ranging vaccine that confers protection against all serotypes. We also aim to reduce production costs so vaccine uptake is not constrained by wealth. These developments will have a huge impact on global health. Designing protein-based vaccines can provide broad specificity and economical costing. We are identifying proteins shared between all pneumococcus serotypes and are evaluating their ability to protect against infection.
Thus far, our group has developed a key tool for testing new candidates: The Human Infection Model with Pneumococcus. We recruit healthy adults, nasally administer a few drops of pneumococcus and then track how the volunteer’s immune system responds to the presence of the bacteria. We have observed that 50% of the population tested clear the infection while 50% become carriers. What makes a person a carrier? Why are some people protected? These are the types of questions needed to shed light on better ways to fight this disease. Our model allows us to test the efficacy of new vaccine candidates by vaccinating healthy adults and then exposing them to our harmless pneumococcal serotype. If the number of protected people has increased, the vaccine candidate is pushed further up a development pipeline.
Abstract: Colonization of the human nasopharynx by pneumococcus is extremely common and is both the primary reservoir for transmission and a prerequisite for disease. Current vaccines targeting the polysaccharide capsule effectively prevent colonization, conferring herd protection within vaccinated communities. However, these vaccines cover only a subset of all circulating pneumococcal strains, and serotype replacement has been observed. Given the success of pneumococcal conjugate vaccine (PCV) in preventing colonization in unvaccinated adults within vaccinated communities, reducing nasopharyngeal colonization has become an outcome of interest for novel vaccines. Here, we discuss the immunological mechanisms that control nasopharyngeal colonization, with an emphasis on findings from human studies. Increased understanding of these immunological mechanisms is required to identify correlates of protection against colonization that will facilitate the early testing and design of novel vaccines.
Pub.: 22 Dec '17, Pinned: 06 Feb '18
Abstract: Commensal organisms with the potential to cause disease pose a challenge in developing treatment options. Using the example featured in this study, pneumococcal disease begins with Streptococcus pneumoniae colonization, followed by triggering events that prompt the release of a virulent subpopulation of bacteria. Current vaccines focus on colonization prevention, which poses unintended consequences of serotype niche replacement. In this study, noncovalent colocalization of two classes of complementary antigens, one to prevent the colonization of the most aggressive S. pneumoniae serotypes and another to restrict virulence transition, provides complete vaccine effectiveness in animal subjects and the most comprehensive coverage of disease reported to date. As a result, the proposed vaccine formulation offers universal pneumococcal disease prevention with the prospect of effectively managing a disease that afflicts tens to hundreds of millions globally. The approach more generally puts forth a balanced prophylactic treatment strategy in response to complex commensal-host dynamics.
Pub.: 24 Oct '17, Pinned: 27 Oct '17
Abstract: Vaccination has been one of the most successful strategies to reduce morbidity and mortality caused by respiratory infections. Recent evidence suggests that differences in the host genetic background and environmental factors may contribute to heterogeneity in the immune response to vaccination. During pre-clinical testing, vaccines are often evaluated in a single mouse inbred strain, which may not translate well to the heterogeneous human population. Here, we examined the influence of host genetic background on vaccine-induced protection against pneumococcal colonization in two commonly used inbred mouse strains, i.e. C57BL/6 and BALB/cas well as the F1 cross of these two strains. Groups of mice were vaccinated intranasally with a vaccine formulation containing a model pneumococcal antigen, i.e. pneumococcal surface protein A (PspA), adjuvanted with cholera toxin subunit B (CTB). Even in the absence of vaccination, differences in colonization density were observed between mouse strains. Although vaccination significantly reduced pneumococcal density in all mouse strains, differences were observed in the magnitude of protection. We therefore examined immunological parameters known to be involved in vaccine-induced mucosal clearance of S. pneumoniae. We found that PspA-specific IgG levels in nasal tissue differed between mouse strains, but in all cases it correlated significantly with a reduction in colonization. Furthermore, increased mucosal IL17A, but not IFNγ, IL10, or IL4, was found to be mouse strain specific. This suggests that the reduction of bacterial load may be accompanied by a Th17 response in all genetic backgrounds, although the cytokine dynamics may differ. Increased insight into the different immune mechanisms that affect pneumococcal carriage will contribute to development of future vaccines against S. pneumoniae.
Pub.: 22 Aug '17, Pinned: 28 Sep '17
Abstract: A pneumococcal whole-cell vaccine (WCV) confers T(H)17-mediated immunogenicity and reduces nasopharyngeal (NP) carriage in mice. Activation of Toll-like receptor 2 (TLR2) has been shown to be important for generating T(H)17 responses, and several lipidated pneumococcal proteins have TLR2-activating properties. Here we investigated the roles of TLR2 and lipidation of proteins in WCV-induced interleukin-17A (IL-17A) responses and protection against NP carriage. Immunization of Tlr2(-/-) mice with WCV conferred significantly lower IL-17A levels and reduced protection against NP carriage, compared to wild-type (WT) mice, suggesting that host TLR2 engagement is required for effective immunity and protection elicited by WCV immunization. Using a WCV with deletion of lgt, the gene encoding the enzyme required for lipidation and membrane attachment of prolipoproteins, we show that lipidation and membrane localization of these proteins are critical for the immunogenicity and protective efficacy of the WCV. To evaluate the roles of diacylglyceryl transferase (Lgt)-mediated processes in the recall of WCV-induced protective responses, we colonized WCV-immunized animals with a strain in which lgt was deleted. WCV-immunized animals still had significantly reduced colonization burdens, compared to control animals, which suggests that lipidation and membrane localization of pneumococcal prolipoproteins are less critical for the recall of the immune responses elicited by WCV immunization than for the priming of such responses. Elucidation of underlying immune mechanisms and the optimal characteristics of WCV formulations can help guide vaccine development and enhance our understanding of host-pneumococcus interactions.
Pub.: 05 Jun '15, Pinned: 19 Sep '17
Abstract: Vaccination with formulations containing pneumococcal protein antigens such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) may extend serotype-related protection of pneumococcal conjugate vaccines (PCVs) against Streptococcus pneumoniae.This phase II, multi-center, observer-blind trial conducted in Europe (NCT01204658) assessed 2 investigational vaccines containing 10 serotype-specific polysaccharide conjugates of PHiD-CV and either 10 or 30µg of dPly and PhtD each. Infants randomized 1:1:1:1 received 4 doses of PHiD-CV/dPly/PhtD-10, PHiD-CV/dPly/PhtD-30, PHiD-CV, or 13-valent PCV (PCV13), co-administered with DTPa-HBV-IPV/Hib, at ages ∼2, 3, 4 and 12-15months. Occurrences of fever >40.0°C following primary vaccination with PHiD-CV/dPly/PhtD vaccines compared to PHiD-CV (non-inferiority objective), dose superiority, safety and immunogenicity were assessed.575 children received primary vaccination, and 564 booster vaccination. The non-inferiority objective was met; no fever >40.0°C causally related to vaccination was reported during primary vaccination. Incidence of adverse events appeared similar between the 3 PHiD-CV groups. Serious adverse events were reported in 13, 9, 21 (1 related to vaccination), and 17 children in the PHiD-CV/dPly/PhtD-10, PHiD-CV/dPly/PhtD-30, PHiD-CV, and PCV13 groups, respectively. PHiD-CV/dPly/PhtD-30 was superior to PHiD-CV/dPly/PhtD-10 in terms of post-dose 3 anti-Ply and Anti-PhtD antibody levels. Anti-Ply and anti-PhtD antibody levels were higher in both PHiD-CV/dPly/PhtD groups than in controls and increased from post-primary to post-booster timepoint. Post-primary and booster vaccination, for each PHiD-CV serotype, ≥98.5% of participants in PHiD-CV/dPly/PhtD groups had antibody concentrations ≥ 0.2μg/mL, except for 6B (≥72.3%) and 23F (≥82.7%) post-primary vaccination. Similar results were observed in the PHiD-CV group. Immune responses to protein D and DTPa-HBV-IPV/Hib were within similar ranges for the 3 PHiD-CV groups.Both PHiD-CV/dPly/PhtD formulations co-administered with DTPa-HBV-IPV/Hib in infants were well-tolerated and immunogenic for dPly and PhtD antigens, while immune responses to serotype-specific, protein D and co-administered antigens did not appear altered in comparison to PHiD-CV group.
Pub.: 22 Jul '17, Pinned: 19 Sep '17
Abstract: Pneumococcal nasopharyngeal carriage occurs early in life. However, the role of vertical transmission is not well understood. The aims of the study are to describe carriage among mothers and their newborns, and assess for risk factors for neonatal carriage.In a nested retrospective cohort study, we analysed data from the control arm of a randomized control trial conducted in The Gambia two to three years after PCV13 introduction. Nasopharyngeal swabs were collected from 374 women and their newborns on the day of delivery, and 3, 6, 14 and 28 days later. Pneumococci were isolated and serotyped using conventional microbiological methods.Carriage increased from 0.3% (1/373) at birth to 37.2% (139/374) at day 28 (p<0.001) among neonates and from 17.1% (64/374) to 24.3% (91/374) [p=0.015] among women. In both groups, PCV13 VT serotypes accounted for approximately one third of the pneumococcal isolates, with serotype 19A being the most common VT. Maternal carriage [adjusted OR=2.82 (95% CI 1.77-4.80)], living with other children in the household [adjusted OR=4.06 (95% CI 1.90-8.86)] and dry season [OR=1.98 (95% CI 1.15-3.43)] were risk factors for neonatal carriage. Over half (62.6%) of the neonatal carriage was attributable to living with other children in the same household.Three years after the introduction of PCV in The Gambia, newborns are still rapidly colonised with pneumococcus, including PCV13 VT. Current strategies for pneumococcal control in Africa do not protect this age group beyond the herd effect.
Pub.: 27 Jul '17, Pinned: 19 Sep '17
Abstract: Streptococcus pneumoniae is an important pathogen causing invasive diseases such as sepsis, meningitis, and pneumonia. The burden of disease is highest in the youngest and oldest sections of the population in both more and less developed countries. The treatment of pneumococcal infections is complicated by the worldwide emergence in pneumococci of resistance to penicillin and other antibiotics. Pneumococcal disease is preceded by asymptomatic colonisation, which is especially high in children. The current seven-valent conjugate vaccine is highly effective against invasive disease caused by the vaccine-type strains. However, vaccine coverage is limited, and replacement by non-vaccine serotypes resulting in disease is a serious threat for the near future. Therefore, the search for new vaccine candidates that elicit protection against a broader range of pneumococcal strains is important. Several surface-associated protein vaccines are currently under investigation. Another important issue is whether the aim should be to prevent pneumococcal disease by eradication of nasopharyngeal colonisation, or to prevent bacterial invasion leaving colonisation relatively unaffected and hence preventing the occurrence of replacement colonisation and disease. To illustrate the importance of pneumococcal colonisation in relation to pneumococcal disease and prevention of disease, we discuss the mechanism and epidemiology of colonisation, the complexity of relations within and between species, and the consequences of the different preventive strategies for pneumococcal colonisation.
Pub.: 05 Mar '04, Pinned: 19 Sep '17
Abstract: Characterizing the immune response to pneumococcal proteins is critical in understanding this bacterium's epidemiology and vaccinology. Probing a custom-designed proteome microarray with sera from 35 healthy US adults revealed a continuous distribution of IgG affinities for 2,190 potential antigens from the species-wide pangenome. Reproducibly elevated IgG binding was elicited by 208 "antibody binding targets" (ABTs), which included 109 variants of the diverse pneumococcal surface proteins A and C (PspA and PspC) and zinc metalloprotease A and B (ZmpA and ZmpB) proteins. Functional analysis found ABTs were enriched in motifs for secretion and cell surface association, with extensive representation of cell wall synthesis machinery, adhesins, transporter solute-binding proteins, and degradative enzymes. ABTs were associated with stronger evidence for evolving under positive selection, although this varied between functional categories, as did rates of diversification through recombination. Particularly rapid variation was observed at some immunogenic accessory loci, including a phage protein and a phase-variable glycosyltransferase ubiquitous among the diverse set of genomic islands encoding the serine-rich PsrP glycoprotein. Nevertheless, many antigens were conserved in the core genome, and strains' antigenic profiles were generally stable. No strong evidence was found for any epistasis between antigens driving population dynamics, or redundancy between functionally similar accessory ABTs, or age stratification of antigen profiles. These results highlight the paradox of why substantial variation is observed in only a subset of epitopes. This result may indicate only some interactions between immunoglobulins and ABTs clear pneumococcal colonization or that acquired immunity to pneumococci is an accumulation of individually weak responses to ABTs evolving under different levels of functional constraint.
Pub.: 06 Jan '17, Pinned: 19 Sep '17
Abstract: Pneumonia, caused by Streptococcus pneumoniae, mainly affects the immunocompromised, the very young and the old, and remains one of the leading causes of death. A steady rise in disease numbers from non-vaccine serotypes necessitates a new vaccine formulation that ideally has better antigen stability and integrity, does not require cold-chain and can be delivered non-invasively. In this study, a dry powder vaccine containing an important antigen of S. pneumoniae, pneumococcal surface protein A (PspA) that has shown cross-reactivity amongst serotypes to be delivered via the pulmonary route has been formulated. The formulation contains the antigen PspA adsorbed onto the surface of polymeric nanoparticles encapsulated in L-leucine microparticles that can be loaded into capsules and delivered via an inhaler. We have successfully synthesized particles of ∼150 nm and achieved ∼20 μg of PspA adsorption per mg of NPs. In addition, the spray-dried powders displayed a FPF of 74.31±1.32% and MMAD of 1.70±0.03 μm suggesting a broncho-alveolar lung deposition facilitating the uptake of the nanoparticles by dendritic cells. Also, the PspA released from the dry powders maintained antigen stability (SDS-PAGE), integrity (Circular dichroism) and activity (lactoferrin binding assay). Moreover, the released antigen also maintained its antigenicity as determined by ELISA.
Pub.: 22 Sep '15, Pinned: 19 Sep '17
Abstract: Several cohort studies have indicated associations between S. pneumoniae and other microbes in the nasopharynx. To study causal relationships between the nasopharyngeal microbiome and pneumococcal carriage, we employed an experimental human pneumococcal carriage model. Healthy adult volunteers were assessed for pneumococcal carriage by culture of nasal wash samples (NWS). Those without natural pneumococcal carriage received an intranasal pneumococcal inoculation with serotype 6B or 23F. The composition of the nasopharyngeal microbiome was longitudinally studied by 16S rDNA pyrosequencing on NWS collected before and after challenge.Among 40 selected volunteers, 10 were natural carriers and 30 were experimentally challenged. At baseline, five distinct nasopharyngeal microbiome profiles were identified. The phylogenetic distance between microbiomes of natural pneumococcal carriers was particularly large compared to non-carriers. A more diverse microbiome prior to inoculation was associated with the establishment of pneumococcal carriage. Perturbation of microbiome diversity upon pneumococcal challenge was strain specific. Shifts in microbiome profile occurred after pneumococcal exposure, and those volunteers who acquired carriage more often diverted from their original profile. S. pneumoniae was little prominent in the microbiome of pneumococcal carriers.Pneumococcal acquisition in healthy adults is more likely to occur in a diverse microbiome and appears to promote microbial heterogeneity.
Pub.: 12 Feb '15, Pinned: 19 Sep '17
Abstract: The ability of pneumococcal conjugate vaccine (PCV) to decrease transmission by blocking the acquisition of colonization has been attributed to herd immunity. We describe the role of mucosal immunoglobulin G (IgG) to capsular polysaccharide (CPS) in mediating protection from carriage, translating our findings from a murine model to humans. We used a flow cytometric assay to quantify antibody-mediated agglutination demonstrating that hyperimmune sera generated against an unencapsulated mutant was poorly agglutinating. Passive immunization with this antiserum was ineffective to block acquisition of colonization compared to agglutinating antisera raised against the encapsulated parent strain. In the human challenge model, samples were collected from PCV and control-vaccinated adults. In PCV-vaccinated subjects, IgG levels to CPS were increased in serum and nasal wash (NW). IgG to the inoculated strain CPS dropped in NW samples after inoculation suggesting its sequestration by colonizing pneumococci. In post-vaccination NW samples pneumococci were heavily agglutinated compared with pre-vaccination samples in subjects protected against carriage. Our results indicate that pneumococcal agglutination mediated by CPS-specific antibodies is a key mechanism of protection against acquisition of carriage. Capsule may be the only vaccine target that can elicit strong agglutinating antibody responses, leading to protection against carriage acquisition and generation of herd immunity.Mucosal Immunology advance online publication, 31 August 2016; doi:10.1038/mi.2016.71.
Pub.: 01 Sep '16, Pinned: 19 Sep '17
Abstract: Pneumococcal pneumonia is a life-threatening disease with high mortality and morbidity among children under 5 years of age, the elderly and immunocompromised individuals worldwide. Protection against pneumococcal pneumonia relies on successful regulation of colonisation in the nasopharynx and a brisk alveolar macrophage-mediated immune response in the lung. Therefore, enhancing pulmonary mucosal immunity (which includes a combination of innate, humoral and cell-mediated immunity) through mucosal vaccination might be the key to prevention of pneumococcal infection. Current challenges include a lack of information in humans on mucosal immunity against pneumococci and a lack of suitable adjuvants for new vaccines. Data from mouse models, however, suggest that mucosally active vaccines will enhance mucosal and systemic immunity for protection against pneumococcal infection.
Pub.: 25 Dec '09, Pinned: 19 Sep '17
Abstract: We have previously demonstrated that experimental pneumococcal carriage enhances immunity and protects healthy adults against carriage reacquisition following re-challenge with homologous strain. Here we have used a heterologous challenge model to investigate the role of naturally acquired pneumococcal protein and polysaccharide (PS)-specific immunity in protection against carriage acquisition.We identified healthy volunteers that were naturally colonised with pneumococcus and, following clearance of their natural carriage episode, challenged them with a heterologous 6B strain. In another cohort of volunteers we assessed 6BPS-specific, PspA-specific and PspC-specific IgG and IgA plasma and memory B-cell populations prior to and 7, 14 and 35 days following experimental pneumococcal inoculation.Heterologous challenge with 6B resulted in 50% carriage among volunteers with previous natural pneumococcal carriage. Protection from carriage was associated with a high number of circulating 6BPS IgG-secreting memory B-cells at baseline. There were no associations between protection from carriage and baseline levels of 6BPS IgG in serum or nasal wash, PspA-specific or PspC-specific memory B-cells or plasma cells. In volunteers who did not develop carriage, the number of circulating 6BPS memory B-cells decreased and the number of 6BPS plasma cells 7 days post inoculation.Our data indicate that naturally acquired polysaccharide-specific memory B-cells, but not levels of circulating IgG at time of pneumococcal exposure, are associated with protection against carriage acquisition.
Pub.: 13 Jul '16, Pinned: 19 Sep '17
Abstract: Conserved pneumococcal proteins are potential candidates for inclusion in vaccines against pneumococcal diseases. In the first part of a two-part study, an investigational vaccine (PHiD-CV/dPly/PhtD-30) containing 10 pneumococcal serotype-specific polysaccharide conjugates (10VT) combined with pneumolysin toxoid and pneumococcal histidine triad protein D (30μg each) was well tolerated by Gambian children. Part two, presented here, assessed the efficacy of two PHiD-CV/dPly/PhtD formulations against pneumococcal nasopharyngeal carriage (NPC) prevalence in infants.In this phase 2, randomized, controlled, observer-blind trial, healthy infants aged 8-10weeks, recruited from a peri-urban health center, were randomized (1:1:1:1:1:1) into six groups. Four groups received PHiD-CV/dPly/PhtD (10 or 30μg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine at ages 2-3-4months (3+0 infant schedule) and two groups PHiD-CV/dPly/PhtD-30 or PHiD-CV at 2-4-9months (2+1 infant schedule). The primary objective was impact on non-10VT NPC at ages 5-9-12months. Secondary objectives included confirmatory analysis of protein dose superiority and safety/reactogenicity. Impact on pneumococcal NPC acquisition, bacterial load, and ply and phtD gene sequencing were explored.1200 infants were enrolled between June 2011 and May 2012. Prevalences of pneumococcal (60-67%) and non-10VT (55-61%) NPC were high at baseline. Across all post-vaccination time points, efficacy of PHiD-CV/dPly/PhtD-10 and PHiD-CV/dPly/PhtD-30 against non-10VT NPC (3+0 schedule) was 1.1% (95% CI -21.5, 19.5) and 2.1% (-20.3, 20.3), respectively; efficacy of PHiD-CV/dPly/PhtD-30 (2+1 schedule) was 0.5% (-22.1, 18.9) versus PHiD-CV. No differences were observed in pneumococcal NPC acquisition, clearance, or bacterial load. Both protein-based vaccines elicited immune responses to pneumococcal proteins.In this high carriage prevalence setting, inclusion of pneumococcal proteins in the PHiD-CV/dPly/PhtD investigational vaccine had no impact on pneumococcal NPC in infants, regardless of protein dose or schedule. Future evaluations will assess its impact against pneumococcal disease endpoints.PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872.
Pub.: 09 Apr '17, Pinned: 19 Sep '17
Abstract: New vaccines are urgently needed to protect the vulnerable from bacterial pneumonia. Clinical trials of pneumonia vaccines are slow and costly, requiring tens of thousands of patients. Studies of pneumococcal vaccine efficacy against colonization have been proposed as a novel method to down-select between vaccine candidates.Using our safe and reproducible experimental human pneumococcal colonization model, we aimed to determine the effect of 13-valent pneumococcal conjugate vaccine (PCV) on colonization.A total of 100 healthy participants aged 18-50 years were recruited into this double-blind randomized placebo-controlled trial. They were randomly assigned to PCV (n = 49) or hepatitis A (control, n = 50) vaccination and inoculated with 80,000 CFU/100 μl of Streptococcus pneumoniae (6B) per naris.Participants were followed up for 21 days to determine pneumococcal colonization by culture of nasal wash. The PCV group had a significantly reduced rate of 6B colonization (10% [5 of 48]) compared with control subjects (48% [23 of 48]) (risk ratio, 0.22; confidence interval, 0.09-0.52; P < 0.001). Density of colonization was reduced in the PCV group compared with the control group following inoculation. The area under the curve (density vs. day) was significantly reduced in the PCV compared with control group (geometric mean, 259 vs. 11,183; P = 0.017).PCV reduced pneumococcal colonization rate, density, and duration in healthy adults. The experimental human pneumococcal colonization model is a safe, cost-effective, and efficient method to determine the protective efficacy of new vaccines on pneumococcal colonization; PCV provides a gold standard against which to test these novel vaccines. Clinical trial registered with45340436.
Pub.: 27 Jun '15, Pinned: 19 Sep '17
Abstract: The immunological and protective role of pneumococcal carriage in healthy adults is not known, but high rates of disease and death in the elderly are associated with low carriage prevalence.We employed an experimental human pneumococcal carriage model to investigate the immunizing effect of a single carriage episode.Seventy healthy adults were challenged, and of those with carriage, 10 were rechallenged intranasally with live 6B Streptococcus pneumoniae up to 11 months after clearance of the first carriage episode. Serum and nasal wash antibody responses were measured before and after each challenge.A total of 29 subjects were experimentally colonized. No subjects were colonized by experimental rechallenge, demonstrating the protective effect of initial carriage against subsequent infection. Carriage increased both mucosal and serum IgG levels to pneumococcal proteins and polysaccharide, resulting in a fourfold increase in opsonophagocytic activity. Importantly, passive transfer of postcarriage sera from colonized subjects conferred 70% protection against lethal challenge by a heterologous strain in a murine model of invasive pneumococcal pneumonia. These levels were significantly higher than the protection conferred by either precarriage sera (30%) or saline (10%).Experimental human carriage resulted in mucosal and systemic immunological responses that conferred protection against recolonization and invasive pneumococcal disease. These data suggest that mucosal pneumococcal vaccination strategies may be important for vulnerable patient groups, particularly the elderly, who do not sustain carriage.
Pub.: 02 Feb '13, Pinned: 19 Sep '17
Abstract: 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 non-vaccine 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 serotype-independent pneumococcal vaccine candidates. We will then review the alternative vaccine candidates that have been or are currently under evaluation in clinical trials.
Pub.: 05 Nov '15, Pinned: 19 Sep '17
Abstract: The pneumococcal whole cell vaccine (PWCV) has been investigated as an alternative to polysaccharide-based vaccines currently in use. It is a non-encapsulated killed vaccine preparation that induces non-capsular antibodies protecting mice against invasive pneumococcal disease (IPD) and reducing nasopharyngeal (NP) carriage via IL-17A activation of mouse phagocytes. Here, we show that PWCV induces antibody and IL-17A production to protect mice against challenge in a fatal aspiration-sepsis model after only one dose. We observed protection even with a boiled preparation, attesting to the stability and robustness of the vaccine. PWCV antibodies were shown to bind to different encapsulated strains, but complement deposition on the pneumococcal surface was observed only on serotype 3 strains; using flow cytometer methodology, variations in PWCV quality, as in the boiled vaccine, were detected. Moreover, anti-PWCV induces phagocytosis of different pneumococcal serotypes by murine peritoneal cells in the presence of complement or IL-17A. These findings suggest that complement and IL-17A may participate in the process of phagocytosis induced by PWCV antibodies. IL-17A can stimulate phagocytic cells to kill pneumococcus and this is enhanced in the presence of PWCV antibodies bound to the bacterial cell surface. Our results provide further support for the PWCV as a broad-range vaccine against all existing serotypes, potentially providing protection for humans against NP colonization and IPD. Additionally, we suggest complement deposition assay as a tool to detect subtle differences between PWCV lots.
Pub.: 06 Feb '17, Pinned: 19 Sep '17
Abstract: Pneumococcal conjugate vaccines have had unprecedented success in controlling vaccine-type invasive pneumococcal disease. As serotype replacement and the complexity of designing vaccines to multiple capsular polysaccharides ultimately pose a threat to these vaccines, the development of alternative protein vaccines is important. Protein vaccines offer the promise of extended serotype coverage, reduced cost, and improved protection against otitis media and pneumococcal pneumonia. As placebo-controlled trials are not currently ethically justifiable, human pneumococcal challenge models using prevention of carriage as a test endpoint offer an attractive link between preclinical studies and clinical efficacy trials. Experimental human pneumococcal carriage studies offer a means of describing mechanisms of protection against carriage and a clinical tool to choose between vaccine candidates.
Pub.: 26 Jul '11, Pinned: 19 Sep '17
Join Sparrho today to stay on top of science
Discover, organise and share research that matters to you