Targeted Transcriptomic Screen of Pneumococcal Genes Expressed during Murine and Human Infection.

The advent of pneumococcal conjugate vaccines led to the near disappearance of most of the included serotypes in high-income settings but also the rise of nonvaccine-type colonization and disease. Alternative strategies, using genetically conserved proteins as antigens, have been evaluated preclinically and clinically for years, so far unsuccessfully. One possible explanation for the failure of these efforts is that the choice of antigens may not have been sufficiently guided by an understanding of the gene expression pattern in the context of infection. Here, we present a targeted transcriptomic analysis of 160 pneumococcal genes encoding bacterial surface-exposed proteins in mouse models, human colonization, and human meningitis. We present the overlap of these different transcriptomic profiles. We identify two bacterial genes that are highly expressed in the context of mouse and human infection: SP_0282, an IID component of a mannose phosphotransferase system (PTS), and SP_1739, encoding RNase Y. We show that these two proteins can confer protection against pneumococcal nasopharyngeal colonization and intraperitoneal challenge in a murine model and generate opsonophagocytic antibodies. This study emphasizes and confirms the importance of studies of pneumococcal gene expression of bacterial surface proteins during human infection and colonization and may pave the way for the selection of a protein-based vaccine candidate.

Overview of the Nontyphoidal and Paratyphoidal Salmonella Vaccine Pipeline: Current Status and Future Prospects.

Nontyphoidal Salmonella and Salmonella Paratyphi are responsible for significant morbidity and mortality worldwide. To date, no vaccine has been licensed against these organisms. The development of effective vaccines remains an urgent priority. In this review, the rationale for and current status of various vaccine candidates against S. Paratyphi and nontyphoidal Salmonella are presented, with a focus on the research findings from the 2019 International Conference on Typhoid and Other Invasive Salmonelloses. Additionally, other vaccine candidates that are currently undergoing clinical development are highlighted. Future approaches, which may include antigens that are genetically conserved across Salmonella and confer broad, non-serotype-specific protection, are also discussed.

Process intensification for production of Streptococcus pneumoniae whole-cell vaccine.

The available pneumococcal conjugate vaccines provide protection against only those serotypes that are included in the vaccine, which leads to a selective pressure and serotype replacement in the population. An alternative low-cost, safe and serotype-independent vaccine was developed based on a nonencapsulated pneumococcus strain. This study evaluates process intensification to improve biomass production and shows for the first time the use of perfusion-batch with cell recycling for bacterial vaccine production. Batch, fed-batch, and perfusion-batch were performed at 10 L scale using a complex animal component-free culture medium. Cells were harvested at the highest optical density, concentrated and washed using microfiltration or centrifugation to compare cell separation methods. Higher biomass was achieved using perfusion-batch, which removes lactate while retaining cells. The biomass produced in perfusion-batch would represent at least a fourfold greater number of doses per cultivation than in the previously described batch process. Each strategy yielded similar vaccines in terms of quality as evaluated by western blot and animal immunization assays, indicating that so far, perfusion-batch is the best strategy for the intensification of pneumococcal whole-cell vaccine production, as it can be integrated to the cell separation process keeping the same vaccine quality.

Screening for Th17-Dependent Pneumococcal Vaccine Antigens: Comparison of Murine and Human Cellular Immune Responses.

Conjugate vaccines against Streptococcus pneumoniae have significantly reduced the incidence of diseases caused by the serotypes included in those vaccines; however, there is still a need for vaccines that confer serotype-independent protection. In the current study, we have constructed a library of conserved surface proteins from S. pneumoniae and have screened for IL-17A and IL-22 production in human immune cells obtained from adenoidal/tonsillar tissues of children and IL-17A production in splenocytes from mice that had been immunized with a killed whole-cell vaccine or previously exposed to pneumococcus. A positive correlation was found between the rankings of proteins from human IL-17A and IL-22 screens, but not between those from human and mouse screens. All proteins were tested for protection against colonization, and we identified protective antigens that are IL-17A dependent. We found that the likelihood of finding a protective antigen is significantly higher for groups of proteins ranked in the top 50% of all three screens than for groups of proteins ranked in the bottom 50% of all three. The results thus confirmed the value of such screens for identifying Th17 antigens. Further, these experiments have evaluated and compared the breadth of human and mouse Th17 responses to pneumococcal colonization and have enabled the identification of potential vaccine candidates based on immunological responses in mouse and human cells.

A Fluorescent Coumarin-Based Probe for the Fast Detection of Cysteine with Live Cell Application.

A new coumarin-based fluorescent probe, containing an allylic esters group, has been designed and synthesized for sensing cysteine in physiological pH. In this fluorescent probe, the coumarin was applied as the fluorophore and an allylic esters group was combined as both a fluorescence quencher and a recognition unit. The probe can selectively and sensitively detect cysteine (Cys) over homocysteine, glutathione, and other amino acids, and has a rapid response time of 30 min and a low detection limit of 47.7 nM. In addition, the probe could be applied for cell imaging with low cytotoxicity.

Transparent ultraviolet photovoltaic cells.

Photovoltaic cells have been fabricated from p-GaN/MgO/n-ZnO structures. The photovoltaic cells are transparent to visible light and can transform ultraviolet irradiation into electrical signals. The efficiency of the photovoltaic cells is 0.025% under simulated AM 1.5 illumination conditions, while it can reach 0.46% under UV illumination. By connecting several such photovoltaic cells in a series, light-emitting devices can be lighting. The photovoltaic cells reported in this Letter may promise the applications in glass of buildings to prevent UV irradiation and produce power for household appliances in the future.

Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity.

Vaccines are among the most effective approaches to prevent and control many infectious diseases. Because of safety and reproducibility concerns, whole-cell vaccines (WCVs), made from live or killed microorganisms and including hundreds of antigenic components, have been mostly replaced by acellular or subunit vaccines composed of well-defined, purified antigen components. The efficacy of acellular vaccines is inferior to that of WCVs, however, for two major reasons: limited antigen diversity and reduced immunogenicity, especially in a lack of activation of antigen-specific T-cell immunity, which plays an important role in protection against mucosal and intracellular pathogens. Here we present the multiple antigen-presenting system (MAPS), which enables the creation of a macromolecular complex that mimics the properties of WCVs by integrating various antigen components, including polysaccharides and proteins, in the same construct and that induces multipronged immune responses, including antibody, Th1, and Th17 responses. Using antigens from various pathogens (Streptococcus pneumoniae, Salmonella typhi, and Mycobacterium tuberculosis), we demonstrate the versatility of the MAPS system and its feasibility for the design of unique defined-structure subunit vaccines to confer comprehensive protection via multiple immune mechanisms. Moreover, MAPS can serve as a tool for structure-activity analysis of cellular immunogens.

Effect of nonheme iron-containing ferritin Dpr in the stress response and virulence of pneumococci.

Streptococcus pneumoniae (pneumococcus) produces hydrogen peroxide as a by-product of metabolism and provides a competitive advantage against cocolonizing bacteria. As pneumococci do not produce catalase or an inducible regulator of hydrogen peroxide, the mechanism of resistance to hydrogen peroxide is unclear. A gene responsible for resistance to hydrogen peroxide and iron in other streptococci is that encoding nonheme iron-containing ferritin, dpr, but previous attempts to study this gene in pneumococcus by generating a dpr mutant were unsuccessful. In the current study, we found that dpr is in an operon with the downstream genes dhfr and clpX. We generated a dpr deletion mutant which displayed normal early-log-phase and mid-log-phase growth in bacteriologic medium but survived less well at stationary phase; the addition of catalase partially rescued the growth defect. We showed that the dpr mutant is significantly more sensitive to pH, heat, iron concentration, and oxidative stress due to hydrogen peroxide. Using a mouse model of colonization, we also showed that the dpr mutant displays a reduced ability to colonize and is more rapidly cleared from the nasopharynx. Our results thus suggest that Dpr is important for pneumococcal resistance to stress and for nasopharyngeal colonization.

Improved performance of ZnO light-emitting devices by introducing a hole-injection layer.

ZnO p-n homojunction light-emitting devices (LEDs) have been fabricated, and by introducing a p-type GaN as the hole-injection layer, the output power of the LEDs can reach 18.5 µW when the drive current is 60 mA, which is almost three orders of magnitude larger than the pristine LEDs without the hole-injection layer. The improved performance can be attributed to the extra holes injected into the p-ZnO layer from the p-GaN hole-injection layer.

Multiple antigen presenting system (MAPS): state of the art and potential applications.

INTRODUCTION: Technological innovations have been instrumental in advancing vaccine design and protective benefit. Improvements in the safety, tolerability, and efficacy/effectiveness profiles have profoundly reduced vaccine-preventable global disease morbidity and mortality. Here we present an original vaccine platform, the Multiple Antigen Presenting System (MAPS), that relies on high-affinity interactions between a biotinylated polysaccharide (PS) and rhizavidin-fused pathogen-specific proteins. MAPS allows for flexible combinations of various PS and protein components. AREAS COVERED: This narrative review summarizes the underlying principles of MAPS and describes its applications for vaccine design against bacterial and viral pathogens in non-clinical and clinical settings. EXPERT OPINION: The utilization of high-affinity non-covalent biotin-rhizavidin interactions in MAPS allows for combining multiple PS and disease-specific protein antigens in a single vaccine. The modular design enables a simplified exchange of vaccine components. Published studies indicate that MAPS technology may support enhanced immunogenic breadth (covering more serotypes, inducing B- and T-cell responses) beyond that which may be elicited via PS- or protein-based conjugate vaccines. Importantly, a more detailed characterization of MAPS-based candidate vaccines is warranted, especially in clinical studies. It is anticipated that MAPS-based vaccines could be adapted and leveraged across numerous diseases of global public health importance.

Existing conjugate vaccines, consisting of pathogen-derived polysaccharides (PSs) and carrier proteins unrelated to the target pathogen, have helped to significantly reduce morbidity and mortality of several bacterial diseases. However, the worldwide burden of infectious diseases targeted by conjugate vaccines is still high. This is mainly due to high pathogen diversity and ongoing evolution, and innovative approaches are needed to respond to these challenges. Multiple Antigen Presenting System (MAPS) is an original vaccine technology that relies on strong molecular interactions between biotin and rhizavidin. MAPS is highly adaptable, as different PS and protein components can be precisely combined and easily exchanged, with limited damage to immunogenic epitopes (PS and protein features recognized by the immune system). Unlike existing conjugate vaccines, MAPS complexes contain pathogen-specific proteins, able to elicit broad immune responses directed against the pathogen. To date, investigational MAPS-based vaccines have been evaluated in several non-clinical studies; one candidate pneumococcal vaccine has been evaluated in early phase clinical studies in healthy children and adults (including older adults). In these clinical studies, the MAPS-based vaccine candidate was well tolerated and induced robust immune responses. If the favorable profile of MAPS-based vaccines is confirmed in further studies, these vaccines could be used against infectious diseases associated with significant morbidity and mortality.

A MAPS Vaccine Induces Multipronged Systemic and Tissue-Resident Cellular Responses and Protects Mice against Mycobacterium tuberculosis.

Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. To date, the mainstay of vaccination involves the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a live-attenuated vaccine that confers protection against extrapulmonary disease in infants and children but not against lung disease. Thus, there is an urgent need for novel vaccines. Here, we show that a multicomponent acellular vaccine (TB-MAPS) induces robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells, and promotes trained innate immunity mediated by γδT and NKT cells in mice. When tested in a mouse aerosol infection model, TB-MAPS significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate. IMPORTANCE Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. Here, we evaluate a novel vaccine which induces a broad immune response to Mycobacterium tuberculosis including robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells. When tested in a mouse aerosol infection model, this vaccine significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate.

Induction of Broad Immunity against Invasive Salmonella Disease by a Quadrivalent Combination Salmonella MAPS Vaccine Targeting Salmonella Enterica Serovars Typhimurium, Enteritidis, Typhi, and Paratyphi A.

Bloodstream infections in low- and middle-income countries (LMICs) are most frequently attributed to invasive Salmonella disease caused by four primary serovars of Salmonella enterica: Typhi, Paratyphi A, Typhimurium, and Enteritidis. We showed previously that a bivalent vaccine targeting S. Typhi and S. Paratyphi A using a Multiple Antigen-Presenting System (MAPS) induced functional antibodies against S. Typhi and S. Paratyphi. In the current study, we describe the preclinical development of a first candidate quadrivalent combination Salmonella vaccine with the potential to cover all four leading invasive Salmonella serotypes. We showed that the quadrivalent Salmonella MAPS vaccine, containing Vi from S. Typhi, O-specific Polysaccharide (OSP) from S. Paratyphi A, S. Enteritidis and S. Typhimurium, combined with the Salmonella-specific protein SseB, elicits robust and functional antibody responses to each of the components of the vaccine. Our data indicates that the application of MAPS technology to the development of vaccines targeting invasive forms of Salmonella is practical and merits additional consideration.

Carrier Proteins Facilitate the Generation of Antipolysaccharide Immunity via Multiple Mechanisms.

Capsular polysaccharides (CPSs) are important antigenic targets against bacterial infections. As T-independent antigens, however, CPSs elicit short-lived immune responses in adults and are poorly immunogenic in young children. Coupling CPS with protein carriers enhances anti-CPS responses and generates long-lasting immune memory. However, the mechanisms whereby carrier proteins accomplish this are not fully understood. Here, we dissect different mechanisms whereby carrier proteins enhance anti-CPS immunity. We show how coupling CPS with protein carriers modifies the interaction of CPS with antigen-presenting cells, enables a dual-activation mechanism for CPS-specific B cells via interaction with CPS- or carrier-specific T helper cells, and potentiates the recall of anti-CPS responses by engaging memory T helper cells during subsequent vaccination or bacterial exposure. Our findings provide new insights into the immunological basis of carrier-mediated anti-CPS immunity and may help in the design of more effective CPS-based vaccines. IMPORTANCE Polysaccharide capsules, the outermost shells of many bacterial pathogens, play a role in pathogenesis and protect bacteria against the immune system. Generating antipolysaccharide antibodies by vaccination has provided effective protection against infectious diseases caused by encapsulated bacteria. However, most pure polysaccharide preparations are poorly immunogenic, particularly in young children. To circumvent this problem, vaccines have been developed using polysaccharides associated with protein carriers. The precise mechanism whereby protein carriers enhance the immunogenicity of the polysaccharide remains unclear. The significance of our research is in elucidating the different roles played by carriers in facilitating polysaccharide processing and presentation, priming polysaccharide-specific B cells, and potentiating recall antipolysaccharide responses. Overall, our work provides new insights into the immunological basis of carrier-mediated antipolysaccharide immunity and may help in the design of more effective polysaccharide-based vaccines.

Induction of T Cell Responses by Vaccination of a Streptococcus pneumoniae Whole-Cell Vaccine.

The induction of T cell responses by vaccination is important for protection against infection. We have previously shown that immunization with a killed Streptococcus pneumoniae whole-cell vaccine (SPWCV) by either intranasal immunization or subcutaneous immunization induced T cell responses to SPWCV. Protection against colonization by S. pneumoniae is dependent on CD4+ IL-17A production induced by immunization. Here, we present detailed protocols for preparation of SPWCV, immunization of mice, and assay for T cell responses in blood and splenocytes in immunized mice.

A Bivalent MAPS Vaccine Induces Protective Antibody Responses against Salmonella Typhi and Paratyphi A.

Infections by Salmonella Typhi and Paratyphi A strain are still a major cause of morbidity and mortality in developing countries. Generation of antibodies against the Vi capsular polysaccharide of S. Typhi via either pure polysaccharide or protein-polysaccharide conjugate is a very effective way to protect against S. Typhi. To date, there is no commercially available vaccine against S. Paratyphi A. The O-specific polysaccharide (OSP) has been generally considered a good vaccine target for Paratyphi A. Here, a bivalent vaccine against Vi and OSP was generated using the Multiple Antigen Presenting System (MAPS). Three different protein constructs, including CRM197, rEPA of Pseudomonas, and a pneumococcal fusion protein SP1500-SP0785, were fused to Rhizavidin (Rhavi) and evaluated their impact on immunogenicity when incorporated as fusion proteins affinity-bound to the two polysaccharides. We compared the antibody responses, antibody avidity, and cidal activity of sera post-immunization with monovalent vs. combination vaccines. We also wished to evaluate the generation of Vi-specific memory B cells in mice. We found little interference when combination vaccine was compared to monovalent vaccines with respect to antibody concentration and cidal activity of sera. Significant affinity maturation was noted for both Vi and OSP antigens. Thus, our preclinical results with a combination Vi- and OSP-MAPS vaccine strongly support the feasibility of this approach and its application of this approach to other important salmonella and Shigella species.

Pneumococcal capsular polysaccharide structure predicts serotype prevalence.

There are 91 known capsular serotypes of Streptococcus pneumoniae. The nasopharyngeal carriage prevalence of particular serotypes is relatively stable worldwide, but the host and bacterial factors that maintain these patterns are poorly understood. Given the possibility of serotype replacement following vaccination against seven clinically important serotypes, it is increasingly important to understand these factors. We hypothesized that the biochemical structure of the capsular polysaccharides could influence the degree of encapsulation of different serotypes, their susceptibility to killing by neutrophils, and ultimately their success during nasopharyngeal carriage. We sought to measure biological differences among capsular serotypes that may account for epidemiological patterns. Using an in vitro assay with both isogenic capsule-switch variants and clinical carriage isolates, we found an association between increased carriage prevalence and resistance to non-opsonic neutrophil-mediated killing, and serotypes that were resistant to neutrophil-mediated killing tended to be more heavily encapsulated, as determined by FITC-dextran exclusion. Next, we identified a link between polysaccharide structure and carriage prevalence. Significantly, non-vaccine serotypes that have become common in vaccinated populations tend to be those with fewer carbons per repeat unit and low energy expended per repeat unit, suggesting a novel biological principle to explain patterns of serotype replacement. More prevalent serotypes are more heavily encapsulated and more resistant to neutrophil-mediated killing, and these phenotypes are associated with the structure of the capsular polysaccharide, suggesting a direct relationship between polysaccharide biochemistry and the success of a serotype during nasopharyngeal carriage and potentially providing a method for predicting serotype replacement.

Percutaneous kyphoplasty for a patient of thoracolumbar osteoporotic vertebral compression fractures with distal lumbosacral pain: a case report.

When patients combined thoracolumbar osteoporotic vertebral compression fracture (OVCF) with lumbar degenerative disease, whose main clinical manifestations are distal lumbosacral pain (DLP), the therapeutic schedule should be made cautiously. We reported an 80-year-old female presented with long-term lumbosacral pain accused of lumbar disc herniation. Percutaneous kyphoplasty (PKP) had been received because of OVCF at L1 vertebral body. Twenty days ago, the elderly felt the DLP was aggravated with no obvious reason. Magnetic resonance imaging (MRI) showed the fresh compression fracture of L2 vertebral body, but the palpation found absence of focal tenderness. Then, we chose to perform PKP at L2 vertebral body, and the patient felt substantial pain relief of lumbosacral area after operation. This case showed that patient manifested as DLP that combined thoracolumbar OVCF with lumbar degenerative disease, PKP has a significant relieving effect on lumbosacral pain.

Comparative Analysis of Cage Subsidence in Anterior Cervical Decompression and Fusion: Zero Profile Anchored Spacer (ROI-C) vs. Conventional Cage and Plate Construct.

Background: Anterior cervical discectomy and fusion (ACDF) has been widely performed to treat cervical generative diseases. Cage subsidence is a complication after ACDF. Although it is known that segmental kyphosis, acceleration of adjacent segmental disease, and restenosis may occur due to cages subsidence; however detailed research comparing zero-profile cages (ROI-C) and conventional plate and cage construct (CPC) on cage subsidence has been lacking. Objective: The objectives of this study was to compare the rate of postoperative cage subsidence between zero profile anchored spacer (ROI-C) and conventional cage and plate construct (CPC) and investigate the risk factors associated with cage subsidence following ACDF. Methods: Seventy-four patients with ACDF who received either ROI-C or CPC treatment from October 2013 to August 2018 were included in this retrospective cohort study. Clinical and radiological outcomes and the incidence of cage subsidence at final follow up-were compared between groups. All patients were further categorized into the cage subsidence (CS) and non-cage subsidence (NCS) groups for subgroup analysis. Results: The overall subsidence rate was higher in the ROI-C group than in the CPC group (66.67 vs. 38.46%, P = 0.006). The incidence of cage subsidence was significantly different between groups for multiple-segment surgeries (75 vs. 34.6%, P = 0.003), but not for single-segment surgeries (54.55 vs. 42.30%, P = 0.563). Male sex, operation in multiple segments, using an ROI-C, and over-distraction increased the risk of subsidence. Clinical outcomes and fusion rates were not affected by cage subsidence. Conclusion: ROI-C use resulted in a higher subsidence rate than CPC use in multi-segment ACDF procedures. The male sex, the use of ROI-C, operation in multiple segments, and over-distraction were the most significant factors associated with an increase in the risk of cage subsidence.

Comparison of the Wiltse Approach and Percutaneous Pedicle Screw Fixation Under O-arm Navigation for the Treatment of Thoracolumbar Fractures.

OBJECTIVES: The aim of this study was to evaluate the clinical outcomes of the Wiltse approach and percutaneous pedicle screw placement under O-arm navigation for the treatment of thoracolumbar fracture. METHODS: We enrolled a total of 54 patients with neurologically intact thoracolumbar fracture who received minimally invasive treatments between October 2014 and October 2018 in this retrospective study. Among these, 28 patients (22 males and six females, with a mean age of 48.6 ± 9.6 years) were treated with pedicle screw fixation through the Wiltse approach (WPSF), and another 26 (15 males and 11 females, with a mean age of 45.7 ± 10.6 years) received percutaneous pedicle screw fixation under O-arm navigation (OPSF). Statistical methods were used to perform a detailed comparison of clinical outcomes, radiologic findings, and complications between the two groups obtained preoperatively, postoperatively, and at last follow-up. RESULTS: All patients underwent surgery successfully and finished a follow-up of more than 12 months. No serious complications, such as infection, blood vessel injury, or spinal cord or nerve root injury occurred. Visual analog scale (VAS) scores, Oswestry disability index (ODI) scores, local Cobb angle (LCA), vertebral wedge angle (VWA), and R value were notably improved after surgery, though there was no clear discrepancy between the groups at each time point (P > 0.05). During the follow-up period, no patients developed neurological impairment or implant-related complications, and no patients underwent revision surgery. The WPSF group had a significantly shorter operation time than the OPSF group (68.1 ± 9.8 vs 76.1 ± 9.0 minutes, P = 0.005). Moreover, the WPSF group showed less cost of surgery than the WPSF group (48142.1 ± 1430.1 vs 59035.4 ± 1152.7 CNY, P < 0.001). There were no significant differences between the two groups in terms of the intraoperative bleeding, length of incision, or postoperative hospitalization time (P > 0.05). The accuracy of pedicle screw placement was 95.2% (160/168) in the WPSF group and 96.8% (151/156) in the OPSF group, with no significant difference between the groups (P = 0.432). CONCLUSION: Both WPSF and OPSF were safe and effective for the treatment of thoracolumbar fracture. Although the two groups showed favorable clinical and radiologic outcomes through to final follow-up, we recommended the minimally invasive WPSF given its shorter operation time and lower cost of surgery.

Interleukin-17A mediates acquired immunity to pneumococcal colonization.

Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell-dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1(-/-) mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-gamma or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines.