Current Pneumococcal Vaccines Research Articles

Clinical and Economic Burden of Pneumococcal Disease Due to Serotypes Contained in Current and Investigational Pneumococcal Conjugate Vaccines in Children Under Five Years of Age.

IntroductionThe widespread implementation of pneumococcal conjugate vaccines (PCVs) has significantly reduced the burden of pneumococcal disease around the world. Although licensed 10-valent (PCV10) and 13-valent (PCV13) vaccines have considerably reduced mortality and morbidity, a sizeable disease burden attributable to serotypes not contained in these PCVs remains. This study aimed to estimate the annual clinical and economic burden of pneumococcal disease attributable to licensed (PCV10 and PCV13) and investigational PCVs, notably 15-valent (PCV15) and 20-valent (PCV20) vaccines, in 13 countries in children under 5 years of age.MethodsA decision-analytic model was created to aggregate total cases [inclusive of invasive pneumococcal disease (IPD), pneumonia, and otitis media (OM)], deaths, and direct costs in each country of interest [stratified by PCV10/PCV13 countries, depending on national immunization programs (NIPs)] over 1 year, using up to the three most recent years of available serotype coverage data. Data inputs were sourced from local databases, surveillance reports, and published literature.ResultsIn 5 PCV10 NIPs (Austria, Finland, Netherlands, New Zealand, Sweden), most remaining PCV20-type disease was due to PCV13-unique serotypes (30–85%), followed by PCV20-unique (9–50%), PCV15-unique (4–15%), and PCV10-unique (2–14%) serotypes. In 8 PCV13 NIPs (Australia, Canada, France, Germany, Italy, South Korea, Spain, United Kingdom), most remaining PCV20-type disease was caused by PCV20-unique serotypes (16–69%), followed by PCV13-unique (11–54%), PCV15-unique (2–33%), and PCV10-unique serotypes (3–19%). Across all countries, PCV20 serotypes caused 3000 to 345,000 cases of disease and cost between $1.3 and $44.9 million USD annually with variability driven by population size, NIP status, and epidemiologic inputs. In aggregate, PCV20 serotypes caused 1,234,000 cases and $213.5 million in annual direct medical costs in children under 5 years of age.ConclusionDespite the success of PCV10 and PCV13 in reducing pneumococcal disease, a substantial clinical and economic burden remains due to serotypes contained in investigational vaccines.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00544-1.

A nanogel-based trivalent PspA nasal vaccine protects macaques from intratracheal challenge with pneumococci

Current polysaccharide-based pneumococcal vaccines are effective but not compatible with all serotypes of Streptococcus pneumoniae. We previously developed an adjuvant-free cationic nanogel nasal vaccine containing pneumococcal surface protein A (PspA), which is expressed on the surfaces of all pneumococcal serotypes. Here, to address the sequence diversity of PspA proteins, we formulated a cationic nanogel-based trivalent pneumococcal nasal vaccine and demonstrated the vaccine’s immunogenicity and protective efficacy in macaques by using a newly developed nasal spray device applicable to humans. Nasal vaccination of macaques with cationic cholesteryl pullulan nanogel (cCHP)-trivalent PspA vaccine effectively induced PspA-specific IgGs that bound to pneumococcal surfaces and triggered complement C3 deposition. The immunized macaques were protected from pneumococcal intratracheal challenge through both inhibition of lung inflammation and a dramatic reduction in the numbers of bacteria in the lungs. These results demonstrated that the cCHP-trivalent PspA vaccine is an effective candidate vaccine against pneumococcal infections.

Invasive pneumococcal disease in Canada 2010–2017: The role of current and next-generation higher-valent pneumococcal conjugate vaccines

BackgroundIn 2010–2011, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7- or 10-valent vaccine (PCV7 and PCV10, respectively) in pediatric immunization programs across Canada. For adults aged ≥65 years, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been publicly funded for several decades; PCV13 funding was not recommended in this population, partly due to expected ongoing vaccine-serotype disease decline stemming from herd effects of the pediatric program. Higher-valent PCVs (ie, 15- and 20-valent PCVs [PCV15 and PCV20, respectively]) currently in development may become available in Canada in the coming years. MethodsUsing the National Microbiology Laboratory surveillance reports, annual case counts and serotype distribution of invasive pneumococcal disease (IPD) from 2010 to 2017 in Canada were examined to assess the impact of existing programs on PCV13-serotype IPD and determine the proportion of IPD that can potentially be prevented by current and forthcoming higher-valent PCVs. ResultsThe percentages of PCV13-serotype IPD decreased from 55% [1492/2708] in 2010 to 30% [902/3006] in 2017 in all age groups combined, including a decline from 67% [221/331] to 18% [40/219] in children aged <5 years and from 50% [487/967] to 23% [287/1238] in adults aged ≥65 years. Overall, IPD cases declined mainly before 2014 and have plateaued since then. In 2017, PCV15- and PCV20-serotypes (inclusive of PCV13 serotypes) accounted for 42% and 58% of IPD cases, respectively, in all ages. ConclusionsIn Canada, publicly funded pediatric PCV13 use was associated with large declines in IPD due to vaccine serotypes. Substantial residual PCV13-serotype IPD proportions observed among all ages imply limits to indirect protection afforded by the pediatric PCV13 program at the current uptake level and suggest the adult PPSV23 program alone is insufficient. Higher-valent PCVs have the potential to address a substantial proportion of remaining IPD cases among all age groups.

Nasopharyngeal carriage of otitis media pathogens in infants receiving 10-valent non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10), 13-valent pneumococcal conjugate vaccine (PCV13) or a mixed primary schedule of both vaccines: A randomised controlled trial

BackgroundAboriginal children in Northern Australia have a high burden of otitis media, driven by early and persistent nasopharyngeal carriage of otopathogens, including non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). In this context, does a combined mixed primary series of Synflorix and Prevenar13 provide better protection against nasopharyngeal carriage of NTHi and Spn serotypes 3, 6A and 19A than either vaccine alone? MethodsAboriginal infants (n = 425) were randomised to receive Synflorix™ (S, PHiD-CV10) or Prevenar13™ (P, PCV13) at 2, 4 and 6 months (_SSS or _PPP, respectively), or a 4-dose early mixed primary series of PHiD-CV10 at 1, 2 and 4 months and PCV13 at 6 months of age (SSSP). Nasopharyngeal swabs were collected at 1, 2, 4, 6 and 7 months of age. Swabs of ear discharge were collected from tympanic membrane perforations. FindingsAt the primary endpoint at 7 months of age, the proportion of nasopharyngeal (Np) swabs positive for PCV13-only serotypes 3, 6A, or 19A was 0%, 0.8%, and 1.5% in the _PPP, _SSS, and SSSP groups respectively, and NTHi 55%, 52%, and 52% respectively, and no statistically significant vaccine group differences in other otopathogens at any age. The most common serotypes (in order) were 16F, 11A, 10A, 7B, 15A, 6C, 35B, 23B, 13, and 15B, accounting for 65% of carriage. Ear discharge swabs (n = 108) were culture positive for NTHi (52%), S. aureus (32%), and pneumococcus (20%). ConclusionsAboriginal infants experience nasopharyngeal colonisation and tympanic membrane perforations associated with NTHi, non-PCV13 pneumococcal serotypes and S. aureus in the first months of life. Nasopharyngeal carriage of pneumococcus or NTHi was not significantly reduced in the early 4-dose combined SSSP group compared to standard _PPP or _SSS schedules at any time point. Current pneumococcal conjugate vaccine formulations do not offer protection from early onset NTHi and pneumococcal colonisation in this high-risk population.

Seasonal Influenza and Pneumococcal Vaccination Rates Among Patients with Cancer in COVID-19 Pandemic: A Cross-Sectional Study

Objective: Influenza and pneumococcal vaccination rates were not in the expected levels before the coronavirus disease-2019 (COVID-19) pandemic among patients with cancer. However, pandemic conditions may have changed the attitude of patients. In this study, we aimed to assess current influenza and pneumococcal vaccination rates of patients with cancer and changing attitudes toward vaccination in these patients. Material and Methods: This cross-sectional study was conducted in a tertiary cancer center in Turkey. A self-administered questionnaire consisting of 20 items was used. Results: A total of 309 patients completed the questionnaires. Most patients did not get a flu shot and pneumococcal vaccine before the COVID-19 pandemic (74.1% for flu shot and 84.1% for pneumococcal vaccine). Moreover, 144 patients (46.6%) stated that they were considering to get a flu shot, and 133 (43%) were considering to get a pneumococcal vaccine because of the COVID-19 pandemic. Only 35 patients (11.3%) got a flu shot, and 56 (18.1%) got a pneumococcal vaccine during the COVID-19 pan-demic. Conclusion: Vaccination rates for seasonal influenza and pneumococcal infections were low in patients with cancer before the COVID-19 pandemic. Although the number of patients who want to be vaccinated against seasonal influenza and pneumococcal infections increased in the COVID-19 pandemic, the number of patients vaccinated with these vaccines is still low. © 2021 by Turkish Society of Medical Oncology.

Non-Invasive Pneumococcal Pneumonia Due to Vaccine Serotypes: A Systematic Review and Meta-Analysis

Background: Non-invasive pneumococcal pneumonia causes significant morbidity and mortality in older adults globally. Understanding pneumococcal sero-epidemiology in adults ≥50 years is necessary to inform pneumococcal vaccination policies and direct the updating of pneumococcal vaccines. Methods: We conducted a systematic review and random-effects meta-analysis to determine the proportion of community-acquired pneumonia (CAP) in people ≥50 years due to pneumococcus and the proportion caused by current pneumococcal vaccine serotypes. Heterogeneity was explored by subgroup analysis according to a) patient group (stratified versus age) and depth of testing, b) detection/serotyping method, and c) continent. The protocol is registered with PROSPERO (CRN42020192002).Findings There were 28 included studies (34,216 patients). The estimated proportion of pneumococcal CAP was highest in studies that mainly used 24-valent serotype-specific urinary antigen detection (ss-UAD)(30% [95%CI 28-31%]), followed by serology (29% [26-32%]), PCR (21% [20-23%]), ss-UAD13 (17% [13-22%]), and culture alone (14% [10-19%]). Inter-continental heterogeneity was observed, with a higher pooled estimate in Europe (26% [21-30%, I2 =92%] than North America (11% [9-12%, I2 =87·2%](p<0·001). PCV13-serotype estimates were also influenced by serotyping methods. Interpretation: Non-invasive pneumococcal CAP, including disease due to current pneumococcal vaccine serotypes, remains a burden in adults aged ≥50 years, despite the introduction of pneumococcal infant immunisation in most countries. Studies heavily reliant on ss-UADs restricted to vaccine-type serotypes may overestimate the proportion of potentially vaccine-preventable pneumococcal pneumonia. Sero-epidemiological data from low-income countries are lacking. Funding LL is funded by the National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, UK. Declaration of Interest: Professor Lim reports grants from National Institute for Health Research (NIHR), grants from Pfizer, outside the submitted work. All other authors declare no competing interests.

Pneumococcal virulence factors in community-acquired pneumonia.

This manuscript reviews the recent literature related to new developments in the understanding of existing and novel virulence factors of the pneumococcus that are of potential importance in the development of novel preventive and therapeutic strategies. The pneumococcal capsule and pneumolysin have long been recognized as being two of the most prominent virulence factors, with much recent research having revealed previously unrecognized mechanisms by which they contribute to the pathogenesis of infection. Although the pneumococcal capsule has been considered a sine qua non for virulence, the emergence of pathogenic nonencapsulated strains with newly recognized virulence determinants has also been described. Not unexpectedly, but of concern, nonencapsulated strains are unaffected by current pneumococcal vaccines. This, together with the finding of novel virulence factors, as well as new mechanisms of pathogenicity of established virulence determinants, underscores the resilience of the pneumococcus in confronting challenges in its environment, most importantly those posed by antibiotics and vaccines. Recent advances in the understanding of pneumococcal virulence factors provide potential opportunities for the development of novel putative therapeutic or preventive strategies.

Lung resident memory B cells are a common and functionally significant component of lung adaptive immunity

Abstract Resident memory B cells (BRM) in influenza-recovered mouse lungs were recently described, but whether other types of infections elicit these cells is unknown. The relevance of BRM in human lungs and to lung immune defenses also remains unexplored. Using flow cytometry and immunofluorescence, we found that respiratory pneumococcal exposures in mice elicited lung BRM without concurrent tertiary lymphoid structure formation. Additionally, flow cytometry analysis of normal human lung tissue showed that human lungs are enriched compared to human blood for B cells bearing a resident memory phenotype. These findings indicate that lung BRM are a common feature of antigen-experienced lungs. Multiple mouse models were used to address the contributions of B cell immunity to anti-pneumococcal lung defenses. Mice exposed to a low virulence pneumococcal strain 4 weeks previously were well-protected from a serotype-mismatched pneumococcal challenge. When previously exposed mice were depleted of circulating B cells (but not lung B cells) with anti-CD20 treatment before the challenge infection, there was no effect on the acquired lung immunity. However, a genetically engineered mouse strain allowed effective depletion of lung B cells bearing PD-L2 (a mouse memory B cell marker) from previously exposed mice, and doing so before the virulent pneumococcal challenge resulted in substantial defects in bacterial clearance compared to mice with lung B cells intact. These results provide the first direct evidence of a role for lung BRM in anti-bacterial lung immunity. Notably, this defense was pneumococcal serotype-independent, distinguishing it from the serotype-specific immunity elicited by current pneumococcal vaccines.

Childhood vaccines and antibiotic use in low- and middle-income countries

Vaccines may reduce the burden of antimicrobial resistance, in part by preventing infections for which treatment often includes the use of antibiotics1–4. However, the effects of vaccination on antibiotic consumption remain poorly understood—especially in low- and middle-income countries (LMICs), where the burden of antimicrobial resistance is greatest5. Here we show that vaccines that have recently been implemented in the World Health Organization’s Expanded Programme on Immunization reduce antibiotic consumption substantially among children under five years of age in LMICs. By analysing data from large-scale studies of households, we estimate that pneumococcal conjugate vaccines and live attenuated rotavirus vaccines confer 19.7% (95% confidence interval, 3.4–43.4%) and 11.4% (4.0–18.6%) protection against antibiotic-treated episodes of acute respiratory infection and diarrhoea, respectively, in age groups that experience the greatest disease burden attributable to the vaccine-targeted pathogens6,7. Under current coverage levels, pneumococcal and rotavirus vaccines prevent 23.8 million and 13.6 million episodes of antibiotic-treated illness, respectively, among children under five years of age in LMICs each year. Direct protection resulting from the achievement of universal coverage targets for these vaccines could prevent an additional 40.0 million episodes of antibiotic-treated illness. This evidence supports the prioritization of vaccines within the global strategy to combat antimicrobial resistance8.

Cost‐Effectiveness of Pneumococcal Vaccination Policies and Uptake Programs in US Older Populations

Recently revised vaccination recommendations for US adults, aged 65 years and older, include both 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13), with PCV13 now recommended for immunocompetent older people based on shared decision making. The public health impact and cost-effectiveness of this recommendation or of pneumococcal vaccine uptake improvement interventions are unclear. Markov decision analysis. Hypothetical 65-year-old general and black population cohorts. Current pneumococcal vaccination recommendations for US older people, an alternative policy omitting PCV13 in immunocompetent older people, and vaccine uptake improvement programs. The current pneumococcal vaccination recommendation was the most effective strategy, but afforded slight public health benefits compared to an alternative (PPSV23 for all older people plus PCV13 for the immunocompromised) and cost greater than $750 000 per quality-adjusted life-year (QALY) gained in either population group with a vaccine uptake improvement program (absolute uptake increase = 12.3%; cost = $1.78/eligible patient) in place. The alternative strategy was more economically favorable, but cost greater than $100 000/QALY in either population, with or without an uptake intervention. Results were robust in sensitivity analyses; however, in black older people, the alternative strategy with an uptake program was most likely to be favored in probabilistic sensitivity analyses at a $150 000/QALY gained threshold. Current pneumococcal vaccination recommendations for US older people are economically unfavorable compared to an alternative strategy omitting PCV13 in the immunocompetent. The alternative recommendation with an uptake improvement program may be economically reasonable in black population analyses and could be worth considering as a population-wide recommendation if mitigating racial disparities is a priority. J Am Geriatr Soc 68:1271-1278, 2020.

IgA-protease activity coupled to cellular enzymes of different &lt;i&gt;Streptococcus pneumonia&lt;/i&gt; serotypes isolated in pediatric bacteria carriers

Streptococcus pneumoniae are significant causative agents of severe and life-threatening acute pneumonia, meningitis, as well as otitis and sinusitis both in children and elderly. As many as 1.2 million pediatric lethal outcomes due to pneumonia and infections of the central nervous system (meningitis) caused by S. pneumoniae, are recorded worldwide annually, a large proportion of which occur in developing countries. Metal-dependent IgA1 proteases derived from pathogenic bacteria comprise an important group of bacterial enzymes cleaving human immunoglobulin A1 (IgA1) at the hinge region, thereby interfering with fully-executed host antibacterial immunity.Objective. To study activity of IgA1proteinases and their class profile (Na2-EDTA and PMSF-inhibited) in various pneumococcal serotypes isolated from nasopharyngeal carrier children.Materials and methods. There were examined 585 children attending preschool facilities residing in Kazan (n = 331) and rural areas (n = 254). Microbiological, molecular genetics and immunochemical methods were used to identify, serotyping composition and protease activity of Streptococcus pneumoniae isolates. Data statistical processing was carried out by using software Graph Pad Prism version 5.0.Results. Prevalence of S. pneumonie in pediatric carriers aged 1.5–3 years was 35.1%, 3–5 years — 23.4%, 5–7 years — 19.6%, and over 7 years — 21.9%. Vaccine serotypes 14, 19F, 23F as a part of current pneumococcal vaccines (Prevenar, Pneumavax-23) comprised as high as 55.8%. However, in 19% of cases were positive for non-vaccine S. pneumoniae strains. Non-typeable strains were detected in 5.8% isolates. IgA-proteinase activity was detected in cell lysates of 45 (86.5%) S. pneumoniae strains isolated from pediatric carriers. Cell lysates of S. pneumoniae strains showing no proteolytic properties, were assigned to serotypes 12F, Sg18. Thus, studies on development of alternative vaccines containing immunogenic proteins, adhesins or other virulence factors common to capsulated and non-typeable (encapsulated) pneumococcal strains hold promise. All the aforementioned accounts for a need for microbiological monitoring of S. pneumoniae carriage and search for new diagnostic approaches for etiological interpretation of S. pneumoniae-associated diseases.

Pneumococcal carriage among adults aged 50 years and older with co-morbidities attending medical practices in Rome, Italy

BackgroundData on Streptococcus pneumoniae carriage in adults with co-morbidities are limited. In this study we estimated the pneumococcal carriage among adults with co-morbidities and evaluated socio-demographic and clinical risk factors. The potential coverage of the current pneumococcal vaccines recommended for adults (PCV13 and PPV23) was also investigated. MethodsA cross-sectional study on S. pneumoniae carriage among unvaccinated adults ≥50 years with co-morbidities, presenting with or without acute respiratory symptoms at general practitioners in Rome, Italy, between October 2015 and July 2016 was conducted. Pneumococcal carriage was investigated by both cultural and molecular methods. Socio-demographic variables and co-morbidities were evaluated by logistic models as possible risk factors for pneumococcal carriage. ResultsOut of 248 patients (median age: 73 yrs; IQR: 65–79), 12 (4.8%) and 83 (33.5%) individuals were found colonized using cultural or molecular methods, respectively. Potential risk factors for pneumococcal colonization as ascertained by molecular methods were: low level of education (adjusted OR = 3.71, 95% CI: 1.62–9.40), winter months (December-March vs other months, adjusted OR = 2.56, 95% CI: 1.29–5.14), and presence of chronic lung diseases (adjusted OR = 2.18, 95% CI: 1.15–4.16). The combination of serotype-specific multiplex RT-PCR and conventional PCR allowed to identify 22 serotypes/group of serotypes, of which the most common were: 24F/24A/24B, 12F/12A/12B/44/46, 6A/6B, 14, 15B/15C, and 22F/22A. Prevalence of pneumococcal carriage due to PCV13 serotypes and non-PCV13 serotypes was 23.6% and 67.3%, respectively. Prevalence of colonization due to PPV23 serotypes was estimated to be 54.6%. ConclusionsA high prevalence of S. pneumoniae carriage was observed among adults with co-morbidities, especially among individuals affected by chronic lung diseases. These results support vaccine strategies based on the sequential administration of PCV13 and PPV23 to control potentially invasive pneumococcal strains in adults, especially in subjects with co-morbidities.

Identification of Pneumococcal Factors Affecting Pneumococcal Shedding Shows that the dlt Locus Promotes Inflammation and Transmission.

Host-to-host transmission is a necessary but poorly understood aspect of microbial pathogenesis. Herein, we screened a genomic library of mutants of the leading respiratory pathogen Streptococcus pneumoniae generated by mariner transposon mutagenesis (Tn-Seq) to identify genes contributing to its exit or shedding from the upper respiratory tract (URT), the limiting step in the organism's transmission in an infant mouse model. Our analysis focused on genes affecting the bacterial surface that directly impact interactions with the host. Among the multiple factors identified was the dlt locus, which adds d-alanine onto lipoteichoic acids (LTA) and thereby increases Toll-like receptor 2-mediated inflammation and resistance to antimicrobial peptides. The more robust proinflammatory response in the presence of d-alanylation promotes secretions that facilitate pneumococcal shedding and allows for transmission. Expression of the dlt locus is controlled by the CiaRH system, which senses cell wall stress in response to antimicrobial activity, including in response to lysozyme, the most abundant antimicrobial along the URT mucosa. Accordingly, in a lysM-/- host, there was no longer an effect of the dlt locus on pneumococcal shedding. Thus, our findings demonstrate how a pathogen senses the URT milieu and then modifies its surface characteristics to take advantage of the host response for transit to another host.IMPORTANCEStreptococcus pneumoniae (the pneumococcus) is a common cause of respiratory tract and invasive infection. The overall effectiveness of immunization with the organism's capsular polysaccharide depends on its ability to block colonization of the upper respiratory tract and thereby prevent host-to-host transmission. Because of the limited coverage of current pneumococcal vaccines, we carried out an unbiased in vivo transposon mutagenesis screen to identify pneumococcal factors other than its capsular polysaccharide that affect transmission. One such candidate was expressed by the dlt locus, previously shown to add d-alanine onto the pneumococcal lipoteichoic acid present on the bacterial cell surface. This modification protects against host antimicrobials and augments host inflammatory responses. The latter increases secretions and bacterial shedding from the upper respiratory tract to allow for transmission. Thus, this study provides insight into a mechanism employed by the pneumococcus to successfully transit from one host to another.

Streptococcus pneumoniae Capsular Polysaccharide.

The polysaccharide capsule of Streptococcus pneumoniae is the dominant surface structure of the organism and plays a critical role in virulence, principally by interfering with host opsonophagocytic clearance mechanisms. The capsule is the target of current pneumococcal vaccines, but there are 98 currently recognised polysaccharide serotypes and protection is strictly serotype-specific. Widespread use of these vaccines is driving changes in serotype prevalence in both carriage and disease. This chapter summarises current knowledge on the role of the capsule and its regulation in pathogenesis, the mechanisms of capsule synthesis, the genetic basis for serotype differences, and provides insights into how so many structurally distinct capsular serotypes have evolved. Such knowledge will inform ongoing refinement of pneumococcal vaccination strategies.

Intranasal Immunization with the Commensal Streptococcus mitis Confers Protective Immunity against Pneumococcal Lung Infection.

Streptococcus pneumoniae is a bacterial pathogen that causes various diseases of public health concern worldwide. Current pneumococcal vaccines target the capsular polysaccharide surrounding the cells. However, only up to 13 of more than 90 pneumococcal capsular serotypes are represented in the current conjugate vaccines. In this study, we used two experimental approaches to evaluate the potential of Streptococcus mitis, a commensal that exhibits immune cross-reactivity with S. pneumoniae, to confer protective immunity to S. pneumoniae lung infection in mice. First, we assessed the immune response and protective effect of wild-type S. mitis against lung infection by S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4). Second, we examined the ability of an S. mitis mutant expressing the S. pneumoniae type 4 capsule (S. mitis TIGR4cps) to elicit focused protection against S. pneumoniae TIGR4. Our results showed that intranasal immunization of mice with S. mitis produced significantly higher levels of serum IgG and IgA antibodies reactive to both S. mitis and S. pneumoniae, as well as enhanced production of interleukin 17A (IL-17A), but not gamma interferon (IFN-γ) and IL-4, compared with control mice. The immunization resulted in a reduced bacterial load in respiratory tissues following lung infection with S. pneumoniae TIGR4 or D39 compared with control mice. With S. mitis TIGR4cps, protection upon challenge with S. pneumoniae TIGR4 was superior. Thus, these findings show the potential of S. mitis to elicit natural serotype-independent protection against two pneumococcal serotypes and to provide the benefits of the well-recognized protective effect of capsule-targeting vaccines.IMPORTANCEStreptococcus pneumoniae causes various diseases worldwide. Current pneumococcal vaccines protect against a limited number of more than 90 pneumococcal serotypes, accentuating the urgent need to develop novel prophylactic strategies. S. pneumoniae and the commensal Streptococcus mitis share immunogenic characteristics that make S. mitis an attractive vaccine candidate against S. pneumoniae In this study, we evaluated the potential of S. mitis and its mutant expressing pneumococcal capsule type 4 (S. mitis TIGR4cps) to induce protection against S. pneumoniae lung infection in mice. Our findings show that intranasal vaccination with S. mitis protects against S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4) in a serotype-independent fashion, which is associated with enhanced antibody and T cell responses. Furthermore, S. mitis TIGR4cps conferred additional protection against S. pneumoniae TIGR4, but not against D39. The findings highlight the potential of S. mitis to generate protection that combines both serotype-independent and serotype-specific responses.

Current US adult pneumococcal vaccination policies cost effective

Current US adult pneumococcal vaccination policies cost effective

An intervention to improve pneumococcal vaccination uptake in high risk 50-64 year olds vs. expanded age-based recommendations: an exploratory cost-effectiveness analysis

ABSTRACT In the U.S., pneumococcal polysaccharide vaccine (PPSV23) uptake among high-risk adults aged <65 years is consistently low and improvement is needed. One barrier to improved vaccine coverage is the complexity of the adult vaccination schedule. This exploratory analysis compared the cost-effectiveness of strategies to increase pneumococcal vaccine uptake in high-risk adults aged 50–64 years. We used a Markov model to compare strategies for non-immunocompromised 50–64 year olds: 1) current pneumococcal polysaccharide vaccine (PPSV23) recommendations; 2) current recommendations enhanced by an intervention; 3) PPSV23 plus pneumococcal conjugate vaccine (PCV13) for high-risk patients with no intervention; or 4) both vaccines for all 50-year-olds with no intervention. Parameters included CDC data and other US data, varied extensively in sensitivity analyses. In the analysis, vaccinating high-risk individuals with PPSV23/PCV13 was the least costly strategy, with total costs of $424/person. Vaccinating all 50 year olds with PPSV23/PCV13 cost $40 more and gained 0.00068 quality-adjusted life years (QALY), or $57,786/QALY gained. Current recommendations with or without an intervention program were more expensive and less effective than other strategies. In multi-way sensitivity analyses, the current recommendations/intervention program strategy was favored at a $100,000/QALY threshold only if non-bacteremic pneumococcal pneumonia rate or PCV13 serotype coverage were substantially lower than base case values. Thus, an intervention program to improve pneumococcal vaccine uptake among high-risk 50–64 year-olds was not cost-effective in most scenarios. High-risk individuals receiving both PCV13 and PPSV23 could be economically favorable, and vaccinating all 50-year-olds with both vaccines could be considered.

The potential impact and cost-effectiveness of current and future pneumococcal conjugate vaccines in India

The potential impact and cost-effectiveness of current and future pneumococcal conjugate vaccines in India

Construction and evaluation of a whole-cell pneumococcal vaccine candidate.

Pneumococcal infections are a major public health problem, especially in developing countries, and the current pneumococcal vaccines do not cover all pathogenic strains. New, more economical serotype-independent vaccines based on species-common protein antigens are being pursued. The pneumococcal whole-cell vaccine which is based on noncapsular antigens common to all strains induces serotype-independent immunity. In the present study, we developed a new candidate for a whole-cell pneumococcal vaccine in which two important virulence factors, the capsule and pneumolysin, were deleted. Protection was elicited by immunization against colonization in mice with a killed mutant strain and the antibody response in the mice serum was evaluated. This candidate vaccine was effective in preventing nasopharyngeal colonization. The mice immunized with this candidate vaccine had significantly higher serum antibody titres than mice that received the adjuvant alone. Based on obtained results in this study, the engineered whole-cell pneumococci can be considered as a vaccine candidate in future studies. This candidate vaccine can overcome the limitations of available polysaccharide vaccines.

A double edge function of type 17 immunity in Streptococcus pneumoniae pathogenesis during a co-infection with Influenza A Virus

Abstract Streptococcus pneumoniae (Spn) is a respiratory pathogen responsible for significant global disease burden (otitis media, pneumonia, sepsis). Despite success with current Pneumococcal Conjugate Vaccines, a significant proportion of humans remain colonized with Spn, rendering them at risk for developing Spn infections. Upper respiratory nasopharyngeal (NP) colonization by Spn is a precursor to disease, and viral induced inflammation is a key risk factor for the transition of commensal colonization to disease pathogenesis. We utilized a mouse co-infection model of Spn and influenza virus to determine the role of virus induced acute inflammation in the transition of Spn colonization to disease pathogenesis. We show that early Spn NP colonization is allowed by an immune quiescence state, maintained by the lack of IL-17 expression. Introduction of influenza virus in Spn colonized mice elicits a robust IL-17 driven inflammatory response, which induces robust neutrophilia and tissue damage in the NP. The IL-17 mediated inflammatory response was associated with a significant increase in Spn NP bacterial density, leading to Spn invasion and bacteremia. Antibody mediated neutralization of IL-17 suppressed NP inflammation and bacterial density and prevented bacteremia. IL-17 receptor expression was also detected in nasal myeloid cell infiltrate. RoRγt-KO mice remained protected from bacteremia, mimicking the reduced pathogenesis of IL-17 neutralized WT mice. Using RoRγtGFP mutant mice, we detected the recruitment of GFP expressing RoRγt cell population in NP lavages and nasal associated lymphoid tissues. We conclude that IL-17 blockade could contain influenza induced NP pathology and protect against Spn invasive pathogenesis.