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PloS One 2020Glycoconjugate vaccines are vaccines in which a bacterial polysaccharide antigen is conjugated to a carrier protein to enhance immunogenicity by promoting T...
Glycoconjugate vaccines are vaccines in which a bacterial polysaccharide antigen is conjugated to a carrier protein to enhance immunogenicity by promoting T cell-dependent immune response. However, the free (unreacted) polysaccharides remaining after the conjugation process can inhibit the immunogenicity of a conjugate vaccine. Thus, we aimed to reduce the unbound free polysaccharides in the polysaccharide-protein conjugation process for the development of a new 15-valent pneumococcal conjugate vaccine (PCV15) by varying some factors that may affect the conjugation results such as polysaccharide/protein ratio, polysaccharide size, and concentration of a coupling agent in a conjugation reaction mixture. Concentrations of a coupling agent, carbodiimide (EDAC), and a carrier protein (CRM197) used in PCV15 production, during the conjugation process, had little effect on the content of free polysaccharides. However, the size of the polysaccharide was identified as the critical factor to control the free polysaccharide content, with an inverse relationship observed between the molecular weight of the polysaccharide and the residual free polysaccharide content after conjugation. Based on these results, a new PCV15 with low free polysaccharide contamination was produced and tested for immunogenicity using a rabbit model to show that it induces similar level of immune responses in rabbits compared to a comparator vaccine Prevnar13®.
Topics: Glycoconjugates; Humans; Immunity; Pneumococcal Infections; Pneumococcal Vaccines; Polysaccharides; T-Lymphocytes; Vaccines, Conjugate
PubMed: 33301525
DOI: 10.1371/journal.pone.0243909 -
Mediators of Inflammation 2020The encapsulated bacteria, as , type b, and , cause serious morbidity and mortality worldwide. The capsular polysaccharide (PS), which could elicit a weak T...
The encapsulated bacteria, as , type b, and , cause serious morbidity and mortality worldwide. The capsular polysaccharide (PS), which could elicit a weak T cell-independent immune response, is a vital virulence determinant. One of the strategies to improve the PS-specific immunogenicity is to conjugate PS with a nontoxic carrier protein. Tetanus toxoid (TT) and CRM are the typical carrier proteins for the PS conjugate vaccines. TT is the inactivated tetanus toxin manipulated with formaldehyde, which suffers from the pollution from residual formaldehyde and the incomplete detoxification. CRM has the disadvantage of low-yield purification with the requirement of sophisticated culture conditions. Thus, a novel carrier protein without these disadvantages is highly required. The tetanus toxin native C-fragment (Hc) is safe, low-cost, and highly immunogenic with easy purification, which can act as a promising carrier protein. Pneumococcal serogroups 14 and 23F were major epidemic causes of pneumococcal infections. In the present study, the capsular PSs (PS14 and PS23F) were conjugated with Hc, TT, and CRM, respectively. TT- and CRM-based conjugates acted as controls for Hc-based conjugates (PS14-Hc and PS23F-Hc). The structural properties of Hc were not fundamentally changed after conjugated with PS. PS14-Hc and PS23F-Hc could potentiate sound PS-specific antibody levels comparable to the controls. Thus, Hc exhibited a practical carrier effect to help the pneumococcal conjugate vaccines perform good immunogenicities.
Topics: Formaldehyde; Pneumococcal Vaccines; Tetanus Toxoid; Vaccines, Conjugate
PubMed: 32714092
DOI: 10.1155/2020/9596129 -
Clinical Infectious Diseases : An... Nov 2012Clinical use of the 7-valent pneumococcal protein conjugate (PCV7) vaccine, which includes serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, dramatically reduced invasive... (Review)
Review
Clinical use of the 7-valent pneumococcal protein conjugate (PCV7) vaccine, which includes serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, dramatically reduced invasive pneumococcal disease (IPD); however, the effectiveness was diminished due to serotype shift. Although shift due to known serotypes was anticipated, shift by misidentified serotypes was unexpected. We describe the experience with newly recognized serotypes 6C and 6D, which were mistyped as serotypes 6A and 6B, respectively. Although serotype 6D caused only occasional infections, IPD due to serotype 6C disease expanded in the PCV7 era. Subsequent studies showed that PCV7 provided cross-protection against serotype 6A but not serotype 6C. The 13-valent pneumococcal protein conjugate (PCV13) vaccine, which includes PCV7 serotypes plus serotypes 1, 3, 5, 6A, 7F, 19A, may provide protection against IPD due to serotypes 6C and 6D. Regardless, this narrative illustrates the potential impact of unrecognized serotypes on the efficacy of a serotype-specific vaccine.
Topics: Heptavalent Pneumococcal Conjugate Vaccine; Humans; Pneumococcal Infections; Pneumococcal Vaccines; Serotyping; Streptococcus pneumoniae
PubMed: 22903767
DOI: 10.1093/cid/cis691 -
Human Vaccines & Immunotherapeutics Aug 2016Pneumococcal infection is a major cause of pneumonia, bacteremia, and meningitis. Incidence of pneumococcal disease (PD) varies worldwide. The 23-valent pneumococcal... (Clinical Trial)
Clinical Trial
UNLABELLED
Pneumococcal infection is a major cause of pneumonia, bacteremia, and meningitis. Incidence of pneumococcal disease (PD) varies worldwide. The 23-valent pneumococcal polysaccharide vaccine (PPV23) displays an acceptable safety profile and has been demonstrated cost-effective in reducing burden of PD.
METHODS
Approximately 100 subjects from the Russian Federation who were either 2 to 49 y of age with increased risk for PD or ≥50 years of age were enrolled into the study (NCT01734239) to receive a single dose of PPV23 administered intramuscularly. Each subject was followed for local and systemic adverse events (AEs) for 5 and 14 days, respectively. Serious AEs were collected for 28 d postvaccination. Blood samples were collected immediately prior to vaccination and 28 d postvaccination for the measurement of IgG to serotypes 1, 6B, 14, 19F, and 23F.
RESULTS
High proportion of subjects had ≥2 -fold increase in IgG following receipt of PPV23. Rates were 92.0%, 83.0%, 89.0%, 81%, 84% for serotypes 1, 6B, 14, 19F, and 23F, respectively. Similar rates of responders and increases in the magnitude of immune responses were observed in both age groups (2-49, ≥50 ). PPV23 was generally safe and well tolerated. Injection site and systemic AEs were reported by 14.7% and 18.6% of study subjects, respectively.
CONCLUSIONS
PPV23 is generally safe, well tolerated, and highly immunogenic when given as a single dose to Russian individuals 50 y of age and older, as well as Russian individuals 2 to 49 y of age who are at high risk for PD.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Bacterial; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunoglobulin G; Injections, Intramuscular; Male; Middle Aged; Pneumococcal Vaccines; Russia; Young Adult
PubMed: 27149114
DOI: 10.1080/21645515.2016.1165373 -
Pneumococcal Phasevarions Control Multiple Virulence Traits, Including Vaccine Candidate Expression.Microbiology Spectrum Jun 2022Streptococcus pneumoniae is the most common cause of bacterial illness worldwide. Current vaccines based on the polysaccharide capsule are only effective against a...
Streptococcus pneumoniae is the most common cause of bacterial illness worldwide. Current vaccines based on the polysaccharide capsule are only effective against a limited number of the >100 capsular serotypes. A universal vaccine based on conserved protein antigens requires a thorough understanding of gene expression in S. pneumoniae. All S. pneumoniae strains encode the SpnIII Restriction-Modification system. This system contains a phase-variable methyltransferase that switches specificity, and controls expression of multiple genes-a phasevarion. We examined the role of this phasevarion during pneumococcal pathobiology, and determined if phase variation resulted in differences in expression of currently investigated conserved protein antigens. Using locked strains that express a single methyltransferase specificity, we found differences in clinically relevant traits, including survival in blood, and adherence to and invasion of human cells. We also observed differences in expression of numerous proteinaceous vaccine candidates, which complicates selection of antigens for inclusion in a universal protein-based pneumococcal vaccine. This study will inform vaccine design against S. pneumoniae by ensuring only stably expressed candidates are included in a rationally designed vaccine. S. pneumoniae is the world's foremost bacterial pathogen. S. pneumoniae encodes a phasevarion (phase-variable regulon), that results in differential expression of multiple genes. Previous work demonstrated that the pneumococcal SpnIII phasevarion switches between six different expression states, generating six unique phenotypic variants in a pneumococcal population. Here, we show that this phasevarion generates multiple phenotypic differences relevant to pathobiology. Importantly, expression of conserved protein antigens varies with phasevarion switching. As capsule expression, a major pneumococcal virulence factor, is also controlled by the phasevarion, our work will inform the selection of the best candidates to include in a rationally designed, universal pneumococcal vaccine.
Topics: Humans; Methyltransferases; Phase Variation; Pneumococcal Vaccines; Streptococcus pneumoniae; Virulence
PubMed: 35536022
DOI: 10.1128/spectrum.00916-22 -
Clinical Microbiology and Infection :... Oct 2012Sir Almroth Wright coordinated the first trial of a whole-cell pneumococcal vaccine in South Africa from 1911 to 1912. Wright started a chain of events that delivered... (Review)
Review
Sir Almroth Wright coordinated the first trial of a whole-cell pneumococcal vaccine in South Africa from 1911 to 1912. Wright started a chain of events that delivered pneumococcal vaccines of increasing clinical and public-health value, as medicine advanced from a vague understanding of the germ theory of disease to today's rational vaccine design. Early whole-cell pneumococcal vaccines mimicked early typhoid vaccines, as early pneumococcal antisera mimicked the first diphtheria antitoxins. Pneumococcal typing systems developed by Franz Neufeld and others led to serotype-specific whole-cell vaccines. Pivotally, Alphonse Dochez and Oswald Avery isolated pneumococcal capsular polysaccharides in 1916-17. Serial refinements permitted Colin MacLeod and Michael Heidelberger to conduct a 1944-45 clinical trial of quadrivalent pneumococcal polysaccharide vaccine (PPV), demonstrating a high degree of efficacy in soldiers against pneumococcal pneumonia. Two hexavalent PPVs were licensed in 1947, but were little used as clinicians preferred therapy with new antibiotics, rather than pneumococcal disease prevention. Robert Austrian's recognition of high pneumococcal case-fatality rates, even with antibiotic therapy, led to additional trials in South Africa, the USA and Papua New Guinea, with 14-valent and 23-valent PPVs licensed in 1977 and 1983 for adults and older children. Conjugation of polysaccharides to proteins led to several pneumococcal conjugate vaccines licensed since 2000, enabling immunization of infants and young children and resultant herd protection for all ages. Today, emergence of disease caused by pneumococcal serotypes not included in various vaccine formulations fuels research into conserved proteins or other means to maximize protection against more than 90 known pneumococcal serotypes.
Topics: History, 20th Century; History, 21st Century; Humans; Pneumococcal Infections; Pneumococcal Vaccines; Vaccination
PubMed: 22882735
DOI: 10.1111/j.1469-0691.2012.03943.x -
Revista de Investigacion Clinica;... 2017A successful strategy to prevent Streptococcus pneumoniae infections is the administration of pneumococcal conjugate vaccines (PCVs).
BACKGROUND
A successful strategy to prevent Streptococcus pneumoniae infections is the administration of pneumococcal conjugate vaccines (PCVs).
OBJECTIVE
To analyze the effectiveness of the 7- and 13-valent PCV for the prevention of all-cause pneumonia.
MATERIALS AND METHODS
A retrospective cohort of children younger than 5 years of age, with congenital heart disease (CHD) and different vaccination schedules, was analyzed. History of vaccination was confirmed with verifiable records. The outcome measure was all-cause pneumonia or bronchopneumonia. Protocol was approved by the Institutional Review Board. For comparisons, we used inferential statistics with Chi-square and Fisher's exact test; a p ≤ 0.5 was considered statistically significant. Relative and absolute risks reduction and number needed to treat were also calculated.
RESULTS
A total of 348 patients were included: 196 with two or more doses of PCV (considered the vaccinated group), and 152 in the unvaccinated group. There was a statistically significant difference for pneumonia events (p < 0.001) between the vaccinated (26/196) and unvaccinated (51/152) groups. The relative risk reduction was 60.5%, and the absolute risk reduction, 20.3%. There were no differences between patients who received two, three or four doses. The number needed to vaccinate to prevent one event of pneumonia was 5 children.
CONCLUSIONS
At least two doses of PCV in children with CHD reduced the risk of all-cause pneumonia.
Topics: Child, Preschool; Cohort Studies; Female; Heart Defects, Congenital; Heptavalent Pneumococcal Conjugate Vaccine; Humans; Immunization Schedule; Infant; Male; Pneumococcal Vaccines; Pneumonia, Pneumococcal; Retrospective Studies
PubMed: 29077699
DOI: 10.24875/ric.17002241 -
The Pediatric Infectious Disease Journal Jan 2014Since second generation pneumococcal conjugate vaccines (PCVs) targeting 10 and 13 serotypes became available in 2010, the number of national policy makers considering... (Review)
Review
Since second generation pneumococcal conjugate vaccines (PCVs) targeting 10 and 13 serotypes became available in 2010, the number of national policy makers considering these vaccines has steadily increased. An important consideration for a national immunization program is the timing and number of doses-the schedule-that will best prevent disease in the population. Data on disease epidemiology and the efficacy or effectiveness of PCV schedules are typically considered when choosing a schedule. Practical concerns, such as the existing vaccine schedule, and vaccine program performance are also important. In low-income countries, pneumococcal disease and deaths typically peak well before the end of the first year of life, making a schedule that provides PCV doses early in life (eg, a 6-, 10- and 14-week schedule) potentially the best option. In other settings, a schedule including a booster dose may address disease that peaks in the second year of life or may be seen to enhance a schedule already in place. A large and growing body of evidence from immunogenicity studies, as well as clinical trials and observational studies of carriage, pneumonia and invasive disease, has been systematically reviewed; these data indicate that schedules of 3 or 4 doses all work well, and that the differences between these regimens are subtle, especially in a mature program in which coverage is high and indirect (herd) effects help enhance protection provided directly by a vaccine schedule. The recent World Health Organization policy statement on PCVs endorsed a schedule of 3 primary doses without a booster or, as a new alternative, 2 primary doses with a booster dose. While 1 schedule may be preferred in a particular setting based on local epidemiology or practical considerations, achieving high coverage with 3 doses is likely more important than the specific timing of doses.
Topics: Child, Preschool; Health Policy; Heptavalent Pneumococcal Conjugate Vaccine; Humans; Immunization Schedule; Infant; Infant, Newborn; Pneumococcal Infections; Pneumococcal Vaccines; United States; Vaccines, Conjugate
PubMed: 24336059
DOI: 10.1097/INF.0000000000000076 -
Chang Gung Medical Journal 2008Streptococcus pneumoniae, an important pathogen causing sepsis, sinusitis, otitis media, bacterial meningitis and bacterial pneumonia, results in global morbidity and... (Review)
Review
Streptococcus pneumoniae, an important pathogen causing sepsis, sinusitis, otitis media, bacterial meningitis and bacterial pneumonia, results in global morbidity and mortality each year. The burden of pneumococcal disease is highest in children and the elderly. Treatment of pneumococcal infection has been hampered by the complexity of the host immune response. In recent decades, the increase of S. pneumoniae strains' resistance to beta-lactam antibiotics and other classes of antimicrobials has made treatment even more complicated. Fortunately, the advent of heptavalent conjugate vaccine confers a high degree of protection against pneumococcal disease and colonization caused by vaccine serotype strains. After the introduction of conjugate pneumococcal vaccine, invasive pneumococcal disease caused by vaccine serotypes and antibiotic-resistant isolates has been reduced. However, naturally transformable pneumococci may escape vaccine-induced immunity by switching their capsular genes to non-vaccine serotypes. Development of cheaper, serotype-independent vaccines based on a combination of protein antigens should be pursued.
Topics: Immunity, Innate; Pneumococcal Vaccines; Streptococcus pneumoniae; Transformation, Bacterial; Virulence Factors
PubMed: 18567411
DOI: No ID Found -
The Journal of Infectious Diseases Sep 2021In 2013, the Dominican Republic introduced 13-valent pneumococcal conjugate vaccine (PCV13) using a 3-dose schedule (at 2, 4 and 12 months of age). We evaluated the...
High Prevalence of Vaccine-Type Infections Among Children with Pneumococcal Pneumonia and Effusion After 13-Valent Pneumococcal Conjugate Vaccine Introduction in the Dominican Republic.
BACKGROUND
In 2013, the Dominican Republic introduced 13-valent pneumococcal conjugate vaccine (PCV13) using a 3-dose schedule (at 2, 4 and 12 months of age). We evaluated the impact of PCV13 on serotypes causing pneumococcal pneumonia with pleural effusion.
METHODS
Surveillance data after PCV13 introduction (July 2014 to June 2016) were compared with data before PCV13 introduction (July 2009 to June 2011). Cases were defined as radiologic evidence of pneumonia with pleural effusion in a child aged <15 years. Pneumococcus was detected in pleural fluid by either culture or polymerase chain reaction, and serotyping was performed. The Ministry of Health's PCV13 uptake data for 2014-2016 were obtained.
RESULTS
The prevalence of pneumococcus among cases was similar before and after PCV13 introduction (56.4% and 52.8%, respectively). The proportion of pneumococcal cases caused by vaccine serotypes was 86% for children <2 years old both before and PCV13 introduction. Compared with before PCV13, serotype 14 accounted for a smaller (28% vs 13%, respectively; P = .02) and serotype 1 for a larger (23% vs 37%; P = .09) proportion of pneumococcal cases after PCV13 introduction. National uptake for the first, second, and third PCV13 doses was 94%, 81%, and 28%, respectively, in 2014 and 75%, 61%, and 26% in 2015.
DISCUSSION
While the decrease in pneumococcal pneumonia with pleural effusion caused by serotype 14 may reflect an early effect of PCV13 implementation, other vaccine serotypes, including serotype 1, are not well controlled. Better PCV13 coverage for all 3 doses is needed.
Topics: Child; Child, Preschool; Dominican Republic; Female; Humans; Infant; Male; Pleural Effusion; Pneumococcal Infections; Pneumococcal Vaccines; Pneumonia, Pneumococcal; Postoperative Complications; Prevalence; Serogroup; Streptococcus pneumoniae; Vaccination; Vaccines, Conjugate
PubMed: 34469563
DOI: 10.1093/infdis/jiab134