Evolución de los serotipos causantes de enfermedad neumocócica invasiva aislados durante 2008-2022 en un Hospital Público Madrileño de nivel dos, en relación con su inclusión en diferentes vacunas conjugadas / Evolution of the serotypes causing invasive pneumococcal disease along 2008-2022 in a Level 2 Public Hospital of the Madrid Region, in relation to their inclusion in different conjugate vaccines

Introducción. El uso de vacunas conjugadas frente a Streptococcus pneumoniae ocasiona cambios en la epidemio logía de la Enfermedad Neumocócica Invasiva (ENI). El objetivo de este estudio fue analizar la evolución de los serotipos de S. pneumoniae aislados en el Hospital Universitario de Getafe entre 2008 y 2022. Material y métodos. Se estudiaron 313 cepas de S. pneu moniae. El serotipado se realizó mediante el test de aglutina ción por látex (Pneumotest-latex) y la reacción de Quellung. Además, se determinó la concentración mínima inhibitoria (CMI) frente a penicilina, eritromicina y levofloxacino por el método de gradiente de concentración (E-test) según los cri terios de corte EUCAST. Resultados. Los serotipos más frecuentes en todo el pe riodo de estudio fueron 8, 3, 19A, 1, 11A y 22F correspondien do con el 46,6 % de los aislados. Durante los años 2008-2012, los serotipos 3, 1, 19A, 7F, 6C y 11A supusieron en conjunto el 53,6% de los aislamientos. Entre 2013 y 2017 los serotipos 3, 8, 12F, 19A, 22F y 19F representaron el 51% de los aislados. Entre 2018-2022 los serotipos 8, 3, 11A, 15A, 4 y 6C incluyeron al 55,5% de los casos. En total, 5 cepas (1,6%) se mostraron resistentes a penicilina, 64 (20,4%) resistentes a eritromicina y 11 (3,5%) resistentes a levofloxacino. Los niveles de CMI50 y CMI90 frente a los tres antibióticos se mantuvieron estables a lo largo del tiempo. Conclusiones. El uso de vacunas conjugadas condicionó un descenso de los serotipos cubiertos junto con un aumento de los no vacunales. Los patrones de sensibilidad a eritromicina y levofloxacino se mantuvieron relativamente estables. La re sistencia a penicilina fue muy baja, no encontrándose este tipo de cepas resistentes en el último periodo de estudio (AU)

Introduction. The use of conjugate vaccines against Streptococcus pneumoniae originates changes in the invasive pneumococcal disease (IPD). The aim of this study was to in vestigate the evolution of S. pneumoniae serotypes isolated in the Hospital Universitario de Getafe between 2008 and 2022. Material and Methods. 313 of S. pneumoniae strains were studied. Serotyping was carried out by latex agglutina tion (Pneumotest-latex) and the Quellung reaction. In addi tion, the minimal inhibitory concentration (MIC) was deter mined against penicillin, erythromycin and levofloxacin by the concentration gradient method (E-test) according the EUCAST breakpoints. Results. The most frequent serotypes throughout the study period were 8, 3, 19A, 1, 11A and 22F corresponding to 46.6% of the isolates. Along 2008-2012 the serotypes 3, 1, 19A, 7F, 6C and 11A represented altogether 53.6% of the isolates. Between 2013 and 2017 the serotypes 3, 8, 12F, 19A, 22F and 19F grouped 51% of the isolates. During 2018-2022 the serotypes 8, 3, 11A, 15A, 4 and 6C included the 55.5% of the cases. In total 5 strains (1.6%) were penicillin resistant, 64 (20.4%) erythromycin resistant and 11 (3.5%) levofloxacin re sistant. The MIC50 and MIC90 levels maintained stables along the time. Conclusion. The conjugate vaccines use with different se rotype coverage conditioned a decrease of the vaccine-includ ed and an increase of non-covered. Despite these changes, the global antimicrobial susceptibility patterns to erythromycin and levofloxacin maintained relatively stables. The resistance a penicillin was low, not finding this type of resistant strains in the last study period (AU)

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) use among adults aged 19­64 years with an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant who previously received a 13-valent pneumococcal conjugate vaccine (PCV13)

On October 19, 2022, the U.S. Advisory Committee on Immunization Practices (ACIP) recommended the use of either a dose of 20-valent pneumococcal conjugate vaccine (PCV20) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) as previously recommended for adults who have received 13-valent pneumococcal conjugate vaccine (PCV13) with an incomplete vaccination status. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for evidence assessment and decision-making informed ACIP's deliberations regarding use of this vaccine.

Phylogeography and resistome of pneumococcal meningitis in West Africa before and after vaccine introduction.

Despite contributing to the large disease burden in West Africa, little is known about the genomic epidemiology of Streptococcus pneumoniae which cause meningitis among children under 5 years old in the region. We analysed whole-genome sequencing data from 185 S. pneumoniae isolates recovered from suspected paediatric meningitis cases as part of the World Health Organization (WHO) invasive bacterial diseases surveillance from 2010 to 2016. The phylogeny was reconstructed, accessory genome similarity was computed and antimicrobial-resistance patterns were inferred from the genome data and compared to phenotypic resistance from disc diffusion. We studied the changes in the distribution of serotypes pre- and post-pneumococcal conjugate vaccine (PCV) introduction in the Central and Western sub-regions separately. The overall distribution of non-vaccine, PCV7 (4, 6B, 9V, 14, 18C, 19F and 23F) and additional PCV13 serotypes (1, 3, 5, 6A, 19A and 7F) did not change significantly before and after PCV introduction in the Central region (Fisher's test P value 0.27) despite an increase in the proportion of non-vaccine serotypes to 40 % (n=6) in the post-PCV introduction period compared to 21.9 % (n=14). In the Western sub-region, PCV13 serotypes were more dominant among isolates from The Gambia following the introduction of PCV7, 81 % (n=17), compared to the pre-PCV period in neighbouring Senegal, 51 % (n=27). The phylogeny illustrated the diversity of strains associated with paediatric meningitis in West Africa and highlighted the existence of phylogeographical clustering, with isolates from the same sub-region clustering and sharing similar accessory genome content. Antibiotic-resistance genotypes known to confer resistance to penicillin, chloramphenicol, co-trimoxazole and tetracycline were detected across all sub-regions. However, there was no discernible trend linking the presence of resistance genotypes with the vaccine introduction period or whether the strain was a vaccine or non-vaccine serotype. Resistance genotypes appeared to be conserved within selected sub-clades of the phylogenetic tree, suggesting clonal inheritance. Our data underscore the need for continued surveillance on the emergence of non-vaccine serotypes as well as chloramphenicol and penicillin resistance, as these antibiotics are likely still being used for empirical treatment in low-resource settings. This article contains data hosted by Microreact.

Pneumococcal Conjugated Vaccines Decreased Acute Otitis Media Burden: A Population-Based Study in Israel.

OBJECTIVE: To study time trends in all-cause acute otitis media (AOM) burden by calculating incidence rates of AOM episodes and recurrent acute otitis media (rAOM) cases in highly immunized pediatric population during the pre- and post-pneumococcal conjugated vaccine (PCV) years. STUDY DESIGN: In this population-based study, AOM episodes and rAOM cases were identified in Clalit Health Services-insured Israeli children aged 0-10 years between 2005 and 2018 by using a data-sharing platform. Because a near-sequential implementation of PCV-7/PCV-13 occurred within a 1-year period (2009/2010), we compared AOM visits before (2005-July 2009) and after (August 2009-2018) the introduction of PCVs. We focused on children younger than 2 years of age, who are the target population of PCVs and are at AOM peak age. RESULTS: We identified 805 389 AOM episodes contributed by 270 137 children. The median number of AOM episodes was 2 (IQR 1-4). A downward trend of incidence rates of AOM episodes was observed during the post-PCV years in children younger than age 9 years (P < .001). The largest decrease (21%) was observed in children younger than 1 year, from 807/1000 children during the pre-PCV years to 640/1000 during the post-PCV years (P < .001). An average annual decrease of ∼14/1000 AOM episodes was calculated in children younger than 1 year old (ß = -13.39, 95% CI -16.25 to -10.53, P < .001). Of rAOM cases, documented in 84 237 (31.2%) children, 74% were in children younger than 2 years, and 55% were in boys. The risk to develop rAOM significantly decreased during the post-PCV years in children younger than 2 years (hazard ratio 0.893, 95% CI 0.878-0.908; P < .001). CONCLUSIONS: AOM burden significantly decreased following PCVs introduction in highly immunized children.

Divergent serotype replacement trends and increasing diversity in pneumococcal disease in high income settings reduce the benefit of expanding vaccine valency.

Streptococcus pneumoniae is a significant cause of otitis media, pneumonia, and meningitis. Only seven of the approximately 100 serotypes were initially included in the pneumococcal polysaccharide conjugate vaccine (PCV) in 2000 before it was expanded in subsequent years. Although the invasive pneumococcal disease (IPD) incidence due to vaccine serotypes (VT) has declined, partial replacement by non-vaccine serotypes (NVT) was observed following widespread vaccine uptake. We conducted a trend analysis assembling the available evidence for PCV impact on European, North American and Australian national IPD. Significant effectiveness against VT IPD in infants was observed, although the impact on national IPD incidence varied internationally due to serotype replacement. Currently, NVT serotypes 8, 9N, 15A and 23B are increasing in the countries assessed, although a variety of other NVTs are affecting each country and age group. Despite these common emerging serotypes, there has not been a dominant IPD serotype post-vaccination as there was pre-vaccination (serotype 14) or post-PCV7 (serotype 19A), suggesting that future vaccines with additional serotypes will be less effective at targeting and reducing IPD in global populations than previous PCVs. The rise of diverse NVTs in all settings' top-ranked IPD-causing serotypes emphasizes the urgent need for surveillance data on serotype distribution and serotype-specific invasiveness post-vaccination to facilitate decision making concerning both expanding current vaccination programmes and increasing vaccine valency.

Residual colonization by vaccine serotypes in rural South Africa four years following initiation of pneumococcal conjugate vaccine immunization.

BACKGROUND: We evaluated pneumococcal colonization in children and adults between the time of 7-valent pneumococcal conjugate vaccine (PCV) introduction in the immunization program in 2009 to two years after transitioning to PCV13 in 2011. METHODS: Community-based carriage surveillance was undertaken between May-November 2013 (Period-3), with similar surveys in 2009 (Period-1) and 2011 (Period-2). Households with children below two years had a similar probability of being sampled in all surveys. Nasopharyngeal swabs were processed using standard methods and serotyped by Quellung. RESULTS: In children>9-59 months old, overall pneumococcal colonization prevalence declined from 81.8% in Period-1 to 65.0% in Period-3 (p<0.001). Reductions of 70% (41.2% vs. 13.6%) in PCV7-serotypes colonization and 66% (15.3% vs. 4.4%) for the six additional PCV13-serotypes (PCV13-add6VT) were observed. There was, however, high residual colonization by PCV7-serotypes 19F (14.9% vs. 6.3%) and 23F (8.5% vs. 4.1%), despite reduction of 57% and 52%, respectively. Among individuals>12 years of age, there was 61% reduction in PCV7-serotype colonization (3.1% vs. 1.3%) and 75% decrease for PCV13-add6VT (2.1% vs. 0.6%) between Period-1 and Period-3. CONCLUSIONS: The residual prevalence of serotypes 19F and 23F, four years after introducing PCV in the South Africa, suggests ongoing community transmission and transient vaccine effects.

Associations between geographic region and immune response variations to pneumococcal conjugate vaccines in clinical trials: A systematic review and meta-analysis.

OBJECTIVE: Geographic region can be an important source of variation in the immune response to pneumococcal conjugate vaccines (PCV). The aim of this study was to collate data from available PCV clinical trials in order to characterize the differences in antibody responses in different countries. METHODS: A systematic review and meta-analysis was conducted to examine the difference in antibody responses after primary series of PCVs in infants, associated with geographic regions, compared with each other and with the different PCVs using random-effects models. RESULTS: A total of 69 trials were included. Studies conducted in the Western Pacific Region (WPR) showed higher geometric mean concentrations (GMC) compared to studies conducted in Europe. The pooled GMC for serotype 4 after three doses of PCV7 in the WPR was 5.19 µg/ml (95% confidence interval 4.85-5.53 µg/ml), while for studies conducted in Europe this was 2.01 µg/ml (95% confidence interval 1.88-2.14 µg/ml). The IgG GMC ratios among the WPR versus European regions ranged from 1.51 to 2.87 for PCV7, 1.69 to 3.22 for PCV10, and 1.49 to 3.08 for PCV13. CONCLUSIONS: Studies conducted in the WPR generally showed greater antibody responses than the studies conducted in Europe. Indications of differences among geographic regions highlight the fact that further research is needed to compare the biological factors contributing to immune responses, which may affect vaccination schedules.

Diphtheria Immunity in Australia: Should we be Concerned?

OBJECTIVES: We report the results of the 2007 national serological survey of immunity to diphtheria in Australia to assess the impact of recent schedule changes on diphtheria immunity, and the adequacy of current policy in the context of increased international travel of people and pathogens. METHODS: Residual sera (n =1656) collected opportunistically from Australian laboratories in 2007 were tested for diphtheria antibody levels using an enzyme immunoassay, with the protective threshold defined as ≥0.1 IU/mL. About 40% of adults aged ≥30 years are susceptible to diphtheria; following the removal of the 18-month booster and its replacement with a dose in adolescence offered through school-based dTpa vaccination program, 59% of children aged 3 years were susceptible to diphtheria, whilst adolescents demonstrated improved immunity. RESULTS: There is no apparent boosting of diphtheria immunity from meningococcal group C conjugate (MCC) or seven-valent pneumococcal conjugate (7vPCV) vaccines in relevant age groups. CONCLUSION: Australians who travel to diphtheria-endemic areas should be up-to-date with their vaccinations. Close monitoring of population immunity levels against diphtheria remains important to ensure that immunity does not decline to a level where wide-spread transmission would be possible.

Resurgence of pneumococcal meningitis in Europe and Northern America.

BACKGROUND: Streptococcus pneumoniae is the most common pathogen causing bacterial meningitis. The routine use of multivalent conjugate pneumococcal vaccines has led to a decline of invasive pneumococcal disease caused by serotypes included in the vaccine serotypes. Recently, several reports have described a concomitant rise in the incidence of non-vaccine serotypes, suggesting serotype replacement. OBJECTIVE: We aim to review the effect of pneumococcal vaccination on the incidence of pneumococcal meningitis in Europe and northern America with a particular interest in serotype replacement. SOURCES: Articles that include data on invasive pneumococcal disease incidence before and after the introduction of vaccination, or on invasive pneumococcal serotype, are discussed, with a focus on pneumococcal meningitis. CONTENT: The introduction of pneumococcal conjugate vaccines has universally resulted in a decline in vaccine-serotype pneumococcal meningitis incidence throughout Europe and northern America. Serotype replacement by non-vaccine serotypes has however been reported following the introduction of the 7-, 10- and 13-valent pneumococcal conjugate vaccines, which in several regions abolished the overall effect of vaccination on pneumococcal meningitis incidence. IMPLICATIONS: The promising decline in the incidence of pneumococcal meningitis following the introduction of vaccination seems to have been temporary. Replacement by non-vaccine serotypes illustrates that pneumococcal meningitis continues to pose a major challenge. We need new approaches to prevention, new vaccines and continued efforts to improve treatment for patients with pneumococcal meningitis.

Persistent Circulation of Vaccine Serotypes and Serotype Replacement After 5 Years of Infant Immunization With 13-Valent Pneumococcal Conjugate Vaccine in the United Kingdom.

BACKGROUND: Following programmatic introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), there is residual carriage and disease due to PCV13-covered serotypes. METHODS: PCV13-immunized children aged 13-48 months, N = 988, were enrolled between February 2014 and August 2015 ("late PCV13"), and had nasopharyngeal pneumococcal carriage compared with 7-valent pneumococcal conjugate vaccine (PCV7) immunized children, N = 567, enrolled between November 2010 and September 2011 ("early PCV13"). Nasopharyngeal pneumococci were molecular-serotyped by microarray. Invasive pneumococcal disease (IPD) cases were identified through enhanced national surveillance. RESULTS: Compared with PCV7-immunized children, carriage among PCV13-immunized children was significantly lower for serotypes 19A (odds ratio [OR], 0.08 [95% confidence interval {CI}, .02-.25]), 6C (OR, 0.11 [95% CI, .03-.32]), and 7F (8 vs 0 cases). IPD incidence in children <5 years was significantly lower for serotypes 1 (incidence rate ratio [IRR], 0.03 [95% CI, 0-.19]) and 7F (IRR, 0.13 [95% CI, .05-.36]) but not 19A (IRR, 0.6 [95% CI, .3-1.12]) or serotype 3 (IRR, 2.3 [95% CI, .86-6.15]) in the late PCV13 period than in the early PCV13 period. The most significant rises in IPD incidence were for serotypes 8, 12F, and 24F. CONCLUSIONS: PCV13 has reduced serotype 19A carriage among vaccinated children. We found no impact of PCV13 on serotype 3 carriage or disease, and emergence of non-PCV13-serotype disease.

Immunogenicity Comparison of a Next Generation Pneumococcal Conjugate Vaccine in Animal Models and Human Infants.

BACKGROUND: Evaluation of a pneumococcal conjugate vaccine (PCV) in an animal model provides an initial assessment of the performance of the vaccine prior to evaluation in humans. Cost, availability, study duration, cross-reactivity and applicability to humans are several factors which contribute to animal model selection. PCV15 is an investigational 15-valent PCV which includes capsular polysaccharides from pneumococcal serotypes (ST) 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F all individually conjugated to cross-reactive material 197 (CRM197). METHODS: Immunogenicity of PCV15 was evaluated in infant rhesus macaques (IRM), adult New Zealand white rabbits (NZWR) and CD1 mice using multiplexed pneumococcal electrochemiluminescent (Pn ECL) assay to measure serotype-specific IgG antibodies, multiplexed opsonophagocytosis assay (MOPA) to measure serotype-specific functional antibody responses and bacterial challenge in mice to evaluate protection against a lethal dose of S. pneumoniae. RESULTS: PCV15 was immunogenic and induced both IgG and functional antibodies to all 15 vaccine serotypes in all animal species evaluated. PCV15 also protected mice from S. pneumoniae serotype 14 intraperitoneal challenge. Opsonophagocytosis assay (OPA) titers measured from sera of human infants vaccinated with PCV15 in a Phase 2 clinical trial showed a good correlation with that observed in IRM (rs=0.69, P=0.006), a medium correlation with that of rabbits (rs=0.49, P=0.06), and no correlation with that of mice (rs=0.04, P=0.89). In contrast, there was no correlation in serum IgG levels between human infants and animal models. CONCLUSIONS: These results demonstrate that PCV15 is immunogenic across multiple animal species, with IRM and human infants showing the best correlation for OPA responses.

Pneumococcal pneumonia and carriage in Africa before and after introduction of pneumococcal conjugate vaccines, 2000-2019: protocol for systematic review.

INTRODUCTION: Africa harbours a high burden of pneumococcal disease, with associated high mortality rates. Despite 34 countries introducing the pneumococcal conjugate vaccine, which reduces the risk of pneumococcal carriage (a prerequisite for disease) of some of the most pathogenic pneumococcal serotypes, it remains uncertain whether they will achieve the sustained direct or indirect protection necessary to reduce pneumococcal carriage to levels sufficient to interrupt transmission and disease. We will therefore summarise the available data on the impact of the pneumococcal conjugate vaccine in reducing vaccine serotype carriage and pneumococcal pneumonia in Africa between 2000 and 2019. METHODS AND ANALYSIS: Using a predetermined search strategy, we will conduct a comprehensive search of PubMed, MEDLINE database, the Excerpta Medica Database, the ISI Web of Science (Science Citation Index), Scopus and the African Index Medicus to identify published studies reporting the prevalence of Streptococcus pneumoniae carriage (vaccine type and non-vaccine type), incidence rates of pneumococcal pneumonia and mortality among children, adults and HIV-infected (all-ages) pre-pneumococcal conjugate vaccine (PCV) and post-PCV introduction (published between 1st January 2000 and 31st December 2019) in African countries that have introduced PCVs (PCV7/PCV10/PCV13) in their routine national immunisation programme. The studies retained and data extracted will be assessed for bias using prevalidated tools and checklists. Heterogeneity across studies will be assessed using the χ2 test on Cochrane Q statistic. A random effect meta-analysis will be used to estimate the overall prevalence of pneumococcal carriage and incidence of pneumococcal pneumonia across studies with similar characteristics. Results will be reported in compliance with the Meta-Analysis Of Observational Studies in Epidemiology guidelines. The protocol has been prepared in accordance to the 2015 guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ETHICS AND DISSEMINATION: This systematic review will not require ethical approval as we will be using already published data. The final manuscript will be submitted for publication in a peer-reviewed journal and presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42019130976.

The changing phenotypes and genotypes of invasive pneumococcal isolates from children in Shenzhen during 2013-2017.

BACKGROUND: The phenotypes and genotypes of Streptococcus pneumoniae isolated from invasive pneumococcal diseases (IPDs) were changing all the time. To monitor these changes of phenotypes and genotypes of S. pneumoniae isolates from children, we examined antibiotic susceptibility, serotype distribution and sequence types (STs) of S. pneumoniae, which were isolated before the 13-valent pneumococcal conjugate vaccine (PCV13) introduced into China. METHODS: Strains were isolated from children less than 14 years old between January 2013 and May 2017 from Shenzhen Children's Hospital. Serotypes, antibiotic resistance, and genotypes of these isolates were determined using capsular swelling, E-test, and multi-locus sequence typing, respectively. RESULTS: A total of 94 S. pneumoniae strains were isolated, which belonged to 15 serotypes. The five most prevalent serotypes were 19F (25.5%), 19A (19%), 14 (17%), 23F (7.5%), and 6B (9.6%). We found 42 STs for these isolates. The most abundant STs were ST271 (24.4%), ST876 (17%), and ST320 (10.6%), mainly related to 19F, 14, and 19A, respectively. The potential coverage of PCV13 was 87.2%. Among non-meningitis isolates, the resistance rates to penicillin and ceftriaxone were 0% and 2%. However, the meningitis isolates showed high resistance to penicillin (80%) and ceftriaxone (20%). Most of these isolates (95.7%) were resistant to erythromycin, and 66 (70.2%) strains carried the ermB gene and 24 (25.5%) strains carried both the ermB and mefA/E genes. Serotype 19A showed the highest mean minimum inhibitory concentration (MIC) for penicillin (MIC = 1.486) than the other serotypes, but no significant difference in penicillin MIC among the three main STs (ST271, ST320, and ST876). CONCLUSIONS: The phenotypes and genotypes of invasive pneumococcal isolates from Shenzhen Children's Hospital have changed with the passage of time. Compared with PCV7, PCV13 can more effectively protect Chinese children from IPDs. To some extent, these changes are possibly related to the usage of antibiotics and vaccines.

Pneumococcal Vaccination Strategies Among HIV-infected Adult Patients: A Review of the Literature.

BACKGROUND/AIM: Streptococcus pneumoniae is the leading cause of bacterial pneumonia and an important cause of invasive disease. Despite the antiretroviral therapies, adults infected with human immunodeficiency virus (HIV) are at particular risk for invasive pneumococcal disease (IPD). The purpose of this study was to report the efficacy of the strategies currently being used in pneumococcal vaccination for HIV-infected adults. MATERIALS AND METHODS: A literature search was performed through electronic databases, for original articles in English, from years 2000 to 2019. Clinical trials controlled or randomized, and cohort studies were included. RESULTS: While 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for immunocompromised patients, it has been reported that it is less suitable for HIV-infected patients. Recent guidelines have added pneumococcal conjugate vaccine (PCV) to the list of recommended vaccines. CONCLUSION: Further studies are needed to determine the optimal vaccines and intervals for subsequent revaccinations during the lifetime.

Stable dynamics of pneumococcal carriage over a decade in the pre-PCV era.

Streptococcus pneumoniae (SP) nasopharyngeal carriage studies are important to understand SP circulation prior to implementation of vaccination programs. It is generally not known how stable these carriage rates are over time. Carriage studies were conducted in Southern Israel during a decade preceding Pneumococcal Conjugate Vaccine (PCV) introduction. We estimated total and vaccine-type SP carriage at 6 months of age to be stable at 35% (95% CI: 26, 44) and 19% (95% CI: 15, 24), respectively in Jewish and 70% (95% CI, 62, 77) and 41% (95% CI: 38, 45) in Bedouin populations. The stability of carriage rates in two disparate populations over 10 years suggests a single survey may be sufficient to characterize pneumococcal carriage pre-PCV.

Persistence of immunity to conjugate and polysaccharide pneumococcal vaccines in frail, hospitalised older adults in long-term follow up.

BACKGROUND: Data on long-term antibody responses to pneumococcal vaccines in the elderly, especially the frail elderly at greatest risk of severe disease, are limited. We followed up participants in a randomised trial of the immunogenicity of 23-valent polysaccharide vaccine (23vPPV) and 7 valent pneumococcal conjugate vaccines (PCV7) in hospitalised older adults. METHODS: We measured antibody to vaccine serotypes by standardised enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic (OPA) assays. A follow up study was conducted six years after vaccination with 23vPPV alone or with PCV7 followed by 23vPPV six months later. RESULTS: Of 215 surviving trial participants, 136 (63%) completed follow up; 62 received 23vPPV and 74 received PCV7 + 23vPPV. There was no significant difference in death and readmission between arms. Antibody levels by ELISA and OPA did not differ significantly between the two study arms at 72 months post-vaccination. ELISA and OPA antibody remained higher than baseline except for OPA antibody to 4, 6A, 6B, 9v, 19F and 23F, including in subjects with undetectable immunity at baseline. DISCUSSION: While ELISA responses in both study arms remained high 6 years post-vaccination, considerable waning was observed by OPA in both study arms, which should be considered given the current single-dose recommendation in Australia. Further research is needed to inform pneumococcal vaccine recommendations in people over the age of 65.

Effectiveness of the seven-valent and thirteen-valent pneumococcal conjugate vaccines in England: The indirect cohort design, 2006-2018.

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the UK childhood immunisation programme in 2006 and replaced with a 13-valent vaccine (PCV13) in 2010. Both vaccines led to rapid declines in vaccine-serotype invasive pneumococcal disease (IPD). Here, we assessed the long-term vaccine-effectiveness (VE) of both vaccines in England. METHODS: Public Health England conducts enhanced national surveillance of IPD in England. VE against IPD was estimated using vaccine-serotype IPD cases and non-vaccine serotype IPD controls among vaccine-eligible children from September 2006 to June 2018 (the Broome method). RESULTS: Vaccine history was available for 3421 IPD cases, including 1299 due to the additional PCV13 serotypes and the PCV13-related serotype 6C, 274 PCV7 serotypes and 1848 non-PCV13 serotypes. For the complete 2 + 1 schedule, both PCV7 and PCV13 showed high effectiveness against PCV7 serotypes with a combined VE of 92.0% (95%CI, 81.7-96.7). For the 2 + 1 schedule, PCV13 VE against the additional PCV13 serotypes plus 6C was 73.7% (31.1-89.9) compared to 90.0% (75.3 - 96.0) for PCV7 against PCV7 serotypes, although PCV13 VE increased to 84.8% (58.7-94.4) if serotype 3 was excluded; all 36 eligible serotype 3 IPD cases were fully-vaccinated with PCV13. Case numbers were low in older ages but there was evidence of waning, which was significant for serotype 19A for which there were sufficient numbers of cases for analysis. CONCLUSIONS: PCVs are highly effective in preventing vaccine-serotype IPD except for serotype 3 which has been increasing in incidence. Serotype 19A IPD has also persisted, likely due to a slightly lower VE and/or more rapid waning of protection.

Estimated impact of revising the 13-valent pneumococcal conjugate vaccine schedule from 2+1 to 1+1 in England and Wales: A modelling study.

BACKGROUND: In October 2017, the United Kingdom Joint Committee on Vaccination and Immunisation (JCVI) recommended removal of one primary dose of the 13-valent pneumococcal conjugate vaccine (PCV13) from the existing 2+1 schedule (2, 4, 12 months). We conducted a mathematical modelling study to investigate the potential impact of a 1+1 (3, 12 month) schedule on invasive pneumococcal disease (IPD) and pneumococcal community-acquired pneumonia (CAP). Our results and those from a 1+1 immunogenicity study formed the key evidence reviewed by JCVI. METHODS AND FINDINGS: We developed age-structured, dynamic, deterministic models of pneumococcal transmission in England and Wales to describe the impact on IPD of 7-valent PCV (PCV7; introduced in 2006) and PCV13 (introduced in 2010). Key transmission and vaccine parameters were estimated by fitting to carriage data from 2001/2002 and post-PCV IPD data to 2015, using vaccine coverage, mixing patterns between ages, and population data. We considered various models to investigate potential reasons for the rapid increase in non-PCV13 (non-vaccine serotype [NVT]) IPD cases since 2014. After searching a large parameter space, 500 parameter sets were identified with a likelihood statistically close to the maximum and these used to predict future cases (median, prediction range from 500 parameter sets). Our findings indicated that the emergence of individual NVTs with higher virulence resulting from ongoing replacement was likely responsible; the NVT increase was predicted to plateau from 2020. Long-term simulation results suggest that changing to a 1+1 schedule would have little overall impact, as the small increase in vaccine-type IPD would be offset by a reduction in NVT IPD. Our results were robust to changes in vaccine assumptions in a sensitivity analysis. Under the base case scenario, a change to a 1+1 schedule in 2018 was predicted to produce 31 (6, 76) additional IPD cases over five years and 83 (-10, 242) additional pneumococcal-CAP cases, with together 8 (-2, 24) additional deaths, none in children under 15 years. Long-term continuation with the 2+1 schedule, or changing to a 1+1, was predicted to sustain current reductions in IPD cases in under-64-year-olds, but cases in 65+-year-olds would continue to increase because of the effects of an aging population. Limitations of our model include difficulty in fitting to past trends in NVT IPD in some age groups and inherent uncertainty about future NVT behaviour, sparse data for defining the mixing matrix in 65+-year-olds, and the methodological challenge of defining uncertainty on predictions. CONCLUSIONS: Our findings suggest that, with the current mature status of the PCV programme in England and Wales, removing one primary dose in the first year of life would have little impact on IPD or pneumococcal CAP cases or associated deaths at any age. A reduction in the number of priming doses would improve programmatic efficiency and facilitate the introduction of new vaccines by reducing the number of coadministered vaccines given at 2 and 4 months of age in the current UK schedule. Our findings should not be applied to other settings with different pneumococcal epidemiology or with immature programmes and poor herd immunity.

Antibody response to the 23-valent pneumococcal polysaccharide vaccine after conjugate vaccine in patients with chronic lymphocytic leukemia.

The 23-valent pneumococcal polysaccharide vaccine (PPV23) given alone is ineffective in patients with chronic lymphocytic leukemia (CLL) and better antibody response is achieved with pneumococcal conjugate vaccines (PCVs). In this study, we determine whether CLL patients would achieve a significant antibody response and broaden their serotype coverage against invasive pneumococcal disease (IPD) with PPV23 given five years after the 7-valent conjugate vaccine (PCV7). A total of 24 patients with CLL and eight controls were vaccinated with PPV23 five years after PCV7. Blood samples for evaluation of antibody response to PCV7 serotypes and PPV23 serotypes 5 and 7 were taken before vaccination and one month after it. Post-vaccination samples were available from 20 patients. IgG antibodies were measured with ELISA. Antibody concentrations after PPV23 were significantly lower in CLL patients for six of the PCV7 serotypes and for both PPV23 serotypes. Only 10% to 15% of CLL patients achieved an antibody response suggested to be protective against IPD. Hence, PCV7 given five years before PPV23 did not improve antibody response in patients with CLL. Based on our results, PPV23 given after a PCV primer is not useful against IPD in CLL patients.