Doses Of Pneumococcal Conjugate Vaccine Research Articles

Vaccine hesitancy and receipt of mandatory and optional pediatric vaccines in Shanghai, China

ABSTRACT Given increased global concern about vaccine hesitancy, this study estimates coverage of mandatory vs non-mandatory vaccines in children, and assesses whether vaccine hesitancy among young parents relates to their childʻs eventual vaccination status in Shanghai, China. In a cohort study within Shanghai, China, we ascertained vaccine hesitancy among parents of young infants, and later abstracted their childʻs electronic immunization records. We measure full coverage of vaccines on the mandatory, and publicly funded Expanded Program on Immunization (EPI). Non-EPI vaccines included pneumococcal conjugate vaccine, Haemophilus influenzae type b vaccine, and rotavirus vaccine. Vaccine hesitancy was linked to vaccine uptake through mixed effects logistic regression models. Among 972 children, full coverage of all EPI vaccines by 15 months was 95%, compared to dose 1 coverage of pneumococcal conjugate vaccine at 13%, Haemophilus influenzae type b vaccine at 68%, and rotavirus vaccine at 52%. Vaccine hesitancy was not significantly linked with full coverage of all EPI vaccines (OR: 1.55, 95% CI: .89, 2.72), but coverage in the vaccine hesitant was lower for pneumococcal conjugate vaccine dose 1 (OR: .70, 95% CI: .53, .91), and rotavirus vaccine dose 1 (OR: .69, 95% CI: .56, .86). Disparities by education level were not significant for EPI vaccines, but were for dose 1 of pneumococcal conjugate vaccine rotavirus vaccine. Overall, vaccine hesitancy was related to lower uptake of non-EPI, but not EPI vaccines. Shanghai has a robust system for insurance equitable access to EPI vaccines, but if vaccine hesitancy grows, it could reduce coverage of non-EPI vaccines.

Levels of pneumococcal conjugate vaccine coverage and indirect protection against invasive pneumococcal disease and pneumonia hospitalisations in Australia: An observational study.

There is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children. Birth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged <5 years, born between 2001 and 2012 in 2 Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD; (2) all-cause pneumonia; and (3) pneumococcal and lobar pneumonia hospitalisation in undervaccinated children. Undervaccinated children received <2 doses of PCV at <12 months of age and no doses at ≥12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph. There were strong inverse associations between PCV coverage and the incidence of PCV7-type IPD (adjusted incidence rate ratio [aIRR] 0.967, 95% confidence interval [CI] 0.958 to 0.975, p-value < 0.001), and pneumonia hospitalisations (all-cause pneumonia: aIRR 0.991 95% CI 0.990 to 0.994, p-value < 0.001) among undervaccinated children. Subgroup analyses for children <4 months old, urban, rural, and Indigenous populations showed similar trends, although effects were smaller for rural and Indigenous populations. Approximately 50% coverage of PCV7 among children <5 years of age was estimated to prevent up to 72.5% (95% CI 51.6 to 84.4) of PCV7-type IPD among undervaccinated children, while 90% coverage was estimated to prevent 95.2% (95% CI 89.4 to 97.8). The main limitations of this study include the potential for differential loss to follow-up, geographical misclassification of children (based on residential address at birth only), and unmeasured confounders. In this study, we observed substantial indirect protection at lower levels of PCV coverage than previously described-challenging assumptions that high levels of PCV coverage (i.e., greater than 90%) are required. Understanding the association between PCV coverage and indirect protection is a priority since the control of vaccine-type pneumococcal disease is a prerequisite for reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to substantially reduce program costs while maintaining vaccine impact.

Pneumococcal vaccination during chemotherapy in children treated for acute lymphoblastic leukemia.

Children treated for acute lymphoblastic leukemia (ALL) are at high risk of invasive pneumococcal disease (IPD). We assessed immunity to S. pneumoniae among children after ALL treatment, and the impact of pneumococcal immunization during and after chemotherapy. We performed an observational retrospective study of children treated for ALL at a single center. All children were fully immunized with three routine doses of pneumococcal conjugate vaccine (PCV) prior to ALL diagnosis. Children from Group 1 received a 13-valent PCV (PCV13) dose during the maintenance phase as well as a PCV13 booster after completing chemotherapy, while Group 2 only received the postchemotherapy dose. Serologic testing was performed after chemotherapy and again after the postchemotherapy dose. A serotype-specific antibody level ≥0.35μg/ml was considered protective, and patients with protective levels for ≥70% of serotypes in the PCV7 vaccine were defined as seroprotected. A total of 71 children (median age 46months, range 12-160) were included. At the end of chemotherapy, 53.1% of children in Group 1 (17/32) and 25.6% in Group 2 (10/39) were seroprotected (p=.018). After the postchemotherapy booster, seroprotection rates increased to 96.9% in Group 1 (31/32) and 100% in Group 2. Rates of pneumococcal seroprotection among children with ALL are low following chemotherapy, despite prior routine immunization. A PCV booster during chemotherapy may shorten the period of susceptibility to IPD in some children. However, irrespective of a booster during chemotherapy, a PCV dose postchemotherapy appears sufficient to confer high rates of seroprotection against IPD.

Estimating pneumococcal vaccine coverage among Australian Indigenous children and children with medically at-risk conditions using record linkage

BackgroundRisk-based recommendations are common for pneumococcal vaccines but little is known about their uptake. In Australia, pneumococcal conjugate vaccine (PCV) was funded only for Aboriginal or Torres Strait Islander (Indigenous) children and those with underlying medical conditions in 2001, and then there were different booster dose recommendations depending on risk after the introduction of universal PCV vaccination in 2005. MethodsWe measured coverage of PCV dose 3 and additional PCV and 23-valent pneumococcal polysaccharide vaccine (PPV23) doses by risk group among children born in July 2001–December 2012 in two Australian states using linked immunisation and hospitalisation data (available until December 2013). We ascertained medical risk conditions using hospitalisation diagnosis codes and Indigenous status using an established algorithm, comparing coverage for children born pre (2001–2004) and post (2005–2012) universal PCV funding. ResultsAmong 1.3 million children, 63,897 (4.9%) were Indigenous and 32,934 (2.5%) had at least one medically at-risk condition identified by age 6 months. For births in 2001–2004, coverage for PCV dose 3 by 1 year of age was 37% for Indigenous, 15% for medically at-risk and 11% in other children, increasing to 83%, 91% and 92%, respectively for births in 2005–2012. In children with medically at-risk conditions, PCV dose 4 coverage by 2 years was 1% for 2001–2004 births, increasing to 9% for 2005–2012 births, with PPV23 coverage by 6 years 3% in both cohorts. Among eligible Indigenous children, PPV23 coverage by 3 years was 45% for 2001–2004 births and 51% for 2005–2012 births. ConclusionsCoverage with additional recommended booster doses was very low among children with medical conditions, and only modest among Indigenous children. If additional PCV doses are recommended for some risk groups, especially in the context of routine schedules with reduced doses (e.g. 2 + 1 and 1 + 1), measures to improve implementation will be required.

16. A Randomized Phase 1 Study of a Novel Pneumococcal Conjugate Vaccine in Healthy Japanese Adults in the United States

BackgroundBecause of the number and variability of serotypes causing pneumococcal disease among different geographic regions, age groups, and environmental backgrounds, expanding serotype coverage with pneumococcal conjugate vaccines (PCVs) is a continued unmet need.MethodsThis phase 1, randomized, double-blind study included healthy Japanese adults aged 18–49 years residing in the United States. Subjects were randomized 1:1:1 to receive a single dose of a 20-valent PCV (containing 13-valent PCV [PCV13] serotypes plus 8, 10A, 11A, 12F, 15B, 22F, 33F), a novel pneumococcal polysaccharide conjugate vaccine with extended coverage, or PCV13 (control). Safety was the primary endpoint and included reactogenicity events occurring ≤ 14 days after vaccination, adverse events (AEs) ≤ 1 month after vaccination, and serious AEs (SAEs) ≤ 6 months after vaccination. The secondary endpoint was pneumococcal serotype-specific immunogenicity as determined by opsonophagocytic activity (OPA) titers on sera collected before and 1 month after vaccination.ResultsOverall, 35 subjects received PCV20 and 35 subjects received PCV13. One subject withdrew before the 1-month follow-up. Local reactions and systemic events across groups were generally mild or moderate (Figure 1). Two vaccine-related AEs occurred (injection site erythema and swelling in the PCV20 group); no severe AEs, SAEs, or safety-related withdrawals were reported. OPA geometric mean titers increased for all 20 serotypes in the PCV20 group and all 13 serotypes in the PCV13 group 1 month after vaccination; corresponding OPA geometric mean fold rises from baseline to 1 month after vaccination are reported (Figure 2; Figure 3).Figure 1 Figure 2 Figure 3 ConclusionPCV20 was well tolerated and induced serotype-specific functional OPA immune responses that are anticipated to be associated with protection in Japanese adults. ClinicalTrials.gov: NCT03642847. Funding: Pfizer Inc.DisclosuresDavid Fitz-Patrick, MD, Pfizer Inc (Grant/Research Support) Mariano Young Jr., MD, Pfizer Inc (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Gary Baugher, PharmD, Pfizer Inc (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

Vaccination Response after Autologous Stem Cell Transplantation

Patients with autologous stem cell transplantation (ASCT) have a variable period of immune deficiency in the post-transplant period. Guidelines recommend revaccination of patients after ASCT as standard care. The response to vaccination may affect the outcome of the transplant patients. We aim to evaluate the vaccination response after ASCT. All myeloma and lymphoma patients with ASCT who had vaccination and measured vaccination response, were included in the study. We retrospectively evaluated 73 ASCT patients, 55 with multiple myeloma (MM) and 18 with lymphoma between 2013 and 2018. The current ASCT protocol for active immunization includes three doses of pneumococcal conjugate vaccine (PCV13) from 6-12 months after ASCT, followed by a 23-valent polysaccharide pneumococcal vaccine (PPSV23). Haemophilus Influenza B (HiB), hepatitis B, and TDAP/TD vaccines are administered within one year after initiation of vaccination. The responses to these vaccines were investigated by checking antibody titers at a minimum of two months after completion of vaccination. Both MM and lymphoma groups had similar pre-vaccination immunologic parameters, including IgG levels, absolute CD4+, and CD4+CD45RA+ cell counts (Table 1). Diphtheria and tetanus had 89% response rate to the vaccination in all patients (Table 2). Only half of the patients (47%) responded to hepatitis B vaccine. The response was higher but not statistically significant in the lymphoma group compared to the MM group (57 % versus 43.9 % P: NS). More than 80% of the patients had a response to H. Influenza vaccine. All patients had a 59% response to pneumococcal vaccination. We then analyzed the pneumococcal responses according to serotype. PCV13 includes vaccine against 13 serotypes of S. pneumonia (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, and 23F). PPSV23 contains additional 11 serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F). 76 % of MM patients responded to PCV13 serotypes, while only 41 % responded to PPSV23 specific serotypes (p: &amp;lt;0.01). Lymphoma patients also showed a similar response pattern. In addition, repeated vaccination with PPSV23 did not improve the response of failure patients. We also evaluated the effects of maintenance treatment in the myeloma patients. We found that maintenance treatment did not interfere with the vaccine response in the patients with myeloma after ASCT. In conclusion, ASCT patients respond well to most vaccinations except for Hepatitis B and PPSV23. Further studies may need to explore pathophysiology of vaccine failure. Strategies to enhance immune reconstitution may augment the immune response and improve the outcome of the patients with ASCT. Disclosures Alpdogan: Seattle Genetics: Research Funding. Binder:Sanofi: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding. Martinez-Outschoorn:Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Porcu:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Cell Medica: Research Funding; Daiichi: Consultancy, Honoraria; Galderma: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Miragen: Research Funding; Verastem: Consultancy. Flomenberg:Tevogen: Consultancy, Honoraria.

Impact of pneumococcal conjugate vaccine uptake on childhood pneumonia mortality across income levels in Brazil, Colombia, and Peru

Background: Pneumococcal conjugate vaccines (PCVs) have prevented deaths due to pneumonia among children. The effect may differ between higher- and lower-income populations due to various factors, such as differences in the distribution of pneumococcal serotypes, healthcare access, and PCV uptake. This study aims to evaluate an association between increasing PCV coverage and population-level declines in death due to pneumonia and its variation by socioeconomic status of subnational regions. Methods: We analyzed municipality-level mortality data from 2005 and 2015 for children aged 2-23 months in Brazil, Colombia, and Peru. We fit Poisson regression models to estimate the relationship between changes in PCV uptake and deaths due to all-cause pneumonia among subnational regions with different income levels. We controlled for changes unrelated to PCV by using data on non-respiratory deaths over time. Results: Uptake of the third dose of PCV varied across subnational regions and was higher in high-income regions. Higher uptake of PCV was associated with larger declines in pneumonia mortality. This association did not differ by income level of the region in Brazil and Colombia. In Peru, low-income regions observed larger declines in pneumonia deaths, but there was large uncertainty in the difference between the low- and high-income regions. We estimated that, with 90% coverage, there would be 4-38% declines in all-cause pneumonia mortality across income levels and countries. Conclusions: Regions with higher PCV coverage experienced larger declines in pneumonia deaths, regardless of the income level. Having more reliable data on mortality records and vaccine uptake would improve the reliability of vaccine impact estimates.

Direct effects of pneumococcal conjugate vaccines among children in Latin America and the Caribbean

In Latin America and the Caribbean, more than 70% of the 52 countries and territories have introduced pneumococcal conjugate vaccines (PCVs) into their national immunisation programmes for infants. More than 73 million children live in the region, and, as of 2018, about 82% had received at least three doses of PCV.1 Many reports have described the benefits of PCVs in North America,2,3 with recent evidence showing these findings in the Latin American and Caribbean countries.4,5 In The Lancet Infectious Diseases, Clara Inés Agudelo and colleagues' observational study6 reports data from the Sistema Regional de Vacunas (SIREVA) network.

Impact of pneumococcal conjugate vaccine uptake on childhood pneumonia mortality across income levels in Brazil, Colombia, and Peru.

Background: Pneumococcal conjugate vaccines (PCVs) have prevented deaths due to pneumonia among children. The effect may differ between higher- and lower-income populations due to various factors, such as differences in the distribution of pneumococcal serotypes, healthcare access, and PCV uptake. This study aims to evaluate an association between increasing PCV coverage and population-level declines in death due to pneumonia and its variation by socioeconomic status of subnational regions. Methods: We analyzed municipality-level mortality data from 2005 and 2015 for children aged 2-23 months in Brazil, Colombia, and Peru. We fit Poisson regression models to estimate the relationship between changes in PCV uptake and deaths due to all-cause pneumonia among subnational regions with different income levels. We controlled for changes unrelated to PCV by using data on non-respiratory deaths over time. Results: Uptake of the third dose of PCV varied across subnational regions and was higher in high-income regions. Higher uptake of PCV was associated with larger declines in pneumonia mortality. This association did not differ by income level of the region in Brazil and Colombia. In Peru, low-income regions observed larger declines in pneumonia deaths, but there was large uncertainty in the difference between the low- and high-income regions. We estimated that, with 90% coverage, there would be 4-38% declines in all-cause pneumonia mortality across income levels and countries. Conclusions: Regions with higher PCV coverage experienced larger declines in pneumonia deaths, regardless of the income level. Having more reliable data on mortality records and vaccine uptake would improve the reliability of vaccine impact estimates.

Immunogenicity of a single-dose compared with a two-dose primary series followed by a booster dose of ten-valent or 13-valent pneumococcal conjugate vaccine in South African children: an open-label, randomised, non-inferiority trial

SummaryBackgroundRoutine childhood immunisation with pneumococcal conjugate vaccine (PCV) has changed the epidemiology of pneumococcal disease across age groups, providing an opportunity to reconsider PCV dosing schedules. We aimed to evaluate the post-booster dose immunogenicity of ten-valent (PCV10) and 13-valent (PCV13) PCVs between infants randomly assigned to receive a single-dose compared with a two-dose primary series.MethodsWe did an open-label, non-inferiority, randomised study in HIV-unexposed infants at a single centre in Soweto, South Africa. Infants were randomly assigned to receive one priming dose of PCV10 or PCV13 at ages 6 weeks (6w + 1 PCV10 and 6w + 1 PCV13 groups) or 14 weeks (14w + 1 PCV10 and 14w + 1 PCV13 groups) or two priming doses of PCV10 or PCV13, one each at ages 6 weeks and 14 weeks (2 + 1 PCV10 and 2 + 1 PCV13 groups); all participants then received a booster dose of PCV10 or PCV13 at 40 weeks of age. The primary endpoint was geometric mean concentrations (GMCs) of serotype-specific IgG 1 month after the booster dose, which was assessed in all participants who received PCV10 or PCV13 as per the assigned randomisation group and for whom laboratory results were available at that timepoint. The 1 + 1 vaccine schedule was considered non-inferior to the 2 + 1 vaccine schedule if the lower bound of the 96% CI for the GMC ratio was greater than 0·5 for at least ten PCV13 serotypes and eight PCV10 serotypes. Safety was a secondary endpoint. This trial is registered with ClinicalTrials.gov (NCT02943902) and is ongoing.FindingsOf 1695 children assessed, 600 were enrolled and randomly assigned to one of the six groups between Jan 9 and Sept 20, 2017; 542 were included in the final analysis of the primary endpoint (86–93 per group). For both PCV13 and PCV10, a 1+1 dosing schedule (either beginning at 6 or 14 weeks) was non-inferior to a 2 + 1 schedule. For PCV13, the lower limit of the 96% CI for the ratio of GMCs between the 1 + 1 and 2 + 1 groups was higher than 0·5 for ten serotypes in the 6w+1 group (excluding 6B, 14, and 23F) and 11 serotypes in the 14w + 1 group (excluding 6B and 23F). For PCV10, the lower limit of the 96% CI for the ratio of GMCs was higher than 0·5 for all ten serotypes in the 6w+1 and 14w + 1 groups. 84 serious adverse events were reported in 72 (12%) of 600 participants. 15 occurred within 28 days of vaccination, but none were considered to be related to PCV injection. There were no cases of culture-confirmed invasive pneumococcal disease.InterpretationThe non-inferiority in post-booster immune responses following a single-dose compared with a two-dose primary series of PCV13 or PCV10 indicates the potential for reducing PCV dosing schedules from a 2 + 1 to 1 + 1 series in low-income and middle-income settings with well established PCV immunisation programmes.FundingThe Bill & Melinda Gates Foundation (OPP1 + 152352).

Lessons learned from recent randomized controlled trials comparing the immunogenicity of different infant vaccination schedules of pneumococcal conjugate vaccine

Background: The technically complex pneumococcal conjugate vaccine (PCV) is arguably one of the most important and widely studied vaccines since the Hib vaccine. Given the complexity of its design, the cost of administering the PCV is tremendous. While we cannot make adjustments to the vaccine itself post licensure, we can manipulate the dosing schedule. And yet little work has been done to understand the differences in immune responses across different dosing schedules. Methods: Accordingly, we conducted a review of three recently published randomized control trials that compared immune responses across commonly used vaccine schedules in both high- and low-income countries. Results: Each of these studies assessed how changes to the number of doses, spacing between doses and the use/timing of a booster dose affected ELISA geometric mean concentrations post-primary and post-booster dose. If the goal is to administer vaccinations in the most immunologically efficient manner as possible, evidence from these studies would suggest that several commonly used vaccine schedules are missing the mark. Conclusions: In order to deliver the most “bang for its buck”, PCV dosing schedules should not only leverage convenience but also immunological data. Without the reexamination of PCV schedules the status quo will remain inefficient, ineffective and needlessly expensive, threatening the sustainability of its implementation long-term.

Pneumococcal Conjugate Vaccine Breakthrough Infections: 2001-2016.

Mostcountries use 3-dose pneumococcal conjugate vaccine (PCV) schedules; a 4-dose (3 primary and 1 booster) schedule is licensed for US infants. We evaluated the invasive pneumococcal disease (IPD) breakthrough infection incidence in children receiving 2 vs 3 primary PCV doses with and without booster doses (2 + 1 vs 3 + 1; 2 + 0 vs 3 + 0). We used 2001-2016 Active Bacterial Core surveillance data to identify breakthrough infections (vaccine-type IPD in children receiving≥1 7-valent pneumococcal conjugate vaccine [PCV7] or 13-valent pneumococcal conjugate vaccine [PCV13] dose) among children aged <5 years. We estimated schedule-specific IPD incidence rates (IRs) per 100 000 person-years and compared incidence by schedule (2 + 1 vs 3 + 1; 2 + 0 vs 3 + 0) using rate differences (RDs) and incidence rate ratios. We identified 71 PCV7 and 49 PCV13 breakthrough infections among children receiving a schedule of interest. PCV13 breakthrough infection rates were higher in children aged <1 year receiving the 2 + 0 (IR: 7.8) vs 3 + 0 (IR: 0.6) schedule (incidence rate ratio: 12.9; 95% confidence interval: 4.1-40.4); PCV7 results were similar. Differences in PCV13 breakthrough infection rates by schedule in children aged <1 year were larger in 2010-2011 (2 + 0 IR: 18.6; 3 + 0 IR: 1.4; RD: 16.6) vs 2012-2016 (2 + 0 IR: 3.6; 3 + 0 IR: 0.2; RD: 3.4). No differences between schedules were detected in children aged≥1 year for PCV13 breakthrough infections. Fewer PCV breakthrough infections occurred in the first year of life with 3 primary doses. Differences in breakthrough infection rates by schedule decreased as vaccine serotypes decreased in circulation.

Prime-boost vaccination strategy enhances immunogenicity compared to single pneumococcal conjugate vaccination in patients receiving conventional DMARDs, to some extent in abatacept but not in rituximab-treated patients

ObjectiveTo explore whether a prime-boost vaccination strategy, i.e., a dose of pneumococcal conjugate vaccine (PCV) and a dose of 23-valent polysaccharide vaccine (PPV23), enhances antibody response compared to single PCV dose in patients with inflammatory rheumatic diseases treated with different immunosuppressive drugs and controls.MethodsPatients receiving rituximab (n = 30), abatacept (n = 23), monotherapy with conventional disease-modifying antirheumatic drugs (cDMARDs, methotrexate/azathioprine/mycophenolate mofetil, n = 27), and controls (n = 28) were immunized with a dose PCV followed by PPV23 after ≥ 8 weeks. Specific antibodies to 12 serotypes included in both vaccines were determined using a multiplex microsphere immunoassay in blood samples before and 4–8 weeks after each vaccination. Positive antibody response was defined as ≥ 2-fold increase from pre- to postvaccination serotype-specific IgG concentration and putative protective level as IgG ≥ 1.3 μg/mL. The number of serotypes with positive antibody response and IgG ≥ 1.3 μg/mL, respectively, after PCV and PCV + PPV23 were compared within each treatment group and to controls. Opsonophagocytic activity (OPA) assay was performed for serotypes 6B and 23F.ResultsCompared to single-dose PCV, prime-boost vaccination increased the number of serotypes with positive antibody response in patients with abatacept, cDMARDs, and controls (p = 0.02, p = 0.01, and p = 0.01), but not in patients on rituximab. After PCV + PPV23, the number of serotypes with positive antibody response was significantly lower in all treatment groups compared to controls but lowest in rituximab, followed by the abatacept and cDMARD group (p < 0.001). Compared to PCV alone, the number of serotypes with putative protective levels after PCV + PPV23 increased significantly only in patients in cDMARDs (p = 0.03) and controls (p = 0.001). Rituximab treatment was associated with large reduction (coefficient − 8.6, p < 0.001) and abatacept or cDMARD with moderate reductions (coefficients − 1.9 and − 1.8, p = 0.005, and p < 0.001) in the number of serotypes with positive antibody response to PCV + PPV23 (multivariate linear regression model). OPA was reduced in rituximab (Pn6B and Pn23F, p < 0.001), abatacept (Pn23F, p = 0.02), and cDMARD groups (Pn6B, p = 0.02) compared to controls.ConclusionsPrime-boost strategy enhances immunogenicity compared to single pneumococcal conjugate vaccination in patients with inflammatory rheumatic diseases receiving cDMARDs, to some extent in abatacept but not in patients on rituximab. Pneumococcal vaccination should be encouraged before the initiation of treatment with rituximab.Trial registrationClinicalTrials.gov, NCT03762824. Registered on 4 December 2018, retrospectively registered

Burden of respiratory infections and otitis media in the Inuit population of Nunavik, Quebec, Canada

ABSTRACT Background Respiratory infections are a major health problem in the Inuit population of Nunavik, province of Quebec, Canada. Objectives A study was undertaken to assess the burden of lower (LRTI) and upper respiratory tract infections (URTI) and otitis media (OM) and to explore some of their determinants including the pneumococcal conjugate vaccine (PCV) status. Methods The reference population includes children less than 5 years of age born in 1994–2010 and a sample of 825 children was selected for this study. Outpatient medical records were reviewed. Visits with a diagnosis of LRTI, URTI and OM were extracted. Univariate and multivariate statistical analyses were performed to identify predictors of disease risk. Results The average number of LRTI, URTI and OM episodes were, respectively, 2.6, 6.2 and 5.9 from birth up to the 5th birthday. Seasonal patterns were similar for URTI and OM, but was different for LRTI. Children who received the recommended 4 PCV doses had a lower LRTI and OM risk than unvaccinated children. There was a trend towards a lower OM risk associated with a mixed PCV10+ PCV13 schedule compared with PCV7. Conclusion Results suggest a lower LRTI and OM risk associated with PCV use in this high-risk population but respiratory disease risk remains high compared with the general population in Quebec.

Antipneumococcal Seroprotection Years After Vaccination in Allogeneic Hematopoietic Cell Transplant Recipients.

International guidelines recommend vaccinating allogeneic hematopoietic cell transplant (HCT) recipients at 3 months after transplant, giving 3 doses of pneumococcal conjugate vaccine (PCV) followed by either a dose of 23-valent pneumococcal polysaccharide vaccine (PSV23) or a fourth PCV dose in the case of graft-versus-host disease (GvHD). However, the long-term immunity after this regimen is unknown, and there is no recommendation from 24 months after transplant regarding boosts. Our objective was to assess the antipneumococcal antibody titers and seroprotection rates of allogeneic HCT recipients years after different schedules of vaccination. We assessed 100 adult HCT recipients a median of 9.3 years (range: 1.7-40) after transplant. All patients had received at least one dose of PCV and were assessed for antipneumococcal immunoglobulin G (IgG) antibody titers against the 7 serotypes shared by PCV7, PCV13, and PSV23. Sixty-six percent of the patients had been vaccinated according to the current guidelines. Considering an IgG titer ≥ 0.35 µg/mL as protective for each serotype, the seroprotection rate was 50% for 7/7 serotypes and 70% for 5/7 serotypes, with no differences between the different vaccination schedules. The lack of seroprotection was associated with a transplant performed not in complete remission or from a cord-blood unit, a relapse after transplant, or chronic GvHD at assessment. Because only half of the vaccinated patients had long-term protection, pending prospective studies defining the best boost program after the initial one, we recommend the assessment of specific IgG titers starting from 24 months to decide for further doses.

Dose-specific Effectiveness of 7- and 13-Valent Pneumococcal Conjugate Vaccines Against Vaccine-serotype Streptococcus pneumoniae Colonization in Children.

Reduced-dose pneumococcal conjugate vaccine (PCV) schedules are under consideration in countries where children are recommended to receive 3 doses. Whereas PCV-derived protection against vaccine-serotype colonization is responsible for herd effects of vaccination, dose-specific PCV effectiveness against colonization endpoints is not known. We aimed to assess the performance of differing PCV schedules against vaccine-serotype colonization in children. From 2009-2016, we monitored pneumococcal carriage in southern Israel, where children should receive PCV at ages 2 months, 4 months, and 12 months (2 primary [p] +1 booster [b] schedule). We analyzed nasopharyngeal swabs and vaccination histories from 5928 children aged 0-59 months without symptoms of diseases potentially attributable to pneumococci. Matching individuals on age, sex, ethnicity, visit timing, and recent antibiotic receipt, we measured schedule-specific 7-valent PCV (PCV7) and 13-valent PCV (PCV13) effectiveness against vaccine-serotype colonization in a modified case-control framework. We sampled from the distribution of all possible case-control match assignments for statistical analyses. Receiving 2 primary-series PCV13 doses conferred 53% (95% confidence interval [CI], 32-67%) protection against PCV13-serotype colonization at ages ≤12 months; 1 primary-series dose was not protective. A 2p+1b PCV13 series conferred 40% (95% CI, 4-67%) and 62% (95% CI, 33-83%) protection against PCV13-serotype colonization at ages 13-24 months and 25-59 months, respectively. Estimates suggested greater PCV13-conferred protection against PCV7-targeted serotypes than the 6 PCV13-only serotypes. As compared to children receiving 2p+1b PCV13 dosing, those receiving 1p+1b and 2p+0b schedules experienced 2.05-fold (95% CI, 1.12-5.00) and 3.33-fold (95% CI, 2.28-4.93) greater odds, respectively, of vaccine-serotype pneumococcal colonization at ages 13-24 months. Our results demonstrate real-world effectiveness of 2p+1b PCV dosing against vaccine-serotype colonization. Reduced-dose schedules may confer lower protection against vaccine-serotype carriage during and beyond the first year of life.

2699. Pneumococcal Vaccination During Chemotherapy in Children Treated for Acute Lymphoblastic Leukemia

BackgroundChildren undergoing therapy for acute lymphoblastic leukemia (ALL) are at high risk of invasive pneumococcal disease (IPD). Immunization with conjugated vaccines following chemotherapy is recommended for pediatric patients. In an attempt to provide an earlier protection against invasive pneumococcal infection, we aimed to assess immunity to S. pneumoniae among children vaccinated during chemotherapy for ALL.MethodsWe retrospectively analyzed the rate of seroprotection among ALL children treated in our institution in accordance with the DFCI ALL Consortium protocol between 2007 and 2014. A pneumococcal conjugate vaccine (PCV) booster was given to all subjects after the end of chemotherapy (groups 1 and 2). In group 2, a PCV dose was also administered during the maintenance phase. Clinical characteristics as well as individual immunization records were collected from our local immunization database. All children were up to date with their vaccination schedule at diagnosis. Serum samples were obtained on a routine follow-up visit, after the end of chemotherapy and after the PCV vaccine booster to measure serotype-specific IgG pneumococcal antibodies. Antibody level ≥0.35µg/mL was considered protective. Patients with seroprotective antibodies level for ≥ 50% of serotypes contained in vaccines were defined as seroprotected.Results62 children [34 girls (54.8%)] were included in the analysis. Median age at diagnosis was 45 months (range:12–160). At the end of chemotherapy, 34.2% of children in group 1 (13/38) and 79.2% in group 2 (19/24) were seroprotected (P < 0.01). Median interval of time between the end of chemotherapy and the PCV booster vaccination was 6 months (range: 2–64 months). After PCV-13 booster, the rate of seroprotection raised to 100% (38/38) in group 1 and 91.7% in group 2 (22/24).ConclusionRates of pneumococcal seroprotected children treated for ALL are low at the end of chemotherapy. However, PCV booster during chemotherapy could be useful to increase the level of seroprotection and shorten the period of susceptibility to IPD. After chemotherapy for ALL, children benefit from a PCV booster to enhance seroprotection. Disclosures All authors: No reported disclosures.

Invasive Pneumococcal Disease in Children's Hospitals: 2014-2017.

The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed in the United States in 2010. We describe invasive pneumococcal disease (IPD) in children at 8 children's hospitals in the US from 2014 to 2017. Children with IPD occurring from 2014 to 2017 were identified from a prospective study. Demographic and clinical data, including results of any immune evaluation along with the number and dates of previous pneumococcal conjugate vaccines administered, were recorded on case report forms. Isolate serotypes were determined in a central laboratory. Pneumococcal conjugate vaccine doses were counted if IPD occurred ≥2 weeks after a dose. PCV13 serotypes accounted for 23.9% (115 out of 482) of IPD isolates from 2014 to 2017. Serotypes 3, 19A, and 19F accounted for 91% of PCV13 serotypes. The most common non-PCV13 serotypes were 35B, 23B, 33F, and 22F. An underlying condition was significantly (P < .0001) more common in children with IPD due to non-PCV13 serotypes (200 out of 367, 54.5%) than for children with PCV13 serotypes (27 out of 115, 23.5%). An immune evaluation was undertaken in 28 children who received ≥2 PCV13 doses before IPD caused by a PCV13 serotype. Only 1 was found to have an immunodeficiency. PCV13 serotypes (especially serotypes 3, 19A, and 19F) continue to account for nearly a quarter of IPD in US children 4 to 7 years after PCV13 was introduced. Underlying conditions are more common in children with non-PCV13 serotype IPD. Immune evaluations in otherwise healthy children with PCV13 serotype IPD despite receiving ≥2 PCV13 doses did not identify an immunodeficiency.

Effectiveness of pneumococcal conjugate vaccine against hospital admissions for pneumonia in Australian children: a retrospective, population-based, record-linked cohort study

Reductions in pneumonia hospitalisations following introduction of pneumococcal conjugate vaccines (PCVs) have been reported from high-incidence and low-incidence settings but long-term data comparing vaccinated with unvaccinated children are sparse. We did a retrospective, population-based, record-linkage cohort study in Australian children using administrative health data from the Western Australian Midwives' Notification System and New South Wales Perinatal Data Collection, and the birth and death registries in both states. PCV vaccination details, pneumonia-coded hospital admissions, and invasive pneumococcal disease notification records were individually linked for children born between 2001 and 2012. The primary outcome was defined as the first hospital admission for all-cause pneumonia. Cox models were used to calculate adjusted hazard ratios (HR) to estimate the effect of PCV doses on pneumonia-coded hospital admissions by Aboriginal status, birth period, remoteness, and pneumonia diagnostic category in children younger than 2 years. Person-time of follow-up time for each child started at birth and was censored at the earliest of first hospital admission for all-cause pneumonia, death, invalid PCV dose, when the child reached age 24 months, or the end date of the study period (Dec 31, 2013) FINDINGS: The study cohort comprised 1 365 893 children liveborn between Jan 1, 2001, and Dec 31, 2012, of whom 66 484 (4·9%) were identified as Aboriginal. The overall rate for all-cause pneumonia hospital admissions for children younger than 2 years over the entire study period was 17·6/1000 child-years in Aboriginal children and 5·5/1000 child-years in non-Aboriginal children. Compared with children born between 2001 and 2004 (ie, the pre-universal PCV period), the incidence of pneumonia-coded hospital admissions decreased in both vaccinated (6·5 vs 5·7 per 1000 child-years [12% reduction, 95% CI 3-21; p=0·01]) and unvaccinated non-Aboriginal children (6·8 vs 3·7 [45% reduction; 41-49]) born 2005-12 (the universal PCV period); among Aboriginal children, declines were significant only among those vaccinated (27·4 vs 14·1 [49% reduction, 40-55]). Among Aboriginal children born 2005-12, the risk of pneumonia-coded hospital admission after three doses of PCV was lower than those unvaccinated (adjusted HR 0·83, 95% CI 0·65-0·99) but, among non-Aboriginal children, the risk was similar (adjusted HR 1·09, 0·98-1·22). Overall, remote-born Aboriginal children had the highest incidence of hospital admission for pneumonia and among children born 2005-12, the adjusted risk was 37% lower (adjusted HR 0·63, 95% CI 0·42-0·96) among those fully vaccinated than those unvaccinated. Reductions in pneumonia-coded hospital admissions in unvaccinated children predominated in non-Aboriginal children with low incidence of pneumonia but were not significant in Aboriginal children with high incidence. These findings have potential implications for measuring PCV effect using a non-specific endpoint such as all-cause pneumonia in high-incidence populations. Commonwealth Government Collaborative Research Infrastructure Strategy and Education Investment Fund Super Science Initiative and the Australian National Health and Medical Research Council.

Immunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial

SummaryBackgroundFew data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13.MethodsIn this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3 + 1 (group A), 3 + 0 (group B), 2 + 1 (group C), or two-dose schedule (group D); PCV13 in a 2 + 1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 μg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov, number NCT01953510.FindingsOf 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 μg/mL did not differ between groups at the 10% level for any serotype (PCV10–PCV13 risk difference −2·1% [95% CI −4·8 to −0·1] for serotype 1; −1·3% [–3·7 to 0·6] for serotype 4; −3·4% [–6·8 to −0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; −1·3% [–3·7 to 0·6] for serotype 7F; −1·6% [–5·1 to 1·7] for serotype 9V; 0·0% [–2·7 to 2·9] for serotype 14; −2·1% [–5·3 to 0·9] for serotype 18C; 0·0% [–2·2 to 2·3] for serotype 19F; and −11·6% [–18·2 to −4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reactogenicity and serious adverse events were monitored according to good clinical practice guidelines, and the profiles were similar in the two groups.InterpretationPCV10 and PCV13 are similarly highly immunogenic when used in 2 + 1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings.FundingNational Health and Medical Research Council of Australia, and Bill & Melinda Gates Foundation.