Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection and hospitalization in infants. Nirsevimab is a monoclonal antibody to the RSV fusion protein that has an extended half-life. The efficacy and safety of nirsevimab in healthy late-preterm and term infants are uncertain. METHODS: We randomly assigned, in a 2:1 ratio, infants who had been born at a gestational age of at least 35 weeks to receive a single intramuscular injection of nirsevimab or placebo before the start of an RSV season. The primary efficacy end point was medically attended RSV-associated lower respiratory tract infection through 150 days after the injection. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after the injection. RESULTS: A total of 1490 infants underwent randomization: 994 were assigned to the nirsevimab group and 496 to the placebo group. Medically attended RSV-associated lower respiratory tract infection occurred in 12 infants (1.2%) in the nirsevimab group and in 25 infants (5.0%) in the placebo group; these findings correspond to an efficacy of 74.5% (95% confidence interval [CI], 49.6 to 87.1; P<0.001) for nirsevimab. Hospitalization for RSV-associated lower respiratory tract infection occurred in 6 infants (0.6%) in the nirsevimab group and in 8 infants (1.6%) in the placebo group (efficacy, 62.1%; 95% CI, -8.6 to 86.8; P = 0.07). Among infants with data available to day 361, antidrug antibodies after baseline were detected in 58 of 951 (6.1%) in the nirsevimab group and in 5 of 473 (1.1%) in the placebo group. Serious adverse events were reported in 67 of 987 infants (6.8%) who received nirsevimab and in 36 of 491 infants (7.3%) who received placebo. CONCLUSIONS: A single injection of nirsevimab administered before the RSV season protected healthy late-preterm and term infants from medically attended RSV-associated lower respiratory tract infection. (Funded by MedImmune/AstraZeneca and Sanofi; MELODY ClinicalTrials.gov number, NCT03979313.).

Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.

BACKGROUND: Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance. METHODS: We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons. RESULTS: Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637. CONCLUSIONS: The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.

A Phase 3, Randomized, Double-Blind, Comparator-Controlled Study to Evaluate Safety, Tolerability, and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Allogeneic Hematopoietic Cell Transplant Recipients (PNEU-STEM).

BACKGROUND: Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. METHODS: Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. RESULTS: A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90. CONCLUSIONS: V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration. clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11.

Dynamics of Pediatric Antibiotic Use Differ between High- and Low-Prescribing Clinics after Pneumococcal Conjugate Vaccines.

OBJECTIVE: To compare dispensed oral antibiotic prescription rates (DAPRs) after implementation of pneumococcal conjugate vaccine (PCV) in high antibiotic-prescribing clinics (HPC) with low antibiotic-prescribing clinics (LPC) in 2 distinct ethnic groups of children (Jewish and Bedouin children) <5 years of age. METHODS: Clinics with ≥50 insured children, active both pre-PCV (2005-2009) and post-PCV (2010-2018) implementation, were included. HPC and LPC were defined by DAPRs above or below the median in each age and ethnic group. Monthly dispensed antibiotic prescription rate (DAPR) trends (adjusted for age and ethnicity) were calculated using interrupted time series. Mean yearly incidence rate-ratios (late PCV13 vs pre-PCV) were calculated. RESULTS: Bedouin HPC had the highest pre-PCV overall-DAPR per 1000 child-years ± SD (2520.4 ± 121.2), followed by Jewish HPC (1885.5 ± 47.6), Bedouin LPC (1314.8 ± 81.6), and Jewish LPC (996.0 ± 19.6). Shortly after PCV implementation, all DAPRs and amoxicillin/amoxicillin-clavulanate DAPRs declined in all groups except Jewish LPC, stabilizing within 4-5 years post-PCV. The rates and magnitudes of declines were directly proportional to the pre-PCV DAPR magnitudes, achieving near-complete closure of the pre-PCV DAPR gaps between the 4 groups (rates during late-PCV13 ranging from 1649.4 ± 23.5 [Bedouin HPC] to 1200.3 ± 72.4 [Jewish LPC]). CONCLUSIONS: PCVs are a powerful tool in reducing outpatient antibiotic consumption among young children, especially in HPC, resulting in partial closure of DAPR gap between HPC and LPC. The higher impact on HPC suggests that PCV-associated declines of respiratory disease may strongly contribute to a judicious antibiotic approach in clinics with high antibiotic consumption.

Dynamics of invasive pneumococcal disease in infants < 2 years old following PCV7/13 implementation using two infant and a booster dose schedule: evidence for indirect protection of young infants, Israel, 2004 to 2019.

BackgroundPneumococcal conjugated vaccine (PCV)7 and PCV13 programmes started in Israel from July 2009 and November 2010 respectively, with a 2+1 schedule (one dose at 2 months old, one at 4 months old, and a booster dose at 12 months old). Thereafter, invasive pneumococcal disease (IPD) rates substantially declined in children. Uptake of all three doses in < 2-year-olds since 2012 is > 90%. For still incompletely vaccinated infants (≤ 12 months old), how well the PCV 2+1 programme shields from IPD is not fully resolved.AimTo assess the adequacy of protection conferred by the 2+1 schedule PCV vaccination programme, particularly among incompletely-vaccinated infants.MethodsThis was a population-based, prospective, nationwide active IPD surveillance study in Israel, 2004-2019, in children < 24 months old. We estimated annual incidence rates (IR) of overall IPD, IPD caused by PCV13 serotypes (VT13), and non-PCV13 serotypes (NVT13). Annual IPD IRs were stratified by age: < 4 months (receiving ≤ 1 dose), 4-6 months (immediately post dose 2), 7-12 months (a few months post dose 2), and 13-23 months (post dose 3). Late-PCV (2004-2008) to pre-PCV13 (2016-2019) mean annual IR ratios (IRRs) were calculated.Results2,569 IPD episodes were recorded. VT13 decreased > 90% in all age groups, while NVT13 seemed to increase. All-IPD rates declined in all age groups by 56-70%. The 2+1 schedule impact on 7-12-month-old infants (pre-booster) was similar to that on 13-23-month-old children (post booster), with PCV13 IPD reductions of 97% and 98%, respectively.ConclusionsIndirect (herd) protection of infants, including < 4 month-olds with ≤ 1 PCV dose, was achieved by the 2+1 PCV schedule programme which thus seems adequate.

Effectiveness of BNT162b2 mRNA Coronavirus Disease 2019 (COVID-19) Vaccine Against Acquisition of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Among Healthcare Workers in Long-Term Care Facilities: A Prospective Cohort Study.

BACKGROUND: We assessed vaccine effectiveness (VE) of BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) acquisition among healthcare workers (HCWs) of long-term care facilities (LTCFs). METHODS: This prospective study, in the framework of the "Senior Shield" program in Israel, included routine weekly nasopharyngeal SARS-CoV-2 RT-PCR testing from all LTCF HCWs since July 2020. All residents and 75% of HCWs were immunized between December 2020 and January 2021. The analysis was limited to HCWs adhering to routine testing. Fully vaccinated (14+ days after second dose; n = 6960) and unvaccinated (n = 2202) HCWs were simultaneously followed until SARS-CoV-2 acquisition or end of follow-up, 11 April 2021. Hazard ratios (HRs) for vaccination versus no vaccination were calculated (Cox proportional hazards regression models, adjusting for sociodemographics and residential-area COVID-19 incidence). VE was calculated as (1- HR) × 100. RT-PCR cycle threshold (Ct) values were compared between vaccinated and unvaccinated HCWs. RESULTS: At >14 days post-second dose, 40 vaccinated HCWs acquired SARS-CoV-2 (median follow-up, 66 days; cumulative incidence, 0.6%) versus 84 unvaccinated HCWs (median follow-up, 43 days; cumulative incidence, 5.1%) (HR, .11; 95% CI, .07-.17; unadjusted VE, 89%; 95% CI, 83-93%). Adjusted VE >7 and >14 days post-second dose were similar. The median PCR Ct targeting the ORF1ab gene among 20 vaccinated and 40 unvaccinated HCWs was 32.0 versus 26.7, respectively (P value  = .008). CONCLUSIONS: VE following 2 doses of BNT162b2 against SARS-CoV-2 acquisition in LTCF HCWs was high. The lower viral loads among SARS-CoV-2-positive HCWs suggest further reduction in transmission.

Dynamics of Invasive Pneumococcal Disease in Israel in Children and Adults in the 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Era: A Nationwide Prospective Surveillance.

BACKGROUND: Following 13-valent pneumococcal conjugate vaccine (PCV13) implementation in infants worldwide, overall and vaccine-type invasive pneumococcal disease (IPD) rates declined in children, with variable indirect impact on adults. METHODS: A population-based, prospective, nationwide active surveillance of IPD in Israel, 2004-2019 (for adults ≥18 years, 2009-2019). The 7-valent PCV (PCV7)/PCV13 were implemented in Israel in July 2009/November 2010, respectively, with >90% uptake in children <2 years. The 23-valent pneumococcal polysaccharide vaccine (PPV-23) uptake among those >65 years was ~75%. For pre-PCV episodes with missing serotype, extrapolations were applied. Overall, PCV13 serotypes (VT13) and non-VT13 (NVT) incidence rate ratios (IRRs) comparing pre-PCV (2004-2008), early-PCV (2009-2011), and late-PCV13 (2016-2019) periods were calculated for different age groups. RESULTS: Overall, 8614 IPD cases were recorded. IPD rates declined by 67% in children <5 and 5-17 years, comparing late-PCV13 versus pre-PCV periods (IRR [95% CI]: .33 [.27-.40] and .33 [.21-.50], respectively). For adults, comparing late-PCV13 with early-PCV periods, rates significantly declined by 53% in those aged 18-44, while rates did not decline significantly in other age groups. VT13 rates significantly declined in all ages, with decline rates ranging between 94% in children <5 years and 60% in adults ≥85 years. NVT rates significantly increased in <5-, 50-64-, and ≥65-year age groups. In the late-PCV13 period, serotypes 3, 14, and 19A remained the predominant VT13, while serotypes 8 and 12F emerged as predominant NVTs. CONCLUSIONS: Continuous monitoring of circulating serotypes in all ages demonstrated direct and indirect PCV effects, which are essential for the development of new vaccination strategies.

Decline in Pneumococcal Disease in Young Children During the Coronavirus Disease 2019 (COVID-19) Pandemic in Israel Associated With Suppression of Seasonal Respiratory Viruses, Despite Persistent Pneumococcal Carriage: A Prospective Cohort Study.

BACKGROUND: The incidence of invasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from nonpharmaceutical interventions. We used multiple ongoing cohort surveillance projects in children <5 years to test this hypothesis. METHODS: The first SARS-CoV-2 cases were detected in February 2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory infections necessitating chest X-rays (NA-LRIs), nasopharyngeal pneumococcal carriage in nonrespiratory visits, nasopharyngeal respiratory virus detection (by polymerase chain reaction), and nationwide IPD. Monthly rates (January 2020 through February 2021 vs mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity were compared. RESULTS: CAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios [IRRs]: .07 and .19, respectively); NA-LRIs and nonpneumonia IPD were also reduced by a lesser magnitude (IRRs: .46 and .42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced, and density of colonization and pneumococcal serotype distributions were similar to previous years. The decline in pneumococcus-associated disease was temporally associated with a full suppression of respiratory syncytial virus, influenza viruses, and human metapneumovirus, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels. CONCLUSIONS: Reductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic in Israel were not predominantly related to reduced pneumococcal carriage and density but were strongly associated with the disappearance of specific respiratory viruses.

The Effect of Macrolides on Mortality in Bacteremic Pneumococcal Pneumonia: A Retrospective, Nationwide Cohort Study, Israel, 2009-2017.

BACKGROUND: Previous cohort studies of pneumonia patients reported lower mortality with advanced macrolides. Our aim was to characterize antibiotic treatment patterns and assess the role of quinolones or macrolides in empirical therapy. MATERIALS: An historical cohort, 1 July 2009 to 30 June 2017, included, through active surveillance, all culture-confirmed bacteremic pneumococcal pneumonia (BPP) among adults in Israel. Cases without information on antibiotic treatment were excluded. Logistic regression analysis was used to assess independent predictors of in-hospital mortality. RESULTS: A total of 2016 patients with BPP were identified. The median age was 67.2 years (interquartile range [IQR] 53.2-80.6); 55.1% were men. Lobar pneumonia was present in 1440 (71.4%), multi-lobar in 576 (28.6%). Median length of stay was 6 days (IQR 4-11). A total of 1921 cases (95.3%) received empiric antibiotics with anti-pneumococcal coverage: ceftriaxone, in 1267 (62.8%). Coverage for atypical bacteria was given to 1159 (57.5%), 64% of these, with macrolides. A total of 372 (18.5%) required mechanical ventilation, and 397 (19.7%) died. Independent predictors of mortality were age (odds ratio [OR] 1.051, 95% confidence interval [CI] 1.039, 1.063), being at high-risk for pneumococcal disease (OR 2.040, 95% CI 1.351, 3.083), multi-lobar pneumonia (OR 2.356, 95% CI 1.741, 3.189). Female sex and macrolide therapy were predictors of survival: (OR 0.702, 95% CI .516, .955; and OR 0.554, 95% CI .394, .779, respectively). Either azithromycin or roxithromycin treatment for as short as two days was predictor of survival. Quinolone therapy had no effect. CONCLUSIONS: Empirical therapy with macrolides reduced odds for mortality by 45%. This effect was evident with azithromycin and with roxithromycin. The effect did not require a full course of therapy.

Characteristics of endovascular pneumococcal infections; a decade of nationwide surveillance study.

In order to characterize pneumococcal endovascular infection in the post-vaccination era, a retrospective nationwide study based on the Israeli Adult IPD database was conducted. Between 2010 and 2019, 0.6% (23 cases) of IPD cases were of endovascular type, occurring mainly in males (72.3%) with underlying medical conditions (78.2%). Additional pneumococcal source (10 patients) and concomitant infections were not uncommon. Penicillin and ceftriaxone susceptibility rates were 65.2% and 91.3%, respectively; 60.9% of the isolates were not covered by the pneumococcal conjugate vaccine. 21.7% of patients died during hospitalization. In conclusion, pneumococcal endovascular infections still carry significant morbidity and mortality.

Effectiveness of Pneumococcal Conjugate Vaccines Against Community-acquired Alveolar Pneumonia Attributable to Vaccine-serotype Streptococcus pneumoniae Among Children.

INTRODUCTION: Streptococcus pneumoniae is a leading cause of pneumonia among children. However, owing to diagnostic limitations, the protection conferred by pneumococcal conjugate vaccines (PCVs) against pediatric pneumonia attributable to vaccine-serotype pneumococci remains unknown. METHODS: We analyzed data on vaccination and nasopharyngeal pneumococcal detection among children <5 years old with community-acquired alveolar pneumonia (CAAP; "cases") and those without respiratory symptoms ("controls"), who were enrolled in population-based prospective surveillance studies in southern Israel between 2009 and 2018. We measured PCV-conferred protection against carriage of vaccine-serotype pneumococci via the relative risk of detecting these serotypes among vaccinated versus unvaccinated controls. We measured protection against progression of vaccine serotypes from carriage to CAAP via the relative association of vaccine-serotype detection in the nasopharynx with CAAP case status, among vaccinated and unvaccinated children. We measured PCV-conferred protection against CAAP attributable to vaccine-serotype pneumococci via the joint reduction in risks of carriage and disease progression. RESULTS: Our analyses included 1032 CAAP cases and 7743 controls. At ages 12-35 months, a PCV13 schedule containing 2 primary doses and 1 booster dose provided 87.2% (95% confidence interval: 8.1-100.0%) protection against CAAP attributable to PCV13-serotype pneumococci, and 92.3% (-0.9%, 100.0%) protection against CAAP attributable to PCV7-serotype pneumococci. Protection against PCV13-serotype and PCV7-serotype CAAP was 67.0% (-424.3%, 100.0%) and 67.7% (-1962.9%, 100.0%), respectively, at ages 36-59 months. At ages 4-11 months, 2 PCV13 doses provided 98.9% (-309.8%, 100.0%) and 91.4% (-191.4%, 100.0%) against PCV13-serotype and PCV7-serotype CAAP. CONCLUSIONS: Among children, PCV-conferred protection against CAAP attributable to vaccine-targeted pneumococcal serotypes resembles protection against vaccine-serotype invasive pneumococcal disease.

A Prospective, Population-based Study to Determine the Incidence and Bacteriology of Bacterial Conjunctivitis in Children <2 Years of Age Following 7-Valent and 13-Valent Pneumococcal Conjugate Vaccine Sequential Implementation.

BACKGROUND: Bacterial conjunctivitis is most commonly caused by nontypeable Haemophilus influenzae (NTHi), followed by Streptococcus pneumoniae. No population-based data on the impact of pneumococcal conjugate vaccines (PCVs) on the incidence of bacterial conjunctivitis have been published. We assessed rate dynamics of overall, pneumococcal, and NTHi conjunctivitis in children aged 2-23 months in southern Israel before and after PCV implementation. METHODS: This is a 12-year prospective, population-based surveillance, from July 2004 through June 2017. Our medical center serves a captive population of approximately 30 000 children < 2 years of age, and its clinical microbiology laboratory processes > 80% of all community-derived cultures, enabling incidence calculation. The 7-valent and 13-valent PCVs (PCV7 and PCV13, respectively) were implemented in the national immunization program in July 2009 and November 2010, respectively. Pneumococci, NTHi, Moraxella catarrhalis, and Streptococcus pyogenes were considered pathogens. Continuous annual incidences and incidence rate ratios comparing the PCV13 period (2015-2017) to the pre-PCV period (2004-2008) were calculated. RESULTS: Disease caused by PCV13 serotypes declined by 93%, without significant replacement with non-PCV13 serotypes. Rates of pneumococcal, NTHi, and overall culture-positive episodes declined by 59%, 41%, and 42%, respectively, while rates of culture-negative and other pathogens episodes did not change significantly. An overall reduction in all submitted culture rates of 35% was observed. This pattern was seen across all ages, including infants aged 2-5 months. CONCLUSIONS: PCV7/PCV13 implementation resulted in a marked and significant decline in pneumococcal, NTHi, and overall conjunctivitis rates in children < 2 years of age. The impact on NTHi episodes alludes to the role of pneumococcus-NTHi interaction in conjunctivitis. The impact in infants aged < 6 months suggests herd protection.

Effectiveness of the 7- and 13-Valent Pneumococcal Conjugate Vaccines Against Vaccine-Serotype Otitis Media.

BACKGROUND: Despite the demonstrated impact of pneumococcal vaccine (PCV) implementation on otitis media (OM), demonstration of real-life serotype-specific effectiveness of the 7-valent and 13-valent PCVs (PCV7 and PCV13) is lacking owing to the paucity of culture-positive cases. Furthermore, prelicensure PCV13 efficacy against OM was not studied. METHODS: The study was conducted from October 2009 to July 2013. Case patients were children aged 5-35 months with OM (mostly complex OM [recurrent/nonresponsive, spontaneously draining, chronic with effusion]) from whom middle-ear fluid culture was obtained; controls were contemporary children with rotavirus-negative gastroenteritis in a prospective population-based rotavirus surveillance, from the same age group with similar ethnic distribution and geographic location. Vaccine effectiveness (VE) was estimated as 1 minus the odds ratio using unconditional logistic regression, adjusting for time since PCV implementation, age, and ethnicity. RESULTS: A total of 223 case patients and 1370 controls were studied. Serotypes 19F and 19A together caused 56.1% of all vaccine-type (VT) OM. VE of ≥2 PCV doses in children aged 5-35 months was demonstrated as follows: PCV7 against OM due to PCV7 serotypes, 57.2% (95% confidence interval, 6.0%-80.5%); PCV13 against OM due to PCV13 serotypes, 77.4% (53.3%-92.1%); PCV13 against OM due to the 6 additional non-PCV7 serotypes 67.4% (17.6%-87.1%); PCV13 against OM due to serotype 19F, 91.3% (1.4%-99.2%); and PCV13 against OM due to serotype 3, 85.2% (23.9%-98.4%). PCV7 and PCV13 VE against OM due to serotype 19A in children aged 12-35 months was 72.4% (95% confidence interval, 6.2%-91.9%) and 94.6% (33.9%-99.6%), respectively. CONCLUSIONS: PCV7 and PCV13 were effective against complex OM caused by the targeted serotypes.

Carrier-Induced Hyporesponsiveness to Pneumococcal Conjugate Vaccines: Unraveling the Influence of Serotypes, Timing, and Previous Vaccine Dose.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) elicit lower immune response against serotypes carried before or at the time of vaccination (hyporesponsiveness) in infants. The limited studies conducted to date did not permit comprehensive insights regarding this phenomenon. This study, the largest ever conducted with both carriage and serologic endpoints, attempted to add insight on serotype-specific hyporesponsiveness in relation to the number of PCV doses administered before carriage acquisition. METHODS: In a double-blind randomized clinical trial (n = 1754 infants), 7-valent or 13-valent PCV was administered at ages 2, 4, 6, and 12 months. New acquisition was defined based on nasopharyngeal swabs at ages 2, 4, 6, 7, and 12 months. Serotype-specific immunoglobulin G levels were obtained 1 month after the infant series and 1 month after the toddler dose. RESULTS: A lower immune response after the infant series and the toddler dose was consistently observed for carriers of serotypes 6A, 6B, 18C, and 19F at predefined time points, with a similar trend observed in carriers of serotype 23F. In contrast, carriage of serotypes 9V, 14, and 19A did not generally affect immune responses. For some but not all serotypes, hyporesponsiveness was decreased with an increased number of vaccine doses received before acquisition. A complex interrelationship between carriage and immune response was observed between cross-reacting serotypes. CONCLUSIONS: Carrier-induced hyporesponsiveness to PCVs is common, differs among serotypes, and depends on timing of carriage acquisition and prior number of administered PCV doses. CLINICAL TRIALS REGISTRATION: NCT00508742.

Unraveling the Impact of Pneumococcal Conjugate Vaccines on Ambulatory Antibiotic Drug Consumption in Young Children: An Interrupted Time-Series Analysis.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) reduce respiratory infections in young children, the main antibiotic consumers. Following PCV implementation, dispensed antibiotic prescription (DAP) rates in young children were expected to decline. METHODS: Computerized data on DAP for children <5 years were examined during a 13-year period (including 4 pre-PCV years). All DAPs from clinics with ≥50 insured children, active both pre- and post-PCV implementation were included. Interrupted time-series with segmented regression was applied to analyze monthly DAP rate trends, adjusted for age, ethnicity, and season. Incidence rate ratios (IRRs) of DAPs during the late PCV13 period versus 4 years pre-PCV were calculated both as absolute rate ratios (aIRRs) and relative to expected rates (rIRRs). RESULTS: Of 1 090 870 DAPs, 57% were in children <2 years. All-DAP rates peaked in the cold season. Post-PCV7/PCV13 implementation, all DAP rates abruptly and significantly declined, reaching a plateau within 5 years. This was largely driven by amoxicillin/amoxicillin-clavulanate (75% of DAPs). Age <2 years and Bedouin ethnicity were significantly associated with higher pre-PCV DAP rates but with faster and greater decline post-PCV, achieving near elimination of gaps between ages and ethnic groups. Overall reduction (95% CIs) in DAP rates per 1000 was estimated between aIRR (344.7 [370.9-358.4]) and rIRR (110.4 [96.9-123.7]) values. CONCLUSIONS: Shortly following PCV implementation, overall DAP rates showed an abrupt, steep decline, stabilizing within 5 years, in parallel to post-PCV respiratory infection trends previously described in this population, suggesting causality. The variable patterns of certain drug categories suggest additional influences beyond PCV.

Serotype Patterns of Pneumococcal Disease in Adults Are Correlated With Carriage Patterns in Older Children.

BACKGROUND: The importance of specific serotypes causing invasive pneumococcal disease (IPD) differs by age. Data on pneumococcal carriage in different age groups, along with data on serotype-specific invasiveness, could help explain these age-related patterns and their implications for vaccination. METHODS: Using pneumococcal carriage and disease data from Israel, we evaluated the association between serotype-specific IPD in adults and serotype-specific carriage prevalence among children in different age categories, while adjusting for serotype-specific invasiveness. We estimated carriage prevalence using different age groupings that were selected a priori. The Deviance Information Criterion was used to determine which age groupings of carriage data best fit the adult IPD data. Serotype-specific disease patterns were further evaluated by stratifying IPD data by comorbidity status. RESULTS: The relative frequency of serotypes causing IPD differed between adults and children, and also differed between older and younger adults and between adults with and without comorbidities. Serotypes overrepresented as causes of IPD in adults were more commonly carried in older children compared with younger children. In line with this, the serotype-specific frequency of carriage in older children, rather than infants, best correlated with serotype-specific IPD in adults. CONCLUSIONS: These analyses demonstrate that the serotype patterns in carriage in older children, rather than infants, are best correlated with disease patterns in adults. This might suggest these older children are more influential for disease patterns in adults. These insights could help in optimizing vaccination strategies to reduce disease burden across all ages.

A Nationwide Outbreak of Invasive Pneumococcal Disease in Israel Caused by Streptococcus pneumoniae Serotype 2.

BACKGROUND: Invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae serotype 2 (Sp2) is infrequent. Large-scale outbreaks were not been reported following pneumococcal conjugate vaccine (PCV) implementation. We describe a Sp2 IPD outbreak in Israel, in the PCV13 era, with focus on Sp2 population structure and evolutionary dynamics. METHODS: The data were derived from a population-based, nationwide active surveillance of IPD since 2009. PCV7/PCV13 vaccines were introduced in July 2009 and November 2010, respectively. Sp2 isolates were tested for antimicrobial susceptibility, multilocus sequence typing, and whole-genome sequencing (WGS) analysis. RESULTS: Overall, 170 Sp2 IPD cases were identified during 2009-2019; Sp2 increased in 2015 and caused 6% of IPD during 2015-2019, a 7-fold increase compared with 2009-2014. The outbreak was caused by a previously unreported molecular type (ST-13578), initially observed in Israel in 2014. This clone caused 88% of Sp2 during 2015-2019. ST-13578 is a single-locus variant of ST-1504, previously reported globally including in Israel. WGS analysis confirmed clonality among the ST-13578 population. Single-nucleotide polymorphism-dense regions support a hypothesis that the ST-13578 outbreak clone evolved from ST-1504 by recombination. All tested strains were penicillin-susceptible (minimum inhibitory concentration <0.06 µg/mL). The ST-13578 clone was identified almost exclusively (99%) in the Jewish population and was mainly distributed in 3 of 7 Israeli districts. The outbreak is still ongoing, although it began declining in 2017. CONCLUSIONS: To the best of our knowledge, this is the first widespread Sp2 outbreak since PCV13 introduction worldwide, caused by the emerging ST-13578 clone.

Post-13-Valent Pneumococcal Conjugate Vaccine Dynamics in Young Children of Serotypes Included in Candidate Extended-Spectrum Conjugate Vaccines.

After worldwide implementation of 10-valent and 13-valent pneumococcal conjugate vaccines (PCV10/PCV13), a 20-valent PCV (PCV20) was developed. We assessed dynamics of non-PCV13 additional PCV20 serotypes (VT20-13), compared with all other non-VT20 serotypes, in children <2 years of age in late PCV13 (2015-2017) and early PCV (2009-2011) periods. Our prospective population-based multifaceted surveillance included isolates from carriage in healthy children, children requiring chest radiography for lower respiratory tract infections (LRTIs), and children with non-LRTI illness, as well as isolates from acute conjunctivitis, otitis media (OM), and invasive pneumococcal disease (IPD). After PCV13 implementation, VT20-13 increased disproportionally in OM, IPD, and carriage in LRTI. VT20-13/non-VT20 prevalence ratio range was 0.26-1.40. VT20-13 serotypes were more frequently antimicrobial-nonsusceptible than non-VT20 serotypes. The disproportionate increase of VT20-13 in respiratory infections and IPD points to their higher disease potential compared with all other non-VT20 as a group.

Nasopharyngeal Carriage of Invasive Pneumococcal Serotypes During Childhood Community-Acquired Alveolar Pneumonia Is Associated With Specific Clinical Presentation.

BACKGROUND: Streptococcus pneumoniae (Pnc) serotypes differ in invasive potential. We examined whether community-acquired alveolar pneumonia (CAAP) in children carrying commonly recognized pneumonia invasive pneumococcal serotypes ([PnIST] 1, 5, 7F, 14, and 19A) differs from CAAP in children carrying less invasive serotypes (non-PnIST) or no Pnc (Pnc-neg). METHODS: Children <5 years, visiting the only regional Pediatric Emergency Room, with radiologically proven CAAP were enrolled. Nasopharyngeal cultures were processed for pneumococcal isolation and serotyping. Clinical and demographic characteristics were recorded. The study was conducted before pneumococcal conjugate vaccine implementation in Israel. RESULTS: A total of 1423 CAAP episodes were recorded: PnIST, 300 (21.1%); non-PnIST, 591 (41.5%); and Pnc-neg, 532 (37.4%). After adjustment for age, ethnicity, seasonality, and previous antibiotics, the following variables were positively associated with PnIST carriage compared with both groups: temperature ≥39°C, peripheral white blood cell count ≥20 000/mm3, C-reactive protein ≥70.0 mg/L, and serum sodium <135 mEq/L. Lower oxygen saturation, viral detection, and comorbidities were negatively associated with Pn-IST carriage (odds ratios, <1.0). Differences between non-PnIST carriers and Pnc-neg groups were smaller or nonsignificant. CONCLUSIONS: Young children with CAAP carrying common PnIST had a lower proportion of comorbidities, hypoxemia, and viral detection and had more intense systemic inflammatory response than those carrying non-PnIST or not carrying Pnc.