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COVID-19 vaccine breakthrough infection surveillance helps monitor trends in disease incidence and severe outcomes in fully vaccinated persons, including the impact of the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19. Reported COVID-19 cases, hospitalizations, and deaths occurring among persons aged ≥18 years during April 4-July 17, 2021, were analyzed by vaccination status across 13 U.S. jurisdictions that routinely linked case surveillance and immunization registry data. Averaged weekly, age-standardized incidence rate ratios (IRRs) for cases among persons who were not fully vaccinated compared with those among fully vaccinated persons decreased from 11.1 (95% confidence interval [CI] = 7.8-15.8) to 4.6 (95% CI = 2.5-8.5) between two periods when prevalence of the Delta variant was lower (

BackgroundPeople with HIV (PWH) are at increased risk for invasive pneumococcal disease (IPD). Thirteen-valent pneumococcal conjugate vaccine (PCV13) was recommended for use in US children in 2010 and for PWH aged 19 years or older in 2012. We evaluated the population-level impact of PCV13 on IPD among PWH and non-PWH aged 19 years or older.MethodsWe identified IPD cases from 2008 to 2018 through the Active Bacterial Core surveillance platform. We estimated IPD incidence using the National HIV Surveillance System and US Census Bureau data. We measured percent changes in IPD incidence from 2008 to 2009 to 2017-2018 by HIV status, age group, and vaccine serotype group, including serotypes in recently licensed 15-valent (PCV15) and 20-valent (PCV20) PCVs.ResultsIn 2008-2009 and 2017-2018, 8.4% (552/6548) and 8.0% (416/5169) of adult IPD cases were among PWH, respectively. Compared with non-PWH, a larger proportion of IPD cases among PWH were in adults aged 19-64 years (94.7%-97.4% vs. 56.0%-60.1%) and non-Hispanic Black people (62.5%-73.0% vs. 16.7%-19.2%). Overall and PCV13-type IPD incidence in PWH declined by 40.3% (95% confidence interval: -47.7 to -32.3) and 72.5% (95% confidence interval: -78.8 to -65.6), respectively. In 2017-2018, IPD incidence was 16.8 (overall) and 12.6 (PCV13 type) times higher in PWH compared with non-PWH; PCV13, PCV15/non-PCV13, and PCV20/non-PCV15 serotypes comprised 21.5%, 11.2%, and 16.5% of IPD in PWH, respectively.ConclusionsDespite reductions post-PCV13 introduction, IPD incidence among PWH remained substantially higher than among non-PWH. Higher-valent PCVs provide opportunities to reduce remaining IPD burden in PWH.

Previous reports of COVID-19 case, hospitalization, and death rates by vaccination status

Background People living with HIV (PLHIV) are at increased risk of invasive pneumococcal disease (IPD). The 13-valent pneumococcal conjugate vaccine (PCV13) was recommended for children in 2010, and for immunocompromised adults (including PLHIV) in series with 23-valent polysaccharide vaccine (PPSV23) in 2012. We evaluated changes in IPD incidence in adults ≥19 years old by HIV status after PCV13 introduction and proportion of remaining IPD due to serotypes included in the 15- (PCV15) and 20-valent (PCV20) conjugate vaccines expected to be licensed in 2021. Methods IPD cases were identified through CDC’s Active Bacterial Core surveillance (ABCs). HIV status was obtained from medical records. Isolates were serotyped by Quellung reaction, or whole-genome sequencing and grouped into PCV13-types, PPV11-types (unique to PPSV23), or non-vaccine types. We estimated IPD incidence (cases per 100,000 people) using national projections of ABCs cases as numerators and national case-based HIV surveillance (PLHIV) or US census data (non-PLHIV) as denominators. We compared IPD incidence in 2011–12 and 2017–18 to pre-PCV13 baseline (2008–09) by serotype groups. We assessed the proportion of IPD due to serotypes included in PCV15 and PCV20. Results Overall IPD incidence at baseline was 306.7 for PLHIV and 15.2 for non-PLHIV. From baseline to 2017–18, IPD incidence declined in PLHIV (-40.3%; 95% CI: -47.7, -32.3%) and non-PLHIV (-28.2%; 95% CI: -30.9, -25.5%). The largest reductions were in PCV13-type IPD during both periods (-44.2% for PLHIV and -42.2% for non-PLHIV in 2011–12; -72.5% for PLHIV and -62.2% for non-PLHIV in 2017–18) compared to baseline (Figures 1, 2). In 2017–2018, overall IPD and PCV13-type rates were 16.8 (95% CI: 15.1, 18.5) and 12.6 (95% CI: 9.9, 15.3) times as high in PLHIV vs non-PLHIV, respectively; PCV13, PCV15/non-PCV13, and PCV20/non-PCV15 serotypes comprised 21.5%, 11.2% and 16.5% of IPD in PLHIV. IPD incidence rates among adults aged ≥19 years old by serotype group in PLHIV, 2008–2018 IPD incidence rates among adults aged ≥19 years old by serotype group in non-PLHIV, 2008–2018 Conclusion IPD rates declined significantly in both PLHIV and non-PLHIV during the study period due to reductions in PCV13-type IPD; however, IPD rates remained 17-fold higher in PLHIV compared to non-PLHIV, mainly due to non-PCV13 types. Higher-valent pneumococcal conjugate vaccines provide opportunities to reduce some of the remaining IPD burden in PLHIV. Disclosures William Schaffner, MD, VBI Vaccines (Consultant) Lee Harrison, MD, GSK, Merck, Pfizer, Sanofi Pasteur (Consultant)

Background Thirteen-valent pneumococcal conjugate vaccine (PCV13) was recommended for U.S. children aged < 5 years in February 2010 and recommended in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23) for adults aged ≥ 65 years in 2014. PCV13 has led to dramatic reductions in invasive pneumococcal disease (IPD) burden. New, higher valency PCVs (PCV15, PCV20) are expected to be licensed for adults in late 2021. We examined remaining PCV13-type IPD among children and adults and assessed IPD burden potentially preventable through PCV15 and PCV20 use. Methods IPD cases (isolation of pneumococcus from sterile sites) were identified through CDC’s Active Bacterial Core surveillance during 1998–2019. Isolates were serotyped by Quellung or whole genome sequencing. Incidence rates (cases/100,000) were calculated using U.S. Census Bureau population denominators. Results After introduction of PCV13 in children, by 2013–2014, PCV13-type IPD declined 89% (from 15 to 2 cases/100,000) in children age < 5 years and 67% (from 19 to 7 cases/100,000) in adults age ≥ 65 years. During 2014–2019, rates of PCV13-type IPD in children and adults remained stable. In 2018–2019, among children age < 5 years, serotypes 3, 19F, 19A, and 6C accounted for most of the remaining PCV13-type IPD (46%, 32%, 14% and 4% respectively) (Figure 1). Among adults age ≥ 65 years, serotypes 3, 6C, 19A, and 19F accounted for most of the remaining PCV13-type IPD (62%, 12%, 10%, and 9% respectively) (Figure 1). During 2015–2019, rates of PCV15 and PCV20-type IPD have remained stable. In 2018–2019, among adults age ≥ 65 years, PCV15 non-PCV13-type IPD rates were 3.6 cases per 100,000 and accounted for 15% of all IPD. PCV20 non-PCV13-type IPD rates were 6.8 cases per 100,000 and accounted for 29% of all IPD (Figure 2). Among children age < 5 years, PCV15 non-PCV13-type IPD rates were 1.6 cases per 100,000 and accounted for 17% of all IPD. PCV20 non-PCV13-type IPD rates were 2.8 cases per 100,000 and accounted for 39% of all IPD (Figure 2). Figure 1. Incidence rates of IPD among children < 5 years old, by pneumococcal conjugate vaccine type and individual PCV13 serotypes, 2011–2019 Figure 2. Incidence rates of IPD among adults ≥ 65 years old, by pneumococcal conjugate vaccine type and individual PCV13 serotypes, 2011–2019 Conclusion Following the dramatic reductions after PCV13 introduction, PCV13-type IPD has remained stable during the past five years. There are opportunities to prevent an additional 30% IPD burden among adults through new PCV use. Disclosures William Schaffner, MD, VBI Vaccines (Consultant) Lee Harrison, MD, GSK, Merck, Pfizer, Sanofi Pasteur (Consultant)

BACKGROUND: Most countries 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). METHODS: 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 RESULTS: 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 CONCLUSIONS: 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.

Background In the United States, approximately 30,000 invasive group B Streptococcus (iGBS) infections occur annually; beta-lactam antibiotics (BL) are the first choice for prevention in young infants and treatment in all age groups. We obtained phenotypic and genotypic data for iGBS isolates from U.S. population-based surveillance sites to describe the emergence and characteristics of strains with reduced beta-lactam susceptibility (RS) over a 20-year period. Methods We analyzed RS iGBS isolates from eight Active Bacterial Core surveillance sites from 1998–2017. Through 2014, minimum inhibitory concentrations (MIC) for six BL were determined by broth microdilution, followed by whole genome sequencing (WGS) of RS isolates exceeding pre-defined breakpoints (Table 1). In 2015, WGS and MIC testing were performed for all isolates. After 2015, all isolates underwent WGS. MIC testing was continued on approximately 25% of isolates; otherwise, only those with modified penicillin binding protein (PBP) 2x transpeptidase amino acid sequence types or suboptimal WGS (< 1 % of isolates) underwent MIC testing. Clinical information on RS cases was abstracted from medical charts. Results Of 26,058 out of 27,269 iGBS isolates (95.6%) tested to date, 107 (0.4%) exhibited RS, increasing from 0% in 1998 to a peak of 1.1% in 2016 (P< 0.05 for trend) (Figure 1). Seven (6.5%) RS strains were from infants aged < 90 days; the rest were from adults aged ≥30 years (Table 2). RS strains consisted of 52 PBP2x types with diverse susceptibility patterns (Table 1). Seven RS strains (6.5%) had wild-type (non-modified) PBP2x; all met the RS criteria based on a single cephalosporin with a confirmed (repeated) MIC value at the break point (Table 1). Compared to non-RS strains, RS strains were more common in patients who presented with cellulitis and osteomyelitis and with underlying conditions such as diabetes or chronic skin breakdown (Table 2). Of 82 (85.4%) patients with RS strains and additional clinical information, 8.3% had known prior GBS infection; 26.8% had known BL exposure in the preceding year. Conclusion Preliminary results show that RS increased in recent years; strains RS to penicillin and ampicillin remain low. Variable pbp2x mutations have emerged and predominant strains have not yet been identified. Disclosures Nisha B. Alden, MPH, CDC (Grant/Research Support) Lee Harrison, MD, Dynavax (Consultant)GSK (Consultant)Merck (Consultant)OMVax (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)

Background PCVs have been recommended for U.S. children since 2000. A 7-valent vaccine (PCV7) was introduced in 2000. This was replaced by a 13-valent vaccine (PCV13) in 2010. PCV13 was also recommended for adults aged ≥ 65 years in August 2014. We evaluated PCV impact on IPD. Methods IPD cases (isolation of pneumococcus from sterile sites) were identified through CDC’s Active Bacterial Core surveillance during 1998-2018. Isolates were serotyped by Quellung or whole genome sequencing and classified as PCV13-type and non-vaccine-type (NVT). Incidence rates (cases/100,000) were calculated using U.S. Census Bureau population denominators. Results From 1998 through 2018, overall IPD rates among children aged < 5 years decreased by 93% (from 95 to 7 cases/100,000). PCV13-type IPD decreased by 98% (from 88 to 2 cases/100,000). Among adults aged ≥ 65 years, overall IPD rates decreased by 60% (from 61 to 25 cases/100,000). PCV13-type IPD rates declined 86% (from 46 to 7 cases/100,000). Declines were most dramatic in the years following PCV7 introduction, with additional declines after PCV13 introduction in children (Figures 1 and 2). Serotypes 3, 19A, and 19F caused most of the remaining PCV13-type IPD. NVT IPD rates did not change significantly among children. Among adults aged 50-64 years, NVT IPD increased by 83% (from 6 to 12 cases/100,000) (p< 0.01). Among adults aged ≥ 65 years, NVT IPD increased by 22% (from 15 to 18 cases/100,000) (p< 0.01). The most common NVTs in 2018 were 22F (10% of all IPD), 9N (7%) and 15A (5%). Among children, the proportion of cases with meningitis increased from 5% to 14% (p< 0.01), and the proportion with pneumonia/empyema increased from 17% to 31% (p< 0.01). Among adults, the proportion of cases with meningitis did not change (3%), while the proportion with pneumonia/empyema increased from 72% to 76% (p=0.01). Figure 1: Incidence of invasive pneumococcal disease among children aged < 5 years, 1998-2018 Figure 2: Incidence of invasive pneumococcal disease among adults aged ≥ 65 years, 1998-2018 Conclusion Overall IPD incidence among children and adults decreased following PCV introduction for children, driven primarily by reductions in PCV-type IPD. NVT IPD increased in older adults, but these increases did not eliminate reductions from PCV13-type IPD. Disclosures Lee Harrison, MD, GSK (Consultant)Merck (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)

In 2010, 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the US for prevention of invasive pneumococcal disease in children. Individual-level socioeconomic status (SES) is a potential confounder of the estimated effectiveness of PCV13 and is often controlled for in observational studies using zip code as a proxy. We assessed the utility of zip code matching for control of SES in a post-licensure evaluation of the effectiveness of PCV13 (calculated as [1-matched odds ratio]*100). We used a directed acyclic graph to identify subsets of confounders and collected SES variables from birth certificates, geocoding, a parent interview, and follow-up with medical providers. Cases tended to be more affluent than eligible controls (for example, 48.3% of cases had private insurance vs. 44.6% of eligible controls), but less affluent than enrolled controls (52.9% of whom had private insurance). Control of confounding subsets, however, did not result in a meaningful change in estimated vaccine effectiveness (original estimate: 85.1%, 95% CI 74.8–91.9%; adjusted estimate: 82.5%, 95% CI 65.6–91.1%). In the context of a post-licensure vaccine effectiveness study, zip code appears to be an adequate, though not perfect, proxy for individual SES., Highlights • Socioeconomic status (SES) may impact enrollment in vaccine effectiveness studies. • We assessed zip code matching as a proxy for SES in a pneumococcal vaccine study. • After zip code matching, we found differences in SES between cases and controls. • Differences did not appear to substantially bias estimated vaccine effectiveness.

Background Rates of invasive group B Streptococcus (GBS) disease, obesity, and diabetes have increased in US adults. We hypothesized that obesity would be independently associated with an increased risk of invasive GBS disease. Methods We identified adults with invasive GBS disease within Active Bacterial Core surveillance during 2010–2012 and used population estimates from the Behavioral Risk Factor Surveillance System to calculate invasive GBS incidence rates. We estimated relative risks (RRs) of invasive GBS using Poisson analysis with offset denominators, with obesity categorized as class I/II (body mass index [BMI] = 30–39.9 kg/m2) and class III (BMI ≥ 40.0 kg/m2). Results In multivariable analysis of 4281 cases, the adjusted RRs of invasive GBS disease were increased for obesity (class I/II: RR, 1.52; 95% confidence interval [CI], 1.14–2.02; and class III: RR, 4.87; 95% CI, 3.50–6.77; reference overweight) and diabetes (RR, 6.04; 95% CI, 4.77–7.65). The adjusted RR associated with class III obesity was 3-fold among persons with diabetes (95% CI, 1.38–6.61) and nearly 9-fold among persons without diabetes (95% CI, 6.41–12.46), compared with overweight. The adjusted RRs associated with diabetes varied by age and BMI, with the highest RR in young populations without obesity. Population attributable risks of invasive GBS disease were 27.2% for obesity and 40.1% for diabetes. Conclusions Obesity and diabetes were associated with substantially increased risk of infection from invasive GBS. Given the population attributable risks of obesity and diabetes, interventions that reduce the prevalence of these conditions would likely reduce the burden of invasive GBS infection.

BACKGROUND Antibiotic-nonsusceptible invasive pneumococcal disease (IPD) decreased substantially after the US introduction of the pediatric 7-valent pneumococcal conjugate vaccine (PCV7) in 2000. However, rates of antibiotic-nonsusceptible non-PCV7-type IPD increased during 2004-2009. In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7. We assessed the impact of PCV13 on antibiotic-nonsusceptible IPD rates. METHODS We defined IPD as pneumococcal isolation from a normally sterile site in a resident from 10 US surveillance sites. Antibiotic-nonsusceptible isolates were those intermediate or resistant to ≥1 antibiotic classes according to 2012 Clinical and Laboratory Standards Institute breakpoints. We examined rates of antibiotic nonsusceptibility and estimated cases prevented between observed cases of antibiotic-nonsusceptible IPD and cases that would have occurred if PCV13 had not been introduced. RESULTS From 2009 to 2013, rates of antibiotic-nonsusceptible IPD caused by serotypes included in PCV13 but not in PCV7 decreased from 6.5 to 0.5 per 100 000 in children aged

ObjectivesExternal validity, or generalisability, is the measure of how well results from a study pertain to individuals in the target population. We assessed generalisability, with respect to socioeconomic status, of estimates from a matched case–control study of 13-valent pneumococcal conjugate vaccine effectiveness for the prevention of invasive pneumococcal disease in children in the USA.DesignMatched case–control study.SettingThirteen active surveillance sites for invasive pneumococcal disease in the USA.ParticipantsCases were identified from active surveillance and controls were age and zip code matched.Outcome measuresSocioeconomic status was assessed at the individual level via parent interview (for enrolled individuals only) and birth certificate data (for both enrolled and unenrolled individuals) and at the neighbourhood level by geocoding to the census tract (for both enrolled and unenrolled individuals). Prediction models were used to determine if socioeconomic status was associated with enrolment.ResultsWe enrolled 54.6% of 1211 eligible cases and found a trend toward enrolled cases being more affluent than unenrolled cases. Enrolled cases were slightly more likely to have private insurance at birth (p=0.08) and have mothers with at least some college education (pConclusionsWe conclude that although enrolled cases are somewhat more affluent than unenrolled cases, our estimates are externally valid with respect to socioeconomic status. Our analysis provides evidence that this study design can yield valid estimates and the assessing generalisability of observational data is feasible, even when unenrolled individuals cannot be contacted.

Background Pneumococcal conjugate vaccine (PCV13) was recommended in series with PPSV23 for all US adults ≥65 years in late 2014. We evaluated effectiveness of PCV13 against invasive pneumococcal disease (IPD) among Medicare beneficiaries ≥65 years old to assess this new policy. Methods We linked records for IPD cases (pneumococcus isolated from sterile sites) in persons ≥65 years old identified through Active Bacterial Core surveillance with those of Medicare beneficiaries. Isolates were serotyped and classified as PCV13 (with or without cross-reacting type 6C), and nonvaccine types. We selected Medicare beneficiaries with no record of IPD or pneumonia as controls, and matched to cases on age, residence census tract, and length of Medicare enrollment; we included all eligible controls. Vaccination and medical histories were obtained through Medicare. We estimated vaccine effectiveness (VE) as 1 minus the IPD odds ratio for vaccinated (PCV13) vs. unvaccinated (no PCV13 or PPSV23) persons using conditional logistic regression, adjusted for sex and underlying conditions. Results From 2,246 IPD cases identified in 2015–2016, 1,017 (45%) were matched to Medicare beneficiaries. After excluding cases in persons residing in long-term care facilities or with 75 years of age (VE 61%, 95% CI 14, 82). VE was 26% (95% CI −58, 65%) against serotype 3 and 67% (95% CI 11, 88%) against other PCV13-types (+6C). PCV13 was not effective against nonvaccine types. Conclusion PCV13 was effective in preventing IPD caused by PCV13 types when excluding type 3; no effectiveness was demonstrated against serotype 3. Disclosures W. Schaffner, Merck: Member, Data Safety Monitoring Board, Consulting fee. Pfizer: Member, Data Safety Monitoring Board, Consulting fee. Dynavax: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. SutroVax: Consultant, Consulting fee. Shionogi: Consultant, Consulting fee.

Objectives Our objective was to evaluate and exploit a whole genome sequence (WGS) bioinformatics pipeline for predicting antimicrobial resistance and capsular serotypes from invasive group B streptococci (iGBS). Methods For 1975 iGBS recovered during 2015 from CDC's Active Bacterial Core surveillance, we compared pipeline predictions with broth dilution testing. Fifty-six isolates from earlier surveillance were included for testing β-lactams. Conventional serotyping was compared to WGS-based assignments for 302 isolates. Results All 28 isolates with reduced susceptibility to β-lactam antibiotics harboured one of 19 rare PBP2x types. Resistances to erythromycin/clindamycin (808/1975 isolates, 41.0%), erythromycin (235/1975, 11.9%) and lincosamide/streptogramin A/pleuromutilins (56/1975, 2.8%) were predicted by the presence of erm -methylase, mef and lsa determinants, respectively (41 of 56 lsa gene-positive isolates also contained lnu , erm and/or mef genes). Presence of both erm and lsa determinants (25 isolates) predicted non-susceptibility to quinupristin/dalfopristin. Most isolates (1680/1975, 85.1%) were tet gene-positive, although 41/1565 (2.6%) tetM -positive isolates were tetracycline-susceptible. All 53 fluoroquinolone-resistant isolates contained ParC and/or GyrA substitutions. Resistances to rifampin (eight isolates), trimethoprim, chloramphenicol and vancomycin (two isolates each) were predicted by the pipeline. Resistance to macrolides/lincosamides without pipeline prediction was rare and correlated to divergent resistance genes or rRNA A2062G substitution. A selection of 267 isolates assigned WGS-based serotypes were also conventionally serotyped. Of these, 246 (92.1%) were in agreement, with the remaining 21 (7.8%) conventionally non-serotypeable. For 32 of 1975 isolates (1.6%), WGS-based serotypes could not be assigned. Conclusion The WGS-based assignment of iGBS resistance features and serotypes is an accurate substitute for phenotypic testing.

Background In 2014, pneumococcal conjugate (PCV13) and polysaccharide (PPSV23) vaccines were recommended in series for all US adults ≥65 years. We conducted a case–control study to evaluate risk factors for invasive pneumococcal disease (IPD) among adults ≥65 years old. Methods IPD cases (isolation of pneumococcus from sterile sites) were identified through Active Bacterial Core surveillance during 2015–2018. Isolates were serotyped using whole genome sequencing. Four controls, identified through a commercial database, were matched per case by age and zip code. We obtained vaccination and medical histories from providers, vaccine registries and participant interviews. A functional status score was calculated based on participant interview. We calculated IPD odds ratios using multivariable conditional logistic regression. Results We enrolled 328 IPD cases and 1,280 matched controls. Fifty percent of case-patients and 55% of controls received a dose of PCV13. Case-patients were more likely than controls to have a chronic condition (heart, liver, or lung disease, diabetes, cochlear implant, alcohol abuse, smoking; 82% vs. 59%), immunosuppression (60% vs. 32%), poor functional status (score of ≥ 3; 71% vs. 50%), annual household income

Summary Background In 2010, 13-valent pneumococcal conjugate vaccine (PCV13) was licensed and recommended in the USA for prevention of invasive pneumococcal disease in children. Licensure was based on immunogenicity data comparing PCV13 with the earlier seven-valent formulation. Because clinical endpoints were not assessed for the new antigens, we did a postlicensure matched case-control study to assess vaccine effectiveness. Methods Cases in children aged 2–59 months were identified through active surveillance in 13 sites. Controls were identified via birth registries and matched to cases by age and postal (zip) code. The primary objective was the vaccine effectiveness of at least one dose against the 13 serotypes included in PCV13. Secondary objectives included vaccine effectiveness against all-cause invasive pneumococcal disease, against antibiotic non-susceptible invasive pneumococcal disease, and among children with and without underlying conditions. Vaccine effectiveness was calculated as (1 – matched odds ratio) × 100%. Findings We enrolled 722 children with invasive pneumococcal disease and 2991 controls; PCV13 serotype cases (217 [30%]) included most commonly serotypes 19A (128 [18%]), 7F (32 [4%]), and 3 (43 [6%]). Vaccine effectiveness against PCV13 serotypes was 86·0% (95% CI 75·5 to 92·3), driven by serotypes 19A and 7F, for which vaccine effectiveness was 85·6% (95% CI 70·6 to 93·5) and 96·5% (82·7 to 100), respectively. We also identified statistically significant effectiveness against serotype 3 (79·5%, 95% CI 30·3 to 94·8) and against antibiotic non-susceptible invasive pneumococcal disease (65·6%, 44·9 to 78·7). Vaccine effectiveness against all-cause invasive pneumococcal disease was 60·2% (95% CI 46·8 to 70·3). Vaccine effectiveness was similar among children with (81·4%, 95% CI 45·4 to 93·6) and without (85·8%, 74·9 to 91·9) underlying conditions. Interpretation PCV13 appears highly effective against invasive pneumococcal disease among children in the USA in the context of routine and catch-up schedules, although some new vaccine antigens could not be assessed. PCV13 immunisation provides a robust strategy for combating pneumococcal antimicrobial resistance. Funding Centers for Disease Control and Prevention.

Our whole genome sequence (WGS) pipeline was assessed for accurate prediction of antimicrobial phenotypes. For 2316 invasive pneumococcal isolates recovered during 2015 we compared WGS pipeline data to broth dilution testing (BDT) for 18 antimicrobials. For 11 antimicrobials categorical discrepancies were assigned when WGS-predicted MICs and BDT MICs predicted different categorizations for susceptibility, intermediate resistance or resistance, ranging from 0.9% (tetracycline) to 2.9% (amoxicillin). For β-lactam antibiotics, the occurrence of at least four-fold differences in MIC ranged from 0.2% (meropenem) to 1.0% (penicillin), although phenotypic retesting resolved 25%–78% of these discrepancies. Non-susceptibility to penicillin, predicted by penicillin-binding protein types, was 2.7% (non-meningitis criteria) and 23.8% (meningitis criteria). Other common resistance determinants included mef (475 isolates), ermB (191 isolates), ermB + mef (48 isolates), tetM (261 isolates) and cat (51 isolates). Additional accessory resistance genes (tetS, tet32, aphA-3, sat4) were rarely detected (one to three isolates). Rare core genome mutations conferring erythromycin-resistance included a two-codon rplD insertion (rplD69-KG-70) and the 23S rRNA A2061G substitution (six isolates). Intermediate cotrimoxazole-resistance was associated with one or two codon insertions within folP (238 isolates) or the folA I100L substitution (38 isolates), whereas full cotrimoxazole-resistance was attributed to alterations in both genes (172 isolates). The two levofloxacin-resistant isolates contained parC and/or gyrA mutations. Of 11 remaining isolates with moderately elevated MICs to both ciprofloxacin and levofloxacin, seven contained parC or gyrA mutations. The two rifampin-resistant isolates contained rpoB mutations. WGS-based antimicrobial phenotype prediction was an informative alternative to BDT for invasive pneumococci.