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Stephen I Pelton,1,2 Kimberly M Shea,1 Rebecca Bornheimer,3 Reiko Sato,4 Derek Weycker31Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; 2Maxwell Finland Laboratories, Boston Medical Center, Boston, MA, USA; 3Policy Analysis Inc. (PAI), Brookline, MA, USA; 4Health Economic & Outcomes Research, Pfizer Inc., Collegeville, PA, USABackground: Recent studies of community-acquired pneumonia (CAP) have recognized acute cardiac complications—such as myocardial infarction, arrhythmia, or congestive heart failure (CHF)—as frequent complications during the acute process. As well, a prolonged vulnerability to exacerbations of underlying comorbidities—such as CHF and COPD—has been observed following CAP. We hypothesized that young adults with underlying asthma could also be adversely impacted over a prolonged time period following CAP.Methods: Using a retrospective matched-cohort design and data from a US private healthcare claims repository (>15 M persons annually), we selected all adults 18–49 years of age with evidence of asthma as their only comorbidity for inclusion in the source population. Then, from the source population, we matched one comparison patient to each CAP patient based on index date, age, sex, and selected markers for health status (eg, history of asthma-related healthcare encounters), and evaluated subsequent outpatient and inpatient encounters for asthma exacerbations.Results: Asthma exacerbations were identified twice as often in the 12 months subsequent to acute CAP. Cumulative incidence proportions for asthma exacerbations requiring hospitalization or emergency department care after 12 months of follow-up were 19.9% for those previously hospitalized with CAP versus 9.0% for matched comparison patients (difference, 10.9%; p

This paper examined whether previously identified community-level factors (high proportion of crowded households and/or persons below the poverty level) remained associated with childhood pneumococcal carriage in the heptavalent pneumococcal conjugate vaccine (PCV7) era. Using logistic regression, individual factors were used to develop base models to which community-level factors were added to evaluate impact on pneumococcal carriage within two paediatric study cohorts from Massachusetts (urban Boston, outside Boston). Six years after introduction of universal childhood PCV7 vaccination, we found no consistent evidence that census tract characteristics (e.g. population size and density, age and race distribution, percent participating in group childcare, parental education, percent lacking in-unit plumbing, poverty, and community stability) affected odds of pneumococcal carriage when added to individual predictors (e.g. younger age, current respiratory tract infections, and attendance in group childcare). How community-level factors influence pneumococcal carriage continues to change in the era of increasing immunization coverage.

As part of an ongoing study of the response of the Streptococcus pneumoniae population to conjugate vaccination, we applied multi-locus sequence typing (MLST) to 291 isolates sampled from nasopharyngeal carriage in Massachusetts children. We found 94 distinct sequence types (STs), including 19 that had not been previously recorded, and a xpt allele containing a large insertion. Comparison with a similar sample collected in 2007 revealed no significant overall difference in the ST composition (p=0.51) suggesting that the population has reached a new equilibrium following the introduction of 7 valent vaccination in 2000. Within serotypes, a large and statistically significant increase (p=0.014 Fisher's Exact test) was noted in the prevalence of the major multiresistant clone ST 320, which is apparently outcompeting ST 199 among serotype 19A strains. This sample will be used as a baseline to study the future evolution of the pneumococcal population in Massachusetts following introduction of vaccines with higher valency.

Defining the propensity of Streptococcus pneumoniae (SP) serotypes to invade sterile body sites following nasopharyngeal (NP) acquisition has the potential to inform about how much invasive pneumococcal disease (IPD) may occur in a typical population with a given distribution of carriage serotypes. Data from enhanced surveillance for IPD in Massachusetts children ≤7 years in 2003/04, 2006/07 and 2008/09 seasons and surveillance of SP NP carriage during the corresponding respiratory seasons in 16 Massachusetts communities in 2003/04 and 8 of the 16 communities in both 2006/07 and 2008/09 were used to compute a serotype specific "invasive capacity (IC)" by dividing the incidence of IPD due to serotype x by the carriage prevalence of that same serotype in children of the same age. A total of 206 IPD and 806 NP isolates of SP were collected during the study period. An approximate 50-fold variation in the point estimates between the serotypes having the highest (18C, 33F, 7F, 19A, 3 and 22F) and lowest (6C, 23A, 35F, 11A, 35B, 19F, 15A, and 15BC) IC was observed. Point estimates of IC for most of the common serotypes currently colonizing children in Massachusetts were low and likely explain the continued reduction in IPD from the pre-PCV era in the absence of specific protection against these serotypes. Invasive capacity differs among serotypes and as new pneumococcal conjugate vaccines are introduced, ongoing surveillance will be essential to monitor whether serotypes with high invasive capacity emerge (e.g. 33F, 22F) as successful colonizers resulting in increased IPD incidence due to replacement serotypes.

Background; The incidence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) has risen dramatically in the U.S., particularly among children. Although Streptococcus pneumoniae colonization has been inversely associated with S. aureus colonization in unvaccinated children, this and other risk factors for S. aureus carriage have not been assessed following widespread use of the heptavalent pneumococcal conjugate vaccine (PCV7). Our objectives were to (1) determine the prevalence of S. aureus and MRSA colonization in young children in the context of widespread use of PCV7; and (2) examine risk factors for S. aureus colonization in the post-PCV7 era, including the absence of vaccine-type S. pneumoniae colonization. Methods: Swabs of the anterior nares (S. aureus) were obtained from children enrolled in an ongoing study of nasopharyngeal pneumococcal colonization of healthy children in 8 Massachusetts communities. Children 3 months to

Background: Response rates and immunologic memory following measles vaccination are reduced in human immunodeficiency virus (HIV)-infected children in the absence of highly active antiretroviral therapy (HAART).Methods: HIV-infected children 2 to <19 years old receiving HAART and with HIV loads <30,000 copies/mL, CD4% ≥15, and ≥1 prior measles-mumps-rubella vaccination (MMR) were given another MMR. Measles antibody concentrations before and 8, 32, and 80 weeks postvaccination were determined by plaque reduction neutralization (PRN). A subset was given another MMR 4-5 years later, and PRN antibody was measured before and 7 and 28 days later.Results: At entry, 52% of 193 subjects were seroprotected (PRN ≥120 mIU/mL). Seroprotection increased to 89% 8 weeks postvaccination, and remained at 80% 80 weeks postvaccination. Of 65 subjects revaccinated 4-5 years later, 85% demonstrated memory based on seroprotection before or 7 days after vaccination. HIV load ≤400 copies/mL at initial study vaccination was associated with higher seroprotection rates, greater antibody concentrations, and memory. Grade 3 fever or fatigue occurred in 2% of subjects.Conclusions: Measles revaccination induced high rates of seroprotection and memory in children receiving HAART. Both endpoints were associated with HIV viral load suppression.Clinical Trials Registration: NCT00013871 (www.clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is a leading cause of invasive illness (meningitis and bacteremia) and the most common cause of noncomplicated pneumonia, sinusitis and otitis media in children worldwide. Even with the availability of effective antibiotics, mortality due to pneumococcal diseases remains high, emphasizing the need for prevention. The 7 valent conjugated pneumococcal vaccine had a major impact on the incidence of invasive disease in vaccinated populations as a result of direct protection of the vaccinees and herd immunity. Further surveillance on S. pneumoniae is important to understand the consequences of emerging nonvaccine serotypes and the additional serotypes that should be incorporated into the second-generation vaccines. [ABSTRACT FROM AUTHOR]

Background: In response to the selective pressure of pneumococcal conjugate vaccine, increased asymptomatic carriage of antibiotic-nonsusceptible nonvaccine serotypes (NVTs) has been observed. Possible mechanisms include de novo acquisition of resistance, serotype switching, introduction of new clones, and expansion of existing clones.Methods: To investigate the process of increased antibiotic nonsusceptibility among replacing serotypes, we applied multilocus sequence typing to samples of 126 and 222 pneumococci collected in 2001 and 2004, respectively, from the nasopharynges of children <7 years of age in 16 Massachusetts communities.Results: We found no evidence of penicillin resistance due to either serotype switching or de novo acquisition. Nonetheless, resistance increased through the expansion of previously recognized clones of NVTs, particularly in serotypes 19A, 15A, and 35B. In 19A, several unrelated clones increased in frequency, whereas, in the other 2 serotypes, single resistant lineages were responsible for the increased prevalence of resistant strains.Conclusions: The decreased prevalence of antibiotic resistance with the introduction of heptavalent pneumococcal conjugate vaccine is likely to be partially eroded over time as vaccine-included serotypes are replaced by resistant clones of NVTs. The clinical significance of this will depend on the pathogenic potential of replacing clones to cause local (e.g., otitis media) or invasive disease. [ABSTRACT FROM AUTHOR]

Nonspecificity of early symptoms makes meningococcal disease difficult to distinguish from more common, primarily self-limited infections. Patients rapidly progress to death despite medical intervention if early shock and/or disseminated intravascular coagulopathy are already present. Although overall incidence of and mortality from meningococcal disease is lower in adolescents than in infants, the case fatality rate is higher, making this population a critical target for prevention. [ABSTRACT FROM AUTHOR]

The clinical course of meningococcal disease represents a diagnostic challenge because early symptoms are often nonspecific and overlap with those of other common infections before rapidly progressing to a life-threatening condition. Clinicians need to prioritize vaccination of preadolescent, adolescent, and other patients who are at risk of meningococcal disease, using a quadrivalent meningococcal conjugate vaccine at the soonest opportunity. [ABSTRACT FROM AUTHOR]

The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection. [ABSTRACT FROM AUTHOR]

Background: S. pneumoniae (SP) serotypes 15B and 15C are frequent causative agents of invasive pneumococcal disease (IPD), otitis media, and nasopharyngeal colonization in the post PCV13 era. The principal difference between serotypes 15B and 15C is the presence of an O-acetyl group on the pentasaccharide repeating unit of 15B polysaccharide. It remains unclear if antibodies against SP15B polysaccharide demonstrate functional cross reaction with SP15C strains. We compared functional activity of polyclonal rabbit anti-capsular 15B sera against SP15B and SP15C isolates., Methods: Using flow cytometry we measured complement factors C3c and C4d deposition on SP15B and 15C in the presence of polyclonal rabbit anti capsular 15B sera. We measured the binding of C3c, common to all complement pathways, and C4d, specific to classical pathway, on SP serotypes 15B and 15C when co-incubated with polyclonal rabbit anti capsular 15B sera and antibody depleted complement. Both the proportion of bacteria with complement deposition and the fluorescence intensity were measured. We also measured agglutination as the increase in forward and side scatter., Results: Polyclonal rabbit anti-capsular 15B sera activated classical pathway resulting in deposition of C4d and C3c at high intensity on all SP15B cells but only achieved limited deposition and intensity of C4 with SP15C. Similarly, polyclonal rabbit anti-capsular 15B sera induced agglutination of SP15B strains in a dose dependent manner and limited agglutination of SP15C., Conclusions: Anti-capsular 15B sera induce limited C4d and C3c deposition, and minimal agglutination with SP15C strains, reflecting lower classical pathway activation in contrast to high C4d and C3c deposition and agglutination of SP15B. These observations support limited functional cross reactivity of anti-15B to SP15C strains and are consistent with the reduction in opsonophagocytic killing of SP15C reported following immunization with vaccines containing 15B polysaccharide., Competing Interests: Declaration of competing interest Dr. Pelton has research support to Boston Medical Center from Pfizer, Inc. and Merck Vaccines related to pneumococcal vaccine. He received honorarium and consulting fees from Pfizer, Inc., Merck Vaccines, GSK, and Sanofi for participation in advisory boards related to Pneumococcal vaccine, Participation in DSMB, and consulting on research design in collaboration with Aval ere Health. Dr. Lapidot has research support to Boston Medical Center and Rambam Healthcare Campus from Pfizer, Inc. and Merck Vaccines. She received honorarium from Pfizer, Inc. and Merck Vaccines for Participation in advisory boards and symposium related to Pneumococcal disease/vaccines. Dr. Moon Nahm received honorarium and consulting fees from MSD., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: This study evaluated relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) vs high-dose trivalent inactivated influenza vaccine (HD-TIV) for prevention of test-confirmed influenza emergency department visits and/or inpatient admissions ("ED/IP") and for IP admissions alone pooled across the 2017-2020 influenza seasons. Exploratory individual season analyses were also performed., Methods: This retrospective test-negative design study included United States (US) adults age ≥65 years vaccinated with aTIV or HD-TIV who presented to an ED or IP setting with acute respiratory or febrile illness during the 2017-2020 influenza seasons. Test-positive cases and test-negative controls were grouped by vaccine received. The rVE of aTIV vs HD-TIV was evaluated using a combination of inverse probability of treatment weighting and logistic regression to adjust for potential confounders., Results: Pooled analyses over the three seasons found no significant differences in the rVE of aTIV vs HD-TIV for prevention of test-confirmed influenza ED/IP (-2.5% [-19.6, 12.2]) visits and admissions or IP admissions alone (-1.6% [-22.5, 15.7]). The exploratory individual season analyses also showed no significant differences., Conclusions: Evidence from the 2017-2020 influenza seasons indicates aTIV and HD-TIV are comparable for prevention of test-confirmed influenza ED/IP visits in US adults age ≥65 years., Competing Interests: Declarations of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: IM, MI, and MH are an employee of CSL Seqirus. IM and MH hold stock in CSL Limited. BC, TB, NW are employees of Optum, which received funding from CSL Seqirus in support of this work. SP received financial support from CSL Seqirus in support of this work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Seasonal influenza significantly affects both health and economic costs in children and adults. This narrative review summarizes published cost-effectiveness analyses (CEAs) of cell-based influenza vaccines in children and adults <65 years of age, critically assesses the assumptions and approaches used in these analyses, and considers the role of cell-based influenza vaccines for children and adults. CEAs from multiple countries demonstrated the cost-effectiveness of cell-based quadrivalent influenza vaccines (QIVc) compared with egg-based trivalent/quadrivalent influenza vaccines (TIVe/QIVe). CEA findings were consistent across models relying on different relative vaccine effectiveness (rVE) estimate inputs, with the rVE of QIVc versus QIVe ranging from 8.1% to 36.2% in favor of QIVc. Across multiple scenarios and types of analyses, QIVc was consistently cost-effective compared with QIVe, including in children and adults across different regions of the world.

Background: In 2012, Botswana introduced 13-valent pneumococcal conjugate vaccine (PCV-13) to its childhood immunization program in a 3+0 schedule, achieving coverage rates of above 90% by 2014. In other settings, PCV introduction has been followed by an increase in carriage or disease caused by non-vaccine serotypes, including some serotypes with a high prevalence of antibiotic resistance., Methods: We characterized the serotype epidemiology and antibiotic resistance of pneumococcal isolates cultured from nasopharyngeal samples collected from infants (≤12 months) in southeastern Botswana between 2016 and 2019. Capsular serotyping was performed using the Quellung reaction. E-tests were used to determine minimum inhibitory concentrations for common antibiotics., Results: We cultured 264 pneumococcal isolates from samples collected from 150 infants. At the time of sample collection, 81% of infants had received at least one dose of PCV-13 and 53% had completed the three-dose series. PCV-13 serotypes accounted for 27% of isolates, with the most prevalent vaccine serotypes being 19F (n = 20, 8%), 19A (n = 16, 6%), and 6A (n = 10, 4%). The most frequently identified non-vaccine serotypes were 23B (n = 29, 11%), 21 (n = 12, 5%), and 16F (n = 11, 4%). Only three (1%) pneumococcal isolates were resistant to amoxicillin; however, we observed an increasing prevalence of penicillin resistance using the meningitis breakpoint (2016: 41%, 2019: 71%; Cochran-Armitage test for trend, p = 0.0003) and non-susceptibility to trimethoprim-sulfamethoxazole (2016: 55%, 2019: 79%; p = 0.04). Three (1%) isolates were multi-drug resistant., Conclusions: PCV-13 serotypes accounted for a substantial proportion of isolates colonizing infants in Botswana during a four-year period starting four years after vaccine introduction. A low prevalence of amoxicillin resistance supports its continued use as the first-line agent for non-meningeal pneumococcal infections. The observed increase in penicillin resistance at the meningitis breakpoint and the low prevalence of resistance to ceftriaxone supports use of third-generation cephalosporins for empirical treatment of suspected bacterial meningitis., Competing Interests: MSK is a consultant for Merck & Co, Inc. and Invivyd, and has research funding from Merck & Co., Inc. through Duke University. SIP has received honoraria from Pfizer, Inc., Merck Vaccines, GSK, and Sanofi for advisory board participation, data safety monitoring board membership, and consulting related to pneumococcal conjugate vaccines. SIP additionally receives research funding from Merck & Co., Inc. and Pfizer through Boston Medical Center. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors report no relevant conflicts of interest”., (Copyright: © 2024 Hurst et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Clinical evidence supports use of enhanced influenza vaccines in older adults. Few economic outcome studies have compared adjuvanted trivalent inactivated (aIIV3) and standard egg-derived quadrivalent inactivated influenza vaccines (IIV4e)., Research Design and Methods: A retrospective cohort study was conducted leveraging deidentified US hospital data linked to claims data during the 2018-19 and 2019-20 influenza seasons. Relative vaccine effectiveness (rVE) was compared in adults aged ≥ 65 years receiving aIIV3 or IIV4e using inverse probability of treatment weighting (IPTW) and Poisson regression. An economic assessment quantified potential real-world cost savings., Results: The study included 715,807 aIIV3 and 320,991 IIV4e recipients in the 2018-19 and 844,169 aIIV3 and 306,270 IIV4e recipients in the 2019-20 influenza seasons. aIIV3 was significantly more effective than IIV4e in preventing cardiorespiratory disease (2018-19 rVE = 6.2%; and 2019-20 rVE = 6.0%) and respiratory disease (2018-19 rVE = 8.9%; and 2019-20 rVE = 10.1%). During the 2018-19 influenza season cardiorespiratory hospitalization cost savings for the aIIV3 population were $392 M, and $221 M for the 2019-20 season. Respiratory hospitalization cost savings for the aIIV3 population were $145 M and $97 M, respectively., Conclusions: Our findings suggest that aIIV3 provides clinical and economic advantages versus IIV4e in the elderly.

Objectives: To identify and synthesize key research advances from the literature published between 2019 and 2023 on the advances in preventative measures, and medical and surgical treatment of uncomplicated otitis media (OM) including the impact of the COVID-19 pandemic on OM management., Data Sources: Medline (PubMed), Embase, and the Cochrane Library., Review Methods: All relevant original articles published in English between June 2019 and February 2023 were identified. Studies related to guideline adherence, impact of treatment on immune response and/or microbiology, tympanoplasty, Eustachian tube balloon dilatation, mastoidectomy procedures, and those focusing on children with Down's syndrome or cleft palate were excluded., Main Findings: Of the 9280 unique records screened, 64 were eligible for inclusion; 23 studies related to medical treatment, 20 to vaccines, 13 to surgical treatment, 6 to prevention (excl. vaccines) and 2 to the impact of COVID-19 on OM management. The level of evidence was judged 2 in 11 studies (17.2 %) and 3 or 4 in the remaining 53 studies (82.8 %) mainly due to the observational design, study limitations or low sample sizes. Some important advances in OM management have been made in recent years. Video discharge instructions detailing the identification and management of pain and fever for parents of children with acute otitis media (AOM) was more effective than paper instructions in reducing symptomatology; compared to placebo, levofloxacin solution was more effective for treating chronic suppurative otitis media, whereas AOM recurrences during two years of follow-up did not differ between children with recurrent AOM who received tympanostomy tube (TT) insertion or medical management. Further, novel pneumococcal conjugate vaccines (PCV) schedules for preventing OM in Aboriginal children appeared ineffective, and a protein-based pneumococcal vaccine had no added value over PCV13 for preventing AOM in native American infants. During the COVID-19 pandemic, a decline in OM and TT case volumes and complications was observed., Implication for Practice and Future Research: Whether the observed impact of the COVID-19 pandemic on OM management extends to the post-pandemic era is uncertain. Furthermore, the impact of the pandemic on the conduct of urgently needed prospective methodologically rigorous interventional studies aimed at improving OM prevention and treatment remains to be elucidated since the current report consisted of studies predominantly conducted in the pre-pandemic era., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Background: Cell-based quadrivalent influenza vaccines (QIVc) can increase effectiveness against seasonal influenza by avoiding mismatch from egg adaption of vaccine viruses. This study evaluates the population-level cost-effectiveness and impacts on health outcomes of QIVc versus an egg-based vaccine (QIVe) in children aged 6 months to 17 years in the US., Research Design and Methods: A dynamic age-structured susceptible-exposed-infected-recovered model was used to simulate influenza transmission in low and high incidence seasons for two scenarios: 1. QIVe for 6 months-17 year-olds, QIVc for 18-64 year-olds, and adjuvanted QIV (aQIV) for ≥ 65 year-olds, and 2. QIVc for 6 months-64 year-olds, and aQIV for ≥ 65 year-olds. Probabilistic sensitivity analysis was performed to account for uncertainty in parameter estimates. Cost-effectiveness was evaluated as incremental cost-effectiveness ratios (ICERs)., Results: Extension of QIVc to children resulted in 3-4% reductions in cases (1,656,271), hospitalizations (16,688), and deaths (2,126) at a population level in a high incidence season, and 65% reductions (cases: 2,856,384; hospitalizations: 31667; deaths: 4,163) in a low incidence season. Use of QIVc would be cost-saving, with ICERs of -$16,427/QALY and -$8,100/QALY from a payer perspective and -$22,669/QALY and -$15,015/QALY from a societal perspective, for low and high incidence seasons respectively. Cost savings were estimated at approximately $468 million and $1.366 billion for high and low incidence seasons, respectively., Conclusion: Use of QIVc instead of QIVe in children > 6 months of age in the US would reduce the disease burden and be cost-saving from both a payer and societal perspective.

Cell-based manufacturing of seasonal influenza vaccines eliminates the risk of egg-adaptation of candidate vaccine viruses, potentially increasing vaccine effectiveness (VE). We present an overview of published data reporting the VE and cost-effectiveness of a cell-based quadrivalent influenza vaccine (QIVc) in preventing influenza-related outcomes in the pediatric population. We identified 16 clinical studies that included data on the VE of a QIVc or the relative VE (rVE) of a QIVc versus an egg-based QIV (QIVe) in children and/or adolescents, 11 of which presented estimates specifically for the pediatric age group. Of these, two studies reported rVE against hospitalizations. Point estimates of rVE varied from 2.1% to 33.0%, with studies reporting significant benefits of using a QIVc against influenza-related, pneumonia, asthma, and all-cause hospitalization. Four studies reported rVE against influenza-related medical encounters, with point estimates against non-strain specific encounters ranging from 3.9% to 18.8% across seasons. One study evaluated rVE against any influenza, with variable results by strain. The other four studies presented VE data against laboratory-confirmed influenza. Three health economics studies focusing on a pediatric population also found the use of QIVc to be cost-effective or cost-saving. Overall, using a QIVc is effective in pediatric patients, with evidence of incremental benefits over using a QIVe in preventing hospitalizations and influenza-related medical encounters in nearly all published studies.

Influenza can exacerbate underlying medical conditions. In this study, we modelled the potential impact of an egg-based quadrivalent influenza vaccine (QIVe) or adjuvanted QIV (aQIV) on hospitalizations and mortality from influenza-related cardiovascular disease (CVD), respiratory, and other complications in adults ≥65 years of age in the US with underlying chronic conditions. We used a stochastic decision-tree model, with 1000 simulations varying input across predicted ranges. Due to the variable nature of influenza across seasons and differences in published estimates for input parameters, data are presented as 95% confidence intervals. Compared with no vaccination, use of aQIV would prevent 135,450-564,360 hospitalizations and 1612-29,226 deaths across outcomes evaluated. Overall, aQIV prevented 1071-18,388 more hospitalizations and 85-1944 more deaths than QIVe. By routine seasonal vaccination against influenza, a substantial number of severe influenza-associated complications and deaths, caused by direct influenza symptoms or by exacerbation of chronic conditions, can be prevented in high-risk adults ≥65 years of age in the US.

Vaccination offers the best way to prevent invasive meningococcal disease (IMD). As demonstrated in countries with national immunization programs (NIPs) against IMD, meningococcal conjugate vaccines have contributed to significant declines in incidence. Since some meningococcal vaccines are associated with modest immunogenicity in infants, possible immunological interference upon concomitant administration with some pediatric vaccines, and administration errors resulting from improper reconstitution, opportunities for improvement exist. A quadrivalent conjugate vaccine, MenQuadfi® (Meningococcal [Serogroups A, C, Y, and W] Conjugate Vaccine; Sanofi, Swiftwater, Pennsylvania), was approved in 2020 for the prevention of IMD caused by meningococcal serogroups A, C, W, and Y in individuals ≥2 years of age in the United States. Five pivotal studies and one ancillary study supported approval in the United States; clinical trials in infants are ongoing. Data on the immunogenicity and safety of this vaccine are presented, and its potential value in clinical practice is discussed.

Background: The effect of pneumococcal vaccination of mothers with human immunodeficiency virus (HIV) on infant responses to childhood vaccination has not been studied. We compared the immunogenicity of 10-valent pneumococcus conjugate vaccine (PCV-10) in HIV-exposed uninfected infants born to mothers who received PCV-10, 23-valent pneumococcus polysaccharide vaccine (PPV-23), or placebo during pregnancy., Methods: Antibody levels against 7 serotypes were measured at birth, before the first and second doses of PCV-10m and after completion of the 2-dose regimen in 347 infants, including 112 born to mothers who received PPV-23, 112 who received PCV-10, and 119 who received placebo during pregnancy. Seroprotection was defined by antibody levels ≥0.35 µg/mL., Results: At birth and at 8 weeks of life, antibody levels were similar in infants born to PCV-10 or PPV-23 recipients and higher than in those born to placebo recipient. After the last dose of PCV-10, infants in the maternal PCV-10 group had significantly lower antibody levels against 5 serotypes than those in the maternal PPV-23 group and against 3 serotypes than those in the maternal placebo group, and they did not have higher antibody levels against any serotype. The seroprotection rate against 7 serotypes was 50% in infants in the maternal PCV-10 group, compared with 71% in both of the maternal PPV-23 and placebo groups (P < .001)., Conclusions: Administration of PCV-10 during pregnancy was associated with decreased antibody responses to PCV-10 and seroprotection rates in infants. Considering that PCV-10 and PPV-23 had similar immunogenicity in pregnant women with HIV and that administration of PPV-23 did not affect the immunogenicity of PCV-10 in infants, PPV-23 in pregnancy may be preferred over PCV-10., Competing Interests: Potential conflicts of interest. M. M. M. P. and G. D. report provision of PCV-10 by donation from Centro de Vigilância Epidemiológica da Secretaria da Saúde do Estado de São Paulo, São Paulo, Brazil. L. L. reports that Westat was the contract research organization contracted through the National Institutes of Health (NIH) for a task order for the current study. S. I. P. reports receipt of personal fees from Merck, Sanofi, and Pfizer; investigator-initiated grants from the NIH and Pfizer and Merck Vaccines to study surveillance of invasive pneumococcal disease, host defenses against Streptococcus pneumoniae, and the impact of severe acute respiratory syndrome coronavirus 2 on nasopharyngeal microbiome; and consulting fees from Pfizer and Merck Vaccine for participation in advisory board meetings, consulting on research projects at PAI Life Sciences and EVIDERA, and participation on a data safety and monitoring board for next-generation PCVs for Sanofi Pasteur. N. C. is employed by the NIH. A. W. has received grants from the NIH, GlaxoSmithKline, Janssen and Merck; consulting fees from Merck; and payment or honoraria from Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Pneumococcal vaccination is recommended in people with HIV, prioritizing PCV. We compared the immunogenicity of PCV-10 and PPV-23 administered antepartum or postpartum., Methods: This double-blind study randomized 346 pregnant women with HIV on antiretrovirals to PCV-10, PPV-23, or placebo at 14-34 weeks gestational age. Women who received placebo antepartum were randomized at 24 weeks postpartum to PCV-10 or PPV-23. Antibodies against 7 serotypes common to both vaccines and 1 serotype only in PPV-23 were measured by ELISA/chemiluminescence; B- and T-cell responses to serotype 1 by FLUOROSPOT; and plasma cytokines/chemokines by chemiluminescence., Results: Antibody responses were higher after postpartum versus antepartum vaccination. PCV-10 generated lower antibody levels than PPV-23 against 4 and higher against 1 of 7 common serotypes. Additional factors associated with high postvaccination antibody concentrations were high prevaccination antibody concentrations and CD4+ cells; low CD8+ cells and plasma HIV RNA; and several plasma cytokines/chemokines. Serotype 1 B- and T-cell memory did not increase after vaccination., Conclusions: Antepartum immunization generated suboptimal antibody responses, suggesting that postpartum booster doses may be beneficial and warrant further studies. Considering that PCV-10 and PPV-23 had similar immunogenicity, but PPV-23 covered more serotypes, use of PPV-23 may be prioritized in women with HIV on antiretroviral therapy., Clinical Trails Registration: NCT02717494., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Pneumococcal conjugate vaccines reduce the burden of invasive pneumococcal disease, but the sustained effect of these vaccines can be diminished by an increase in disease caused by non-vaccine serotypes. To describe pneumococcal serotype epidemiology in Botswana following introduction of 13-valent pneumococcal conjugate vaccine (PCV-13) in July 2012, we performed molecular serotyping of 268 pneumococcal strains isolated from 221 children between 2012 and 2017. The median (interquartile range) age of the children included in this analysis was 6 (3,12) months. Fifty-nine percent of the children had received at least one dose of PCV-13 and 35% were fully vaccinated with PCV-13. While colonization by vaccine serotypes steadily declined following PCV-13 introduction, 25% of strains isolated more than 3 years after vaccine introduction were PCV-13 serotypes. We also observed an increase in colonization by non-vaccine serotypes 21 and 23B, which have been associated with invasive pneumococcal disease and antibiotic resistance in other settings., Competing Interests: The authors have declared that no competing interests exist.

Background: Pneumonia in infancy has been linked to long-term consequences for the rapidly developing lung. We examined the impact of hospitalized community-acquired pneumonia (CAP) on subsequent respiratory health., Methods: We conducted a retrospective matched-cohort study using the Optum® de-identified Electronic Health Record Dataset (2009-2018). Study population comprised healthy infants hospitalized for CAP ("CAP patients"), and matched comparators without pneumonia ("comparison patients"), before age 2 years. Study outcomes included any chronic respiratory disorder, reactive airway disease (asthma, hyperactive airway disease, recurrent wheezing), and CAP hospitalization occurring between age 2-5 years, and were evaluated overall as well as by age and etiology at first CAP hospitalization., Results: Study population totaled 1,343 CAP patients and 6,715 comparison patients. Rates per 100 patient-years and relative rates (RR) of study outcomes from age 2-5 years for CAP patients versus comparison patients were: any chronic respiratory disorder, 11.6 vs. 4.9 (RR = 2.4 [95% CI: 2.1-2.6]); reactive airway disease, 6.1 vs 1.9 (RR = 3.2 [2.6-3.8]); and CAP hospitalization, 1.0 vs 0.2 (RR = 6.3 [3.6-10.9]). Rates of study outcomes were highest among CAP patients who had their initial hospitalization in the second year of life., Conclusions: Infant CAP foreshadows an increased risk of subsequent chronic respiratory disorders, which may be elevated when CAP occurs closer to pre-school age (i.e., age 2-5 years). These findings are most consistent with the hypothesis that inflammation persists beyond the acute stage of pneumonia and plays a role in the development of chronic respiratory sequelae., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cell-derived influenza vaccines are not subject to egg-adaptive mutations that have potential to decrease vaccine effectiveness. This retrospective analysis estimated the relative vaccine effectiveness (rVE) of cell-derived quadrivalent influenza vaccine (IIV4c) compared to standard egg-derived quadrivalent influenza vaccines (IIV4e) among recipients aged 4-64 years in the United States during the 2019-2020 influenza season., Methods: The IQVIA PharMetrics Plus administrative claims database was utilized. Study outcomes were assessed postvaccination through the end of the study period (7 March 2020). Inverse probability of treatment weighting (IPTW) was implemented to adjust for covariate imbalance. Adjusted rVE against influenza-related hospitalizations/emergency room (ER) visits and other clinical outcomes was estimated through IPTW-weighted Poisson regression models for the IIV4c and IIV4e cohorts and for the subgroup with ≥1 high-risk condition. Sensitivity analyses modifying the outcome assessment period as well as a doubly-robust analysis were also conducted. IPTW-weighted generalized linear models were used to estimate predicted annualized all-cause costs., Results: The final sample comprised 1 150 134 IIV4c and 3 924 819 IIV4e recipients following IPTW adjustment. IIV4c was more effective in preventing influenza-related hospitalizations/ER visits as well as respiratory-related hospitalizations/ER visits compared to IIV4e. IIV4c was also more effective for the high-risk subgroup and across the sensitivity analyses. IIV4c was also associated with significantly lower annualized all-cause total costs compared to IIV4e (-$467), driven by lower costs for outpatient medical services and inpatient hospitalizations., Conclusions: IIV4c was significantly more effective in preventing influenza-related hospitalizations/ER visits compared to IIV4e and was associated with significantly lower all-cause costs., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Biorepositories provide a critical resource for gaining knowledge of emerging infectious diseases and offer a mechanism to rapidly respond to outbreaks; the emergence of the novel coronavirus, SARS-CoV-2, has proved their importance. During the COVID-19 pandemic, the absence of centralized, national biorepository efforts meant that the onus fell on individual institutions to establish sample repositories. As a safety-net hospital, Boston Medical Center (BMC) recognized the importance of creating a COVID-19 biorepository to both support critical science at BMC and ensure representation in research for its urban patient population, most of whom are from underserved communities. This article offers a realistic overview of the authors' experience in establishing this biorepository at the onset of the COVID-19 pandemic during the height of the first surge of cases in Boston, Massachusetts, with the hope that the challenges and solutions described are useful to other institutions. Going forward, funders, policymakers, and infectious disease and public health communities must support biorepository implementation as an essential element of future pandemic preparedness.

The burden of influenza is disproportionally higher among older adults. We evaluated the relative vaccine effectiveness (rVE) of adjuvanted trivalent (aIIV3) compared to high-dose trivalent influenza vaccine (HD-IIV3e) against influenza and cardio-respiratory disease (CRD)-related hospitalizations/ER visits among adults ≥65 years during the 2019-2020 influenza season. Economic outcomes were also compared. A retrospective cohort analysis was conducted using prescription, professional fee claims, and hospital data. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding. IPTW-adjusted Poisson regression was used to evaluate the adjusted rVE of aIIV3 versus HD-IIV3e. All-cause and influenza-related healthcare resource utilization (HCRU) and costs were examined post-IPTW. Recycled predictions from generalized linear models were used to estimate adjusted costs. Adjusted analysis showed that aIIV3 ( n = 798,987) was similarly effective compared to HD-IIV3e ( n = 1,655,979) in preventing influenza-related hospitalizations/ER visits (rVE 3.1%; 95% CI: -2.8%; 8.6%), hospitalizations due to any cause (-0.7%; 95% CI: -1.6%; 0.3%), and any CRD-related hospitalization/ER visit (0.9%; 95% CI: 0.01%; 1.7%). Adjusted HCRU and annualized costs were also statistically insignificant between the two cohorts. The adjusted clinical and economic outcomes evaluated in this study were comparable between aIIV3 and HD-IIV3e during the 2019-2020 influenza season.

Amid the current US opioid crisis, hepatitis C virus (HCV) infection rates continue to rise in young adults, including among pregnant women, yet few studies describe linkage to care and treatment in pregnant or postpartum women with HCV infection. We used electronic health record data to estimate HCV treatment rates for postpartum women before (January 2014-September 2016) and during (October 2016-March 2018) implementation of a maternal-infant HCV linkage program in combination with a multidisciplinary clinic to colocate mother and infant care. Using Poisson regression models, we compared HCV treatment initiation rates, adjusting for demographics, substance use, and treatment. From January 2014 through March 2018, 343 women who were HCV seropositive delivered at our institution. Of these, 95% completed HCV nucleic acid testing and 255 women had chronic HCV infection. Mean age was 30 years, 96% were publicly insured, and 94% had documented substance use. HCV treatment initiation increased from 28/164 (17.1%) women with chronic HCV infection in the preintervention period to 16/66 (24.2%) with the linkage-only intervention and 13/25 (52.0%) with the linkage intervention and colocated care. Adjusted analyses demonstrated that women delivering during the intervention period initiated HCV treatment at 2.40 times (95% confidence interval [CI], 1.10-5.25; linkage only) and 3.36 times (95% CI, 1.57-7.17; linkage and colocated care) the rate of women delivering preintervention. Women on buprenorphine had higher HCV treatment initiation rates compared with those on methadone (rate ratio, 2.10; 95% CI, 1.05-4.21). Conclusion: HCV linkage to care and treatment rates improved in the setting of mother-infant linkage and colocated care interventions. Perinatal care may represent a critical venue to identify, link, and treat women for HCV infection to improve their own health and prevent transmission to subsequent pregnancies., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Increasing evidence suggests the impact of pneumonia persists beyond hospital discharge and the acute phase of respiratory symptoms. We characterized short-term and long-term risks of mortality and hospital readmission across the adult age span and spectrum of comorbidities., Methods: Retrospective cohort design and Optum's de-identified Integrated Claims-Clinical dataset (2012-2018) were employed. Study population comprised adults who had ≥1 pneumonia hospitalization; each hospitalization ≥365 days apart was considered. Cumulative risks of all-cause mortality (from pneumonia hospitalization through 360-day post-discharge period) and all-cause hospital readmission (during 360-day post-discharge period) were summarized on an overall basis as well as by age and comorbidity profile (i.e., healthy, at-risk, high-risk)., Results: Study population totaled 37,006 patients who contributed 38,809 pneumonia hospitalizations; mean age was 71 years, 51% were female, and 88% had at-risk (33%) or high-risk (55%) conditions. Mortality was 3.5% in hospital, 8.2% from admission to 30 days post-discharge, and 17.7% from admission to 360 days post-discharge. Hospital readmission was 12.5% during the 30-day post-discharge period, and 42.3% during the 360-day post-discharge period. Mortality risk increased with age and severity of comorbidity profile; readmission risk was highest for persons aged 65-74 years and persons with high-risk conditions., Conclusions: All-cause mortality up to 1 year following pneumonia hospitalization was substantial, and was associated with increasing age and worsening comorbidity profile. Both readmission and mortality were greater at all ages in at-risk and high-risk subgroups (vs. healthy counterparts). Strategies that prevent pneumonia and/or associated pathophysiologic changes, especially among individuals with comorbidities, have the potential to reduce morbidity and mortality., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Pneumococcus remains an important cause of morbidity in pregnant women with HIV and their infants. We compared the safety and immunogenicity of PCV-10 and PPV-23 with placebo administered in pregnancy., Methods: This double-blind, multicentre, randomised controlled trial was done at eight outpatient clinics in Brazil. Eligible participants were adult women with HIV who were pregnant at a gestational age between 14 weeks and less than 34 weeks and who were taking antiretroviral therapy at study entry. Participants were randomly assigned (1:1:1) to receive either PCV-10, PPV-23, or placebo. Participants and study teams were unaware of treatment allocation. Antibodies against seven vaccine serotypes in PCV-10 and PPV-23 were measured by ELISA. The primary outcomes were maternal and infant safety assessed by the frequency of adverse events of grade 3 or higher; maternal seroresponse (defined as ≥2-fold increase in antibodies from baseline to 28 days after immunisation) against five or more serotypes; and infant seroprotection (defined as anti-pneumococcus antibody concentration of ≥0·35 μg/mL) against five or more serotypes at 8 weeks of life. The study was powered to detect differences of 20% or higher in the primary immunological outcomes between treatment groups. This trial is registered with ClinicalTrials.gov, NCT02717494., Findings: Between April 1, 2016, and Nov 30, 2017, we enrolled 347 pregnant women with HIV, of whom 116 were randomly assigned to the PCV-10 group, 115 to the PPV-23 group, and 116 to the placebo group. One participant in the PCV-10 group did not receive the vaccine and was excluded from subsequent analyses. The frequency of adverse events of grade 3 or higher during the first 4 weeks was similar in the vaccine and placebo groups (3% [90% CI 1-7] for the PCV-10 group, 2% [0-5] for the PPV-23 group, and 3% [1-8] for the placebo group). However, injection site and systemic grade 2 adverse reactions were reported more frequently during the first 4 weeks in the vaccine groups than in the placebo group (14% [9-20] for the PCV-10 group, 7% [4-12] for the PPV-23 group, and 3% [1-7] for the placebo group). The frequency of grade 3 or higher adverse effects was similar across maternal treatment groups (20% [14-27] for the PCV-10 group, 21% [14-28] for the PPV-23 group, and 20% [14-27] for the placebo group). Seroresponses against five or more serotypes were present in 74 (65%) of 114 women in the PCV-10 group, 72 (65%) of 110 women in the PPV-23 group, and none of the 113 women in the placebo group at 4 weeks post vaccination (p<0·0001 for PPV-23 group vs placebo and PCV-10 group vs placebo). Seroresponse differences of 20% or higher in vaccine compared with placebo recipients persisted up to 24 weeks post partum. At birth, 76 (67%) of 113 infants in the PCV-10 group, 62 (57%) of 109 infants in the PPV-23 group, and 19 (17%) of 115 infants in the placebo group had seroprotection against five or more serotypes (p<0·0001 for PPV-23 vs placebo and PCV-10 vs placebo). At 8 weeks, the outcome was met by 20 (19%) of 108 infants in the PCV-10 group, 24 (23%) of 104 infants in the PPV-23 group, and one (1%) of 109 infants in the placebo group (p<0·0001). Although a difference of 20% or higher compared with placebo was observed only in the infants who received PPV-23 at 8 weeks of life, the difference between the two vaccine groups was not appreciable., Interpretation: PCV-10 and PPV-23 were equally safe and immunogenic in pregnant women with HIV and conferred similar levels of seroprotection to their infants. In areas in which childhood PCV administration decreased the circulation of PCV serotypes, PPV-23 administration to pregnant women with HIV might be more advantageous than PCV by virtue of including a broader range of serotypes., Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development., Translation: For the Portuguese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AW receives grants from the US National Institutes of Health, GlaxoSmithKline, Janssen, and Merck. TF and PM receive grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. SIP receives personal fees from Merck, Sanofi, and Pfizer, and grants from the US National Institutes of Health and Pfizer. DG receives personal fees from Merck and grants from GlaxoSmithKline and Merck. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the relative vaccine effectiveness (rVE) against influenza-related hospitalizations/emergency room (ER) visits, influenza-related office visits, and cardio-respiratory disease (CRD)-related hospitalizations/ER visits and compare all-cause and influenza-related costs associated with two vaccines specifically indicated for older adults (≥65 years), adjuvanted (aTIV) and high-dose trivalent influenza vaccine (TIV-HD), for the 2018-19 influenza season., Methods: A retrospective analysis of older adults was conducted using claims and hospital data in the United States. For clinical evaluations, adjusted analyses were conducted following inverse probability of treatment weighting (IPTW) to control for selection bias. Poisson regression was used to estimate the adjusted rVE against influenza-related hospitalizations/ER visits, influenza-related office visits, and any CRD-related hospitalizations/ER visits. For the economic evaluation, treatment selection bias was adjusted through 1:1 propensity score matching (PSM). All-cause and influenza-related costs associated with hospitalizations/ER, physician office and pharmacy visits were adjusted using generalized estimating equation (GEE) models., Results: After IPTW and Poisson regression, aTIV (n = 561,315) was slightly more effective in reducing influenza-related office visits compared to TIV-HD (n = 1,672,779) (6.6%; 95% CI: 2.8-10.3%). aTIV was statistically comparable to TIV-HD (2.0%; 95% CI: -3.7%-7.3%) in preventing influenza-related hospitalizations/ER visits but more effective in reducing hospitalizations/ER visits for any CRD (2.6%; 95% CI: 2.0-3.2%). In the PSM-adjusted cohorts (n = 561,243 pairs), following GEE adjustments, predicted mean annualized all-cause and influenza-related total costs per patient were statistically similar between aTIV and TIV-HD (US$9676 vs. US$9625 and US$18.74 vs. US$17.28, respectively; both p > 0.05). Finally, influenza-related pharmacy costs were slightly lower for aTIV as compared to TIV-HD ($1.75 vs $1.85; p < 0.0001)., Conclusions: During the 2018-19 influenza season, influenza-related hospitalization/ER visits and associated costs among people aged ≥ 65 were comparable between aTIV and TIV-HD. aTIV was slightly more effective in preventing influenza-related office visits and any CRD event as compared to TIV-HD in this population., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. This study was funded by Seqirus Vaccines Ltd., Summit, NJ, USA. VD, MD and DS have disclosed that they are employees of IQVIA which received funding for this study from Seqirus. GK and JM have disclosed that they are employees and shareholders of Seqirus. SIP and MJP received financial support for time and effort from Seqirus for this study., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)