Understanding the influence of the microbiome on childhood infections.

INTRODUCTION: The microbiome is known to have a substantial impact on human health and disease. However, the impacts of the microbiome on immune system development, susceptibility to infectious diseases, and vaccine-elicited immune responses are emerging areas of interest. AREAS COVERED: In this review, we provide an overview of development of the microbiome during childhood. We highlight available data suggesting that the microbiome is critical to maturation of the immune system and modifies susceptibility to a variety of infections during childhood and adolescence, including respiratory tract infections, Clostridioides difficile infection, and sexually transmitted infections. We discuss currently available and investigational therapeutics that have the potential to modify the microbiome to prevent or treat infections among children. Finally, we review the accumulating evidence that the gut microbiome influences vaccine-elicited immune responses among children. EXPERT OPINION: Recent advances in sequencing technologies have led to an explosion of studies associating the human microbiome with the risk and severity of infectious diseases. As our knowledge of the extent to which the microbiome influences childhood infections continues to grow, microbiome-based diagnostics and therapeutics will increasingly be incorporated into clinical practice to improve the prevention, diagnosis, and treatment of infectious diseases among children.

Immunogenicity of Monovalent mRNA-1273 and BNT162b2 Vaccines in Children Less Than 5 Years of Age.

BACKGROUND AND OBJECTIVES: The mRNA-based COVID-19 vaccines approved for use in children less than 5 years of age have different antigen doses and administration schedules that could affect vaccine immunogenicity and effectiveness. We sought to compare the strength and breadth of serum binding and neutralizing antibodies to SARS-CoV-2 elicited by monovalent mRNA-based COVID-19 vaccines in young children. METHODS: We conducted a prospective cohort study of children 6 months to 4 years of age who completed primary series vaccination with monovalent mRNA-1273 or BNT162b2 vaccines. Serum was collected one month after primary vaccine series completion for measurement of SARS-CoV-2-specific humoral immune responses, including antibody binding responses to Spike proteins from an ancestral strain (D614G) and major variants of SARS-CoV-2 and antibody neutralizing activity against D614G and Omicron subvariants (BA.1, BA.4/5). RESULTS: Of 75 participants, 40 (53%) received mRNA-1273 and 35 (47%) received BNT162b2. Children receiving either primary vaccine series developed robust and broad SARS-CoV-2-specific binding and neutralizing antibodies, including to Omicron subvariants. Children with a prior history of SARS-CoV-2 infection developed significantly higher antibody binding responses and neutralization titers to Omicron subvariants, consistent with the occurrence of identified infections during the circulation of Omicron subvariants in the region. CONCLUSIONS: Monovalent mRNA-1273 and BNT162b2 elicited similar antibody responses one month after vaccination in young children. Further, prior infection significantly enhanced the strength of antibody responses to Omicron subvariants. Future studies should evaluate incorporation of these vaccines into the standard childhood immunization schedule.

Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury.

Cardiac surgery-associated acute kidney injury (CS-AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS-AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age-, disease-, and bypass-related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS-AKI using population PK modeling techniques and an opportunistic, electronic health record-integrated trial design. We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS-AKI. Twenty-seven neonates were included in model development. A 1-compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty-three neonates with caffeine exposure and 109 controls were included in the exposure-response analysis. Over half of neonates developed CS-AKI. On multivariable analysis, there were no significant differences between CS-AKI with and without caffeine exposure. Neonates with single-ventricle heart disease without CS-AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease- and bypass-specific effects on drug disposition and identify populations where caffeine may be beneficial.

What Do Child Abuse and Neglect Medical Evaluation Consultation Notes Tell Researchers and Clinicians?

Child abuse and neglect (CAN) medical experts provide specialized multidisciplinary care to children when there is concern for maltreatment. Their clinical notes contain valuable information on child- and family-level factors, clinical concerns, and service placements that may inform the needed supports for the family. We created and implemented a coding system for data abstraction from these notes. Participants were 1,397 children ages 0-17 years referred for a consultation with a CAN medical provider at an urban teaching and research hospital between March 2013 and December 2017. Coding themes were developed using an interdisciplinary team-based approach to qualitative analysis, and descriptive results are presented using a developmental-contextual framework. This study demonstrates the potential value of developing a coding system to assess characteristics and patterns from CAN medical provider notes, which could be helpful in improving quality of care and prevention and detection of child abuse.

Child Sexual Abuse Documentation in Primary Care Settings.

Primary care providers (PCPs) can play an important role in the continuity of care for children who experience sexual abuse (SA). We performed a retrospective, chart-based study of children 3 to 17 years old with SA history. Primary care medical records were reviewed for 2 years after a subspecialty SA evaluation. Descriptive statistics and logistic regression were used to assess factors associated with documentation of SA history and mental health management by the PCP. Of 131 included patients, 43% had PCP documentation of their SA history, which was associated with care from resident providers (P < .01). There was greater mental health management and mental health referrals by PCPs for the group with documentation compared with the group without documentation (52% vs 23%, P < .001). Overall, child SA history was poorly documented in primary care settings. Identifying mechanisms to improve communication about a child's SA history with PCPs is important for the child's ongoing care.

In utero human cytomegalovirus infection expands NK cell-like FcγRIII-expressing CD8+ T cells that mediate antibody-dependent functions.

Human cytomegalovirus (HCMV) profoundly modulates host T and natural killer (NK) cells across the lifespan, expanding unique effector cells bridging innate and adaptive immunity. Though HCMV is the most common congenital infection worldwide, how this ubiquitous herpesvirus impacts developing fetal T and NK cells remains unclear. Using computational flow cytometry and transcriptome profiling of cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify major shifts in fetal cellular immunity marked by an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells (FcRT) following HCMV exposure in utero. FcRT cells from cCMV-infected neonates express a cytotoxic NK cell-like transcriptome and mediate antigen-specific antibody-dependent functions including degranulation and IFNγ production, the hallmarks of NK cell antibody-dependent cellular cytotoxicity (ADCC). FcRT cells may represent a previously unappreciated effector population with innate-like functions that could be harnessed for maternal-infant vaccination strategies and antibody-based therapeutics in early life.

Differential host responses within the upper respiratory tract and peripheral blood of children and adults with SARS-CoV-2 infection.

Age is among the strongest risk factors for severe outcomes from SARS-CoV-2 infection. We sought to evaluate associations between age and both mucosal and systemic host responses to SARS-CoV-2 infection. We profiled the upper respiratory tract (URT) and peripheral blood transcriptomes of 201 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 64 uninfected individuals. Among uninfected children and adolescents, young age was associated with upregulation of innate and adaptive immune pathways within the URT, suggesting that young children are primed to mount robust mucosal immune responses to exogeneous respiratory pathogens. SARS-CoV-2 infection was associated with broad induction of innate and adaptive immune responses within the URT of children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents were dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways was observed only in adults. Systemic symptoms among SARS-CoV-2-infected subjects were associated with blunted innate and adaptive immune responses in the URT and upregulation of many of these same pathways within peripheral blood. Finally, within individuals, robust URT immune responses were correlated with decreased peripheral immune activation, suggesting that effective immune responses in the URT may promote local viral control and limit systemic immune activation and symptoms. These findings demonstrate that there are differences in immune responses to SARS-CoV-2 across the lifespan, including between young children and adolescents, and suggest that these varied host responses contribute to observed differences in the clinical presentation of SARS-CoV-2 infection by age. One Sentence Summary: Age is associated with distinct upper respiratory and peripheral blood transcriptional responses among children and adults with SARS-CoV-2 infection.

Comparing Natural Language Processing and Structured Medical Data to Develop a Computable Phenotype for Patients Hospitalized Due to COVID-19: Retrospective Analysis.

Background: Throughout the COVID-19 pandemic, many hospitals conducted routine testing of hospitalized patients for SARS-CoV-2 infection upon admission. Some of these patients are admitted for reasons unrelated to COVID-19 and incidentally test positive for the virus. Because COVID-19-related hospitalizations have become a critical public health indicator, it is important to identify patients who are hospitalized because of COVID-19 as opposed to those who are admitted for other indications. Objective: We compared the performance of different computable phenotype definitions for COVID-19 hospitalizations that use different types of data from electronic health records (EHRs), including structured EHR data elements, clinical notes, or a combination of both data types. Methods: We conducted a retrospective data analysis, using clinician chart review-based validation at a large academic medical center. We reviewed and analyzed the charts of 586 hospitalized individuals who tested positive for SARS-CoV-2 in January 2022. We used LASSO (least absolute shrinkage and selection operator) regression and random forests to fit classification algorithms that incorporated structured EHR data elements, clinical notes, or a combination of structured data and clinical notes. We used natural language processing to incorporate data from clinical notes. The performance of each model was evaluated based on the area under the receiver operator characteristic curve (AUROC) and an associated decision rule based on sensitivity and positive predictive value. We also identified top words and clinical indicators of COVID-19-specific hospitalization and assessed the impact of different phenotyping strategies on estimated hospital outcome metrics. Results: Based on a chart review, 38.2% (224/586) of patients were determined to have been hospitalized for reasons other than COVID-19, despite having tested positive for SARS-CoV-2. A computable phenotype that used clinical notes had significantly better discrimination than one that used structured EHR data elements (AUROC: 0.894 vs 0.841; P<.001) and performed similarly to a model that combined clinical notes with structured data elements (AUROC: 0.894 vs 0.893; P=.91). Assessments of hospital outcome metrics significantly differed based on whether the population included all hospitalized patients who tested positive for SARS-CoV-2 or those who were determined to have been hospitalized due to COVID-19. Conclusions: These findings highlight the importance of cause-specific phenotyping for COVID-19 hospitalizations. More generally, this work demonstrates the utility of natural language processing approaches for deriving information related to patient hospitalizations in cases where there may be multiple conditions that could serve as the primary indication for hospitalization.

ADCC-activating antibodies correlate with decreased risk of congenital human cytomegalovirus transmission.

Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence indicates that antibody Fc effector functions may be a previously underappreciated component of maternal immunity against HCMV. We recently reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with protection against cCMV transmission, leading us to hypothesize that additional Fc-mediated antibody functions may be important. In this same cohort of HCMV-transmitting (n = 41) and nontransmitting (n = 40) mother-infant dyads, we report that higher maternal sera antibody-dependent cellular cytotoxicity (ADCC) activation is also associated with lower risk of cCMV transmission. We investigated the relationship between ADCC and IgG responses against 9 viral antigens and found that ADCC activation correlated most strongly with sera IgG binding to the HCMV immunoevasin protein UL16. Moreover, we determined that higher UL16-specific IgG binding and FcγRIII/CD16 engagement were associated with the greatest risk reduction in cCMV transmission. Our findings indicate that ADCC-activating antibodies against targets such as UL16 may represent an important protective maternal immune response against cCMV infection that can guide future HCMV correlates studies and vaccine or antibody-based therapeutic development.

Host microbiome-pathogen interactions in pediatric infections.

PURPOSE OF REVIEW: In this review, we discuss recent research that has furthered our understanding of microbiome development during childhood, the role of the microbiome in infections during this life stage, and emerging opportunities for microbiome-based therapies for infection prevention or treatment in children. RECENT FINDINGS: The microbiome is highly dynamic during childhood and shaped by a variety of host and environmental factors. In turn, the microbiome influences risk and severity of a broad range of infections during childhood, with recent studies highlighting potential roles in respiratory, gastrointestinal, and systemic infections. The microbiome exerts this influence through both direct interactions with potential pathogens and indirectly through modulation of host immune responses. The elucidation of some of these mechanisms by recent studies and the development of effective microbiome-based therapies for adults with recurrent Clostridioides difficile infection highlight the enormous promise that targeting the microbiome has for reducing the burden of infectious diseases during childhood. SUMMARY: The microbiome has emerged as a key modifier of infection susceptibility and severity among children. Further research is needed to define the roles of microbes other than bacteria and to elucidate the mechanisms underlying microbiome-host and microbiome-pathogen interactions of importance to infectious diseases in children.

Leveraging the human microbiota to target bacterial respiratory pathogens: new paths toward an expanded antimicrobial armamentarium.

Acute respiratory infections are the most frequent infections across the lifespan and are the leading infectious cause of death among children globally. Bacterial respiratory infections are routinely treated with antibiotics, nearly all of which are derived from microbial natural products. Unfortunately, antibiotic-resistant bacteria are an increasingly frequent cause of respiratory infections, and there are few new antibiotics in development that target these pathogens. In the article by Stubbendieck et al., the authors identified Rothia species that demonstrate in vitro and ex vivo growth inhibition of the respiratory pathobiont Moraxella catarrhalis. The authors present experiments suggesting that this activity is mediated at least in part through the secretion of a novel peptidoglycan endopeptidase that targets the M. catarrhalis cell wall. In this commentary, we discuss these findings in the context of the urgent threat of antimicrobial resistance and highlight the promise of the human respiratory microbiota as a source of novel biotherapeutics.

ADCC-activating antibodies correlate with protection against congenital human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no licensed vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence from studies of natural infection and HCMV vaccine trials indicates that antibody Fc effector functions may defend against HCMV infection. We previously reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with reduced risk of cCMV transmission, leading us to hypothesize that other Fc-mediated antibody functions may also contribute to protection. In this same cohort of HCMV transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads, we found that higher maternal sera antibody-dependent cellular cytotoxicity (ADCC) activation was also associated with decreased risk of cCMV infection. We determined that NK cell-mediated ADCC responses correlated strongly with anti-HCMV IgG FcγRIII/CD16 activation and IgG binding to the HCMV immunoevasin protein UL16. Notably, anti-UL16 IgG binding and engagement of FcγRIII/CD16 were higher in non-transmitting versus transmitting dyads and interacted significantly with ADCC responses. These findings indicate that ADCC-activating antibodies against novel targets such as UL16 may represent an important protective maternal immune response against cCMV infection, which can guide future HCMV correlates studies and vaccine development.

Use of Structured Electronic Health Records Data Elements for the Development of Computable Phenotypes to Identify Potential Adverse Events Associated with Intravenous Immunoglobulin Infusion.

INTRODUCTION: Detection of adverse reactions to drugs and biologic agents is an important component of regulatory approval and post-market safety evaluation. Real-world data, including insurance claims and electronic health records data, are increasingly used for the evaluation of potential safety outcomes; however, there are different types of data elements available within these data resources, impacting the development and performance of computable phenotypes for the identification of adverse events (AEs) associated with a given therapy. OBJECTIVE: To evaluate the utility of different types of data elements to the performance of computable phenotypes for AEs. METHODS: We used intravenous immunoglobulin (IVIG) as a model therapeutic agent and conducted a single-center, retrospective study of 3897 individuals who had at least one IVIG administration between 1 January 2014 and 31 December 2019. We identified the potential occurrence of four different AEs, including two proximal AEs (anaphylaxis and heart rate alterations) and two distal AEs (thrombosis and hemolysis). We considered three different computable phenotypes: (1) an International Classification of Disease (ICD)-based phenotype; (2) a phenotype-based on EHR-derived contextual information based on structured data elements, including laboratory values, medication administrations, or vital signs; and (3) a compound phenotype that required both an ICD code for the AE in combination with additional EHR-derived structured data elements. We evaluated the performance of each of these computable phenotypes compared with chart review-based identification of AEs, assessing the positive predictive value (PPV), specificity, and estimated sensitivity of each computable phenotype method. RESULTS: Compound computable phenotypes had a high positive predictive value for acute AEs such as anaphylaxis and bradycardia or tachycardia; however, few patients had both ICD codes and the relevant contextual data, which decreased the sensitivity of these computable phenotypes. In contrast, computable phenotypes for distal AEs (i.e., thrombotic events or hemolysis) frequently had ICD codes for these conditions in the absence of an AE due to a prior history of such events, suggesting that patient medical history of AEs negatively impacted the PPV of computable phenotypes based on ICD codes. CONCLUSIONS: These data provide evidence for the utility of different structured data elements in computable phenotypes for AEs. Such computable phenotypes can be used across different data sources for the detection of infusion-related adverse events.

Assisted reproductive technology and association with childhood cancer subtypes.

OBJECTIVES: To investigate the association between assisted reproductive technology (ART) use and childhood cancer subtype. STUDY DESIGN: We deployed a cross-sectional survey of 1701 parents of children with cancer about their ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use, birthweight and multiple gestation status with childhood cancer, by subtype. RESULTS: ART use was highest among children with osteosarcoma relative to children with other cancer types, and this association was statistically significant in multivariable models (OR = 4.4; 95% CI = 1.7-11.3; p = 0.0020). ART use was also elevated among children with hepatoblastoma, but this relationship appeared to be due to the strong associations between ART use and lower birthweight in our sample. No specific ART modality appeared to drive these associations. In univariate models, multiple gestation was associated with a 2.7-fold increased odds of hepatoblastoma (OR = 2.71; 95% CI = 1.14-6.42; p = 0.02) and a 1.6-fold increased odds of neuroblastoma (OR = 1.62; 95% CI = 1.03-2.54; p = 0.03), but these associations were not retained in multivariable models. CONCLUSIONS: Associations between ART use and hepatoblastoma risk may be attributable to birthweight, a known hepatoblastoma risk factor. ART use may also be associated with osteosarcoma, independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.

Do children evaluated for maltreatment have higher subsequent emergency department and inpatient care utilization compared to a general pediatric sample?

BACKGROUND: Child maltreatment leads to substantial adverse health outcomes, but little is known about acute health care utilization patterns after children are evaluated for a concern of maltreatment at a child abuse and neglect medical evaluation clinic. OBJECTIVE: To quantify the association of having a child maltreatment evaluation with subsequent acute health care utilization among children from birth to age three. PARTICIPANTS AND SETTING: Children who received a maltreatment evaluation (N = 367) at a child abuse and neglect subspecialty clinic in an academic health system in the United States and the general pediatric population (N = 21,231). METHODS: We conducted a retrospective cohort study that compared acute health care utilization over 18 months between the two samples using data from electronic health records. Outcomes were time to first emergency department (ED) visit or inpatient hospitalization, maltreatment-related ED use or inpatient hospitalization, and ED use or inpatient hospitalization for ambulatory care sensitive conditions (ACSCs). Multilevel survival analyses were performed. RESULTS: Children who received a maltreatment evaluation had an increased hazard for a subsequent ED visit or inpatient hospitalization (hazard ratio [HR]: 1.3, 95 % confidence interval [CI]: 1.1, 1.5) and a maltreatment-related visit (HR: 4.4, 95 % CI: 2.3, 8.2) relative to the general pediatric population. A maltreatment evaluation was not associated with a higher hazard of health care use for ACSCs (HR: 1.0, 95 % CI: 0.7, 1.3). CONCLUSION: This work can inform targeted anticipatory guidance to aid high-risk families in preventing future harm or minimizing complications from previous maltreatment.

Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank. We found that high-avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development.

An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition.

Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs) that increase late-onset Alzheimer's disease (LOAD) risk. To identify additional LOAD-associated variants and provide insight into underlying disease biology, we performed a phenome-wide association study on 23 known LOAD-associated SNPs and 4:1 matched control SNPs using UK Biobank data. LOAD-associated SNPs were significantly enriched for associations with 8/778 queried traits, including 3 platelet traits. The strongest enrichment was for platelet distribution width (PDW) (p = 1.2 × 10-5), but increased PDW was not associated with LOAD susceptibility in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk (17,008 cases; 37,154 controls) and 5 survived false-discovery rate correction. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in epidermal growth factor receptor. Integrating GWAS and phenome-wide association study data reveals substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicates epidermal growth factor receptor - a mediator of ß-amyloid toxicity - in Alzheimer's disease susceptibility.

Kinetics of pneumococcal antibodies among HIV-exposed, uninfected infants in Botswana.

BACKGROUND: Streptococcus pneumoniae is a leading cause of severe infections among children. Despite vaccination, HIV-exposed, uninfected (HEU) children have a higher incidence of invasive pneumococcal disease than HIV-unexposed, uninfected (HUU) children. We sought to compare the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV-13) in HEU and HUU infants. METHODS: We conducted a prospective cohort study of 134 mother-infant dyads in Botswana. Infants received PCV-13 doses at 2, 3, and 4 months through routine clinical care. We measured IgG antibodies specific to vaccine serotypes in sera collected from infants at 0, 5, and 12 months of age. We calculated the proportion of infants with protective IgG levels (≥0.35 µg/mL) to specific pneumococcal serotypes. RESULTS: At birth, fewer than half of infants had protective IgG levels to serotypes 1 (38%), 3 (46%), 4 (33%), 5 (23%), 6B (40%), 7F (44%), 9 V (44%), and 23F (46%). Compared to HUU infants (n = 97), HEU infants (n = 37) had lower antibody concentrations at birth to serotypes 5 (p = 0.046) and 19A (p = 0.008) after adjustment for maternal age and infant birth weight. More than 80% of HEU and HUU infants developed protective antibody levels to each of the 13 vaccine serotypes following PCV-13 vaccination. Median concentrations of antibodies to pneumococcal serotypes declined by 55-93% between 5 and 12 months of age, with fewer than half of infants having protective antibody levels to serotypes 1 (47%), 3 (28%), 9 V (44%), 18C (24%), and 23F (49%) at 12 months of age. CONCLUSIONS: Both HEU and HUU infants developed protective antibody responses to PCV-13 administered in a 3 + 0 schedule. However, antibody concentrations to many pneumococcal serotypes waned substantially by 12 months of age, suggesting that a PCV-13 booster dose in the second year of life may be needed to maintain protective pneumococcal antibody levels in older infants and young children.