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The number of physicians who are underrepresented in medicine within the pediatric infectious diseases workforce remains disproportionate compared to the US population. Physician workforce diversity plays an important role in reducing health care disparities. Pathways to careers in pediatric infectious diseases require that a diverse pool of students enter medicine and subsequently choose pediatric residency followed by subspecialty training. Efforts must be made to expose learners to pediatric infectious diseases earlier in the education timeline. Along with recruitment and creation of pathways, cultures of inclusivity must be created and fostered within institutions of learning along the entire spectrum of medical training.

Background The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference. Methods We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage. Results Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0–40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17–208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02–1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28–.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23–1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants. Conclusions Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.

BACKGROUND: There is limited information on perinatal outcomes in HIV-hepatitis B virus (HBV) coinfection. METHODS: HIV Prevention Trials Network (HPTN) 046 was a randomized double-blind placebo-controlled trial of perinatal transmission that evaluated 6 months of infant nevirapine versus placebo among breast-fed infants. Women living with HIV and their infants enrolled in sub-Saharan Africa from 2007 to 2010; 78% received antiretroviral therapy (ART). Maternal samples were tested for hepatitis B surface antigen (HBsAg). High and low HBV viral load (VL) was defined as ≥10 IU/mL and

Purpose We describe the design of a longitudinal cohort study to determine SARS-CoV-2 incidence and prevalence among a population-based sample of adults living in six San Francisco Bay Area counties. Methods Using an address-based sample, we stratified households by county and by census-tract risk. Risk strata were determined by using regression models to predict infections by geographic area using census-level sociodemographic and health characteristics. We disproportionately sampled high and medium risk strata, which had smaller population sizes, to improve precision of estimates, and calculated a desired sample size of 3400. Participants were primarily recruited by mail and were followed monthly with PCR testing of nasopharyngeal swabs, testing of venous blood samples for antibodies to SARS-CoV-2 spike and nucleocapsid antigens, and testing of the presence of neutralizing antibodies, with completion of questionnaires about socio-demographics and behavior. Estimates of incidence and prevalence will be weighted by county, risk strata and sociodemographic characteristics of non-responders, and will take into account laboratory test performance. Results We enrolled 3842 adults from August to December, 2020, and completed follow-up March 31, 2021. We reached target sample sizes within most strata. Conclusions Our stratified random sampling design will allow us to recruit a robust general population cohort of adults to determine the incidence of SARS-CoV-2 infection. Identifying risk strata was unique to the design and will help ensure precise estimates, and high-performance testing for presence of virus and antibodies will enable accurate ascertainment of infections.

A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG–Fc-gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-FcγR interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19.

Background:The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Methods:Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.Results:We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer–BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2–7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Conclusions:Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Funding:Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford’s Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

Background Preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2_ infections in healthcare workers (HCWs) is critical for healthcare delivery. We aimed to estimate and characterize the prevalence and incidence of coronavirus disease 2019 (COVID-19) in a US HCW cohort and to identify risk factors associated with infection. Methods We conducted a longitudinal cohort study of HCWs at 3 Bay Area medical centers using serial surveys and SARS-CoV-2 viral and orthogonal serological testing, including measurement of neutralizing antibodies. We estimated baseline prevalence and cumulative incidence of COVID-19. We performed multivariable Cox proportional hazards models to estimate associations of baseline factors with incident infections and evaluated the impact of time-varying exposures on time to COVID-19 using marginal structural models. Results A total of 2435 HCWs contributed 768 person-years of follow-up time. We identified 21 of 2435 individuals with prevalent infection, resulting in a baseline prevalence of 0.86% (95% confidence interval [CI], .53%–1.32%). We identified 70 of 2414 incident infections (2.9%), yielding a cumulative incidence rate of 9.11 cases per 100 person-years (95% CI, 7.11–11.52). Community contact with a known COVID-19 case was most strongly correlated with increased hazard for infection (hazard ratio, 8.1 [95% CI, 3.8–17.5]). High-risk work-related exposures (ie, breach in protective measures) drove an association between work exposure and infection (hazard ratio, 2.5 [95% CI, 1.3–4.8). More cases were identified in HCWs when community case rates were high. Conclusions We observed modest COVID-19 incidence despite consistent exposure at work. Community contact was strongly associated with infections, but contact at work was not unless accompanied by high-risk exposure.

Background Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. Methods We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2–10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir’s impact on mutagenesis. Results We randomized 149 participants with 116 included in the mITT cohort. The participants’ mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48–1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54–1.29]; sustained: HR, 0.87 [95% CI, .52–1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. Conclusions Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. Clinical Trials Registration NCT04346628.

Background Live attenuated vaccines such as oral polio vaccine (OPV) can stimulate innate immunity and may have off-target protective effects on other pathogens. We aimed to address this hypothesis by examining changes in infectious diseases (ID)-related hospitalizations in all hospital discharges in California during OPV (1985–1996) and non-OPV immunization periods (2000–2010). Methods We searched the Office of Statewide Health Planning and Development database for all hospital discharges with any ID-related discharge diagnosis code during 1985–2010. We compared the proportion of ID-related hospitalizations (with at least 1 ID-related discharge diagnosis) among total hospitalizations during OPV immunization (1985–1996) versus non-OPV immunization (2000–2010) periods. Results There were 19 281 039 ID-related hospitalizations (8 464 037 with an ID-related discharge diagnosis as the principal discharge diagnosis for the hospitalization) among 98 117 475 hospitalizations in 1985–2010; 9 520 810 ID hospitalizations/43 456 484 total hospitalizations in 2000–2010 versus 7 526 957/43 472 796 in 1985–1996. The risk ratio for ID-related hospitalizations in 2000–2010 versus 1985–1996 was 1.27 (95% confidence interval [CI], 1.26–1.27) for all diagnoses and 1.15 (95% CI: 1.15–1.16) for principal diagnoses. Increases also existed in the proportion of lower respiratory and gastrointestinal infections. Discussion The proportion of ID-related hospitalizations was lower in the OPV immunization period compared to the period after OPV was discontinued. When focused only on hospitalizations with ID as the principal discharge diagnosis, the signal remained significant but was smaller. These findings require replication in additional studies.

BackgroundGiven the persistence of viral RNA in clinically recovered COVID-19 patients, subgenomic RNAs (sgRNA) have been reported as potential molecular viability markers for SARS-CoV-2. However, few data are available on their longitudinal kinetics, compared with genomic RNA (gRNA), in clinical samples.MethodsWe analyzed 536 samples from 205 patients with COVID-19 from placebo-controlled, outpatient trials of Peginterferon Lambda-1a (Lambda; n=177) and favipiravir (n=359). Nasal swabs were collected at three time points in the Lambda (Day 1, 4 and 6) and favipiravir (Day 1, 5, and 10) trials. N-gene gRNA and sgRNA were quantified by RT-qPCR. To investigate the decay kinetics in vitro, we measured gRNA and sgRNA in A549ACE2+ cells infected with SARS-CoV-2, following treatment with remdesivir or DMSO control.ResultsAt six days in the Lambda trial and ten days in the favipiravir trial, sgRNA remained detectable in 51.6% (32/62) and 49.5% (51/106) of the samples, respectively. Cycle threshold (Ct) values for gRNA and sgRNA were highly linearly correlated (Pearson’s r=0.87) and the rate of increase did not differ significantly in Lambda (1.36 cycles/day vs 1.36 cycles/day; p = 0.97) or favipiravir (1.03 cycles/day vs 0.94 cycles/day; p=0.26) trials. From samples collected 15-21 days after symptom onset, sgRNA was detectable in 48.1% (40/83) of participants. In SARS-CoV-2 infected A549ACE2+ cells treated with remdesivir, the rate of Ct increase did not differ between gRNA and sgRNA.ConclusionsIn clinical samples and in vitro, sgRNA was highly correlated with gRNA and did not demonstrate different decay patterns to support its application as a viability marker.SummaryWe observed prolonged detection of subgenomic RNA in nasal swabs and equivalent decay rates to genomic RNA in both longitudinal nasal swabs and in remdesivir-treated A549ACE2+ cells infected with SARS-CoV-2. Taken together, these findings suggest that subgenomic RNA from SARS-CoV-2 is comparably stable to genomic RNA and that its detection is therefore not a more reliable indicator of replicating virus.

The increasing diversity in the US population is reflected in the patients who healthcare professionals treat. Unfortunately, this diversity is not always represented by the demographic characteristics of healthcare professionals themselves. Patients from underrepresented groups in the United States can experience the effects of unintentional cognitive (unconscious) biases that derive from cultural stereotypes in ways that perpetuate health inequities. Unconscious bias can also affect healthcare professionals in many ways, including patient-clinician interactions, hiring and promotion, and their own interprofessional interactions. The strategies described in this article can help us recognize and mitigate unconscious bias and can help create an equitable environment in healthcare, including the field of infectious diseases.

Background Currently, the primary mechanism for poliovirus detection is acute flaccid paralysis (AFP) surveillance, with environmental sampling serving as a complement. However, as AFP cases drop, environmental surveillance will become increasingly critical for poliovirus detection. Mexico provides a natural environment to study oral polio vaccine (OPV) transmission, as it provides routine injected polio vaccine immunization and biannual OPV campaigns in February and May. Methods As part of a study of OPV transmission in which 155 children were vaccinated with OPV, monthly sewage samples were collected from rivers leading from 3 indigenous Mexican villages (Capoluca, Campo Grande, and Tuxpanguillo) from February to May 2015. Samples were also collected from October 2015 to October 2017, during which time there were standard OPV campaigns. Samples were analyzed for the presence of OPV serotypes, using a real-time qualitative polymerase chain reaction assay capable of detecting as few as 9, 12, and 10 copies/100 µL of viral ribonucleic acid for OPV serotypes 1, 2, and 3 (OPV-1, -2, and -3), respectively. Included here are 54 samples, taken up to November 2016. Results Of the 54 samples, 13 (24%) were positive for OPV. After the vaccination of 155 children in February 2015, OPV was found 2 months after vaccination. After unrestricted OPV administration in February 2016, OPV was detected in sewage up to 8 months after vaccination. OPV-3 was found in 11 of the 13 positive samples (85%), OPV-2 was found in 3 positive samples (23%), and OPV-1 was found in 1 sample (8%). Conclusions OPV can be detected even when small amounts of the vaccine are introduced into a community, as shown by OPV-positive sewage samples even when only 155 children were vaccinated. When OPV vaccination was unrestricted, sewage samples were positive up to 8 months after vaccination, implying community OPV circulation for at least 8 months. OPV-3 was the serotype most found in these samples, indicating prolonged transmission of OPV-3 when compared to the other serotypes. Future work could compare the phylogenetic variance of OPV isolates from sewage after OPV vaccinations.

Background Global polio eradication efforts rely in part on molecular methods of detecting polioviruses, both wild and vaccine strains, from human and environmental samples. Previous assays used for detection of Sabin oral polio vaccine (OPV) in fecal samples have been labor and time intensive and vary in their sensitivity and specificity. Methods We developed a high-throughput, multiplex reverse-transcription quantitative polymerase chain reaction assay able to detect all 3 OPV strains in fecal samples. The assay used a KingFisher Duo Prime system for viral RNA isolation and extraction. Positive samples were retested and Sanger sequenced for verification of Sabin serotype identity. Results The 95% lower limit of detection was determined to be 3 copies per reaction for Sabin 1 and 3 and 4 copies per reaction for Sabin 2, with no cross-reactivity between the 3 serotypes and their primers. A total of 554 samples (3.6%) were positive, with 304 positive samples (54.9%) containing >1 serotype. Of the positive samples, 476 (85.9%) contained enough RNA to be sequenced, and of these all sequences were Sabin serotypes. The previous assay we used could process 48 samples in a 10-hour period, whereas the new assay processed >100 samples in 6 hours. Conclusions The new high-throughput, multiplex reverse-transcription quantitative polymerase chain reaction assay allowed for sensitive and specific detection of OPV serotypes while greatly decreasing sample handling and processing time. We were able to sequence 72.4% of the 210 positive samples in the cycle threshold range of 35–37.

Background We aimed to elucidate household and community-level shedding and transmission of trivalent oral polio vaccine (tOPV) in communities with inactivated polio vaccine (IPV) routine immunization after tOPV is administered during a national health week (NHW). Methods We conducted a 3-arm, randomized trial with data collected at baseline through 10 weeks post-NHW in households with at least 1 child

Background The Polio Eradication and Endgame Strategic Plan 2013–2018 calls for the gradual withdrawal of oral poliovirus vaccine (OPV) from routine immunization. We aimed to quantify the transmission potential of Sabin strains from OPV when it is reintroduced, accidentally or deliberately, in a community vaccinated with inactivated poliovirus vaccine alone. Methods We built an individual-based stochastic epidemiological model that allows independent spread of 3 Sabin serotypes and differential transmission rates within versus between households. Model parameters were estimated by fitting to data from a prospective cohort in Mexico. We calculated the effective reproductive number for the Mexico cohort and simulated scenarios of Sabin strain resurgence under postcessation conditions, projecting the risk of prolonged circulation, which could lead to circulating vaccine-derived poliovirus (cVDPV). Results The estimated effective reproductive number for naturally infected individuals was about 1 for Sabin 2 and Sabin 3 (OPV2 and OPV3) in a postcessation setting. Most transmission events occurred between households. We estimated the probability of circulation for >9 months to be (1) <

Background Mutations associated with prolonged replication of the attenuated polioviruses found in oral poliovirus vaccine (OPV) can lead to vaccine-derived poliovirus (VDPV) and cause paralysis indistinguishable from that caused by wild poliovirus. In response, the World Health Organization has initiated the transition to exclusive use of inactivated poliovirus vaccine (IPV), with OPV administration in cases of outbreak. However, it is currently unclear how IPV-only vaccination, well known to provide humoral but not mucosal immunity, will impact the development of paralysis causing OPV variants. Children infected with human immunodeficiency virus (HIV) have been documented to show decreased mucosal immunity following OPV vaccination. Thus, HIV-infected children vaccinated with OPV may serve as proxy for children with IPV-only vaccination. Methods We conducted a prospective study of Zimbabwean infants receiving OPV as part of their routine vaccination schedule. Stool samples collected from OPV-vaccinated children serially until age 24 months were tested for OPV serotypes using a real-time polymerase chain reaction protocol that quantifies the amount of mutant OPV variants found in each sample. Results Out of 2130 stool samples collected from 402 infants 365 stool samples were OPV positive: 313 from 212 HIV-noninfected (HIV−) infants and 52 from 34 HIV-infected (HIV+) infants. HIV− infants showed significantly higher proportions of OPV mutants when compared to HIV+ infants. Conclusions HIV infection is associated with a reduced proportion of OPV vaccine associated paralytic polio mutants. These results suggest that OPV administered to individuals previously vaccinated only with IPV will show decreased propensity for OPV mutations.

Background The World Health Assembly 2012 Polio Eradication and Endgame Strategic Plan calls for the eventual cessation of all oral polio vaccines (OPVs), to be replaced with inactivated polio vaccine (IPV); however, IPV induces less robust mucosal immunity than OPV. This study characterized household and community OPV shedding and transmission after OPV vaccination within primarily IPV-vaccinated communities. Methods Households in 3 IPV-vaccinated Mexican communities were randomized to receive 3 levels of OPV vaccination coverage (70%, 30%, or 10%). Ten stool samples were collected from all household members over 71 days. Analysis compared vaccinated subjects, household contacts of vaccinated subjects, and subjects in unvaccinated households. Logistic and Cox regression models were fitted to characterize transmission of OPV by coverage and household vaccination status. Results Among 148 vaccinated children, 380 household contacts, and 1124 unvaccinated community contacts, 78%, 18%, and 7%, respectively, shed OPV. Community and household contacts showed no differences in transmission (odds ratio [OR], 0.67; 95% confidence interval [CI], .37–1.20), in shedding trajectory (OR, 0.61; 95% CI, .35–1.07), or in time to shedding (hazard ratio, 0.68; 95% CI, .39–1.19). Transmission began as quickly as 1 day after vaccination and persisted as long as 71 days after vaccination. Transmission within unvaccinated households differed significantly across vaccination coverage communities, with the 70% community experiencing the most transmissions (15%), and the 10% community experiencing the least (4%). These trends persisted over time and in the time to first shedding analyses. Conclusions Transmission did not differ between household contacts of vaccinees and unvaccinated households. Understanding poliovirus transmission dynamics is important for postcertification control.

Objective:We assessed the magnitude of unidentified coronavirus disease 2019 (COVID-19) in our healthcare personnel (HCP) early in the COVID-19 pandemic, and we evaluated risk factors for infection to identify areas for improvement in infection control practice in a northern California academic medical center.Methods:We reviewed anti–severe acute respiratory coronavirus virus 2 (SARS-CoV-2) receptor-binding domain (RBD) IgG serologic test results and self-reported risk factors for seropositivity among 10,449 asymptomatic HCP who underwent voluntary serology testing between April 20 and May 20, 2020.Results:In total, 136 employees (1.3%) tested positive for SARS-CoV-2 IgG. This included 41 individuals (30.1%) who had previously tested positive for SARS-CoV-2 by nasopharyngeal reverse-transcription polymerase chain reaction (RT-PCR) between March 13 and April 16, 2020. In multivariable analysis, employees of Hispanic ethnicity (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.22–3.46) and those working in environmental services, food services, or patient transport (OR, 4.81; 95% CI, 2.08–10.30) were at increased risk for seropositivity compared to other groups. Employees reporting a household contact with COVID-19 were also at higher risk for seropositivity (OR, 3.25; 95% CI, 1.47–6.44), but those with a work, exposure alone were not (OR, 1.27; 95% CI, 0.58–2.47). Importantly, one-third of seropositive individuals reported no prior symptoms, no suspected exposures, and no prior positive RT-PCR test.Conclusion:In this study, SARS-CoV-2 seropositivity among HCP early in the northern California epidemic appeared to be quite low and was more likely attributable to community rather than occupational exposure.

BACKGROUND: Effects of prolonged nevirapine prophylaxis exposure on growth among HIV-exposed uninfected (HEU) infants are unknown. This study examines the impact of extended nevirapine prophylaxis from 6 weeks to 6 months on the growth of HEU infants followed for 18 months and also identifies correlates of incident wasting, stunting, underweight, and low head circumference in the HPTN 046 trial. METHODS: Intention-to-treat analysis examined the effect of extended nevirapine exposure on: weight-for-age Z-score (WAZ), length-for-age Z-score (LAZ), weight-for-length Z-score (WLZ) and head circumference-for-age (HCZ). Multivariable linear mixed-effects and Cox proportional hazard models were used to compare growth outcomes between the study arms and identify correlates of incident adverse growth outcomes, respectively. RESULTS: Compared to placebo, extended prophylactic nevirapine given daily from 6 weeks to 6 months did not affect growth in HEU breastfeeding (BF) infants over time (treatment x time: p>.05). However, overall growth declined over time (time effect: p

Background: Instrumental variable (IV) analyses are a common causal inference technique used in the absence of randomized data. Combination Antiretroviral Therapy (cART) was first introduced in 1996 and calendar periods have been used as a proxy for cART use. However, cART use misclassification can bias IV analyses. Objective: We aim to highlight the differences in the effects of antiretroviral therapy on clinical outcomes between the applications of traditional and adapted IV analysis techniques. Methods: This study includes children with perinatal human immunodeficiency virus (HIV-1) infection followed from 1988 to 2009. We describe an application of traditional and adapted IV analysis techniques. Noncompliance adjustments were applied to correct the misclassification of cART-use. Weighting the inverse probability of calendar era, the selected covariates were performed to control for variables that may be related to both the IV and outcome. Results: During 48,380 person-days, 78 HIV-positive children progressed to an initial stage-3- defining diagnosis or death. The Intention to Treat (ITT) rate ratio (RR) of stage-3-defining diagnosis or death comparing the pre-cART and cART eras was estimated at 2·67 (95% confidence interval (CI): 1·.47, 4·84). The IV estimator was used to adjust for cART use misclassification, yielding an IV RR of 5·42 (95% CI: 2·99, 9·83). Weighting analyses did not markedly alter the results. Conclusion: cART use decreased progression to stage-3-defining diagnosis or death. The use of noncompliance adjustments for cART misclassification in IV analyses may provide more robust evidence of cART's effectiveness than traditional ITT analysis.

The potential role of enteric viral infections and the developing infant virome in affecting immune responses to the oral poliovirus vaccine (OPV) is unknown. Here we performed viral metagenomic sequencing on 3 serially collected stool samples from 30 Bangladeshi infants following OPV vaccination and compared findings to stool samples from 16 age-matched infants in the United States (US). In 14 Bangladeshi infants, available post-vaccination serum samples were tested for polio-neutralizing antibodies. The abundance (p = 0.006) and richness (p = 0.013) of the eukaryotic virome increased with age and were higher than seen in age-matched US infants (p 10 vs. 2.25 log10, p = 0.002), particularly from potential viral pathogens (2.78log10 vs. 0.83log10, p = 0.002), and richness (p = 0.016) were inversely associated with poliovirus shedding. Following vaccination, 28.6% of 14 infants tested developed neutralizing antibodies to all three Sabin types and also exhibited higher rates of poliovirus shedding (p = 0.020). No vaccine-derived poliovirus variants were detected. These results reveal an inverse association between eukaryotic virome abundance and poliovirus shedding. Overall gut virome ecology and concurrent viral infections may impact oral vaccine responsiveness in Bangladeshi infants.

Background Acute Toxoplasma infection (ATI) during pregnancy, if left untreated, can cause severe adverse outcomes for the fetus and newborn. Here, we undertook a meta-analysis to estimate the worldwide prevalence of ATI in pregnant women. Methods We searched international databases for studies published between January 1988 and November 2018. We included population-based cross-sectional and prospective cohort studies that reported the prevalence of ATI in pregnant women. Data were synthesized using a random effect model to calculate the overall prevalence of ATI (with a 95% CI) in six WHO regions and globally. We also performed linear meta-regression analyses to investigate associations of maternal, socio-demographic, geographical and climate parameters with the prevalence of ATI. Results In total, 217 studies comprising 902,228 pregnant women across 74 countries were included in the meta-analysis. The overall prevalence of ATI in pregnant women globally was 1.1% (95% CI: 0.9–1.2%). In studies where more strict criteria for ATI were used, the overall prevalence was 0.6% (95% CI: 0.4–0.7%). The prevalence was highest in the Eastern Mediterranean region (2.5%; 95%CI: 1.7–3.4%) and lowest in the European region (0.5%; 95% CI: 0.4–0.7%). A significantly higher prevalence of ATI was found in countries with lower income levels (P = 0.027), lower human development indices (P = 0.04), higher temperatures (P = 0.02) and lower latitudes (P = 0.005) and longitudes (P = 0.02). Conclusions The risk of acquiring ATI during gestation is clinically important and preventive measures to avoid exposure of pregnant women to Toxoplasma infection should be strictly applied., Author summary Acute infection during pregnancy with the protozoan parasite Toxoplasma gondii, if left undiagnosed and untreated, is linked to a wide range of medical complications, and severe adverse outcomes for the infected fetus and newborn. This is the first comprehensive systematic review and meta-analysis of the global prevalence of ATI in pregnant women, and was based on 217 studies of a total of 902,228 pregnant women from 74 countries. The overall global prevalence of ATI was 1.1%. According to studies that used strict criteria (seroconversion and low IgG avidity) for the definition of ATI, 0.6% of pregnant women had ATI during gestation. Countries with high-income levels and higher human development indices had significantly lower prevalence of ATI. In addition, the prevalence of ATI varied among countries depending on geographical location and climatic features. The findings of this study should increase awareness among public health leaders and educators regarding the global burden of ATI in pregnant women—which translates to a significant number of children worldwide being at risk of acquiring congenital toxoplasmosis and developing long-term sequelae—if maternal infection is left undiagnosed and untreated. The findings also indicate a need for universal prenatal screening for early diagnosis and treatment.

Background Understanding the spatial dynamics of oral polio vaccine (OPV) transmission will improve resource targeting. Mexico provides a natural laboratory, as it uses inactivated polio vaccine routinely as well as OPV bi-annually. Methods Using geospatial maps, we measured the distance and density of OPV vaccinees’ shedding in the areas nearest to unvaccinated households in 3 Mexican villages. Comparison of transmission to unvaccinated households utilized a mixed effects logistic regression with random effects for household and time, adjusted for age, gender, area, and running water. Results The median distance from an unvaccinated household to its nearest OPV-shedding household was 85 meters (interquartile range, 46–145) and the median number of vaccinees shedding OPV within 200 m was 3 (2–6). Transmission to unvaccinated households occurred by day 1. There was no association (odds ratio [OR] 1.04; 95% credible interval [CrI] 0.92–1.16) between the distance from OPV shedding and the odds of transmission. The number of OPV vaccinees shedding within 200 m came close to a significant association with unvaccinated transmission (OR 0.93; CrI 0.84–1.01), but this was not the case for households 100 or 500 m apart. Results were consistent across the 3 villages. Conclusions Geospatial analysis did not predict community transmission from vaccinated to unvaccinated households, because OPV use resulted in rapid, low transmission levels. This finding supports the global cessation of OPV.

Background The cost of conventional serological testing for toxoplasmosis discourages universal adoption of prenatal monthly screening programs to prevent congenital toxoplasmosis. Point-of-care (POC) technology may constitute a cost-effective approach. Methods We evaluated the diagnostic accuracy of 3 Toxoplasma POC tests against gold-standard testing performed at Palo Alto Medical Foundation Toxoplasma Serology Laboratory (PAMF-TSL). The POC tests included the following: Toxo IgG/IgM Rapid Test (Biopanda) and the OnSite Toxo IgG/IgM Combo-Rapid-test that detect IgG and IgM separately, and the Toxoplasma ICT-IgG-IgM-bk (LDBIO) that detects either or both immunoglobulin IgG/IgM in combination. Samples were selected from PAMF-TSL biobank (n = 210) and Centers for Disease Control and Prevention Toxoplasma 1998 Human Serum Panel (n = 100). Based on PAMF-TSL testing, Toxoplasma-infection status was classified in 4 categories: acute infections (n = 85), chronic infections (n = 85), false-positive Toxoplasma IgM (n = 60), and seronegative (n = 80). The POC testing was performed in duplicate following manufacturer’s instructions by investigators blinded to PAMF-TSL results. Sensitivity and specificity were calculated. Results A total of 1860 POC tests were performed. For detection of Toxoplasma IgG, sensitivity was 100% (170 of 170; 95% confidence interval [CI], 97.8%–100%) for all 3 POC kits; specificity was also comparable at 96.3% (77 of 80; 95% CI, 89.5%–98.9%), 97.5% (78 of 80; 95% CI, 91.3%–99.6%), and 98.8% (79 of 80; 95% CI, 93.2%–99.9%). However, sensitivity for detection of Toxoplasma IgM varied significantly across POC tests: Biopanda, 62.2% (51 of 82; 95% CI, 51.4%–71.9%); OnSite, 28% (23 of 82; 95% CI, 19.5%–38.6%); and LDBIO combined IgG/IgM, 100% (82 of 82; 95% CI, 95.5%–100%). Diagnostic accuracy was significantly higher for the LDBIO POC kit. The POC kits did not exhibit cross-reactivity for false-positive Toxoplasma-IgM sera. Conclusions The 3 evaluated POC kits revealed optimal sensitivity for Toxoplasma-IgG antibodies. The LDBIO-POC test exhibited 100% sensitivity for the combined detection of IgG/IgM in acute and chronic Toxoplasma infection. Biopanda and Onsite POC tests exhibited poor sensitivity for Toxoplasma-IgM detection.

Background Vaccine hesitancy, the reluctance or refusal to receive vaccination, is a growing public health problem in the United States and globally. State policies that eliminate nonmedical (“personal belief”) exemptions to childhood vaccination requirements are controversial, and their effectiveness to improve vaccination coverage remains unclear given limited rigorous policy analysis. In 2016, a California policy (Senate Bill 277) eliminated nonmedical exemptions from school entry requirements. The objective of this study was to estimate the association between California’s 2016 policy and changes in vaccine coverage. Methods and findings We used a quasi-experimental state-level synthetic control analysis and a county-level difference-in-differences analysis to estimate the impact of the 2016 California policy on vaccination coverage and prevalence of exemptions to vaccine requirements (nonmedical and medical). We used publicly available state-level data from the US Centers for Disease Control and Prevention on coverage of measles, mumps, and rubella (MMR) vaccination, nonmedical exemption, and medical exemption in children entering kindergarten. We used county-level data individually requested from state departments of public health on overall vaccine coverage and exemptions. Based on data availability, we included state-level data for 45 states, including California, from 2011 to 2017 and county-level data for 17 states from 2010 to 2017. The prespecified primary study outcome was MMR vaccination in the state analysis and overall vaccine coverage in the county analysis. In the state-level synthetic control analysis, MMR coverage in California increased by 3.3% relative to its synthetic control in the postpolicy period (top 2 of 43 states evaluated in the placebo tests, top 5%), nonmedical exemptions decreased by 2.4% (top 2 of 43 states evaluated in the placebo tests, top 5%), and medical exemptions increased by 0.4% (top 1 of 44 states evaluated in the placebo tests, top 2%). In the county-level analysis, overall vaccination coverage increased by 4.3% (95% confidence interval [CI] 2.9%–5.8%, p < 0.001), nonmedical exemptions decreased by 3.9% (95% CI 2.4%–5.4%, p < 0.001), and medical exemptions increased by 2.4% (95% CI 2.0%–2.9%, p < 0.001). Changes in vaccination coverage across counties after the policy implementation from 2015 to 2017 ranged from −6% to 26%, with larger increases in coverage in counties with lower prepolicy vaccine coverage. Results were robust to alternative model specifications. The limitations of the study were the exclusion of a subset of US states from the analysis and the use of only 2 years of postpolicy data based on data availability. Conclusions In this study, implementation of the California policy that eliminated nonmedical childhood vaccine exemptions was associated with an estimated increase in vaccination coverage and a reduction in nonmedical exemptions at state and county levels. The observed increase in medical exemptions was offset by the larger reduction in nonmedical exemptions. The largest increases in vaccine coverage were observed in the most “high-risk” counties, meaning those with the lowest prepolicy vaccine coverage. Our findings suggest that government policies removing nonmedical exemptions can be effective at increasing vaccination coverage., In an empirical policy analysis, Nyathi and colleagues estimate changes in vaccine coverage associated with the 2016 California policy (Senate Bill 277) restricting non-medical exemptions for children’s school immunization requirements, Author summary Why was this study done? Vaccine hesitancy, often parental reluctance or refusal to vaccinate their children, is a growing challenge in public health; however, there is debate on the role of government-level vaccination policies to address this problem. Limited empirical research has evaluated the impact of governmental vaccination policies that restrict the ability of parents to obtain nonmedical exemptions from routine vaccination requirements. The 2016 California vaccine policy (Senate Bill 277) that eliminated nonmedical childhood vaccination exemptions provides an opportunity to empirically estimate the impact of a governmental state-level policy on vaccine coverage. What did the researchers do and find? We evaluated the 2016 California vaccine policy by applying a synthetic control analysis with state-level data and a difference-in-differences analysis with county-level data to estimate the relationship between the policy and changes in measles, mumps, and rubella (MMR) or overall vaccine coverage, nonmedical exemptions, and medical exemptions. At the state level, the California vaccine policy was associated with a 3.3% increase in MMR vaccination coverage, a 2.4% decrease in nonmedical exemptions, and a 0.4% increase in medical exemptions. At the county level, the California vaccine policy was associated with a 4.3% increase in overall vaccination, a 3.9% decrease in nonmedical exemptions, and a 2.4% increase in medical exemptions. The largest increases in postpolicy county-level coverage occurred in counties with lower prepolicy vaccine coverage. What do these findings mean? Our study found that the 2016 California policy to eliminate nonmedical childhood vaccination exemptions was associated with an increase in vaccination coverage and a decrease in nonmedical exemptions. The study findings support the hypothesis that government policies can be an effective tool to increase vaccination coverage, especially in the most “high-risk” (low vaccine coverage) settings.

Background As wild poliovirus is nearing global eradication and countries switch from Oral Polio Vaccine (OPV) to Inactivated Polio Vaccine (IPV), preventing circulating vaccine-derived poliovirus is a top priority. However, the circulation of OPV serotypes remains a concern in undervaccinated communities. We sought to examine the relationship between pediatric nutritional status and OPV shedding based on length-for-age categorizations. Mexico provides a natural environment to study these patterns as it provides routine IPV immunization and bi-annual OPV campaigns. Methods We enrolled 466 households with children eligible for OPV before the February 2015 national health week from 3 semi-rural Indigenous communities near Orizaba, Mexico. In each community, a different proportion of eligible children received OPV (10%, 30%, 70%), with a total of 155 vaccinated children. OPV shedding was measured by RT-qPCR detection of OPV in samples collected serially over 10 weeks. Anthropometric measurements were collected and compared with the WHO Multicenter Growth Reference Study growth curves to assign stunting. Associations between stunting, OPV shedding, and shedding duration were tested by Fisher exact test and Wilcoxon-Man-Whitney Test (α = 0.05). Results Samples of fecal OPV isolates were collected over time and analyzed from 148 vaccinees. 25 (17%) of the vaccinees were stunted. There was no relationship between pediatric stunting and likelihood of ever shedding any serotype of OPV (P = 0.82). The mean duration of OPV shedding by stunted and non-stunted children differed, but not significantly (10.9 days vs. 9.3 days, respectively, P = 0.32). We did not find any statistically significant differences between stunting status and shedding of any individual OPV serotype. Conclusion Further understanding of factors related to OPV shedding is necessary to approach efficient worldwide poliovirus control. We found no relationship between stunting status and both OPV shedding and shedding duration post-vaccination, suggesting that nutritional status does not play a role in OPV shedding. The ongoing analysis includes longitudinal analysis of OPV shedding patterns by nutritional status, and the impact of stunting on viral load and reversion of OPV to vaccine-associated paralytic polio mutants. Disclosures All authors: No reported disclosures.

Background Vaccine hesitancy in low vaccine coverage “hot spots” has led to recent outbreaks of vaccine-preventable diseases across the United States. State policies to improve vaccine coverage by restricting non-medical (personal belief) exemptions are heavily debated and their effectiveness is unclear due to limited rigorous policy analysis. In 2016, a California policy (SB 277) eliminated non-medical exemptions from kindergarten requirements. To address the ongoing debate on such policies, we performed a quasi-experimental, controlled analysis of the policy’s impact on vaccine and exemption outcomes. Methods We used state vaccine coverage and exemption data (2011–2017) from the CDC and health data from public sources. We prespecified a primary outcome of MMR coverage (%) and secondary outcomes of medical and non-medical exemptions (%). We included covariates related to socioeconomic and health measures (e.g., insurance, well child visits) and pre-2016 mean coverage. Using the synthetic control method, with 2016 as the treatment year and a 2-year post-policy period, we constructed a “control” California, from a weighted sum of states. We used permutation testing to repeat the process for each of the other states and their unique synthetic control, to determine whether there was a meaningful difference in California (i.e., a change in California’s coverage relative to its control in the top 5th percentile of states). We tested the model’s sensitivity to various analytical assumptions. Results Of 43 control states, synthetic California was predominantly comprised of Idaho, Mississippi, and Arkansas, and had a good pre-policy match on outcomes. MMR coverage in California increased by 3.2% relative to synthetic California in the post period (Top 1 of 44 states, Figure 1). Medical exemptions increased by 0.4%, while non-medical exemptions decreased by 2.2% in the post-period (Top 1 of 43 states). The model was robust to changes in covariates and control states. Conclusion The policy resulted in a meaningful increase in MMR coverage and reduction in non-medical exemptions. We measured a modest increase in medical exemptions, but this was offset by the larger reduction in non-medical exemptions. State policies removing non-medical exemptions can be effective in increasing vaccination coverage. Disclosures All authors: No reported disclosures.

Background Mexico introduced inactivated polio vaccine (IPV) into its routine immunization (RI) schedule in 2007 but continued to give trivalent oral polio vaccine (tOPV) twice a year during national health weeks (NHW) through 2015. Objectives To evaluate individual variables associated with poliovirus (PV) shedding among children with IPV-induced immunity after vaccination with tOPV and their household contacts. Materials and methods We recruited 72 children (both genders, ≤30 months, vaccinated with at least two doses of IPV) and 144 household contacts (both genders, 2 per household, children and adults) between 08/2010 and 09/2010 in Orizaba, Veracruz. Three NHW took place (one before and two after enrollment). We collected fecal samples monthly for 12 months, and tested 2500 samples for polioviruses types 1, 2 and 3 with three serotype-specific singleplex real-time RT-PCR (rRT-PCR) assays. In order to increase the specificity for OPV virus, all positive and 112 negative samples were also processed with a two-step, OPV serotype-specific multiplex rRT-PCR. Analysis We estimated adjusted hazard ratios (HR) and 95% CI using Cox proportional hazards regression for recurrent events models accounting for individual clustering to assess the association of individual variables with the shedding of any poliovirus for all participants and stratifying according to whether the participant had received tOPV in the month of sample collection. Results 216 participants were included. Of the 2500 collected samples, using the singleplex rRT-PCR assay, PV was detected in 5.7% (n = 142); PV1 in 1.2% (n = 29), PV2 in 4.1% (n = 103), and PV3 in 1.9% (n = 48). Of the 256 samples processed by multiplex rRT-PCR, PV was detected in 106 (PV1 in 16.41% (n = 42), PV2 in 21.09% (n = 54), and PV3 in 23.05% (n = 59). Both using singleplex and multiplex assays, shedding of OPV among non-vaccinated children and subjects older than 5 years of age living in the same household was associated with shedding of PV2 by a household contact. All models were adjusted by sex, age, IPV vaccination and OPV shedding by the same individual during the previous month of sample collection. Conclusion Our results provide important evidence regarding the circulation of poliovirus in a mixed vaccination context (IPV+OPV) which mimics the “transitional phase” that occurs when countries use both vaccines simultaneously. Shedding of OPV2 by household contacts was most likely the source of infection of non-vaccinated children and subjects older than 5 years of age living in the same household.

Background Vaccine-derived polioviruses (VDPVs), strains of poliovirus mutated from the oral polio vaccine, pose a challenge to global polio eradication. Immunodeficiency-related vaccine-derived polioviruses (iVDPVs) are a type of VDPV which may serve as sources of poliovirus reintroduction after the eradication of wild-type poliovirus. This review is a comprehensive update of confirmed iVDPV cases published in the scientific literature from 1962 to 2012, and describes clinically relevant trends in reported iVDPV cases worldwide. Methods We conducted a systematic review of published iVDPV case reports from January 1960 to November 2012 from four databases. We included cases in which the patient had a primary immunodeficiency, and the vaccine virus isolated from the patient either met the sequencing definition of VDPV (>1% divergence for serotypes 1 and 3 and >0.6% for serotype 2) and/or was previously reported as an iVDPV by the World Health Organization. Results We identified 68 iVDPV cases in 49 manuscripts reported from 25 countries and the Palestinian territories. 62% of case patients were male, 78% presented clinically with acute flaccid paralysis, and 65% were iVDPV2. 57% of cases occurred in patients with predominantly antibody immunodeficiencies, and the overall all-cause mortality rate was greater than 60%. The median age at case detection was 1.4 years [IQR: 0.8, 4.5] and the median duration of shedding was 1.3 years [IQR: 0.7, 2.2]. We identified a poliovirus genome VP1 region mutation rate of 0.72% per year and a higher median percent divergence for iVDPV1 cases. More cases were reported from high income countries, which also had a larger age variation and different distribution of immunodeficiencies compared to upper and lower middle-income countries. Conclusion Our study describes the incidence and characteristics of global iVDPV cases reported in the literature in the past five decades. It also highlights the regional and economic disparities of reported iVDPV cases.

Background Inclusion of vaccine herd-protection effects in cost-effectiveness analyses (CEAs) can impact the CEAs-conclusions. However, empirical epidemiologic data on the size of herd-protection effects from original studies are limited. Methods We performed a quantitative comparative analysis of the impact of herd-protection effects in CEAs for four childhood vaccinations (pneumococcal, meningococcal, rotavirus and influenza). We considered CEAs reporting incremental-cost-effectiveness-ratios (ICERs) (per quality-adjusted-life-years [QALY] gained; per life-years [LY] gained or per disability-adjusted-life-years [DALY] avoided), both with and without herd protection, while keeping all other model parameters stable. We calculated the size of the ICER-differences without vs with-herd-protection and estimated how often inclusion of herd-protection led to crossing of the cost-effectiveness threshold (of an assumed societal-willingness-to-pay) of $50,000 for more-developed countries or X3GDP/capita (WHO-threshold) for less-developed countries. Results We identified 35 CEA studies (20 pneumococcal, 4 meningococcal, 8 rotavirus and 3 influenza vaccines) with 99 ICER-analyses (55 per-QALY, 27 per-LY and 17 per-DALY). The median ICER-absolute differences per QALY, LY and DALY (without minus with herd-protection) were $15,620 (IQR: $877 to $48,376); $54,871 (IQR: $787 to $115,026) and $49 (IQR: $15 to $1,636) respectively. When the target-vaccination strategy was not cost-saving without herd-protection, inclusion of herd-protection always resulted in more favorable results. In CEAs that had ICERs above the cost-effectiveness threshold without herd-protection, inclusion of herd-protection led to crossing of that threshold in 45% of the cases. This impacted only CEAs for more developed countries, as all but one CEAs for less developed countries had ICERs below the WHO-cost-effectiveness threshold even without herd-protection. In several analyses, recommendation for the adoption of the target vaccination strategy depended on the inclusion of the herd protection effect. Conclusions Inclusion of herd-protection effects in CEAs had a substantial impact in the estimated ICERs and made target-vaccination strategies more attractive options in almost half of the cases where ICERs were above the societal-willingness to pay threshold without herd-protection. More empirical epidemiologic data are needed to determine the size of herd-protection effects across diverse settings and also the size of negative vaccine effects, e.g. from serotype substitution.

Otolaryngologic conditions are common among HIV-1-infected children. In this study, we provide data regarding prevalence of pediatric HIV-1 otolaryngologic manifestations in the era of antiretroviral therapy (ART).We conducted population-based, prospective, multicenter pediatric HIV-1 surveillance among 276 children with perinatally acquired HIV-1 from 1988 to 2009. All Center for Disease Control (CDC) mild, moderate and severe otolaryngologic conditions were evaluated.CDC-defined, HIV-1-related otolaryngologic conditions among the 276 children were: 103, mild; 50, moderate and 20, severe. The majority [23.3% (24/103), 40.0% (20/50) and 50% (10/20)] of mild, moderate and severe diagnoses, respectively, occurred in the first year of life, with 53.4% (55/103), 66.0% (33/50) and 70% (14/20), respectively, occurring in the first 2 years of life. The most frequent diagnoses were otitis media [21% (58/276)] and oropharyngeal thrush [17.4% (48/276)]. There was a temporal decline by cohort in prevalence of mild and moderate otolaryngologic diagnoses which was significant for mild conditions: 90, pre-ART cohort and 13, ART cohort (P0.001) and moderate conditions: 47, pre-ART and 3, ART (P0.001).In our study, many CDC-defined, HIV-related otolaryngologic conditions occur in the first 2 years of life. Over 22 years of longitudinal follow up, there was a significant decline in prevalence of CDC-defined otolaryngologic conditions by temporal cohorts when comparing pre-ART and ART eras. This finding supports early ART administration to decrease morbidity in HIV-1-positive infants and children as well as current US and World Health Organization guidelines to prevent early HIV disease progression.

We investigated 32 families of persons with acute toxoplasmosis in whichor = 1 other family member was tested for Toxoplasma gondii infection; 18 (56%) families hador = 1 additional family member with acute infection. Family members of persons with acute toxoplasmosis should be screened for infection, especially pregnant women and immunocompromised persons.

Background As wild poliovirus is eradicated and countries switch from oral polio vaccine (OPV) to inactivated polio vaccine (IPV), preventing circulating vaccine-derived poliovirus is a top priority. However, the stability of Sabin vaccine serotypes remains a concern in undervaccinated communities. We sought to measure the canonical point mutation rates associated with OPV serotype neuroreversion and vaccine-associated paralytic polio (VAPP) as possible markers of serotype fitness. Mexico provides a natural environment to study these patterns as it provides routine IPV immunization and bi-annual OPV campaigns. Methods We enrolled 450 households with children eligible for OPV before the February 2015 national immunization week from three communities near Orizaba, Mexico. In each community, a different proportion of eligible children received OPV (10, 30, and 70%). Transmission was measured by PCR detection of OPV in samples collected serially from vaccinated children, their households, and other families in the community. Positive samples were reanalyzed to quantify revertant proportion (RP), the percent of OPV VAPP mutants found in positive samples. Results 15,109 samples were collected and analyzed from 1,828 participants. 554 (3.7%) were OPV positive, and 194 have been reanalyzed for RP to date. The majority of OPV 1 positive samples showed 75% revertant by Day 7 (Figure 2), while the majority of OPV 3 positive samples were >75% revertant by Day 4 (Figure 3). Conclusion OPV 1 appears to be more stable than OPV 2 and OPV 3, remaining

Background Children with intestinal failure (IF) represent 20% of bloodstream infection (BSI) pediatric hospitalizations. We studied the microbiology and associated outcomes of this population. Methods Retrospective cohort study of children ≤18 years with IF dependent on parenteral nutrition (PN), with ≥1 BSI from January 2007 to December 2016. Organisms causing BSI were divided into skin or GI bacteria and fungi based on human habitat and kingdom. The impact of ethanol lock therapy (ELT) and clinical diagnosis of small intestine bacterial overgrowth (SIBO) on the type of these organisms was evaluated. Antimicrobial utilization and outcome measures for BSI were collected. Results There were 254 BSIs in 54 children resulting from GI bacteria (58%), skin bacteria (39%), and fungi (16%) with 11% containing >1 group. The proportion of skin bacteria was significantly higher on ELT (27% off vs. 45% on ELT; P = 0.003), while the proportion of GI bacteria was lower (67% off vs. 52% on ELT; P = 0.018). Significantly more fungal BSIs were seen in older children: mean age 4.2 years (95% CI: 2.9–5.5) vs. 2.7 years (95% CI: 2.3–3) with other organisms; P = 0.014. Fungal BSIs were more common with SIBO (18% vs. 5% with and without SIBO; P = 0.013). Twenty-eight organisms were resistant to ceftazidime, and five to cefepime. Hospitalization days totaled 2,432 (median 8 days), with 21 pediatric critical care admissions totaling 156 days. There were six deaths, none related to BSI, 18/54 children were weaned off PN, and four had liver and intestinal transplants. Median course of antimicrobial therapy was 14 days. Conclusion The majority BSIs in children resulted from GI bacteria, suggesting intestinal translocation; these infections were not less common in older children despite increased intestinal mass, signifying continued translocation. BSI with GI organisms was not more common in children with SIBO despite increased intestinal bacterial load, possibly due to antibiotic suppressive therapy, which instead lead to more fungal BSIs. Prevention of BSI by ELT was less effective for skin bacteria which may require different regimens or strategies. BSI causes frequent and prolonged hospitalizations including need for intensive care, but deaths are rare. Disclosures All authors: No reported disclosures.

Background. With prolonged replication, attenuated polioviruses used in oral polio vaccine (OPV) can mutate into vaccine-derived poliovirus (VDPV) and cause poliomyelitis outbreaks. Individuals with primary humoral immunodeficiencies can become chronically infected with vaccine poliovirus, allowing it to mutate into immunodeficiency-associated VDPV (iVDPV). It is unclear if children perinatally infected with the human immunodeficiency virus (HIV), who have humoral as well as cellular immunodeficiencies, might be sources of iVDPV. Methods. We conducted a prospective study collecting stool and blood samples at multiple time points from Zimbabwean infants receiving OPV according to the national schedule. Nucleic acid extracted from stool was analyzed by real-time polymerase chain reaction for OPV serotypes. Results. We analyzed 825 stool samples: 285 samples from 92 HIV-infected children and 540 from 251 HIV-uninfected children. Poliovirus shedding was similar after 0–2 OPV doses but significantly higher in the HIVinfected versus uninfected children after ≥3 OPV doses, particularly within 42 days of an OPV dose, independent of seroconversion status. HIV infection was not associated with prolonged or persistent poliovirus shedding. HIV infection was associated with significantly lower polio seroconversion rates. Conclusions. HIV infection is associated with decreased mucosal and humoral immune responses to OPV but not the prolonged viral shedding required to form iVDPV.

In low and middle-income countries (LMIC), transmission of HIV during breastfeeding represents a major public health challenge. Several viral, maternal clinical, immunological and genetic factors, as well as maternal-infant host factors and type of infant feeding may influence the risk of breastfeeding transmission of HIV. The mechanisms of breast milk HIV transmission are poorly understood. For mothers who are healthy and do not need combination antiretroviral therapy for their own health, randomized controlled trials have proven that administration of extended maternal triple-drug antiretroviral (ARV) prophylaxis or extended infant ARV prophylaxis can significantly reduce the risk of HIV transmission during breastfeeding. Based on this evidence, the World Health Organization (WHO) published new guidance in 2010 on the use of ARVs for treating pregnant women, and preventing mother-to-child HIV transmission (PMTCT). Although, remarkable advances have occurred in prevention of postnatal transmission during breastfeeding using antiretroviral strategies, a number of challenges remain. Future research must focus on field studies to evaluate programmatic implementation of new WHO PMTCT regimens, monitor long-term safety of ART exposure during pregnancy and lactation, and study emergence of ARV resistance (in mothers and infected infants despite prophylaxis).

Objective: Review key topics and recent literature regarding reproductive health and family planning needs for HIV-infected women in Sub-Saharan Africa. Methods: Electronic searches performed in PubMed, JSTOR, and Web of Science; identified articles reviewed for inclusion. Findings: Most HIV-infected women in Sub-Saharan Africa bear children, and access to antiretroviral therapy may increase childbearing desires and/or fertility, resulting in greater need for contraception. Most contraceptive options can be safely and effectively used by HIV-infected women. Unmet need for contraception is high in this population, with 66- 92% of women reporting not wanting another child (now or ever), but only 20-43% using contraception. During pregnancy and delivery, HIV-infected women need access to prevention of mother-to-child transmission (PMTCT) services, a skilled birth attendant, and quality post-partum care to prevent HIV infection in the infant and maximize maternal health. Providers may lack resources as well as appropriate training and support to provide such services to women with HIV. Innovations in biomedical and behavioral interventions may improve reproductive healthcare for HIVinfected women, but in Sub-Saharan Africa, models of integrating HIV and PMTCT services with family planning and reproductive health services will be important to improve reproductive outcomes. Conclusions: HIV-infected women in Sub-Saharan Africa have myriad needs related to reproductive health, including access to high-quality family planning information and options, high-quality pregnancy care, and trained providers. Integrated services that help prevent unintended pregnancy and optimize maternal and infant health before, during and after pregnancy will both maximize limited resources as well as provide improved reproductive outcomes.

High-risk human papillomavirus anal infections are common in human immunodeficiency virus-infected women. We conducted a cross-over study in 30 women seen in a California human immunodeficiency virus clinic, to test the feasibility of self-performed anal Pap smears. Women found the tests acceptable and feasible. Compared with physician-collected specimens, results were highly concordant for anal cytology (κ = 0.53) and high-risk human papillomavirus typing (κ = 0.59 inclusive of equivocal results, or κ = 0.81 excluding equivocal results).

Treatment with highly active antiretroviral therapy (HAART) reduces overall perinatal human immunodeficiency virus (HIV) type 1-related mortality. The effect of timing of HAART initiation on reduction of morbidity is not well defined. We evaluated the association of timing of HAART initiation on progression to moderate or severe disease.Retrospective, population-based study of 196 perinatally HIV-infected children followed from birth in northern California from 1988 to 2009.Of 196 children, 58% received HAART and were followed for a median of 6.2 years after HAART initiation. HAART use was associated with improved survival to the age of 5 years: no HAART, 50% versus HAART, 88%; P0.0001. However, the advantage of initial HAART over mono or dual therapy transitioning to HAART was small and not statistically significant (P = 0.23). Starting HAART before the development of moderate or severe disease delayed the median age of diagnosis of moderate disease from 0.4 years (interquartile range, [0.3-0.8]) without HAART to 3.0 years ([interquartile range, 1.9-5.8]; P0.0001) with HAART. HAART initiation after progression to moderate or severe disease was associated with decreased progression to severe disease or death, respectively (moderate to severe: 8% [3/36] with HAART vs. 84% [70/83] with no HAART, P0.0001; severe to death: 9% [6/68] with HAART vs. 73% [49/67] with no HAART, P0.0001).In perinatal HIV infection, HAART is associated with delayed progression and reduced mortality regardless of disease severity at HAART initiation. This finding reinforces US guidelines regarding HAART initiation at1 year of age if children present with most clinical category B diagnoses, regardless of CD4 measurements or plasma HIV RNA level.

Background Bloodstream infection (BSI) is a major cause of morbidity and mortality in children with intestinal insufficiency, but studies defining risk factors are lacking. We aim to identify risk factors of BSI in children with intestinal insufficiency on parenteral nutrition (PN). Methods Retrospective cohort study of children ≤ 18 years of age with intestinal insufficiency dependent on PN, who were followed at Lucile Packard Children’s Hospital (LPCH). The outcome of interest was rate of BSI. We studied proposed risk factors for BSI including sex, age, small intestine length at the time of surgery, diagnosis of short bowel syndrome (SBS), citrulline level (a marker of functioning enterocytes mass), central line (CL) days and CL breaks within 3 months. Data were represented in 6-monthintervals to study time dependent variables. Univariate analyses using t-test and regression analysis were conducted. Results Records between 2014 and 2016 were reviewed identifying 43 children who met the inclusion criteria. The rate of infection was 3.39 per 1000 CL days. Younger age increased rate of BSI by 0.23/1000 CL days per year (95% confidence interval (CI): 0.14–0.32; P = 0.015) and shorter small bowel increased it by 0.27/1000 CL days for every 10-cm of small bowel (95% CI: 0.14–0.4; P = 0.045). Recent line breaks increased BSI rate by 3.47/1000 CL days (95% CI: 2.1–4.8; P = 0.014), and diagnosis of SBS increased it by 2.69/1000 CL days (95% CI: 2.02–3.36); P < 0.001). Rates of BSI increased by 0.33/1000 CL days for every 5 nmol/ml decrease in citrulline level, but this did not reach statistical significance (P = 0.059). We found no significant association between CVL days and the rate of BSI. Conclusion Factors associated with disturbance in intestinal integrity such as shorter small intestine and diagnosis with SBS are significant risk factors for BSI, highlighting the importance of intestinal translocation in its pathogenesis. Recent line breaks are important risk factor for BSI; an opportunity for prevention. BSI rates are higher in younger children likely due to immature bowel and/or difficult compliance with hygienic precautions handling CLs. No association was found between CL days and rate of BSI, which could guide the decision of CL removal vs. salvage. Disclosures All authors: No reported disclosures.

Background As wild poliovirus is eradicated and countries switch from Oral Polio Vaccine (OPV) to Inactivated Polio Vaccine (IPV) per WHO recommendations, preventing circulation of vaccine-derived poliovirus is a top priority. However, spatial dynamics of OPV transmission are not well understood. Understanding these trends will improve resource targeting in the event of OPV reintroduction in undervaccinated communities. Mexico provides a natural environment to study OPV as it provides IPV routinely and bi-annual OPV campaigns. Methods Children in three villages near Orizaba, Mexico were randomized to three levels (10%, 30%, 70%) to receive OPV. We measured distance to nearest OPV shedding, and the amount of shedding close to unvaccinated individuals. We used maps to show the proximity and amount of shedding. Distance and density of shedding was analyzed separately using mixed effects logistic regression with random effects for household and time, adjusted for age, gender, area, and running water. Results The median distance to nearest OPV shedding was 85 meters (IQR 46, 145). The median number of shedding individuals within 200m was 3 (2, 6). Shedding and between household transmission occurred rapidly with unvaccinated individuals shedding on day one of the study (Figure 1). There was little evidence (Odds Ratio [OR] 1.04 (95% Highest Posterior Density [HPD] 0.92, 1.16)) of an association between distance (per 100 m) from OPV shedding and odds of shedding. There was some suggestion that the number of OPV shedding within 200 m may have some effect on unvaccinated shedding with OR 0.93 (HPD 0.·84, 1·01) but not at 100 or 500m. Results were consistent across the three villages. Conclusion Household structure appears to have limited value in predicting transmission of poliovirus shedding. The use of OPV results in rapid but low levels of transmission throughout the community and this would usually go undetected. The only way to avoid this is to not use OPV or to have strong controls such as quarantine, or strict hygiene protocols. After withdrawal of OPV worldwide the decision to reintroduce due to an outbreak should not be taken lightly as it appears a small amount of OPV is needed to result in transmission. Disclosures All authors: No reported disclosures.

Community circulation of oral poliovirus vaccine (OPV) likely begins with household transmission. We analyzed stool collected from Zimbabwean mothers who were infected with human immunodeficiency virus (HIV) and those who were uninfected with HIV 1 to 24 weeks after infant oral poliovirus vaccination. Overall, only 5% of the mothers had detectable OPV (16 of 304) despite high infant shedding rates. OPV shedding was similar between HIV-infected mothers and those who were uninfected (11 [6.4%] of 171 vs 5 [3.8%] of 133, respectively) and between mothers of HIV-infected infants and those of uninfected infants (2 [3.5%] of 57 vs 9 [6.3%] of 144, respectively). Mothers of vaccinated infants are unlikely to shed OPV, even when they are infected with HIV.

The new rotavirus vaccines RV5 and RV1 have been associated with small increase in intussusception risk in active vaccine surveillance studies. It is unclear what the impact might be on the overall trends of intussusception hospitalizations at a large population basis.We conducted an ecological study of hospital discharges of infants with intussusception discharge diagnosis using the California Office of Statewide Health Planning and Development database (1985-2010). We measured incidence rates (IR) of intussusception hospitalizations per 100,000 births within 3 periods (1985-1997; 2000-2005; 2006-2010) related to past, pre-introduction and post-introduction of the new rotavirus vaccines. We estimated slopes of yearly IRs within each period, changes in slopes between periods and IR ratios (IRR) of the mean IRs between periods. We did subgroup analyses for 5 age-subgroups. We also analyzed intussusception hospitalizations of infants who also had a surgical repair and/or radiologic reduction procedure code (restricted cohort).We identified 6241 intussusception hospitalizations; 4696 also had pertinent procedure codes. There was an upward trend in yearly IRs during 2006-2010 (+2 excess cases per 100,000 births per year; P = 0.023); the change in slopes between 2006-2010 and 2000-2005 was +3.2 excess cases per 100,000 births per year (P = 0.052), and the IR in 2006-2010 was 10% higher than in 2000-2005 (IRR: 1.10; 95% confidence intervals: 1.01-1.19). The IRR in 2006-2010 versus 2000-2005 for the 6-14 weeks age-subgroup was 1.90 (95% confidence intervals: 1.33-2.74). In the restricted cohort, trends were similar, though not nominally significant.We documented at a population-level a small increased risk in intussusception hospitalizations post-introduction of the new rotavirus vaccines.

Globally, paralytic poliomyelitis rates from wild poliovirus have dropped by >99% since 1988, with 406 cases reported in 2013, and only 3 countries remain with uninterrupted endemic transmission [1]. Much of this success is due to oral polio vaccine (OPV), which is used for polio vaccination in most of the developing world. However, as a live virus, OPV can mutate into forms capable of causing paralytic poliomyelitis, such as vaccine-derived poliovirus (VDPV), which caused 6 outbreaks of paralytic poliomyelitis in 2013 alone [2]. Because of these risks from OPV, the recent Polio Eradication and Endgame Strategic Plan 2013–2018 proposed by the World Health Organization (WHO) includes initiating at least 1 dose of inactivated polio vaccine (IPV) for children in all countries and subsequently phasing out OPV [3]. In addition, 2 recent studies have demonstrated that a booster dose of IPV results in significantly higher humoral and mucosal polio immunity than a booster dose of OPV in children who received OPV as their primary regimen [4, 5]. IPV has also been shown to significantly increase seroconversion rates in children who did not respond to OPV [6]. Consequently, IPV may also have a role as a booster dose in supplementary immunization campaigns to control outbreaks of wild poliovirus or VDPV infection. One difficulty with these plans is that IPV is currently too expensive for many developing countries, costing approximately 20-fold more than OPV per dose [7]. A potential method to make IPV more affordable is to decrease the dose by using intradermal instead of intramuscular administration. The skin has a particularly high concentration of dendritic cells, and it has been possible to reduce the dose of other vaccines to 20%–60% of the standard intramuscular dose without decreasing immunogenicity through intradermal administration [8]. For influenza vaccines, some studies have shown superior immunogenicity despite using fractional intradermal doses [9, 10]. However, past clinical studies of fractional-dose intradermal IPV have only used 20% of the standard dose and have all resulted in significantly lower antibody titers, compared with full-dose intramuscular IPV [7, 11–15]. To determine whether a booster of intradermal IPV using a fractional dose >20% of the standard dose can be equally effective as the full standard dose of intramuscular IPV, we conducted a randomized, controlled clinical trial comparing booster doses of 40% fractional-dose intradermal IPV, 20% fractional-dose intradermal IPV, full-dose intramuscular IPV, and 40% fractional-dose intramuscular IPV. Because this was a proof-of-concept study and the first time 40% fractional-dose intradermal IPV had been tested in humans, we elected to enroll adult volunteers at our home institution. Because all past studies of intradermal IPV were in healthy children and adults, we chose to limit enrollment to subjects infected with human immunodeficiency virus (HIV). HIV-infected adults have a reduced immunologic response to most vaccines. Although some of the decreased immunologic response seen in these individuals can be explained by the low number of CD4+ T cells associated with advanced HIV infection, the decreased immunologic response to vaccines persists even in HIV-infected individuals who are receiving antiretroviral therapy and have CD4+ T-cell counts in the normal range [16, 17]. This has been shown for multiple vaccines, including the pneumococcal vaccines [17], hepatitis B vaccines [18, 19], and influenza vaccines [16]. We have previously shown that HIV infection significantly reduces the immunologic response to OPV in Zimbabwean infants [20]. Prior studies evaluating the effect of HIV infection on the immunologic response to IPV were all conducted prior to the development of combined antiretroviral therapy, and all used full IPV doses administered intramuscularly [21–26]. In general, these studies show that advanced HIV infection decreased the response to intramuscular IPV but that HIV-infected subjects with higher CD4+ T-cell counts had similar seroprotection rates, although lower antibody titers, after intramuscular IPV vaccination, compared with uninfected controls. Since the countries with the highest rates of HIV infection primarily use OPV and will need to transition to IPV with the new WHO polio eradication plan, it is important to know whether fractional-dose intradermal IPV would be effective even in immunocompromised populations.