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

2022

4764-4771

06/2022

1873-2518

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.

10.1016/j.vaccine.2022.06.059

Vaccine

35773120

Optimising the management of childhood acute diarrhoeal disease using a rapid test-and- treat strategy and/or Lactobacillus reuteri DSM 17938: a multicentre, randomised, controlled, factorial trial in Botswana.

2022

2022 Apr

2059-7908

<p><strong>INTRODUCTION: </strong>The study aim was to determine if rapid enteric diagnostics followed by the provision of targeted antibiotic therapy ('test-and-treat') and/or&nbsp;<em>Lactobacillus reuteri</em> DSM 17938 would improve outcomes in children hospitalised in Botswana with acute gastroenteritis.</p>

<p><strong>METHODS: </strong>This was a multicentre, randomised, factorial, controlled, trial. Children aged 2-60 months admitted for acute non-bloody diarrhoea to four hospitals in southern Botswana were eligible. Participants were assigned to treatment groups by web-based block randomisation. Test-and-treat results were not blinded, but participants and research staff were blinded to <em>L. reuteri</em>/placebo assignment; this was dosed as 1×10⁸ cfu/mL by mouth daily and continued for 60 days. The primary outcome was 60-day age-standardised height (HAZ) adjusted for baseline HAZ. All analyses were by intention to treat. The trial was registered at Clinicaltrials.gov.</p>

<p><strong>RESULTS: </strong>Recruitment began on 12 June 2016 and continued until 24 October 2018. There were 66 participants randomised to the test-and-treat plus <em>L. reuteri&nbsp;</em>group, 68 randomised to the test-and-treat plus placebo group, 69 to the standard care plus <em>L. reuteri&nbsp;</em>group and 69 to the standard care plus placebo group. There was no demonstrable impact of the test-and-treat intervention (mean increase of 0.01 SD, 95% CI -0.14 to 0.16 SD) or the&nbsp;<em>L. reuteri</em> intervention (mean decrease of 0.07 SD, 95% CI -0.22 to 0.08 SD) on adjusted HAZ at 60 days.</p>

<p><strong>CONCLUSIONS: </strong>In children hospitalised for acute gastroenteritis in Botswana, neither a test-and-treat algorithm targeting enteropathogens, nor a 60-day course of <em>L. reuteri&nbsp;</em>DSM 17938, were found to markedly impact linear growth or other important outcomes. We cannot exclude the possibility that test-and-treat will improve the care of children with significant enteropathogens (such as <em>Shigella</em>) in their stool.</p>

<p><strong>TRIAL REGISTRATION NUMBER: </strong>NCT02803827.</p>

10.1136/bmjgh-2021-007826

BMJ Glob Health

35418412

Evolution of pneumococcal serotype epidemiology in Botswana following introduction of 13-valent pneumococcal conjugate vaccine.

2022

e0262225

2022

1932-6203

<p>Pneumococcal conjugate vaccines reduce the burden of invasive pneumococcal disease, but the sustained effect of these vaccines can be diminished by an increase in disease caused by non-vaccine serotypes. To describe pneumococcal serotype epidemiology in Botswana following introduction of 13-valent pneumococcal conjugate vaccine (PCV-13) in July 2012, we performed molecular serotyping of 268 pneumococcal strains isolated from 221 children between 2012 and 2017. The median (interquartile range) age of the children included in this analysis was 6 (3,12) months. Fifty-nine percent of the children had received at least one dose of PCV-13 and 35% were fully vaccinated with PCV-13. While colonization by vaccine serotypes steadily declined following PCV-13 introduction, 25% of strains isolated more than 3 years after vaccine introduction were PCV-13 serotypes. We also observed an increase in colonization by non-vaccine serotypes 21 and 23B, which have been associated with invasive pneumococcal disease and antibiotic resistance in other settings.</p>

10.1371/journal.pone.0262225

PLoS One

34986196

Non-diphtheriae Corynebacterium species are associated with decreased risk of pneumococcal colonization during infancy.

2021

2021 Sep 11

1751-7370

<p>Streptococcus pneumoniae (pneumococcus) is a leading cause of severe infections among children and adults. Interactions between commensal microbes in the upper respiratory tract and S. pneumoniae are poorly described. In this study, we sought to identify interspecies interactions that modify the risk of S. pneumoniae colonization during infancy and to describe development of the upper respiratory microbiome during infancy in a sub-Saharan African setting. We collected nasopharyngeal swabs monthly (0-6 months of age) or bimonthly (6-12 months of age) from 179 mother-infant dyads in Botswana. We used 16S ribosomal RNA gene sequencing to characterize the nasopharyngeal microbiome and identified S. pneumoniae colonization using a species-specific PCR assay. We detect S. pneumoniae colonization in 144 (80%) infants at a median age of 71 days and identify a strong negative association between the relative abundance of the bacterial genera Corynebacterium within the infant nasopharyngeal microbiome and the risk of S. pneumoniae colonization. Using in vitro cultivation experiments, we demonstrate growth inhibition of S. pneumoniae by secreted factors from strains of several Corynebacterium species isolated from these infants. Finally, we demonstrate that antibiotic exposures and the winter season are associated with a decline in the relative abundance of Corynebacterium within the nasopharyngeal microbiome, while breastfeeding is associated with an increase in the Corynebacterium relative abundance. Our findings provide novel insights into the interspecies interactions that contribute to colonization resistance to S. pneumoniae and suggest that the nasopharyngeal microbiome may be a previously unrecognized mechanism by which environmental factors influence the risk of pneumococcal infections during childhood. Moreover, this work lays the foundation for future studies seeking to use targeted manipulation of the nasopharyngeal microbiome to prevent infections caused by S. pneumoniae.</p>

10.1038/s41396-021-01108-4

ISME J

34511605

Broad spectrum antibiotics and risk of graft-versus-host disease in pediatric patients transplanted for acute leukemia: association of carbapenem use with risk of acute GVHD.

2021

177.e1-177.e8

2021 Feb

2666-6367

<p>Variation in the gastrointestinal microbiota after hematopoietic cell transplantation has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD-risk in pediatric patients transplanted for acute leukemia. We performed a retrospective analysis in a dataset merged from two sources: (1) Center for International Blood and Marrow Transplant Research, an observational transplant registry, and (2) Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to three classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) anti-pseudomonal penicillins and (3) carbapenems. The primary outcome was grade 2-4 aGVHD; secondary outcomes were grade 3-4 aGVHD and lower gastrointestinal (GI) GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (sub-cohort) included transplant characteristics, GVHD-risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2,550 patients at 36 centers; the sub-cohort included 1,174 patients. In adjusted models, carbapenems were associated with an increased risk of grade 2-4 aGVHD in the full cohort (aOR 1.24, 95%CI 1.02-1.51) and sub-cohort (subHR 1.31, 95%CI 0.99-1.72), as well as with an increased risk of grade 3-4 aGVHD (subHR 1.77, 95%CI 1.25-2.52). Early carbapenem exposure (prior to day 0) especially impacted aGVHD-risk. For antipseudomonal penicillins the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad spectrum antibiotics, should be used judiciously in pediatric transplant patients to minimize aGVHD-risk. Further research is needed to clarify the mechanism underlying this association.</p>

10.1016/j.jtct.2020.10.012

Transplant Cell Ther

33718896

Effect of Haemophilus influenzae type b and 13-valent pneumococcal conjugate vaccines on childhood pneumonia hospitalizations and deaths in Botswana.

2020

2020 Jul 08

1537-6591

<p><strong>BACKGROUND: </strong>Globally, pneumonia is the leading cause of death among children. Few data exist regarding the effect of Haemophilus influenzae type b (Hib) vaccine and 13-valent pneumococcal conjugate vaccine (PCV-13) on the burden of childhood pneumonia in African settings.</p>

<p><strong>METHODS: </strong>We collected data on children 1 to 59 months of age at three hospitals in Botswana. Hib vaccine and PCV-13 were introduced in Botswana in November 2010 and July 2012, respectively. We compared pneumonia hospitalizations and deaths pre-vaccine (January 2009 to October 2010) to post-vaccine (January 2013 to December 2017) using seasonally-adjusted interrupted time-series analyses.</p>

<p><strong>FINDINGS: </strong>We identified 6943 pneumonia hospitalizations and 201 pneumonia deaths. In the pre-vaccine period, pneumonia hospitalizations and deaths increased by 24% (rate: 1.24; 95% CI: 0.94, 1.64) and 59% (rate: 1.59; 95% CI: 0.87, 2.90) per year, respectively. Vaccine introduction was associated with a 48% (95% CI: 29%, 62%) decrease in the number of pneumonia hospitalizations and a 50% (95% CI: 1%, 75%) decrease in the number of pneumonia deaths between the end of the pre-vaccine period (October 2010) and the beginning of the post-vaccine period (January 2013). During the post-vaccine period, pneumonia hospitalizations and deaths declined by 6% (rate 0.94; 95% CI: 0.89, 0.99) and 22% (rate: 0.78; 95% CI: 0.67, 0.92) per year, respectively.</p>

<p><strong>INTERPRETATION: </strong>Pneumonia hospitalizations and deaths among children declined sharply following introduction of Hib vaccine and PCV-13 in Botswana. This effect was sustained for more than five years after vaccine introduction, supporting the long-term effectiveness of these vaccines in preventing childhood pneumonia in Botswana.</p>

10.1093/cid/ciaa919

Clin. Infect. Dis.

32634831

Interpretation of pediatric chest radiographs by non-radiologist clinicians in Botswana using World Health Organization criteria for endpoint pneumonia.

2020

913-922

2020 Jun

1432-1998

<p><strong>BACKGROUND: </strong>In low- and middle-income countries, chest radiographs are most frequently interpreted by non-radiologist clinicians.</p>

<p><strong>OBJECTIVE: </strong>We examined the reliability of chest radiograph interpretations performed by non-radiologist clinicians in Botswana and conducted an educational intervention aimed at improving chest radiograph interpretation accuracy among non-radiologist clinicians.</p>

<p><strong>MATERIALS AND METHODS: </strong>We recruited non-radiologist clinicians at a referral hospital in Gaborone, Botswana, to interpret de-identified chest radiographs for children with clinical pneumonia. We compared their interpretations with those of two board-certified pediatric radiologists in the United States. We evaluated associations between level of medical training and the accuracy of chest radiograph findings between groups, using logistic regression and kappa statistics. We then developed an in-person training intervention led by a pediatric radiologist. We asked participants to interpret 20 radiographs before and immediately after the intervention, and we compared their responses to those of the facilitating radiologist. For both objectives, our primary outcome was the identification of primary endpoint pneumonia, defined by the World Health Organization as presence of endpoint consolidation or endpoint effusion.</p>

<p><strong>RESULTS: </strong>Twenty-two clinicians interpreted chest radiographs in the primary objective; there were no significant associations between level of training and correct identification of endpoint pneumonia; concordance between respondents and radiologists was moderate (κ=0.43). After the training intervention, participants improved agreement with the facilitating radiologist for endpoint pneumonia from fair to moderate (κ=0.34 to κ=0.49).</p>

<p><strong>CONCLUSION: </strong>Non-radiologist clinicians in Botswana do not consistently identify key chest radiographic findings of pneumonia. A targeted training intervention might improve non-radiologist clinicians' ability to interpret chest radiographs.</p>

10.1007/s00247-020-04625-0

Pediatr Radiol

32524176

The stepwise assembly of the neonatal virome is modulated by breastfeeding.

2020

470-474

2020 May

1476-4687

<p>The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which-in some cases-leads to gastrointestinal disorders. Here we show that the assembly of the viral community in neonates takes place in distinct steps. Fluorescent staining of virus-like particles purified from infant meconium or early stool samples shows few or no particles, but by one month of life particle numbers increase to 10 per gram, and these numbers seem to persist throughout life. We investigated the origin of these viral populations using shotgun metagenomic sequencing of virus-enriched preparations and whole microbial communities, followed by targeted microbiological analyses. Results indicate that, early after birth, pioneer bacteria colonize the infant gut and by one month prophages induced from these bacteria provide the predominant population of virus-like particles. By four months of life, identifiable viruses that replicate in human cells become more prominent. Multiple human viruses were more abundant in stool samples from babies who were exclusively fed on&nbsp;formula milk compared with those fed partially or fully on breast milk, paralleling reports that breast milk can be protective against viral infections. Bacteriophage populations also differed depending on whether or not the infant was breastfed. We show that the colonization of the infant gut is stepwise, first mainly by temperate bacteriophages induced from pioneer bacteria, and later by viruses that replicate in human cells; this second phase is modulated by breastfeeding.</p>

10.1038/s41586-020-2192-1

Nature

32461640

The prevalence and clinical characteristics of pertussis-associated pneumonia among infants in Botswana.

2019

444

2019 Nov 16

1471-2431

<p><strong>BACKGROUND: </strong>There are scant data on the prevalence and clinical course of pertussis disease among infants with pneumonia in low- and middle-income countries. While pertussis vaccination coverage is high (≥90%) among infants in Botswana, human immunodeficiency virus (HIV) infection affects nearly one-third of pregnancies. We aimed to evaluate the prevalence and clinical course of pertussis disease in a cohort of HIV-unexposed uninfected (HUU), HIV-exposed uninfected (HEU), and HIV-infected infants with pneumonia in Botswana.</p>

<p><strong>METHODS: </strong>We recruited children 1-23 months of age with clinical pneumonia at a tertiary care hospital in Gaborone, Botswana between April 2012 and June 2016. We obtained nasopharyngeal swab specimens at enrollment and tested these samples using a previously validated in-house real-time PCR assay that detects a unique sequence of the porin gene of Bordetella pertussis.</p>

<p><strong>RESULTS: </strong>B. pertussis was identified in 1/248 (0.4%) HUU, 3/110 (2.7%) HEU, and 0/33 (0.0%) HIV-infected children. All pertussis-associated pneumonia cases occurred in infants 1-5 months of age (prevalence, 1.0% [1/103] in HUU and 4.8% [3/62] in HEU infants). No HEU infants with pertussis-associated pneumonia were taking cotrimoxazole prophylaxis at the time of hospital presentation. One HUU infant with pertussis-associated pneumonia required intensive care unit admission for mechanical ventilation, but there were no deaths.</p>

<p><strong>CONCLUSIONS: </strong>The prevalence of pertussis was low among infants and young children with pneumonia in Botswana. Although vaccination against pertussis in pregnancy is designed to prevent classical pertussis disease, reduction of pertussis-associated pneumonia might be an important additional benefit.</p>

10.1186/s12887-019-1820-0

BMC Pediatr

31733643

Placental Transfer of Respiratory Syncytial Virus Antibody Among HIV-Exposed, Uninfected Infants.

2019

2019 Sep 24

2048-7207

<p><strong>BACKGROUND: </strong>Maternal human immunodeficiency virus (HIV) infection is associated with lower placental transfer of antibodies specific to several childhood pathogens. Our objective for this study was to evaluate the effect of maternal HIV infection on the placental transfer of respiratory syncytial virus (RSV)-neutralizing antibodies.</p>

<p><strong>METHODS: </strong>We conducted a cross-sectional study of mothers and their newborn infants at a tertiary hospital in Gaborone, Botswana, between March 2015 and December 2015. We measured serum RSV antibody levels by using a microneutralization assay. We used multivariable linear regression to evaluate the effect of maternal HIV infection on maternal RSV antibody levels, placental transfer of RSV antibodies, and newborn RSV antibody levels.</p>

<p><strong>RESULTS: </strong>Of 316 mothers, 154 (49%) were infected with HIV. The placental transfer ratios for RSV antibodies to HIV-exposed, uninfected (HEU) and HIV-unexposed, uninfected infants were 1.02 and 1.15, respectively. The geometric mean titer (95% confidence interval) of RSV-neutralizing antibodies was 2657 (2251-3136) among HEU newborns and 2911 (2543-3331) among HIV-unexposed, uninfected newborns. In multivariable analyses, maternal HIV infection was associated with lower placental transfer of RSV antibodies (P = .02) and a lower level of RSV antibodies among newborns (P = .002). Among HEU newborns, higher birth weight (P = .004) and an undetectable maternal antenatal viral load (P = .01) were associated with more effective placental transfer of RSV antibodies.</p>

<p><strong>CONCLUSIONS: </strong>Maternal human immunodeficiency virus (HIV) infection is associated with lower mother-to-fetus transfer of serum RSV-neutralizing antibodies. HEU infants should be prioritized for preventive interventions for RSV. Maternal viral suppression through combination antiretroviral therapy has the potential to improve immunity to RSV among HIV-exposed infants.</p>

10.1093/jpids/piz056

J Pediatric Infect Dis Soc

31549157