First name
Mohamed
Middle name
Z
Last name
Patel

Title

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

Year of Publication

2022

Number of Pages

4764-4771

Date Published

06/2022

ISSN Number

1873-2518

Abstract

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.

DOI

10.1016/j.vaccine.2022.06.059

Alternate Title

Vaccine

PMID

35773120
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Title

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

Year of Publication

2022

Number of Pages

e0262225

Date Published

2022

ISSN Number

1932-6203

Abstract

<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>

DOI

10.1371/journal.pone.0262225

Alternate Title

PLoS One

PMID

34986196
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Title

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

Year of Publication

2021

Number of Pages

Date Published

2021 Sep 11

ISSN Number

1751-7370

Abstract

<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>

DOI

10.1038/s41396-021-01108-4

Alternate Title

ISME J

PMID

34511605
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Title

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

Year of Publication

2020

Number of Pages

470-474

Date Published

2020 May

ISSN Number

1476-4687

Abstract

<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>

DOI

10.1038/s41586-020-2192-1

Alternate Title

Nature

PMID

32461640
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Title

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

Year of Publication

2019

Number of Pages

444

Date Published

2019 Nov 16

ISSN Number

1471-2431

Abstract

<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>

DOI

10.1186/s12887-019-1820-0

Alternate Title

BMC Pediatr

PMID

31733643
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Title

Predictors of Poor Outcomes among Infants with Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection in Botswana.

Year of Publication

2018

Number of Pages

Date Published

2018 Dec 05

ISSN Number

1532-0987

Abstract

<p>Among children one to 23 months of age with respiratory syncytial virus-associated acute lower respiratory infection in Botswana, young age (&lt;6 months), household use of wood as a cooking fuel, moderate or severe malnutrition, and oxygen saturation &lt;90% on room air were independent predictors of clinical non-response at 48 hours. Among HIV-uninfected infants less than six months of age, HIV exposure was associated with a higher risk of in-hospital mortality.</p>

DOI

10.1097/INF.0000000000002168

Alternate Title

Pediatr. Infect. Dis. J.

PMID

30543564
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Title

Investigating Mediators of the Poor Pneumonia Outcomes of Human Immunodeficiency Virus-Exposed but Uninfected Children.

Year of Publication

2017

Number of Pages

Date Published

2017 Nov 20

ISSN Number

2048-7207

Abstract

<p><strong>Background: </strong>Human immunodeficiency virus-exposed but uninfected (HIV-EU) children have a higher mortality rate than the children of HIV-negative mothers (HIV-unexposed). Causal mediators of the poor health outcomes of HIV-EU children remain poorly defined.</p>

<p><strong>Methods: </strong>We conducted a hospital-based prospective cohort study of children aged 1 to 23 months with clinically defined pneumonia. The children were recruited at a referral hospital in Gaborone, Botswana, between April 2012 and June 2016. The primary outcome, treatment failure at 48 hours, was assessed by an investigator blinded to the children's HIV-exposure status. We examined associations between HIV exposure and pneumonia outcomes in HIV-uninfected children. We next determined whether the effect of HIV exposure on outcomes was mediated by low-birth-weight status, nonbreastfeeding, malnutrition, in utero exposure to combination antiretroviral therapy, or pneumonia severity.</p>

<p><strong>Results: </strong>A total of 352 HIV-uninfected children were included in these analyses, including 245 (70%) HIV-unexposed and 107 (30%) HIV-EU children. Their median age was 7.4 months, and 57% were male. Treatment failure occurred in 111 (32%) children, and 19 (5.4%) children died. HIV-EU children were more likely to fail treatment (risk ratio [RR], 1.57 [95% confidence interval (CI), 1.19-2.07]; P = .002) and had a higher in-hospital mortality rate (RR, 4.50 [95% CI, 1.86-10.85]; P = .001) than HIV-unexposed children. Nonbreastfeeding mediated 47% of the effect of HIV exposure on the risk of in-hospital death.</p>

<p><strong>Conclusions: </strong>HIV-EU children have worse pneumonia outcomes than HIV-unexposed children. Nonbreastfeeding mediates nearly half of the effect of HIV exposure on pneumonia mortality. Our findings provide additional evidence for a mortality benefit of breastfeeding by HIV-EU children.</p>

DOI

10.1093/jpids/pix092

Alternate Title

J Pediatric Infect Dis Soc

PMID

29165579
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Title

Treatment Failures and Excess Mortality Among HIV-Exposed, Uninfected Children With Pneumonia.

Year of Publication

2015

Number of Pages

e117-26

Date Published

2015 Dec

ISSN Number

2048-7207

Abstract

<p><strong>BACKGROUND: </strong>Human immunodeficiency virus (HIV)-exposed, uninfected (HIV-EU) children are at increased risk of infectious illnesses and mortality compared with children of HIV-negative mothers (HIV-unexposed). However, treatment outcomes for lower respiratory tract infections among HIV-EU children remain poorly defined.</p>

<p><strong>METHODS: </strong>We conducted a hospital-based, prospective cohort study of N = 238 children aged 1-23 months with pneumonia, defined by the World Health Organization. Children were recruited within 6 hours of presentation to a tertiary hospital in Botswana. The primary outcome-treatment failure at 48 hours-was assessed by an investigator blinded to HIV exposure status.</p>

<p><strong>RESULTS: </strong>Median age was 6.0 months; 55% were male. One hundred fifty-three (64%) children were HIV-unexposed, 64 (27%) were HIV-EU, and 20 (8%) were HIV-infected; the HIV exposure status of 1 child could not be established. Treatment failure at 48 hours occurred in 79 (33%) children, including in 36 (24%) HIV-unexposed, 30 (47%) HIV-EU, and 12 (60%) HIV-infected children. In multivariable analyses, HIV-EU children were more likely to fail treatment at 48 hours (risk ratio [RR]: 1.83, 95% confidence interval [CI]: 1.27-2.64, P = .001) and had higher in-hospital mortality (RR: 4.31, 95% CI: 1.44-12.87, P = .01) than HIV-unexposed children. Differences in outcomes by HIV exposure status were observed only among children under 6 months of age. HIV-EU children more frequently received treatment with a third-generation cephalosporin, but this did not reduce the risk of treatment failure in this group.</p>

<p><strong>CONCLUSIONS: </strong>HIV-EU children with pneumonia have higher rates of treatment failure and in-hospital mortality than HIV-unexposed children during the first 6 months of life. Treatment with a third-generation cephalosporins did not improve outcomes among HIV-EU children.</p>

DOI

10.1093/jpids/piu092

Alternate Title

J Pediatric Infect Dis Soc

PMID

26582879
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