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

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

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

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

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

2018

2018 Dec 05

1532-0987

<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>

10.1097/INF.0000000000002168

Pediatr. Infect. Dis. J.

30543564

Pneumococcal Colonization and the Nasopharyngeal Microbiota of Children in Botswana.

2018

2018 Aug 27

1532-0987

<p><strong>BACKGROUND: </strong>Nasopharyngeal colonization precedes infections caused by Streptococcus pneumoniae. A more detailed understanding of interactions between S. pneumoniae and the nasopharyngeal microbiota of children could inform strategies to prevent pneumococcal infections.</p>

<p><strong>METHODS: </strong>We collected nasopharyngeal swabs from children 1 to 23 months of age in Botswana between August 2012 and June 2016. We tested samples for S. pneumoniae and common respiratory viruses using PCR. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used random forest models to identify clinical variables and bacterial genera that were associated with pneumococcal colonization.</p>

<p><strong>RESULTS: </strong>Mean age of the 170 children included in this study was 8.3 months. Ninety-six (56%) children were colonized with S. pneumoniae. Pneumococcal colonization was associated with older age (P=0.0001), a lack of electricity in the home (P=0.02), and household use of wood as a cooking fuel (P=0.002). Upper respiratory symptoms were more frequent in children with S. pneumoniae colonization (60% vs. 32%; P=0.001). Adjusting for age, nasopharyngeal microbiota composition differed in colonized and noncolonized children (P=0.001). S. pneumoniae colonization was associated with a higher relative abundance of Moraxella (P=0.001) and lower relative abundances of Corynebacterium (P=0.001) and Staphylococcus (P=0.03). A decision tree model containing the relative abundances of bacterial genera had 81% sensitivity and 85% specificity for the determination of S. pneumoniae colonization status.</p>

<p><strong>CONCLUSIONS: </strong>S. pneumoniae colonization is associated with characteristic alterations of the nasopharyngeal microbiota of children. Prospective studies should determine if nasopharyngeal microbial composition alters the risk of pneumococcal colonization and thus could be modified as a novel pneumonia prevention strategy.</p>

10.1097/INF.0000000000002174

Pediatr. Infect. Dis. J.

30153231

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

2017

2017 Nov 20

2048-7207

<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>

10.1093/jpids/pix092

J Pediatric Infect Dis Soc

29165579

The Nasopharyngeal Microbiota of Children with Respiratory Infections in Botswana.

2017

2017 Apr 10

1532-0987

<p><strong>BACKGROUND: </strong>Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the nasopharynx are a reservoir for pneumonia pathogens and remain poorly described in African children.</p>

<p><strong>METHODS: </strong>Nasopharyngeal swabs were collected from children with pneumonia (N=204), children with upper respiratory infection symptoms (N=55), and healthy children (N=60) in Botswana between April 2012 and April 2014. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used partitioning around medoids to cluster samples into microbiota biotypes. We then used multivariable logistic regression to examine whether microbiota biotypes were associated with pneumonia and upper respiratory infection symptoms.</p>

<p><strong>RESULTS: </strong>Mean ages of children with pneumonia, children with upper respiratory infection symptoms, and healthy children were 8.2, 11.4, and 8.0 months, respectively. Clustering of nasopharyngeal microbiota identified five distinct biotypes: Corynebacterium/Dolosigranulum-dominant (23%), Haemophilus-dominant (11%), Moraxella-dominant (24%), Staphylococcus-dominant (13%), and Streptococcus-dominant (28%). The Haemophilus-dominant [odds ratio (OR): 13.55, 95% confidence interval (CI): 2.10-87.26], the Staphylococcus-dominant (OR: 8.27, 95% CI: 2.13-32.14), and the Streptococcus-dominant (OR: 39.97, 95% CI: 6.63-241.00) biotypes were associated with pneumonia. The Moraxella-dominant (OR: 3.71, 95% CI: 1.09-12.64) and Streptococcus-dominant (OR: 12.26, 95% CI: 1.81-83.06) biotypes were associated with upper respiratory infection symptoms. In children with pneumonia, HIV infection was associated with a lower relative abundance of Dolosigranulum (P=0.03).</p>

<p><strong>CONCLUSIONS: </strong>Pneumonia and upper respiratory infection symptoms are associated with distinct nasopharyngeal microbiota biotypes in African children. A lower abundance of the commensal genus Dolosigranulum may contribute to the higher pneumonia risk of HIV-infected children.</p>

10.1097/INF.0000000000001607

Pediatr. Infect. Dis. J.

28399056