Epidemiology and prevention of sepsis in young infants and the potential impact of maternal HIV infection on neonatal sepsis

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy Johannesburg, South Africa 2016Introduction: Neonatal infections contribute to 25% of all neonatal deaths, which account for approximately 44% of all under-5 childhood deaths globally. Pathogens responsible for sepsis in neonates and young infants can be acquired vertically prior to or during labour, or from the environment (community or hospital). This project evaluated the burden and aetiology of sepsis in neonates and young infants (≤90 days), and explored this association to in-utero exposure to human immunodeficiency virus. The study also included a specific focus on the epidemiology of invasive Group B Streptococcal disease in young infants. Additionally, we assessed the efficacy of intrapartum chlorhexidine vaginal washes for: (i) preventing early-onset neonatal sepsis; and (ii) vertical transmission of potentially pathogenic bacteria to the newborns. Furthermore, we evaluated risk factors for poor outcomes due to neonatal sepsis. Materials and methods: (i) A bacterial surveillance system was established at Chris Hani Baragwanath Academic Hospital (CHBAH) from 2004-2008 to identify young infants with bacterial sepsis hospitalised in the neonatal and paediatric wards. Medical and microbiological records were utilised to obtain clinical and laboratory data. Maternal HIV results were obtained from antenatal testing records or admission records. (ii) A blinded, randomised, placebo-controlled trial of 0.5% chlorhexidine maternal vaginal intrapartum wipes and newborn skin wipes was conducted at CHBAH between 2004 and 2007. Consented, eligible participants were randomised during labour to receive either chlorhexidine vaginal wipes or water external genitalia wipes. Newborns received either chlorhexidine full-body wipes (intervention arm) or foot wipes (control arm). Maternal and infant participants were followed up for admissions during the first month after delivery/ birth. A subset of 5144 maternal participants had an intrapartum lower vaginal swab collected, and skin swabs were collected from their newborns to assess colonisation with potentially pathogenic bacteria (Group B streptococcus, Escherichia coli and Klebsiella pneumoniae). Results: Group B streptococcus (GBS) was the most commonly isolated bacterial pathogen, causing 35.2% of culture-confirmed sepsis in infants ≤90 days, 41.6% of early-onset disease (EOD, 0-6 days), 40.5% of late-onset neonatal disease (LOD, 7-27 days) and 18.7% of young-infant community-acquired disease (YI-CAD, 28-90 days). Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) contribute 16.2%, 12.2% and 3.4% to sepsis in young infants. Overall, incidence (per 1000 live births) of invasive GBS disease was 2.72 (95% confidence interval [95% CI]: 2.46 to 3.01), including an incidence of 1.50 and 1.22, respectively, in infants 0-6 days and 7-90 days of age. HIV-exposed infants were at greater risk of EOD (Relative risk [RR]: 1.69; 95% CI: 1.28-2.24) and LOD (RR= 3.18; 95% CI: 2.34-4.36) than HIV-unexposed infants. GBS serotypes Ia and III caused 84.0% of invasive GBS disease in young infants. Intrapartum chlorhexidine interventional wipes was not efficacious in prevention of any of: (i) vertical transmission of pathogenic bacteria (54% vs. 55%; efficacy -0.05, 95% CI: -9.5 to 7.9) to the newborns; (ii) sepsis in first 3 days of life (3% vs. 4%; p=0.65,); (iii) sepsis in the later neonatal period (both <1%; p=0.4444); or (iv) maternal puerperal sepsis(both <1%; p=0.56). Conclusion: GBS, S. aureus, E. coli and K. pneumoniae are the most commonly isolated bacterial pathogens in neonates and infants ≤90 days old. HIV-exposed infants are at greater risk of GBS sepsis. Intrapartum chlorhexidine intervention was not efficacious in reducing vertical transmission of pathogenic bacteria, neonatal or maternal sepsis. Alternative interventions to prevent sepsis in young infants, including maternal immunisation, need to be investigated in setting such as ours where there is a high prevalence of maternal HIV infection.MT201

Assessing New York City's COVID-19 Vaccine Rollout Strategy: A Case for Risk-Informed Distribution.

From PubMed via Jisc Publications RouterHistory: accepted 2024-03-08Publication status: aheadofprintDaniel Reidpath - ORCID: 0000-0002-8796-0420 https://orcid.org/0000-0002-8796-0420This study reviews the impact of eligibility policies in the early rollout of the COVID-19 vaccine on coverage and probable outcomes, with a focus on New York City. We conducted a retrospective ecological study assessing age  65+, area-level income, vaccination coverage, and COVID-19 mortality rates, using linked Census Bureau data and New York City Health administrative data aggregated at the level of modified zip code tabulation areas (MODZCTA). The population for this study was all individuals in 177 MODZCTA in New York City. Population data were obtained from Census Bureau and New York City Health administrative data. The total mortality rate was examined through an ordinary least squares (OLS) regression model, using area-level wealth, the proportion of the population aged 65 and above, and the vaccination rate among this age group as predictors. Low-income areas with high proportions of older people demonstrated lower coverage rates (mean vaccination rate 52.8%; maximum coverage 67.9%) than wealthier areas (mean vaccination rate 74.6%; maximum coverage 99% in the wealthiest quintile) in the first 3 months of vaccine rollout and higher mortality over the year. Despite vaccine shortages, many younger people accessed vaccines ahead of schedule, particularly in high-income areas (mean coverage rate 60% among those 45-64 years in the wealthiest quintile). A vaccine program that prioritized those at greatest risk of COVID-19-associated morbidity and mortality would have prevented more deaths than the strategy that was implemented. When rolling out a new vaccine, policymakers must account for local contexts and conditions of high-risk population groups. If New York had focused limited vaccine supply on low-income areas with high proportions of residents 65 or older, overall mortality might have been lower. [Abstract copyright: © 2024. The Author(s).]pubpu

Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trial

Background Neonates born to women infected with HIV are at increased risk for invasive group B streptococcus (GBS) disease. We aimed to compare safety and immunogenicity of trivalent glycoconjugate GBS vaccine in pregnant women with and without HIV in Malawi and South Africa. Methods In our non-randomised phase 2, open-label, multicentre study, we recruited pregnant women attending two antenatal clinics, one in Blantyre, Malawi, and one in Soweto, Johannesburg, South Africa. Participants were divided into three groups on the basis of their HIV infection status (no infection, infection and high CD4 cell count [>350 cells per mu L], and infection and low CD4 cell count [>50 to <= 350 cells per mu L]) and received a 5 mu g dose of glycoconjugate GBS vaccine (serotypes Ia, Ib, and III, with CRM197 [Novartis Vaccines, Siena, Italy]) intramuscularly at 24-35 weeks' gestation. GBS serotype-specific antibody concentrations were measured before vaccination (day 1), day 15, day 31, and at delivery, and in infants at birth and day 42 of life. The primary outcomes were safety in mothers and infants and the amount of placental transfer of GBS serotype-specific antibodies from mothers to their infants. All immunogenicity and safety analyses were done on the full analysis set, including participants who, or whose mother, correctly received the vaccine and who provided at least one valid assessable serum sample. This study is registered with ClinicalTrials.gov, number NCT01412801. Findings 270 women and 266 infants were enrolled between Sept 26, 2011, and Dec 4, 2012 (90 women and 87 infants without HIV, 89 and 88 with HIV and high CD4 cell counts, and 91 and 91 with HIV and low CD4 cell counts, respectively). Seven women were lost to follow-up, six withdrew consent, one died, and two relocated. Eight infants died or were stillborn and two were lost to follow-up. Across serotypes, fold change in antibody concentrations were higher for the HIV-uninfected group than the HIV-infected groups. Transfer ratios were similar across all three groups (0.49-0.72; transfer ratio is infant geometric mean antibody concentration in blood collected within 72 h of birth divided by maternal geometric mean antibody concentration in blood collected at delivery); however, at birth, maternally derived serotype-specific antibody concentrations were lower for infants born to women infected with HIV (0.52-1.62 mu g/mL) than for those born to women not infected with HIV (2.67-3.91 mu g/mL). 151 (57%) of 265 women reported at least one solicited adverse reaction: 39 (45%) of 87 women with HIV and low CD4 cell counts, 52 (59%) of 88 women with HIV and high CD4 cell counts, and 60 (67%) of 90 women in the HIV-uninfected group. 49 (18%) of 269 women had at least one adverse event deemed possibly related to the vaccine (six [7%] in the HIV and low CD4 cell count group, 12 [13%] in the HIV and high CD4 cell count group, and 21 [23%] in the HIV-uninfected group), as did three (1%) of 266 neonates (zero, two [1%], and one [1%]); none of these events was regarded as serious. Interpretation The vaccine was less immunogenic in women infected with HIV than it was in those not infected, irrespective of CD4 cell count, resulting in lower levels of serotype-specific maternal antibody transferred to infants, which could reduce vaccine protection against invasive GBS disease. A validated assay and correlate of protection is needed to understand the potential protective value of this vaccine. Copyright (C) Heyderman et al. Open Access article distributed under the terms of CC BY

Guidance for the collection of case report form variables to assess safety in clinical trials of vaccines in pregnancy.

Vaccination in pregnancy is an effective strategy to prevent serious infections in mothers and their infants. Safety of this strategy is of principal importance to all stakeholders. As the number of studies assessing safety of vaccines in pregnancy increases, the need to ensure consistent collection and reporting of critical data to allow comparisons and data pooling becomes more important. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project aims to improve data collection and create a shared understanding of maternal, fetal and neonatal outcomes in order to progress the global agenda for vaccination in pregnancy. The guidance in this document has been developed to harmonize the data collected in case report forms used for safety monitoring in clinical trials of vaccination in pregnant women. Data to be collected is prioritized to allow applicability in diverse research settings, including low and middle-income countries. Standardized data will enable the research community to have a common base upon which to conduct meta-analyses, strengthening the applicability of outcomes to different settings

HIV-Exposed Uninfected Infants Have Increased Regulatory T Cells That Correlate With Decreased T Cell Function

Background: HIV-exposed uninfected infants (HEU) are at higher risk of severe infections, hospitalizations and death compared with HIV-unexposed uninfected infants (HUU), but the immune deficit underlying it is not known. To address this gap, we investigated T cell functionality and its relationship to phenotypic profiles of T cells and antigen presenting cells (APC) in HEU and HUU.Methods: Blood mononuclear cells from 55 HEU and 16 HUU were stimulated with Staphylococcal Enterotoxin B (SEB) or mock for 72 h, and tested by flow cytometry for proliferation and expression of Th1, Th2, and regulatory (Treg) markers. In parallel, cells were phenotypically assessed for differentiation profiles of Treg, conventional T cell (Tconv) and APC in unstimulated cells.Results: HEU had lower CD4+ functional responses to SEB/mock and similar CD8+ responses compared with HUU. In the phenotypic T cell panel, HEU showed higher proportions of CD4+ and CD8+ Treg expressing IL10, FOXP3, and CD25; higher effector Tconv and Treg; and lower naïve and CD4+TGFβ+ Treg compared with HUU. In the phenotypic APC panel, HEU showed higher proportions of CD1c+ cDC2, CD123+ pDC, CD16+ inflammatory monocytes and cDC and higher expression of CD103 on CD1c-CD123-CD16-cDC1 compared with HUU. Regression analyses adjusted for HIV exposure and multiple comparisons showed that higher CD8+IL10+ and CD8+FOXP3+ Treg in unstimulated cells were associated with lower CD8+ T cell functional responses to SEB/mock. Functionality was not affected by Tconv differentiation, but higher APC activation in aggregate was associated with higher CD8+IL10+ Treg responses to SEB.Conclusions: T cell functionality was decreased in HEU compared with HUU. High CD8+ Treg proportions were the most important predictors of decreased T cell functionality in HEU and HUU

Low birth weight: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data

Need for developing case definitions and guidelines for data collection, analysis, and presentation for low birth weight as an adverse event following maternal immunization The birth weight of an infant is the first weight recorded after birth, ideally measured within the first hours after birth, before significant postnatal weight loss has occurred. Low birth weight (LBW) is defined as a birth weight of less than 2500 g (up to and including 2499 g), as per the World Health Organization (WHO) [1]. This definition of LBW has been in existence for many decades. In 1976, the 29th World Health Assembly agreed on the currently used definition. Prior to this, the definition of LBW was ‘2500 g or less’. Low birth weight is further categorized into very low birth weight (VLBW, <1500 g) and extremely low birth weight (ELBW, <1000 g) [1]. Low birth weight is a result of preterm birth (PTB, short gestation <37 completed weeks), intrauterine growth restriction (IUGR, also known as fetal growth restriction), or both. The term low birth weight refers to an absolute weight of <2500 g regardless of gestational age. Small for gestational age (SGA) refers to newborns whose birth weight is less than the 10th percentile for gestational age. This report will focus specifically on birth weight <2500 g. Further details related to case definitions for PTB [2], IUGR and SGA are included in separate GAIA reports

Assessing Community Acceptance of Maternal Immunisation in Rural KwaZulu-Natal, South Africa: A Qualitative Investigation.

Despite the significant benefits of maternal immunisation, uptake remains low in many parts of the world. In this qualitative study, we aimed to assess the factors that influence pregnant women's decision to engage with maternal immunisation in rural KwaZulu-Natal, South Africa. We conducted in-depth interviews with a total of 28 purposively sampled pregnant women and key informants using semi-structured topic guides. Data analysis was conducted using a modified Health Belief Model framework that included constructs of barriers to action, modifying factors of cue to action and perceived social norms. The findings show that traditional customs and institutional barriers such as low-quality health service delivery, long queues, and distance to the health facilities, immunisation vaccine stockouts and low levels of maternal knowledge influence the choice and decision to engage with maternal immunisation. Understanding health-related behaviours and addressing barriers to care is important in facilitating vaccination uptake. This study contributes to the understanding of maternal immunisation uptake in low-resource settings