Publications
177 results found
Seddon J, Whittaker E, Kampmann B, et al., 2019, The evolving research agenda for paediatric tuberculosis infection, Lancet Infectious Diseases, Vol: 19, Pages: e323-e329, ISSN: 1473-3099
Following exposure to tuberculosis and subsequent infection, children often progress to tuberculosis disease more rapidly than adults. And yet the natural history of tuberculosis in children, as a continuum from exposure to infection and then to disease, is poorly understood. Children are rarely diagnosed with tuberculosis infection in routine care in international settings and few receive tuberculosis infection treatment. In this Personal View, we review the most up-to-date knowledge in three areas of childhood tuberculosis infection—namely, pathophysiology, diagnosis, and treatment. We then outline what is missing in each of these three areas to generate a priority research agenda. Finally, we suggest potential study designs that might answer these questions. Understanding of pathophysiology could be improved through animal models, laboratory studies assessing the immunological responses of blood or respiratory samples to Mycobacterium spp in vitro, as well as investigating immune responses in children exposed to tuberculosis. Identification of children with sub-clinical disease and at high risk of progression to clinically overt disease, would allow treatment to be targeted at those most likely to benefit. Optimisation and discovery of novel treatments for tuberculosis infection in children should account for mechanisms of action of tuberculosis drugs, as well as child-specific factors including pharmacokinetics and appropriate formulations. To conduct these studies, a change in mindset is required, with a recognition that the diagnosis and treatment of tuberculosis infection in children is a necessary component in addressing the overall tuberculosis epidemic. Collaboration between stakeholders will be required and funding will need to increase, both for research and implementation. The consequences of inaction, however, will lead to further decades of children suffering from what should increasingly be recognised as a preventable disease.
Rice T, Diavatopoulos D, Smits G, et al., 2019, Antibody responses to Bordetella pertussis and other childhood vaccines in infants born to mothers who received pertussis vaccine in pregnancy- a prospective, observational cohort study from the UK, Clinical and Experimental Immunology, Vol: 197, Pages: 1-10, ISSN: 1365-2249
The maternal Tdap (tetanus, diphtheria and acellular pertussis) vaccination program in the UK has successfully reduced cases of pertussis in young infants. In addition to prevention of pertussis cases, it is also important to investigate persistence of maternal antibody during infancy and possible interference of maternal antibodies with infant responses to vaccines. We recruited mother‐infant pairs from vaccinated and unvaccinated pregnancies and measured concentrations of IgG against pertussis toxin (PTx), filamentous hemagglutinin (FHA), pertactin (Prn), diphtheria toxin (DTx), tetanus toxoid (TTx) Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae in mothers and infants at birth, and in infants at 7 weeks and at 5 months. 31 mother‐infant pairs were tested. Tdap‐vaccinated women had significantly higher antibody against Tdap antigens, compared to unvaccinated women (DTx p=0.01; PTx, FHA, Prn and TTx p<0.001). All antibodies were actively transferred to the infants (transfer ratio >1) with higher transfer of DTx (P=0.04) and TTx (P=0.02) antibody in Tdap‐vaccinated pregnancies compared to unvaccinated. Infants from Tdap‐vaccinated pregnancies had significantly elevated antibodies to all antigens at birth (p<0.001) and at 7 weeks (FHA, Prn, TTx p<0.001; DTx p=0.01; PTx p=0.004) compared to infants from unvaccinated pregnancies. Infants from Tdap‐vaccinated and unvaccinated pregnancies had comparable antibody concentrations following primary pertussis immunization (PTx p=0.77; FHA p=0.58; Prn p=0.60; DTx p=0.09; TTx p=0.88). These results support maternal immunisation as a method of protecting vulnerable infants during their first weeks of life.
Roy RB, Sambou B, Uhia I, et al., 2019, An auto-luminescent fluorescent BCG whole blood assay to enable evaluation of paediatric mycobacterial responses using minimal blood volumes, Frontiers in Pediatrics, Vol: 7, ISSN: 2296-2360
Introduction: Understanding protective human immunity against mycobacteria is critical to developing and evaluating new vaccines against tuberculosis. Children are the most susceptible population to infection, disease, and death from tuberculosis, but also have the strongest evidence of BCG-inducible protection. Limited amounts of blood can be obtained for research purposes in paediatrics and therefore there is a need for high-yield, low-volume, human immunology assays.Methods: We transformed BCG Danish with plasmids encoding luciferase full operon derived from Photorhabdus luminescens together with Green Fluorescent Protein and antibiotic selection markers. We characterised the luminescent and fluorescent properties of this recombinant BCG strain (BCG-GFP-LuxFO) using a luminometer and flow cytometry and developed a paediatric whole blood in vitro infection model.Results: Luminescence of BCG-GFP-LuxFO correlated with optical density (Spearman Rank Correlation coefficient r = 0.985, p < 0.0001) and colony forming units (CFUs) in liquid culture medium (r = 0.971, p < 0.0001). Fluorescence of BCG-GFP-LuxFO in paediatric whole blood was confirmed by flow cytometry in granulocytes and monocytes 1 h following infection. Luminescence of BCG-GFP-LuxFO in whole blood corresponded with CFUs (r = 0.7123, p < 0.0001).Conclusion: The BCG-GFP-LuxFO assay requires 225 μL whole blood per sample, from which serial luminescence measurements can be obtained, together with biochemical analysis of supernatants and cellular assay applications using its fluorescent properties. This offers the opportunity to study human-mycobacterial interactions using multiple experimental modalities with only minimal blood volumes. It is therefore a valuable method for investigating paediatric immunity to tuberculosis.
Praharaj I, Parker EPK, Giri S, et al., 2019, Influence of nonpolio enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: A study from south India, Journal of Infectious Diseases, Vol: 219, Pages: 1178-1186, ISSN: 0022-1899
BackgroundOral poliovirus vaccine (OPV) is less immunogenic in low- or middle-income than in high-income countries. We tested whether bacterial and viral components of the intestinal microbiota are associated with this phenomenon.MethodsWe assessed the prevalence of enteropathogens using TaqMan array cards 14 days before and at vaccination in 704 Indian infants (aged 6–11 months) receiving monovalent type 3 OPV (CTRI/2014/05/004588). Nonpolio enterovirus (NPEV) serotypes were identified by means of VP1 sequencing. In 120 infants, the prevaccination bacterial microbiota was characterized using 16S ribosomal RNA sequencing.ResultsWe detected 56 NPEV serotypes on the day of vaccination. Concurrent NPEVs were associated with a reduction in OPV seroconversion, consistent across species (odds ratio [95% confidence interval], 0.57 [.36–.90], 0.61 [.43–.86], and 0.69 [.41–1.16] for species A, B, and C, respectively). Recently acquired enterovirus infections, detected at vaccination but not 14 days earlier, had a greater interfering effect on monovalent type 3 OPV seroresponse than did persistent infections, with enterovirus detected at both time points (seroconversion in 44 of 127 infants [35%] vs 63 of 129 [49%]; P = .02). The abundance of specific bacterial taxa did not differ significantly according to OPV response, although the microbiota was more diverse in nonresponders at the time of vaccination.ConclusionEnteric viruses have a greater impact on OPV response than the bacterial microbiota, with recent enterovirus infections having a greater inhibitory effect than persistent infections.
Lindsey BB, Armitage EP, Kampmann B, et al., 2019, The efficacy, effectiveness, and immunogenicity of influenza vaccines in Africa: a systematic review, The Lancet Infectious Diseases, Vol: 19, Pages: e110-e119, ISSN: 1473-3099
The burden of influenza in Africa is substantial and underappreciated. Although surveillance has increased, the medical community's understanding of seasonal influenza vaccine performance remains limited. We did a systematic review, using PRISMA guidelines (PROSPERO CRD42017058107), on the efficacy, effectiveness, and immunogenicity of influenza vaccines in populations within Africa with the aim of identifying key data gaps to help direct future research. We searched Embase, MEDLINE, Global Health database, and Web of Science for published studies from database inception to May 9, 2018. Unpublished studies were identified by searching ClinicalTrials.gov and the Pan-African Clinical Trial Registry, and by contacting experts within the field. Human studies that reported influenza vaccine immunogenicity, effectiveness, and efficacy were included. 1746 articles were assessed and 23 articles were included. Only three of the 23 studies were of high quality and many studies were underpowered. All 23 studies came from only six African countries (16 from South Africa), highlighting the need for data from a broader range of African populations. The majority of studies focused on effectiveness or efficacy against laboratory supported influenza with limited data for severe outcomes. Several factors known to interfere with influenza immunisation, such as malaria, HIV, and malnutrition were under-represented in this Review and require further study. Substantial gaps exist in our understanding of influenza vaccine performance across all WHO high-risk groups in Africa. Filling these knowledge gaps is vital to guide future influenza vaccine policies.
Basu Roy R, Whittaker E, Seddon JA, et al., 2019, Tuberculosis susceptibility and protection in children, Lancet Infectious Diseases, Vol: 19, Pages: e96-e108, ISSN: 1473-3099
Children represent both a clinically important population susceptible to tuberculosis and a key group in whom to study intrinsic and vaccine-induced mechanisms of protection. After exposure to Mycobacterium tuberculosis, children aged under 5 years are at high risk of progressing first to tuberculosis infection, then to tuberculosis disease and possibly disseminated forms of tuberculosis, with accompanying high risks of morbidity and mortality. Children aged 5–10 years are somewhat protected, until risk increases again in adolescence. Furthermore, neonatal BCG programmes show the clearest proven benefit of vaccination against tuberculosis. Case-control comparisons from key cohorts, which recruited more than 15 000 children and adolescents in total, have identified that the ratio of monocytes to lymphocytes, activated CD4 T cell count, and a blood RNA signature could be correlates of risk for developing tuberculosis. Further studies of protected and susceptible populations are necessary to guide development of novel tuberculosis vaccines that could facilitate the achievement of WHO's goal to eliminate deaths from tuberculosis in childhood.
Keshavjee S, Amanullah F, Cattamanchi A, et al., 2019, Moving toward tuberculosis elimination: critical issues for research in diagnostics and therapeutics for tuberculosis infection, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 564-571, ISSN: 1073-449X
Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, causing almost 2 million deaths annually. Although this airborne disease has been treatable since 1948, global rates of TB have dropped less than two percent per year; an estimated 10 million incident cases continue to occur annually, including one million in children. While transmission of active disease is an important driver of the epidemic, the seedbed that feeds the epidemic is the more than two billion people estimated to have TB infection, five to ten percent of whom will progress to active disease during their lifetime. While any successful strategy aimed at TB elimination needs to address this reservoir of TB infection worldwide, much remains to be understood about host and pathogen factors that can be used to identify increased risk for progression to disease, and intervened upon to prevent progression from occurring. The Division of AIDS of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA, and the Harvard Medical School Center for Global Health Delivery–Dubai convened a group of scientists and stakeholders on September 28 and 29, 2017, to address knowledge gaps that affect our ability to rapidly find and treat individuals infected with Mycobacterium tuberculosis who are most likely to progress to active disease. The meeting identified a number of efforts underway to address this important gap in the collective ability to stop the global TB epidemic. Here, we review and outline the priority areas for research, diagnosis and treatment of TB infection that emerged from the meeting (Table 1), building on recent reviews in this area
White M, Idoko O, Sow S, et al., 2019, Antibody kinetics following vaccination with MenAfriVac: an analysis of serological data from randomised trials, LANCET INFECTIOUS DISEASES, Vol: 19, Pages: 327-336, ISSN: 1473-3099
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Zhong Z, Haltalli M, Holder B, et al., 2019, The impact of timing of maternal influenza immunisation on infant antibody levels at birth., Clinical and Experimental Immunology, Vol: 195, Pages: 139-152, ISSN: 1365-2249
Pregnant women and infants are at an increased risk of severe disease after influenza infection. Maternal immunisation is a potent tool to protect both of these at-risk groups. Whilst the primary aim of maternal influenza vaccination is to protect the mother, a secondary benefit is the transfer of protective antibodies to the infant. A recent study using the tetanus, diphtheria and acellular pertussis (Tdap) vaccine indicated that children born to mothers immunised in the second trimester of pregnancy had the highest antibody titres compared to children immunised in the third trimester. The aim of the current study was to investigate how timing of maternal influenza immunisation impacts infant antibody levels at birth. Antibody titres were assessed in maternal and cord blood samples by both IgG-binding ELISA and haemagglutination inhibition assay (HAI). Antibody titres to the H1N1 component were significantly higher in infants born to mothers vaccinated in either the second or third trimesters than infants born to unvaccinated mothers. HAI levels in the infant were significantly lower when maternal immunisation was performed less than four weeks before birth. These studies confirm that immunisation during pregnancy increases the antibody titre in infants. Importantly antibody levels in cord blood were significantly higher when mother was vaccinated in either trimester two or three, though titres were significantly lower if the mother was immunised less than 4 weeks before birth. Based on this data, seasonal influenza vaccination should continue to be given in pregnancy as soon as it becomes available.
Rachow A, Ivanova O, Wallis R, et al., 2019, TB sequel: incidence, pathogenesis and risk factors of long-term medical and social sequelae of pulmonary TB - a study protocol, BMC PULMONARY MEDICINE, Vol: 19, ISSN: 1471-2466
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- Citations: 26
Munoz FM, Van Damme P, Dinleyici E, et al., 2018, The Fourth International Neonatal and Maternal Immunization Symposium (INMIS 2017): Toward Integrating Maternal and Infant Immunization Programs, MSPHERE, Vol: 3
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Whittaker EA, Nicol M, Zar H, et al., 2018, Age-related waning of immune responses to BCG in healthy children supports the need for a booster dose of BCG in TB endemic countries, Scientific Reports, Vol: 8, ISSN: 2045-2322
In the absence of a more effective vaccine against TB and in the interest of developing one, it is essential to understand immune responses associated with BCG protection. We comprehensively characterized T cell populations in BCG-vaccinated children over time. Blood from 78 healthy, BCG-vaccinated children representing four age groups (<1 yr, ≥1 yr <2 yr, ≥2 yr <5 yr, ≥5 yr), was stimulated in vitro for 24 hours and 6 days with live BCG to induce effector and central memory responses. Antigen-specific CD4, CD8, γδ and regulatory T cell populations were phenotyped and intracellular and secreted cytokines measured by flow cytometry and multiplex ELISA respectively. Our results demonstrated that populations of naïve T cells predominated in infants, compared to older children. However, BCG-specific effector CD4 T cell responses were equivalent and antigen-specific CD4 T cell proliferative capacity was increased in infants compared to older children. Increases in innate immune responses including γδ T cell responses and secreted pro-inflammatory cytokines were noted with increasing age. In conclusion, we identified that the capacity to expand and differentiate effector T cells in response to BCG stimulation wanes with increasing age, which may indicate waning central memory immunity. Booster vaccination could be considered to maintain the antigen-specific central memory pool and possibly enhance the duration of protection.
Bah SY, Forster T, Dickinson P, et al., 2018, Meta-Analysis Identification of Highly Robust and Differential Immune-Metabolic Signatures of Systemic Host Response to Acute and Latent Tuberculosis in Children and Adults, FRONTIERS IN GENETICS, Vol: 9, ISSN: 1664-8021
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- Citations: 11
Rice T, Donaldson B, Bouqueau M, et al., 2018, Macrophage- but not monocyte-derived extracellular vesicles induce placental pro-inflammatory responses, Placenta, Vol: 69, Pages: 92-95, ISSN: 0143-4004
The placenta sheds extracellular vesicles (EVs), including exosomes, into the maternal circulation. We recently demonstrated that this trafficking of EVs is bi‐directional; with uptake of macrophage exosomes by the placenta inducing cytokine release. The specificity of this response is currently unknown. THP-1 cells were cultured as monocytes or differentiated to macrophages, and EVs isolated by ultra-centrifugation. The effect of EVs on human placental explants was measured by cytokine ELISA/luminex. Macrophage, but not monocyte, EVs induce the release of pro-inflammatory cytokines by the placenta. Thus, placental responses to immune cell EVs, including exosomes, reflects the phenotype of the source cell.
Whittaker EA, Nicol M, Zar H, et al., 2018, Evidence of waning BCG responses in healthy children; time to introduce a booster?, Scientific Reports, ISSN: 2045-2322
Harausz EP, Garcia-Prats AJ, Law S, et al., 2018, Treatment and outcomes in children with multidrug-resistant tuberculosis: a systematic review and individual patient data meta-analysis, PLoS Medicine, Vol: 15, ISSN: 1549-1277
BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared t
Usuf E, Mackenzie G, Ceesay L, et al., 2018, Vaccine wastage in The Gambia: a prospective observational study, BMC PUBLIC HEALTH, Vol: 18, ISSN: 1471-2458
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Kampmann B, Seddon JA, Paton J, et al., 2018, Evaluating UK National Guidance for Screening of Children for TB: A prospective multi-centre study, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1058-1064, ISSN: 1073-449X
Rationale and Objective In order to identify infected contacts of tuberculosis (TB) cases, the UK National Institute for Health and Care Excellence (NICE) recommended the addition of interferon-gamma release assays (IGRA) to the tuberculin skin test (TST) in its 2006 TB guidelines. Treatment for TB infection was no longer recommended for children screened TST-positive but IGRA-negative. We carried out a cohort study to evaluate the risk of TB disease in this group. Methods Children exposed to an infectious case of TB in their household were recruited from 11 paediatric TB clinics. TST and IGRA were carried out at baseline, IGRA repeated at 8 weeks and TST repeated if initially negative. Children were treated according to 2006 NICE guidelines and followed for 24 months. Measurements and Main Results Of 431 recruited children 392 completed the study. We diagnosed 48 (12.2%) cases of prevalent TB disease, 105 (26.8%) with TB infection and 239 (60.9%) without TB infection or disease. 18 children aged two years and above had a positive TST but persistently negative IGRA. None received TB infection treatment and none developed TB disease. 90 (26.1%) children qualified for TB infection treatment according to 2006 NICE guidelines. In contrast, 147 (42.7%) children would have qualified under revised NICE guidance, issued in 2016. Conclusions In this low prevalence setting we saw no incident cases of TB disease in children who were TST-positive but IGRA-negative and did not receive treatment for TB infection. Following the latest NICE guidance, significantly more children will require medication.
Armitage E, Camara J, Bah S, et al., 2018, Acceptability of intranasal live attenuated influenza vaccine, influenza knowledge and vaccine intent in The Gambia, Vaccine, Vol: 36, Pages: 1772-1780, ISSN: 0264-410X
BackgroundThe burden of influenza is increasingly recognised in Africa. The WHO recommends introducing influenza vaccination to high-risk groups: pregnant women, children <5 years, and the elderly. The Gambia currently has no influenza vaccination policy, but the NASIMMUNE study, a clinical trial of intranasal live attenuated influenza vaccines (LAIV) in young children provided an opportunity to study maternal attitudes towards LAIV for the first time in sub-Saharan Africa. We assess acceptability of LAIV, influenza knowledge and attitudes towards influenza vaccination in Gambian women. Additionally, we investigate predictors of willingness to receive influenza vaccine (intent) in pregnancy or seasonally for children <5.MethodsA cross-sectional survey was conducted in Gambian women at two urban health facilities. To assess LAIV acceptability, the exposure group (women whose children had received LAIV during the NASIMMUNE study) were compared to a control group (women whose children were not enrolled in the NASIMMUNE study). Demographics and health belief constructs were analysed as predictors of influenza knowledge and vaccine intent.FindingsThe exposure group (n = 150) expressed a higher preference for a nasal spray vaccine than an injection compared to the control group (n = 304) (93.3% vs. 34.9%, OR = 26.15, p < 0.0001). Those in the exposure group who preferred the nasal spray found it less distressing, safer or equally safe, and easier or equally easy to give (all p < 0.001) than injections. Influenza knowledge increased with education level (p = 0.006 for higher education vs. none), and varied between sites (p = 0.0005). Vaccine intent was >98%, but no association with influenza knowledge or difference between groups was observed. Various health belief constructs were associated with vaccine intent.ConclusionLAIV acceptability was higher in those with first-hand experience. Influenza vaccine intent was also high. Incorporation of seasonal LAIV i
Parker EPK, Praharaj I, Zekavati A, et al., 2017, Influence of the intestinal microbiota on the immunogenicity of oral rotavirus vaccine given to infants in south India, Vaccine, Vol: 36, Pages: 264-272, ISSN: 0264-410X
Oral rotavirus vaccines have consistently proven to be less immunogenic among infants in developing countries. Discrepancies in the intestinal microbiota, including a greater burden of enteropathogens and an altered commensal community composition, may contribute to this trend by inhibiting the replication of vaccine viruses. To test this possibility, we performed a nested case–control study in Vellore, India, in which we compared the intestinal microbiota of infants who responded serologically or not after two doses of Rotarix delivered at 6 and 10 weeks of age as part of a clinical trial (CTRI/2012/05/002677). The prevalence of 40 bacterial, viral, and eukaryotic pathogen targets was assessed in pre-vaccination stool samples from 325 infants using singleplex real-time PCR on a Taqman array card (TAC). In a subset of 170 infants, we assessed bacterial microbiota composition by sequencing the 16S rRNA gene V4 region. Contrary to expectations, responders were more likely than non-responders to harbor ≥1 bacterial enteropathogen at dose 1 (26% [40/156] vs 13% [21/157] of infants with TAC results who completed the study per protocol; χ2, P = .006), although this was not apparent at dose 2 (24% [38/158] vs 23% [36/158]; P = .790). Rotavirus shedding after dose 1 was negatively correlated with the replication of co-administered oral poliovirus vaccine (OPV). We observed no consistent differences in composition or diversity of the 16S bacterial microbiota according to serological response, although rotavirus shedding was associated with slightly more bacterial taxa pre-vaccination. Overall, our findings demonstrate an inhibitory effect of co-administered OPV on the first dose of Rotarix, consistent with previous studies, but in the context of OPV co-administration we did not find a strong association between other components of the intestinal microbiota at the time of vaccination and Rotarix immunogenicity.
Mensah VA, Roetynck S, Kanteh EK, et al., 2017, Safety and Immunogenicity of Malaria Vectored Vaccines Given with Routine Expanded Program on Immunization Vaccines in Gambian Infants and Neonates: A Randomized Controlled Trial, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Background: Heterologous prime-boost vaccination with chimpanzee adenovirus 63(ChAd63) and modified vaccinia virus Ankara (MVA) encoding multiple epitope stringthrombospondin-related adhesion protein (ME-TRAP) has shown acceptable safetyand promising immunogenicity in African adult and pediatric populations. If licensed,this vaccine could be given to infants receiving routine childhood immunizations. Wetherefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered withroutine Expanded Program on Immunization (EPI) vaccines.Methods: We enrolled 65 Gambian infants and neonates, aged 16, 8, or 1 week at firstvaccination and randomized them to receive either ME-TRAP and EPI vaccines or EPIvaccines only. Safety was assessed by the description of vaccine-related adverse events(AEs). Immunogenicity was evaluated using IFNγ enzyme-linked immunospot, wholebloodflow cytometry, and anti-TRAP IgG ELISA. Serology was performed to confirm allinfants achieved protective titers to EPI vaccines.Results: The vaccines were well tolerated in all age groups with no vaccine-relatedserious AEs. High-level TRAP-specific IgG and T cell responses were generated afterboosting with MVA. CD8+ T cell responses, previously found to correlate with protection,were induced in all groups. Antibody responses to EPI vaccines were not alteredsignificantly. Conclusion: Malaria vectored prime-boost vaccines co-administered with routine childhoodimmunizations were well tolerated. Potent humoral and cellular immunity inducedby ChAd63 MVA ME-TRAP did not reduce the immunogenicity of co-administered EPIvaccines, supporting further evaluation of this regimen in infant populations.Clinical Trial Registration: The clinical trial was registered on http://Clinicaltrials.gov(NCT02083887) and the Pan-African Clinical Trials Registry (PACTR201402000749217).
Le Doare K, O'Driscoll M, Turner K, et al., 2017, Intrapartum Antibiotic Chemoprophylaxis Policies for the Prevention of Group B Streptococcal Disease Worldwide: Systematic Review, Clinical Infectious Diseases, Vol: 65, Pages: S143-S151, ISSN: 1058-4838
BackgroundIntrapartum antibiotic chemoprophylaxis (IAP) prevents most early-onset group B streptococcal (GBS) disease. However, there is no description of how IAP is used around the world. This article is the sixth in a series estimating the burden of GBS disease. Here we aimed to review GBS screening policies and IAP implementation worldwide.MethodsWe identified data through (1) systematic literature reviews (PubMed/Medline, Embase, Literature in the Health Sciences in Latin America and the Caribbean [LILACS], World Health Organization library database [WHOLIS], and Scopus) and unpublished data from professional societies and (2) an online survey and searches of policies from medical societies and professionals. We included data on whether an IAP policy was in use, and if so whether it was based on microbiological or clinical risk factors and how these were applied, as well as the estimated coverage (percentage of women receiving IAP where indicated).ResultsWe received policy information from 95 of 195 (49%) countries. Of these, 60 of 95 (63%) had an IAP policy; 35 of 60 (58%) used microbiological screening, 25 of 60 (42%) used clinical risk factors. Two of 15 (13%) low-income, 4 of 16 (25%) lower-middle–income, 14 of 20 (70%) upper-middle–income, and 40 of 44 (91%) high-income countries had any IAP policy. The remaining 35 of 95 (37%) had no national policy (25/33 from low-income and lower-middle–income countries). Coverage varied considerably; for microbiological screening, median coverage was 80% (range, 20%–95%); for clinical risk factor–based screening, coverage was 29% (range, 10%–50%). Although there were differences in the microbiological screening methods employed, the individual clinical risk factors used were similar.ConclusionsThere is considerable heterogeneity in IAP screening policies and coverage worldwide. Alternative global strategies, such as maternal vaccination, are needed to enhance the scope of global preve
Hemingway C, Berk M, Anderson ST, et al., 2017, Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function., PLoS ONE, Vol: 12, ISSN: 1932-6203
The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.
Saso A, Kampmann B, 2017, Vaccine responses in newborns., Springer Seminars in Immunopathology, Vol: 39, Pages: 627-642, ISSN: 0344-4325
Immunisation of the newborn represents a key global strategy in overcoming morbidity and mortality due to infection in early life. Potential limitations, however, include poor immunogenicity, safety concerns and the development of tolerogenicity or hypo-responsiveness to either the same antigen and/or concomitant antigens administered at birth or in the subsequent months. Furthermore, the neonatal immunological milieu is polarised towards Th2-type immunity with dampening of Th1-type responses and impaired humoral immunity, resulting in qualitatively and quantitatively poorer antibody responses compared to older infants. Innate immunity also shows functional deficiency in antigen-presenting cells: the expression and signalling of Toll-like receptors undergo maturational changes associated with distinct functional responses. Nevertheless, the effectiveness of BCG, hepatitis B and oral polio vaccines, the only immunisations currently in use in the neonatal period, is proof of concept that vaccines can be successfully administered to the newborn via different routes of delivery to induce a range of protective mechanisms for three different diseases. In this review paper, we discuss the rationale for and challenges to neonatal immunisation, summarising progress made in the field, including lessons learnt from newborn vaccines in the pipeline. Furthermore, we explore important maternal, infant and environmental co-factors that may impede the success of current and future neonatal immunisation strategies. A variety of approaches have been proposed to overcome the inherent regulatory constraints of the newborn innate and adaptive immune system, including alternative routes of delivery, novel vaccine configurations, improved innate receptor agonists and optimised antigen-adjuvant combinations. Crucially, a dual strategy may be employed whereby immunisation at birth is used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous
Saso A, Donaldson B, Kampmann B, 2017, Uptake of Pertussis and Influenza Vaccinations in Pregnancy, Publisher: SPRINGER, Pages: 1508-1508, ISSN: 0340-6199
Mehring-Le Doare KEK, Bellis K, Faal A, et al., 2017, SIgA, TGF-ß1, IL-10 and TNFa in colostrum are associated with infant Group B Streptococcus colonisation, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Background: Group B Streptococcus is a major cause of mortality and morbidity in infants and is associated with transmission from a colonised mother at birth and via infected breastmilk. Although maternal/infant colonisation with Group B Streptococcus (GBS) is common, the majority of infants exposed to GBS remain unaffected. The association between breastmilk immune factors and infant colonisation and disease prevention has not been elucidated. Objectives: We have investigated the association between SIgA and cytokines in breastmilk and infant GBS colonisation and clearance. Methods: Mother/infant GBS colonisation was determined in a prospective cohort of 750 Gambian mother/infant pairs followed to day 90 of life. Anti-GBS secretory IgA bound to the surface of whole bacteria was assessed by flow cytometry and a panel of 12 cytokines quantified by mesoscale discovery in colostrum, breastmilk and serum.Results: Compared with infants receiving low anti-GBS SIgA in colostrum, infants receiving high anti-GBS SIgA were at decreased risk of GBS colonisation for serotypes III and V. Infants colonised at day 6 were twice as likely to receive colostrum with high TGF- β1, TNFα, IL10 and IL-6 compared to uncolonised infants. Infants receiving high colostral TGF- β1, TNFα and IL-6 had two-fold enhanced GBS clearance between birth and day 90. Conclusion: Our results suggest that the infant GBS colonisation risk diminishes with increasing anti-GBS SIgA antibody in breastmilk and that key maternally-derived cytokines might contribute to protection against infant colonisation. These findings might be leveraged to develop interventions including maternal vaccination that may reduce infant GBS colonisation.
Parker EPK, Praharaj I, John J, et al., 2017, Changes in the intestinal microbiota following the administration of azithromycin in a randomised placebo-controlled trial among infants in south India, Scientific Reports, Vol: 7, ISSN: 2045-2322
Macrolides are among the most widely prescribed antibiotics worldwide. However, their impact on the gut’s bacterial microbiota remains uncertain. We characterised the intestinal microbiota in 6–11 month-old infants in India who received a 3-day course of azithromycin or placebo during a randomised trial of oral poliovirus vaccine immunogenicity (CTRI/2014/05/004588). In 60 infants per study arm, we sequenced the V4 region of the bacterial 16S rRNA gene in stool samples collected before and 12 days after finishing treatment. We also tested for the presence of common bacterial, viral, and eukaryotic enteropathogens in the same samples using real-time PCR in a Taqman array card (TAC) format. Azithromycin induced a modest decline in microbiota richness and a shift in taxonomic composition driven by a reduction in the relative abundance of Proteobacteria and Verrucomicrobia (specifically Akkermansia muciniphila). The former phylum includes pathogenic strains of Escherichia coli and Campylobacter spp. that declined in prevalence based on the TAC assay. These findings differ from previous observations among older children and adults in Europe and North America, suggesting that the effects of azithromycin on the bacterial flora may be specific to the age and geographic setting of its recipients.
Nonyane BAS, Nicol MP, Andreas NJ, et al., 2017, Serologic Responses in Childhood Pulmonary Tuberculosis., Pediatric Infectious Disease Journal, Vol: 37, Pages: 1-9, ISSN: 0891-3668
BACKGROUND: Identification of the Mycobacterium tuberculosis immunoproteome and antigens associated with serologic responses in adults has renewed interest in developing a serologic test for childhood tuberculosis (TB). We investigated IgG antibody responses against M. tuberculosis antigens in children with well-characterized TB. METHODS: We studied archived sera obtained from hospitalized children with suspected pulmonary TB, and classified as having confirmed TB (culture-confirmed), unlikely TB (clinical improvement without TB treatment), or unconfirmed TB (all others). A multiplexed bead-based assay for IgG antibodies against 119 M. tuberculosis antigens was developed, validated and used to test sera. The areas under the curves (AUC) of the empiric receiver-operator characteristic curves were generated as measures of predictive ability. A cross-validated generalized linear model was used to select the most predictive combinations of antigens. RESULTS: For the confirmed TB versus unlikely TB comparison, the maximal single antigen AUC was 0.63, corresponding to sensitivity 0.60 and specificity 0.60. Older (age 60+ months) children's responses were better predictive of TB status than younger (age 12-59 months) children's, with a maximal single antigen AUC of -0.76. For the confirmed TB versus unlikely TB groups, the most predictive combinations of antigens assigned TB risk probabilities of 0.33 and 0.33, respectively, when all ages were considered, and 0.57 (IQR 0.48, 0.64) and 0.35 (IQR 0.32, 0.40) when only older children were considered. CONCLUSION: An antigen-based IgG test is unlikely to meet the performance characteristics required of a TB detection test applicable to all age groups.
Turkova A, Tebruegge M, Brinkmann F, et al., 2017, Management of child MDR-TB contacts across countries in the WHO European Region: a survey of current practice, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 21, Pages: 774-777, ISSN: 1027-3719
The World Health Organization European Region has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) in the world, resulting in many vulnerable children being exposed each year. Evidence for preventive therapy following MDR-TB exposure is limited and current guidance is conflicting. An internet-based survey was performed to determine clinical practice in this region. Seventy-two clinicians from 25 countries participated. Practices related to screening and decision-making were highly variable. Just over half provided preventive therapy for children exposed to MDR-TB; the only characteristic associated with provision was practice within the European Union (adjusted OR 4.07, 95%CI 1.33–12.5).
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