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1.
Sci Adv ; 5(9): eaaw0109, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517041

RESUMO

Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess Plasmodium growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.

2.
J Clin Microbiol ; 57(9)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270180

RESUMO

The pathogenesis of human rhinovirus (HRV) during severe respiratory disease remains undefined; thus, we aimed to explore the relationship between the HRV molecular subtyping results obtained during severe and asymptomatic childhood infections. Nasopharyngeal/oropharyngeal swabs from children (1 to 59 months of age) hospitalized with pneumonia and from age-frequency-matched controls were collected between August 2011 and August 2013. Swabs were tested for respiratory pathogens, including HRV, using quantitative real-time PCR assays. HRV-positive samples were sequenced for phylogenetic analysis by targeting the 5' noncoding region (5'NCR). Our data showed that there were no differences in the prevalence of HRV detection among cases and controls (21% versus 20%, P = 0.693); however, among children 13 to 59 months old, HRV detection was more often case associated (21% versus 16%; P = 0.009), with the results mainly driven by HRV-C (12% versus 7%; P = 0.001). Overall, there were no differences in the results of molecular subtyping of the HRV species prevalence among cases (for HRV-A, 48%; for HRV-B, 7%; for HRV-C, 45%) and controls (for HRV-A, 45%; for HRV-B, 10%; for HRV-C, 45% [P = 0.496]). Those with pneumonia and HRV-C were older (12.1 versus 9.4 months, P = 0.033) and more likely to present with wheeze (35% versus 25%, P = 0.031) than those with HRV-A cases. Thus, the rate of HRV detection was high, with similar degrees of genetic diversity among cases and controls, confounding the interpretation of the presence of HRV in nasopharyngeal samples for attribution of a causal role in the pathogenesis of severe pneumonia in infants. However, among children 13 to 59 months of age, HRV detection, in particular, HRV-C detection, was associated with case status, especially among children with wheezing disease.

3.
Vaccine ; 37(36): 5397-5403, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31331777

RESUMO

INTRODUCTION: The purpose of this study was to evaluate the association of influenza vaccine during pregnancy and adverse fetal outcomes. Preventing fetal death, low birth weight, small for gestational age birth and preterm birth are important potential effects of antenatal maternal influenza immunization for which there are conflicting data. MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled clinical trial of trivalent inactivated influenza vaccine was conducted in South Africa from March 2011 until after the 2012 influenza season when the infants born had reached the age of 24 weeks. Mothers were administered the vaccine or placebo during pregnancy at a gestation of 20 to 36 weeks. A comparison of rates of fetal death, low birth weight, small for gestational age birth, and preterm birth, between vaccinated and placebo groups was made. Fetal outcome differences between the groups were measured using Student's t-tests, vaccine efficacy with 95% confidence intervals, and Poisson regression for incidence rates. All analyses except fetal death excluded mothers who were administered vaccine or placebo after 34 weeks gestational age. RESULTS: There were 2116 HIV-uninfected pregnant women age 18 to 38 years in the trial; 2005 infants were born to mothers where vaccine or placebo had been administered ≥ 14 days prior to delivery, and there were 6 miscarriages and 23 stillbirths. There was no significant vaccine efficacy (with [95% confidence interval]) on fetal death (-21.2% [-150.8, 41.4]), low birth weight (-11.1% [-42.3, 12.5]), small for gestational age birth (-9.9% [-35.6, 11.0]), or preterm birth (-21.3% [-60.5, 8.3]). Neither was vaccine efficacy demonstrated when the analysis was restricted to infants of mothers who were exposed to an influenza season (1832 outcomes available). CONCLUSION: We did not find a beneficial effect of trivalent inactivated influenza vaccine during pregnancy on adverse fetal outcomes.

4.
Vaccine ; 37(35): 4877-4885, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31303524

RESUMO

Group B Streptococcus (GBS) is an important cause of disease in young infants, stillbirths, pregnant and post-partum women. GBS vaccines for maternal immunization are in development aiming to reduce this burden. Standardisation of case definitions and ascertainment methodologies for GBS disease is needed to support future trials of maternal GBS vaccines. Considerations presented here may also serve to promote consistency in observational studies and surveillance, to better establish disease burden. The World Health Organization convened a working group to provide consensus guidance for case ascertainment and case definitions of GBS disease in stillbirths, infants, pregnant and post-partum women, with feedback sought from external stakeholders. In intervention studies, case capture and case ascertainment for GBS disease should be based on antenatal recruitment of women, with active follow-up, systematic clinical assessment, standardised sampling strategies and optimised laboratory methods. Confirmed cases of invasive GBS disease in stillbirths or infants should be included in a primary composite endpoint for vaccine efficacy studies, with GBS cultured from a usually sterile body site (may be post-mortem). For additional endpoints, or observational studies, confirmed cases of GBS sepsis in pregnant and post-partum women should be assessed. Culture independent diagnostic tests (CIDTs) may detect additional presumed cases, however, the use of these diagnostics needs further evaluation. Efficacy of vaccination against maternal and neonatal GBS colonisation, and maternal GBS urinary tract infection could be included as additional, separate, endpoints and/or in observational studies. Whilst the focus here is on specific GBS disease outcomes, intervention studies also present an opportunity to establish the contribution of GBS across adverse perinatal outcomes, including all-cause stillbirth, preterm birth and neonatal encephalopathy.

5.
J Infect Dis ; 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31282539

RESUMO

BACKGROUND: Measles morbidity and mortality are greatest in children <12 months old, with increased susceptibility in HIV-exposed children. We evaluated the immunogenicity and safety of an early 2-dose measles vaccine regimen administered at 6 and 12 months of age in South Africa. METHODS: HIV-unexposed (n=212) and HIV-exposed uninfected (HEU) (n=71) children received measles vaccination (CAM-70) at 6 and 12 months of age. Measles immunoglobulin G titers were measured by enzyme-linked immunosorbent assay before and one month after each vaccine dose. RESULTS: The majority of children (88.2% HIV-unexposed, 95.8% HEU; p=0.044) were seronegative (<150 mIU/mL) to measles at 4.2 months of age. This was particularly evident among infants of mothers born after 1992 (year of public nation-wide measles vaccine availability). One-month post-first measles vaccine, 42.3% HIV-unexposed and 46.4% HEU children were seropositive (≥330 mIU/mL). Post-second dose, the proportion seropositive increased to 99.0% in HIV-unexposed and 95.3% in HEU children. Safety profiles were similar between HIV-unexposed and HEU children. CONCLUSIONS: Early 2-dose measles vaccination at 6 and 12 months of age was safe and induced antibody responses in HIV-unexposed and HEU children, which could partly offset the early loss of maternally derived antibodies in infants born to predominantly measles-vaccinated mothers. CLINICAL TRIALS REGISTRATION: NCT03330171.

6.
Microb Genom ; 5(7)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31184299

RESUMO

The pneumococcus produces a polysaccharide capsule, encoded by the cps locus, that provides protection against phagocytosis and determines serotype. Nearly 100 serotypes have been identified with new serotypes still being discovered, especially in previously understudied regions. Here we present an analysis of the cps loci of more than 18  000 genomes from the Global Pneumococcal Sequencing (GPS) project with the aim of identifying novel cps loci with the potential to produce previously unrecognized capsule structures. Serotypes were assigned using whole genome sequence data and 66 of the approximately 100 known serotypes were included in the final dataset. Closer examination of each serotype's sequences identified nine putative novel cps loci (9X, 11X, 16X, 18X1, 18X2, 18X3, 29X, 33X and 36X) found in ~2.6  % of the genomes. The large number and global distribution of GPS genomes provided an unprecedented opportunity to identify novel cps loci and consider their phylogenetic and geographical distribution. Nine putative novel cps loci were identified and examples of each will undergo subsequent structural and immunological analysis.

7.
Influenza Other Respir Viruses ; 13(5): 438-452, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165580

RESUMO

BACKGROUND: Pregnant women have an elevated risk of illness and hospitalisation from influenza. Pregnant women are recommended to be prioritised for influenza vaccination during any stage of pregnancy. The risk of seasonal influenza varies substantially throughout the year in temperate climates; however, there is limited knowledge of how vaccination timing during pregnancy impacts the benefits received by the mother and foetus. OBJECTIVES: To compare antenatal vaccination timing with regard to influenza vaccine immunogenicity during pregnancy and transplacental transfer to their newborns. METHODS: Studies were eligible for inclusion if immunogenicity to influenza vaccine was evaluated in women stratified by trimester of pregnancy. Haemagglutination inhibition (HI) titres, stratified by trimester of vaccination, had to be measured at either pre-vaccination and within one month post-vaccination, post-vaccination and at delivery in the mother, or in cord/newborn blood. Authors searched PubMed, Scopus, Web of Science and EMBASE databases from inception until June 2016 and authors of identified studies were contacted for additional data. Extracted data were tabulated and summarised via random-effect meta-analyses and qualitative methods. RESULTS: Sixteen studies met the inclusion criteria. Meta-analyses found that compared with women vaccinated in an earlier trimester, those vaccinated in a later trimester had a greater fold increase in HI titres (1.33- to 1.96-fold) and higher HI titres in cord/newborn blood (1.21- to 1.64-fold). CONCLUSIONS: This review provides comparative analysis of the effect of vaccination timing on maternal immunogenicity and protection of the infant that is informative and relevant to current vaccine scheduling for pregnant women.

8.
Paediatr Int Child Health ; : 1-8, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31156062

RESUMO

Background: There are limited data on paediatric invasive bacterial infections (IBI) and the impact of pneumococcal conjugate vaccine (PCV) on the spectrum of IBI pathogens, specifically in African countries with a high prevalence of HIV infection. Aim: To describe the epidemiology of IBI in a cohort of children <5 years of age in Soweto, South Africa. Methods: A cohort of children enrolled into a PCV9 efficacy trial conducted from 1998 until 2005 was used for secondary data analysis. Surveillance data were collected from admission wards at Chris Hani Baragwanath Academic Hospital. The incidence of IBI was calculated using person-time, stratified by age group, gender, PCV9 vaccination status and HIV infection status. Risk factors for IBI were investigated using binomial logistic regression. Results: A total of 395 cases of laboratory-confirmed IBI were identified. HIV infection and not receiving PCV9 vaccination were risk factors for IBI hospitalisation. PCV9 vaccination was associated with reductions in IBI hospitalisation (IRR 0.76, p = 0.006) solely owing to reductions in the incidence of Streptococcus pneumoniae (IRR 0.56, p < 0.001). PCV9 vaccination had no effect on the incidence of Haemophilus influenza type b or Salmonella species IBI. There was an increase in Klebsiella species IBI (IRR 3.50, p = 0.019) and a trend towards a higher incidence of Staphylococcus aureus IBI (IRR 1.90, p = 0.099) in PCV9-vaccinated children. Conclusions: PCV9 vaccination was effective in reducing the incidence of IBI hospitalisation in children through reductions in the incidence of S. pneumoniae. The results show that trends in other IBI causative pathogens (specifically S. aureus and Klebsiella species) should be monitored in the era of PCV vaccination. Abbreviations: ART, antiretroviral therapy; CI, confidence interval; Hib, Haemophilus influenza type b; HIV, human immunodeficiency virus; HIV+PCV-, HIV-infected, placebo-vaccinated group; HIV+PCV+, HIV-infected, PCV9-vaccinated group; HIV-PCV-, HIV-uninfected, placebo-vaccinated group; HIV+PCV+, HIV-infected, PCV9-vaccinated group; IBI, invasive bacterial infection; IPD, invasive pneumococcal disease; IRR, incidence rate ratio; IQR, interquartile range; OR, odds ratio; PCV, pneumococcal conjugate vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; PCV9, 9-valent pneumococcal conjugate vaccine; PY, person-years; RCT, randomised control trial.

10.
Expert Rev Vaccines ; 18(7): 751-754, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31194605

RESUMO

Background: South Africa transitioned from using live-attenuated trivalent oral polio vaccine (tOPV), to a combination of tOPV and inactivated polio vaccine (IPV) in April 2009. We evaluated the immunogenicity of the South African combined tOPV-IPV schedule versus the tOPV-only schedule in South African infants. Methods: Serum samples of HIV-unexposed infants were analysed retrospectively from two cohorts; infants enrolled from April 2005 through June 2006 and infants enrolled from December 2009 to April 2010. The primary vaccination series of the tOPV-only schedule included doses at birth, 6, 10 and 14 weeks, and the tOPV-IPV schedule included tOPV at birth and 6 weeks and IPV at 6, 10 and 14 weeks. Serum polio neutralising antibody titres to serotype-1, serotype-2 and serotype-3 were evaluated in infants at 18 weeks of age. Results: Infants who received the tOPV-IPV schedule had higher GMTs than infants who received tOPV-only for serotype-2 (9.63 vs. 8.80, P < 0.001) and serotype-3 (10.01 vs. 8.53, P < 0.001), as well as higher sero-protective titres for serotype-1 (100% vs. 96%, P = 0.014). Conclusion: Our data support the option of the South African combined polio vaccination schedule as an immunogenic option for a combined schedule.

11.
Clin Infect Dis ; 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31111870

RESUMO

BACKGROUND: In 2015, pneumonia remained the leading cause of mortality in children between 1-59 months old. METHODS: Data from 1802 HIV-negative children between 1-59 months old enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-14 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the c-statistic. RESULTS: Predictors of mortality, across seven low and middle-income countries, were: age <1 year, female sex, 3 or more days of illness prior to presentation to hospital, low weight-for-height, unresponsiveness, deep breathing, hypoxemia, grunting and the absence of cough. The model discriminated well between those who died and those who survived (c-statistic: 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (c=0.76). The performance of the Respiratory Index of Severity in Children (RISC) score was similar (c=0.76). The number of WHO danger signs demonstrated the highest discrimination (c=0.82; 1.5% died if no danger signs, 10% if 1 danger sign and 33% if 2 or more danger signs). CONCLUSIONS: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful, of the currently available tools, to aid clinical management of pneumonia.

12.
Clin Infect Dis ; 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31125061

RESUMO

BACKGROUND: Post-licensure studies have shown an association between rotavirus vaccination and intussusception. We assessed the risk of intussusception associated with Rotarix® (RV1) administration, at six and 14 weeks of age, in an upper-middle income country, South Africa. METHODS: Active prospective surveillance for intussusception was conducted in eight hospitals from September 2013-December 2017. Retrospective case enrolment was done at one hospital from July 2012-August 2013. Demographic characteristics, symptom onset and rotavirus vaccine status were ascertained. Using the self-controlled case-series method, we estimated age-adjusted incidence-rate ratios within 1-7, 8-21, and 1-21 days of rotavirus vaccination in children aged 28-275 days at onset of symptoms. In addition, age-matched controls were enrolled for a subset of cases (n=169), and a secondary analysis performed. RESULTS: There were 346 cases included in the case-series analysis. Post-dose one, there were zero intussusception cases within 1-7 days, and five cases within 8-21 days of vaccination. Post-dose two, 15 cases occurred within 1-7 days, and 18 cases within 8-21 days of vaccination. There was no increased risk of intussusception 1-7 days after dose one (no cases observed) or dose two (relative incidence (RI): 1·71; 95% confidence interval (CI) 0·83-3·01). Similarly, there was no increased risk 8-21 days after the first (RI: 4·01; 95% CI 0·87-10·56) or second dose (RI: 0·96; 95% CI 0·52-1·60). Results were similar for the case-control analysis. CONCLUSIONS: The risk of intussusception in the 21 days after the first or second dose of RV1 was not higher than the background risk among South Africa infants.

13.
Clin Infect Dis ; 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31056692

RESUMO

BACKGROUND: Animal-model studies demonstrated less group B streptococcal (GBS) invasive disease and gastrointestinal colonization after enteral administration of serotype-specific capsular antibody. There is however a paucity of information on the association of breastmilk GBS serotype-specific capsular antibody and risk for invasive disease in infants. The aim of this study was to explore the association between natural secretory IgA (sIgA) capsular antibody in breastmilk, and the occurrence of late-onset disease (LOD) in young infants. METHODS: A matched case-control study was undertaken in infants <3months of age in Johannesburg, South Africa. Breastmilk samples were collected on cases and controls matched for gestational age, maternal age and HIV-status at time of enrolment. Capsular serotype Ia, Ib, III and V sIgA antibody concentrations were measured using the fluorescence based micro-bead immunosorbent assay. RESULTS: Breastmilk samples were available for 31 LOD (8 serotype Ia and 23 serotype III), 10 serotype Ia and 11 serotype III recto-vaginally colonized matched controls, and 84 and 105 non-colonized matched controls. Using a Bayesian model to estimate the probability of disease, there was a 90% reduction in the risk of developing serotype Ia and III LOD with sIgA concentrations ≥0.14 µg/mL and ≥2.52 µg/mL, respectively. CONCLUSION: Breastmilk sIgA capsular antibody was associated with lower risk for LOD in young infants. The ability of GBS polysaccharide-protein conjugate vaccines currently under development to induce sIgA responses warrant investigation as a potential mediator of protection against LOD.

14.
PLoS One ; 14(4): e0214077, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30970036

RESUMO

BACKGROUND: Globally, over 400,000 neonatal deaths in 2015 were attributed to sepsis, however, the incidence and etiologies of these infections are largely unknown in low-middle income countries. We aimed to determine incidence and etiology of community-acquired early-onset (<72 hours age) sepsis (EOS) using culture and molecular diagnostics. METHODS: This was a prospective observational study, in which we conducted a surveillance for pathogens using a combination of blood culture and a polymerase chain reaction (PCR)-based test. Blood culture was performed on all neonates with suspected EOS. Among the subset fulfilling criteria for protocol-defined EOS, blood and nasopharyngeal (NP) respiratory swabs were tested by quantitative real-time reverse-transcriptase PCR using a Taqman Array Card (TAC) with 15 bacterial and 12 viral targets. Blood and NP samples from 312 healthy newborns were also tested by TAC to estimate background positivity rates. We used variant latent-class methods to attribute etiologies and calculate pathogen-specific proportions and incidence rates. RESULTS: We enrolled 2,624 neonates with suspected EOS and from these 1,231 newborns met criteria for protocol-defined EOS (incidence- 39.3/1,000 live-births). Using the partially latent-class modelling, only 26.7% cases with protocol-defined EOS had attributable etiology, and the largest pathogen proportion were Ureaplasma spp. (5.4%; 95%CI: 3.6-8.0) and group B Streptococcus (GBS) (4.8%; 95%CI: 4.1-5.8), and no etiology was attributable for 73.3% of cases. Blood cultures were positive in 99/1,231 (8.0%) with protocol-defined EOS (incidence- 3.2/1,000 live-births). Leading pathogens on blood culture included GBS (35%) and viridans streptococci (24%). Ureaplasma spp. was the most common organism identified on TAC among cases with protocol-defined EOS. CONCLUSION: Using a combination of blood culture and a PCR-based test the common pathogens isolated in neonates with sepsis were Ureaplasma spp. and GBS. Despite documenting higher rates of protocol-defined EOS and using a combination of tests, the etiology for EOS remains elusive.

16.
Bioinformatics ; 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30942877

RESUMO

SUMMARY: HLA*LA implements a new graph alignment model for HLA type inference, based on the projection of linear alignments onto a variation graph. It enables accurate HLA type inference from whole-genome (99% accuracy) and whole-exome (93% accuracy) Illumina data; from long-read Oxford Nanopore and Pacific Biosciences data (98% accuracy for whole-genome and targeted data); and from genome assemblies. Computational requirements for a typical sample vary between 0.7 and 14 CPU hours per sample. AVAILABILITY AND IMPLEMENTATION: HLA*LA is implemented in C ++ and Perl and freely available as a bioconda package or from https://github.com/DiltheyLab/HLA-LA (GPL v3). SUPPLEMENTARY INFORMATION: Supplementary data are available online.

17.
EBioMedicine ; 43: 338-346, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31003929

RESUMO

BACKGROUND: Pneumococcal conjugate vaccines have reduced the incidence of invasive pneumococcal disease, caused by vaccine serotypes, but non-vaccine-serotypes remain a concern. We used whole genome sequencing to study pneumococcal serotype, antibiotic resistance and invasiveness, in the context of genetic background. METHODS: Our dataset of 13,454 genomes, combined with four published genomic datasets, represented Africa (40%), Asia (25%), Europe (19%), North America (12%), and South America (5%). These 20,027 pneumococcal genomes were clustered into lineages using PopPUNK, and named Global Pneumococcal Sequence Clusters (GPSCs). From our dataset, we additionally derived serotype and sequence type, and predicted antibiotic sensitivity. We then measured invasiveness using odds ratios that relating prevalence in invasive pneumococcal disease to carriage. FINDINGS: The combined collections (n = 20,027) were clustered into 621 GPSCs. Thirty-five GPSCs observed in our dataset were represented by >100 isolates, and subsequently classed as dominant-GPSCs. In 22/35 (63%) of dominant-GPSCs both non-vaccine serotypes and vaccine serotypes were observed in the years up until, and including, the first year of pneumococcal conjugate vaccine introduction. Penicillin and multidrug resistance were higher (p < .05) in a subset dominant-GPSCs (14/35, 9/35 respectively), and resistance to an increasing number of antibiotic classes was associated with increased recombination (R2 = 0.27 p < .0001). In 28/35 dominant-GPSCs, the country of isolation was a significant predictor (p < .05) of its antibiogram (mean misclassification error 0.28, SD ±â€¯0.13). We detected increased invasiveness of six genetic backgrounds, when compared to other genetic backgrounds expressing the same serotype. Up to 1.6-fold changes in invasiveness odds ratio were observed. INTERPRETATION: We define GPSCs that can be assigned to any pneumococcal genomic dataset, to aid international comparisons. Existing non-vaccine-serotypes in most GPSCs preclude the removal of these lineages by pneumococcal conjugate vaccines; leaving potential for serotype replacement. A subset of GPSCs have increased resistance, and/or serotype-independent invasiveness.

18.
Vaccine ; 37(24): 3190-3198, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31031031

RESUMO

The development of a group B Streptococcus (GBS) vaccine for maternal immunization constitutes a global public health priority, to prevent GBS-associated early life invasive disease, stillbirth, premature birth, maternal sepsis, adverse neurodevelopmental consequences, and to reduce perinatal antibiotic use. Sample size requirements for the conduct of a randomized placebo-controlled trial to assess vaccine efficacy against the most relevant clinical endpoints, under conditions of appropriate ethical standards of care, constitute a significant obstacle on the pathway to vaccine availability. Alternatively, indirect evidence of protection based on immunologic data from vaccine and sero-epidemiological studies, complemented by data from opsonophagocytic in vitro assays and animal models, could be considered as pivotal data for licensure, with subsequent confirmation of effectiveness against disease outcomes in post-licensure evaluations. Based on discussions initiated by the World Health Organization we present key considerations about the potential role of correlates of protection towards an accelerated pathway for GBS vaccine licensure and wide scale use. Priority activities to support progress to regulatory and policy decision are outlined.

19.
Front Immunol ; 10: 595, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972079

RESUMO

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+TGFß+ 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.

20.
PLoS One ; 14(4): e0215079, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002702

RESUMO

INTRODUCTION: The prevalence of HIV infection in South African pregnant women has been approximately 30% over the past decade; however, there has been a steady decline in mother-to-child transmission of HIV from 8% in 2008 to <2% in 2015. We evaluated the immunogenicity of live-attenuated trivalent oral polio vaccine (OPV) following the primary vaccination series (doses at birth, 6, 10 and 14 weeks of age) in HIV-exposed uninfected (HEU), HIV-infected infants initiated on early anti-retroviral treatment (HIV+/ART+), HIV-infected infants on deferred ART (HIV+/ART-) and HIV-unexposed infants (HU) as the referent group. METHODS: Serum polio neutralization antibody titres were evaluated to serotype-1, serotype-2 and serotype-3 at 6, 10 and 18 weeks of age. Antibody titres ≥8 were considered seropositive and sero-protective. RESULTS: At 18 weeks of age, following the complete primary series of four OPV doses, no differences in GMTs, percentage of infants with sero-protective titres and median fold change in antibody titre (18 weeks vs 6 weeks) were observed in HEU infants (n = 114) and HIV+/ART+ infants (n = 162) compared to HU infants (n = 104) for the three polio serotypes. However, comparing HIV+/ART- infants (n = 70) to HU infants at 18 weeks of age, we observed significantly lower GMTs for serotype-1 (p = 0.022), serotype-2 (p<0.001) and serotype-3 (p<0.001), significantly lower percentages of infants with sero-protective titres for the three serotypes (p<0.001), and significantly lower median fold change in antibody titre for serotype-1 (p = 0.048), serotype-2 (p = 0.003) and serotype-3 (p = 0.008). CONCLUSION: Delaying initiation of ART in HIV-infected infants was associated with an attenuated immune response to OPV following a four-dose primary series of vaccines, whereas immune responses to OPV in HIV-infected children initiated on ART early in infancy and HEU children were similar to HU infants.

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