Publications by authors named "Jenny M MacLennan"

15 Publications

  • Page 1 of 1

Meningococcal carriage in periods of high and low invasive meningococcal disease incidence in the UK: comparison of UKMenCar1-4 cross-sectional survey results.

Lancet Infect Dis 2021 Jan 19. Epub 2021 Jan 19.

Department of Zoology, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK. Electronic address:

Background: The incidence of invasive meningococcal disease in the UK decreased by approximately four times from 1999 to 2014, with reductions in serogroup C and serogroup B disease. Lower serogroup C invasive meningococcal disease incidence was attributable to implementation of the meningococcal serogroup C conjugate vaccine in 1999, through direct and indirect protection, but no vaccine was implemented against serogroup B disease. UK Meningococcal Carriage surveys 1-3 (UKMenCar1-3), conducted in 1999, 2000, and 2001, were essential for understanding the impact of vaccination. To investigate the decline in invasive meningococcal disease incidence, we did a large oropharyngeal carriage survey in 2014-15, immediately before the changes to meningococcal vaccines in the UK national immunisation schedule.

Methods: UKMenCar4 was a cross-sectional survey in adolescents aged 15-19 years who were enrolled from schools and colleges geographically local to one of 11 UK sampling centres between Sept 1, 2014, and March 30, 2015. Participants provided an oropharyngeal swab sample and completed a questionnaire on risk factors for carriage, including social behaviours. Samples were cultured for putative Neisseria spp, which were characterised with serogrouping and whole-genome sequencing. Data from this study were compared with the results from the UKMenCar1-3 surveys (1999-2001).

Findings: From the 19 641 participants (11 332 female, 8242 male, 67 not stated) in UKMenCar4 with culturable swabs and completed risk-factor questionnaires, 1420 meningococci were isolated, with a carriage prevalence of 7·23% (95% CI 6·88-7·60). Carriage prevalence was substantially lower in UKMenCar4 than in the previous surveys: carriage prevalence was 16·6% (95% CI 15·89-17·22; 2306/13 901) in UKMenCar1 (1999), 17·6% (17·05-18·22; 2873/16 295) in UKMenCar2 (2000), and 18·7% (18·12-19·27; 3283/17 569) in UKMenCar3 (2001). Carriage prevalence was lower for all serogroups in UKMenCar4 than in UKMenCar1-3, except for serogroup Y, which was unchanged. The prevalence of carriage-promoting social behaviours decreased from 1999 to 2014-15, with individuals reporting regular cigarette smoking decreasing from 2932 (21·5%) of 13 650 to 2202 (11·2%) of 19 641, kissing in the past week from 6127 (44·8%) of 13 679 to 7320 (37·3%) of 19 641, and attendance at pubs and nightclubs in the past week from 8436 (62·1%) of 13 594 to 7662 (39·0%) of 19 641 (all p<0·0001).

Interpretation: We show that meningococcal carriage prevalence in adolescents sampled nationally during a low incidence period (2014-15) was less than half of that in an equivalent population during a high incidence period (1999-2001). Disease and carriage caused by serogroup C was well controlled by ongoing vaccination. The prevalence of behaviours associated with carriage declined, suggesting that public health policies aimed at influencing behaviour might have further reduced disease.

Funding: Wellcome Trust, UK Department of Health, and National Institute for Health Research.
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http://dx.doi.org/10.1016/S1473-3099(20)30842-2DOI Listing
January 2021

'Be on the TEAM' Study (Teenagers Against Meningitis): protocol for a controlled clinical trial evaluating the impact of 4CMenB or MenB-fHbp vaccination on the pharyngeal carriage of meningococci in adolescents.

BMJ Open 2020 10 22;10(10):e037358. Epub 2020 Oct 22.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Introduction: Capsular group B (MenB) is the most common cause of invasive meningococcal disease (IMD) in many parts of the world. A MenB vaccine directed against the polysaccharide capsule remains elusive due to poor immunogenicity and safety concerns. The vaccines licensed for the prevention of MenB disease, 4CMenB (Bexsero) and MenB-fHbp (Trumenba), are serogroup B 'substitute' vaccines, comprised of subcapsular proteins and are designed to provide protection against most MenB disease-causing strains. In many high-income countries, such as the UK, adolescents are at increased risk of IMD and have the highest rates of meningococcal carriage. Beginning in the late 1990s, immunisation of this age group with the meningococcal group C conjugate vaccine reduced asymptomatic carriage and disrupted transmission of this organism, resulting in lower group C IMD incidence across all age groups. Whether vaccinating teenagers with the novel 'MenB' protein-based vaccines will prevent acquisition or reduce duration of carriage and generate herd protection was unknown at the time of vaccine introduction and could not be inferred from the effects of the conjugate vaccines. 4CMenB and MenB-fHbp may also impact on non-MenB disease-causing capsular groups as well as commensal spp. This study will evaluate the impact of vaccination with 4CMenB or MenB-fHbp on oropharyngeal carriage of pathogenic meningococci in teenagers, and consequently the potential for these vaccines to provide broad community protection against MenB disease.

Methods And Analysis: The 'Be on the TEAM' (Teenagers Against Meningitis) Study is a pragmatic, partially randomised controlled trial of 24 000 students aged 16-19 years in their penultimate year of secondary school across the UK with regional allocation to a 0+6 month schedule of 4CMenB or MenB-fHbp or to a control group. Culture-confirmed oropharyngeal carriage will be assessed at baseline and at 12 months, following which the control group will be eligible for 4CMenB vaccination. The primary outcome is the carriage prevalence of potentially pathogenic meningococci (defined as those with genogroups B, C, W, Y or X), in each vaccine group compared separately to the control group at 12 months post-enrolment, that is, 12 months after the first vaccine dose and 6 months after the second vaccine dose. Secondary outcomes include impact on carriage of: genogroup B meningococci; hyperinvasive meningococci; all meningococci; those meningococci expressing vaccine antigens and; other spp. A sample size of 8000 in each arm will provide 80% power to detect a 30% reduction in meningococcal carriage, assuming genogroup B, C, W, Y or X meningococci carriage of 3.43%, a design effect of 1.5, a retention rate of 80% and a significance level of 0.05. Study results will be available in 2021 and will inform the UK and international immunisation policy and future vaccine development.

Ethics And Dissemination: This study is approved by the National Health Service South Central Research Ethics Committee (18/SC/0055); the UK Health Research Authority (IRAS ID 239091) and the UK Medicines and Healthcare products Regulatory Agency. Publications arising from this study will be submitted to peer-reviewed journals. Study results will be disseminated in public forums, online, presented at local and international conferences and made available to the participating schools.

Trial Registration Numbers: ISRCTN75858406; Pre-results, EudraCT 2017-004609-42.
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http://dx.doi.org/10.1136/bmjopen-2020-037358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583083PMC
October 2020

Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia.

N Engl J Med 2020 01;382(4):318-327

From the Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network (H.S.M.), the Robinson Research Institute and Adelaide Medical School (H.S.M., M.M.), and the School of Public Health (T.R.S.), University of Adelaide, the Communicable Disease Control Branch, SA Health (A.P.K.), and SA Pathology (A.L.), Adelaide, and the Marshall Centre for Infectious Disease Research and Training, School of Biomedical Science (C.M.K.), and the School of Medicine (P.R.), University of Western Australia, the Departments of General Paediatrics and Immunology, Perth Children's Hospital (P.R.), and Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kid's Institute (P.R.), Perth - all in Australia; the Department of Zoology, University of Oxford, Oxford (J.M.M., M.C.J.M.), the Immunization Department, Public Health England, London (S.N.L., M.E.R., C.T.), the Departments of Pathology and Veterinary Medicine, University of Cambridge, Cambridge (C.T.), the Meningococcal Reference Unit, Public Health England, Manchester (R.B.), and Bristol Children's Vaccine Centre, Schools of Cellular and Molecular Medicine and of Population Health Sciences, University of Bristol, Bristol (A.F.) - all in the United Kingdom; GlaxoSmithKline Vaccines, Amsterdam (J.W.); and GlaxoSmithKline Vaccines, Rockville, MD (K.V.).

Background: The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain.

Methods: We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for (encoding porin protein A) and genogroups. Secondary outcomes included carriage prevalence and acquisition of all and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline.

Results: A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified.

Conclusions: Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).
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http://dx.doi.org/10.1056/NEJMoa1900236DOI Listing
January 2020

UKMenCar4: A cross-sectional survey of asymptomatic meningococcal carriage amongst UK adolescents at a period of low invasive meningococcal disease incidence.

Wellcome Open Res 2019 28;4:118. Epub 2019 Oct 28.

Peter Medawar Building for Pathogen Research, Department of Zoology, University of Oxford, Oxford, OX1 3SY, UK.

Carriage of , the meningococcus, is a prerequisite for invasive meningococcal disease (IMD), a potentially devastating infection that disproportionately afflicts infants and children. Humans are the sole known reservoir for the meningococcus, and it is carried asymptomatically in the nasopharynx of ~10% of the population. Rates of carriage are dependent on age of the host and social and behavioural factors. In the UK, meningococcal carriage has been studied through large, multi-centre carriage surveys of adolescents in 1999, 2000, and 2001, demonstrating carriage can be affected by immunisation with the capsular group C meningococcal conjugate vaccine, inducing population immunity against carriage. Fifteen years after these surveys were carried out, invasive meningococcal disease incidence had declined from a peak in 1999.  The UKMenCar4 study was conducted in 2014/15 to investigate rates of carriage amongst the adolescent population during a period of low disease incidence. The protocols and methodology used to perform UKMenCar4, a large carriage survey, are described here.
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http://dx.doi.org/10.12688/wellcomeopenres.15362.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749934PMC
October 2019

B Part of It protocol: a cluster randomised controlled trial to assess the impact of 4CMenB vaccine on pharyngeal carriage of in adolescents.

BMJ Open 2018 07 10;8(7):e020988. Epub 2018 Jul 10.

Vaccine Development, GlaxoSmithKline Vaccines, Siena, Italy.

Introduction: South Australia (SA) has the highest notification rate of invasive meningococcal disease in Australia with the majority of cases due to serogroup B. is carried in the pharynx, with adolescents having the highest rates of carriage. A vaccine designed to offer protection against serogroup B (4CMenB) is licensed in Australia. The SA MenB vaccine carriage study aims to assess the impact of 4CMenB on carriage of in adolescents.

Methods And Analysis: This is a parallel cluster randomised controlled trial enrolling year 10, 11 and 12 school students (approximately 16-18 years of age) throughout SA, in metropolitan and rural/remote areas. Schools are randomised to intervention (4CMenB vaccination at baseline) or control (4CMenB vaccination at study completion) with randomisation stratified by school size and socioeconomic status, as measured by the Index of Community Socio-Educational Advantage (Australian Curriculum). Oropharyngeal swabs will be taken from all students at visit 1, and 12 months later from year 11 and 12 students. Students unvaccinated in 2017 will receive vaccine at the 12-month follow-up. Carriage prevalence of will be determined by PCR at baseline and 12 months following 4CMenB vaccination and compared with carriage prevalence at 12 months in unvaccinated students. A questionnaire will be completed at baseline and 12 months to assess risk factors associated with carriage. The primary outcome of carriage prevalence of disease causing at 12 months will be compared between groups using logistic regression, with generalised estimating equations used to account for clustering at the school level. The difference in carriage prevalence between groups will be expressed as an OR with 95% CI.

Ethics And Dissemination: The study was approved by the Women's and Children's Health Network Human Research Ethics Committee (WCHN HREC). The protocol, informed consent forms, recruitment materials, social media and all participant materials have been reviewed and approved by the WCHN HREC and updated on ClinicalTrials.gov. Results will be published in international peer-reviewed journals and presented at national and international conferences. The study findings will be provided in public forums and to study participants and participating schools.

Trial Registration Number: ACTRN12617000079347. NCT03089086; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-020988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082482PMC
July 2018

Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4.

Nat Commun 2018 03 9;9(1):1014. Epub 2018 Mar 9.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.

Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.
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http://dx.doi.org/10.1038/s41467-017-02398-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844948PMC
March 2018

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study.

PLoS Negl Trop Dis 2017 12 7;11(12):e0006027. Epub 2017 Dec 7.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.
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http://dx.doi.org/10.1371/journal.pntd.0006027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745124PMC
December 2017

Age- and sex-related changes in hematological parameters in healthy Malawians.

J Blood Med 2017 28;8:123-130. Epub 2017 Aug 28.

The Malaria Immunology Group, Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi.

Aim: The aim of the study was to determine how values for white blood cell (WBC) counts, hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (mcv), and platelet counts vary with age and sex in healthy Malawians.

Methods: We recruited 660 (316 male and 344 female) participants in 12 different age groups. An ethylenediaminetetraacetic acid-anticoagulated blood sample collected from each participant was analyzed using a hematological analyzer.

Results: WBC counts decreased with age with the lowest counts observed in the 20 to <60 years old group. Median WBC counts for 20 to <60 year old females (5.9×10/L) were significantly higher than those for men (4.7×10/L; =0.015) of the same age. Hb and Hct increased between 5 and 10 years in males and 10 and 15 years in females to adult levels. Males aged 5 to <10 years had significantly higher Hb (13.05 g/dL) and Hct (42.50%) compared to females of the same age (10.40 g/dL and 32.55%, respectively; <0.0001 for both parameters). Platelet counts in males, which were highest between 3 and 5 years (376×10/L), decreased to lowest counts among 5 to <10 year olds (238×10/L), while in females these decreased from 402×10/L in 6 to <10 years olds to 226×10/L in 10 to <15 year olds. mcv median values were high in neonates reaching a nadir at 13-18 months and then increased throughout life. Females aged 0 to <6 months had significantly higher mcv values (81.85 fL) than males of the same age (69.3 fL; <0.0001).

Conclusion: This study provides hematological values according to age and sex that are suitable for reference use in studies among Malawian subjects.
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http://dx.doi.org/10.2147/JBM.S142189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587168PMC
August 2017

Leukocyte counts and lymphocyte subsets in relation to pregnancy and HIV infection in Malawian women.

Am J Reprod Immunol 2017 Sep 6;78(3). Epub 2017 Apr 6.

Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi.

Problem: We investigated leukocyte and lymphocyte subsets in HIV-infected or HIV-uninfected, pregnant or non-pregnant Malawian women to explore whether HIV infection and pregnancy may act synergistically to impair cellular immunity.

Method Of Study: We recruited 54 pregnant and 48 non-pregnant HIV-uninfected women and 24 pregnant and 20 non-pregnant HIV-infected Malawian women. We compared peripheral blood leukocyte and lymphocyte subsets between women in the four groups.

Results: Parturient HIV-infected and HIV-uninfected women had more neutrophils (each P<.0001), but fewer lymphocytes (P<.0001; P=.0014) than non-pregnant women. Both groups had fewer total T cells (P<.0001; P=.002) and CD8 T cells (P<.0001; P=.014) than non-pregnant women. HIV-uninfected parturient women had fewer CD4 and γδ T cells, B and NK cells (each P<.0001) than non-pregnant women. Lymphocyte subset percentages were not affected by pregnancy.

Conclusion: Malawian women at parturition have an increased total white cell count due to neutrophilia and an HIV-unrelated pan-lymphopenia.
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http://dx.doi.org/10.1111/aji.12678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573949PMC
September 2017

Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children.

Clin Vaccine Immunol 2016 07 5;23(7):601-9. Epub 2016 Jul 5.

School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom

Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.
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http://dx.doi.org/10.1128/CVI.00128-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933780PMC
July 2016

Editorial commentary: fifteen years of protection by meningococcal C conjugate vaccines: lessons from disease surveillance.

Clin Infect Dis 2014 Nov 28;59(9):1222-4. Epub 2014 Jul 28.

Department of Zoology, University of Oxford, United Kingdom.

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http://dx.doi.org/10.1093/cid/ciu599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191561PMC
November 2014

Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.

J Allergy Clin Immunol 2010 Jan 26;125(1):203-8. Epub 2009 Nov 26.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

Background: CD4(+)T lymphocyte measurements are the most important indicator of mortality in HIV-infected individuals in resource-limited settings. There is currently a lack of comprehensive immunophenotyping data from African populations to guide the immunologic assessment of HIV infection.

Objective: To quantify variation in absolute and relative lymphocyte subsets with age in healthy Malawians.

Methods: Lymphocyte subsets in peripheral blood of 539 healthy HIV-uninfected Malawians stratified by age were enumerated by flow cytometry.

Results: B and T-lymphocyte and T-lymphocyte subset absolute concentrations peaked in early childhood then decreased to adult levels, whereas lymphocyte subset proportions demonstrated much less variation with age. Adult lymphocyte subsets were similar to those in developed countries. In contrast, high B-lymphocyte and CD8(+)T-lymphocyte levels among children under 2 years, relative to those in developed countries, resulted in low CD4(+)T-lymphocyte percentages that varied little between 0 and 5 years (35% to 39%). The CD4(+)T-lymphocyte percentages in 35% of healthy children under 1 year and 18% of children age 1 to 3 years were below the World Health Organization threshold defining immunodeficiency in HIV-infected children in resource-limited settings. Thirteen percent of healthy children under 18 months old had a CD4:CD8T-lymphocyte ratio <1.0, which is commonly associated with HIV infection. All immunologic parameters except absolute natural killer lymphocyte concentration varied significantly with age, and percentage and overall absolute CD4(+)T-lymphocyte counts were higher in females than males.

Conclusion: Although lymphocyte subsets in Malawian adults are similar to those from developed countries, CD4(+)T-lymphocyte percentages in young children are comparatively low. These findings need to be considered when assessing the severity of HIV-related immunodeficiency in African children under 3 years.
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http://dx.doi.org/10.1016/j.jaci.2009.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887487PMC
January 2010

Demonstration of immunologic memory using serogroup C meningococcal glycoconjugate vaccine.

Pediatr Infect Dis J 2009 Feb;28(2):92-7

Department of Paediatrics, University of Oxford, Oxford, UK.

Background: Studies of glycoconjugate vaccines have traditionally used an immune challenge with a plain polysaccharide vaccine to demonstrate immunologic memory. Plain polysaccharide vaccines are poorly immunogenic in children and can induce subsequent immunologic hyporesponsiveness. We therefore assessed the use of glycoconjugate vaccines as an alternative method of demonstrating immunologic memory.

Methods: Children immunized with hepatitis B vaccine or serogroup C meningococcal glycoconjugate vaccine (MenCC) at age 2, 3, 4 months received a plain polysaccharide meningococcal serogroup A/C vaccine (MenACP) or MenCC at age 12 months. A post hoc analysis of serum bactericidal activity responses to MenCC assessed whether this differed in MenCC primed and MenCC naive infants.

Results: MenCC primed children displayed higher geometric mean serum bactericidal titers than MenCC naive children following MenACP (1518 compared with 30; P = 0.003). A similar difference was seen after a dose of MenCC to toddlers (MenCC primed: 8663, MenCC naive: 710; P < 0.001). The latter comparison became a borderline significance after adjusting for higher pretoddler immunization serum bactericidal geometric mean titers in the MenCC primed group (P = 0.068).

Conclusions: Administration of glycoconjugate vaccines provides an important alternative method of demonstrating immunologic memory, avoiding the use of plain polysaccharide vaccines that are potentially deleterious in children. This has implications for the design of all future clinical trials of glycoconjugate vaccines.
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http://dx.doi.org/10.1097/INF.0b013e3181861dbaDOI Listing
February 2009

Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans.

J Infect Dis 2004 Nov 7;190(10):1755-7. Epub 2004 Oct 7.

Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, University of Birmingham, Birmingham, Alabama, USA.

Patients with inherited deficiency of the interleukin (IL)-12/IL-23-interferon (IFN)- gamma axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23-component deficiency had a history of salmonella disease than did those with IFN- gamma -component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN- gamma -independent pathways. Investigation of the IL-12/IL-23-IFN- gamma axis should be considered in patients with invasive salmonella disease.
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http://dx.doi.org/10.1086/425021DOI Listing
November 2004