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Papers by Sarah Joseph

The Journal of Immunology, 2004

Infection and Immunity, 2004

The human host is continuously exposed to the egg and the adult worm developmental stages of Schi... more The human host is continuously exposed to the egg and the adult worm developmental stages of Schistosoma mansoni during chronic infections with the parasite. To assess the cytokine responses induced by these different costimulating stages and how they are influenced by host age and infection intensity, whole blood samples from a cross-sectional cohort of 226 members of a Ugandan fishing community who had been resident in an area with high transmission of S. mansoni for the previous 10 years or from birth were stimulated with S. mansoni egg antigen (SEA) or worm antigen (SWA). SWA-specific gamma interferon (IFN-γ) production increased with age, and the levels of SWA- and SEA-specific interleukin 3 (IL-3) were weakly correlated with schistosome infection intensity. The production of most cytokines was little affected by age or infection intensity but was either SEA or SWA specific. One hundred thirty-two members of the cohort coproduced IL-5 and IL-13 specifically in response to SWA, ...

Clinical and Vaccine Immunology, 2006

Eosinophil activity in vivo and in vitro was studied in relation to infection intensities and pla... more Eosinophil activity in vivo and in vitro was studied in relation to infection intensities and plasma cytokine profiles of 51 Schistosoma mansoni -infected Ugandan fishermen before treatment and 24 h and 3 weeks posttreatment. Blood eosinophil numbers significantly declined 24 h posttreatment, but significant eosinophilia had developed by 3 weeks posttreatment. Cellular eosinophil cationic protein (ECP) content increased significantly during the transient eosinopenia but was significantly reduced 3 weeks later. No similar reduction in cellular eosinophil protein X (EPX) content was seen. Before treatment, S. mansoni infection intensity was positively correlated with 24-h boosts in plasma interleukin-5 (IL-5) and IL-6 levels, which were in turn negatively correlated with the posttreatment fall in eosinophil numbers. Significant correlations were observed between pretreatment infection intensities and plasma IL-10 and eotaxin levels. Treatment induced significant fluctuations in plasma...

F1000 - Post-publication peer review of the biomedical literature, 2009

The immunologic basis for the potential enhanced HIV-1 acquisition in Ad5 seropositive individual... more The immunologic basis for the potential enhanced HIV-1 acquisition in Ad5 seropositive individuals who received the Merck rAd5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5 seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5 seronegative subjects following vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study. In the phase 2b efficacy study (the STEP study) evaluating the Merck recombinant adenovirus serotype 5 (rAd5) vector-based HIV-1 vaccine, vaccinees with baseline Ad5specific neutralizing antibodies (NAbs) exhibited a 2.3-fold increased rate of HIV-1 acquisition as compared with controls1,2. This potential increased HIV-1 susceptibility appeared to be durable for >52 weeks of follow-up and remains unexplained. These findings largely paralyzed the HIV-1 vaccine field and emphasized the importance of evaluating vector-specific immunity in the context of HIV-1 vaccine studies. A hypothesis has been proposed in which baseline Ad5-specific NAbs may have been surrogate markers for Ad5specific T lymphocyte responses, and anamnestic Ad5-specific CD4 + T lymphocytes following vaccination in Ad5 seropositive subjects may have served as increased targets for HIV-1 infection. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is co... more Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is common in communities along the shore of Lake Albert. In this study, we have identified cellular immune responses associated with fibrosis. A cohort of 199 individuals aged 6-50, resident in the village for at least 10 years or since birth, were examined for evidence of periportal fibrosis by ultrasound using the Niamey protocol. Whole-blood samples were assayed for levels of nine cellular immune molecules (IL-3, IL-4, IL-5, IL-10, IL-13, TNF-␣, IFN-␥, IL-1␤, and RANTES) in the absence of in vitro Ag stimulation, and after stimulation with egg and worm Ags. A lack of Ag specificity allowed the number of variables in the analysis to be reduced by factor analysis. The resulting factor scores were then entered into a risk analysis using a classification tree algorithm. Children, adult males, and adult females had different factors associated with fibrosis. Most cases of fibrosis in children (eight of nine) were associated with low (<47th percentile) IL-10 factor scores. Adult females at lowest risk had relatively high IFN-␥ factor scores (>83rd percentile), whereas those at highest risk had a combination of intermediate (32nd to 83rd percentile) IFN-␥ and relatively high (>60th percentile) TNF-␣ factor scores. Adult males at lowest risk of fibrosis had moderate TNF-␣ factor scores (55th to 82nd percentile), and a high risk was associated with either high TNF-␣ factor scores (>82nd percentile), or intermediate TNF-␣ combined with low RANTES factor scores (<58th percentile). These results demonstrate that periportal fibrosis is associated with cytokine production profiles that vary with both age and gender.

PLOS ONE

Background We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given... more Background We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given with/without intradermal electroporation (EP) as prime and (ii) the impact of boosting with modified vaccinia virus Ankara (HIV-MVA) administered with or without subtype C CN54rgp140 envelope protein adjuvanted with Glucopyranosyl Lipid A (GLA-AF) in volunteers from Tanzania and Mozambique. Methods Healthy HIV-uninfected adults (N = 191) were randomized twice; first to one of three HIV-DNA intradermal priming regimens by needle-free ZetaJet device at weeks 0, 4 and 12 (Group I: 2x0.1mL [3mg/mL], Group II: 2x0.1mL [3mg/mL] plus EP, Group III: 1x0.1mL

Scientific Reports

In cross-sectional studies increased vaginal bacterial diversity has been associated with vaginal... more In cross-sectional studies increased vaginal bacterial diversity has been associated with vaginal inflammation which can be detrimental for health. We describe longitudinal changes at 5 visits over 8 weeks in vaginal microbiota and immune mediators in African women. Women (N = 40) with a normal Nugent score at all visits had a stable lactobacilli dominated microbiota with prevailing Lactobacillus iners. Presence of prostate-specific antigen (proxy for recent sex) and being amenorrhoeic (due to progestin-injectable use), but not recent vaginal cleansing, were significantly associated with microbiota diversity and inflammation (controlled for menstrual cycle and other confounders). Women (N = 40) with incident bacterial vaginosis (Nugent 7-10) had significantly lower concentrations of lactobacilli and higher concentrations of Gardnerella vaginalis, Atopobium vaginae, and Prevotella bivia, at the incident visit and when concentrations of proinflammatory cytokines (IL-1β, IL-12p70) were increased and IP-10 and elafin were decreased. A higher 'composite-qPCR vaginal-health-score' was directly associated with decreased concentrations of proinflammatory cytokines (IL-1α, IL-8, IL-12(p70)) and increased IP-10. This longitudinal study confirms the inflammatory nature of vaginal dysbiosis and its association with recent vaginal sex and progestin-injectable use. A potential role for proinflammatory mediators and IP-10 in combination with the vaginal-health-score as predictive biomarkers for vaginal dysbiosis merits further investigation.

Frontiers in immunology, 2017

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvan... more There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization...

Journal of Virology, 2016

ABSTRACTInterleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates H... more ABSTRACTInterleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replicationin vitroand facilitates homeostatic proliferation of CD25+FoxP3+CD4+T cells. CD25+FoxP3+CD4+T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25+FoxP3+CD4+T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV+and HIV−study volunteers. Different memory CD4+T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV+subjects, 51% (median) of CD25+FoxP3+CD4+T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67+cells were detected in CD25+FoxP3+memory CD4+T cells (median, 27.6%) in comparison to CD25−FoxP3−memory CD4+T cells (median, 4.1%;P< 0.0001). HIV DNA content was 15-fold higher in CD25...

Journal of Immunology, Mar 1, 2008

The immune response to vaccination with Bacillus Calmette-Guerin (BCG), the only tuberculosis vac... more The immune response to vaccination with Bacillus Calmette-Guerin (BCG), the only tuberculosis vaccine available, has not been fully characterized. We used multiparameter flow cytometry to examine specific T cell cytokine production and phenotypic profiles in blood from 10-week old infants, routinely vaccinated with BCG at birth. Ex vivo stimulation of whole blood with BCG for 12 hours induced expression of predominantly IFN-γ, IL-2 and TNF-α in CD4+ T cells, in 7 distinct cytokine combinations. IL-4 and IL-10 expression were detected in CD4+ T cells at low frequencies, and only in cells that did not co-express Type 1 cytokines. Specific CD8+ T cells were less frequent than CD4+ T cells, and produced mainly IFN-γ and/or IL-2, and less TNF-α, IL-4 and IL-10. Importantly, many mycobacteria-specific CD4+ and CD8+ T cells did not produce IFN-γ. The predominant phenotype of BCG-specific Type 1 T cells was that of effector cells, i.e., CD45RA–CCR7–CD27+, which may reflect persistence of M. bovis BCG in infants until 10 weeks of age. Among 5 phenotypic patterns of CD4+ T cells, central memory cells were more likely to be IL-2+, and effector cells more likely to be IFN-γ+. We concluded that neonatal vaccination with BCG induces T cells with a complex pattern of cytokine expression and phenotypes. Measuring IFN-γ production alone underestimates the magnitude and complexity of the host cytokine response to BCG vaccination, and may not be an optimal readout in studies of BCG and novel tuberculosis vaccination.

PloS one, 2016

A vaccine against HIV is widely considered the most effective and sustainable way of reducing new... more A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA). Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart. The vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding ...

PLOS ONE, 2016

Background Defining optimal routes for induction of mucosal immunity represents an important rese... more Background Defining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.

F1000 - Post-publication peer review of the biomedical literature, 2009

Virus-specific CD8 + T cells probably mediate control over HIV replication in rare individuals, t... more Virus-specific CD8 + T cells probably mediate control over HIV replication in rare individuals, termed long-term nonprogressors (LTNPs) or elite controllers. Despite extensive investigation, the mechanisms responsible for this control remain incompletely understood. We observed that HIVspecific CD8 + T cells of LTNPs persisted at higher frequencies than those of treated progressors with equally low amounts of HIV. Measured on a per-cell basis, HIV-specific CD8 + T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4 + T cells. This function required lytic granule loading of effectors and delivery of granzyme B to target cells. Defective cytotoxicity of progressor effectors could be restored after treatment with phorbol ester and calcium ionophore. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. They also demonstrate that lytic granule contents of memory cells are a critical determinant of cytotoxicity that must be induced for maximal per-cell killing capacity.

Clinical and Vaccine Immunology, 2015

Data on immune mediators in the genital tract and the factors that modulate them in sub-Saharan w... more Data on immune mediators in the genital tract and the factors that modulate them in sub-Saharan women are limited. Cervicovaginal lavage (CVL) samples from 430 sexually active women from Kenya, South Africa, and Rwanda were analyzed for 12 soluble immune mediators using Bio-Plex and Meso Scale Discovery multiplex platforms, as well as single enzyme-linked immunosorbent assays. Ten bacterial species were quantified in vaginal swab samples. Bacterial vaginosis (BV) was defined by Nugent scoring. CVL samples from HIV-infected women showed a clear-cut proinflammatory profile. Pregnant women, adolescents, and women engaging in traditional vaginal practices differed in specific soluble markers compared to reference groups of adult HIV-negative women. Cervical mucus, cervical ectopy, abnormal vaginal discharge, and having multiple sex partners were each associated with an increase in inflammatory mediators. The levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-12(p70), and IL-8 were elevat...

BMC immunology, Jan 21, 2004

Parasite-specific IgE levels correlate with human resistance to reinfection with Schistosoma spp.... more Parasite-specific IgE levels correlate with human resistance to reinfection with Schistosoma spp. after chemotherapy. Although the role of eosinophils in schistosomiasis has been the focus of a great deal of important research, the involvement of other Fcepsilon receptor-bearing cells, such as mast cells and basophils, has not been investigated in relation to human immunity to schistosomes. Chemotherapy with praziquantel (PZQ) kills schistosomes living in an in vivo blood environment rich in IgE, eosinophils and basophils. This releases parasite Ags that have the potential to cross-link cell-bound IgE. However, systemic hypersensitivity reactions are not induced by treatment. Here, we describe the effects of schistosomiasis, and its treatment, on human basophil function by following changes in total cellular histamine and in vitro histamine-release induced by schistosome Ags or anti-IgE, in blood samples from infected Ugandan fishermen, who are continuously exposed to S. mansoni inf...

Genital Tract Immunological Markers in Sub-Saharan African Women with Relevance to HIV Risk and Prevention

AIDS Research and Human Retroviruses, 2014

Bacterial Vaginosis and HIV: An Analysis of the MDP301 Trial

AIDS Research and Human Retroviruses, 2014

Immune Responses after Two Immunizations with rgp140/GLA Following Priming with HIV-DNA and HIV-MVA in Healthy Tanzanian Volunteers

AIDS Research and Human Retroviruses, 2014

Transactions of the Royal Society of Tropical Medicine and Hygiene, 2003

It has been proposed that helminth infection may exacerbate HIV progression by promoting activati... more It has been proposed that helminth infection may exacerbate HIV progression by promoting activation of 'type 2' immune responses. To examine this hypothesis, we investigated helminth infection in a cohort of HIV-l-seropositive adults in Entebbe, Uganda, during November 1999 to January 2000. Individuals with helminths were treated. At enrolment, after 5 weeks and after 4 months, CD4 + and CD8 + T cell counts and viral load were measured. Cytokine responses (interferon [IFN]-y, interleukin [ILl-2, IL-4 and IL-5) to Schiswsoma mansoni adult worm antigen (SWA), Mycobacterium tuberculosis culture filtrate proteins (CFPs) and phytohaemagglutinin (PHA) were measured in a whole blood assay. At baseline, CD4 + T cell counts and CD4+:CD8 + ratios were higher in individuals with helminths than in those without (median CD4 + T cell counts 467/pL and 268/pL, respectively, P = 0.005). Viral load was lower among those with helminths but this was not statistically significant. During follow-up, CD4 ÷ T cell counts and cytokine responses to PHA fell among individuals without helminths. Among those treated for helminths, CD4 ÷ counts remained stable. Viral loads showed a transient increase at 5 weeks, which was more marked among those treated for helminths, but the levels at 4 months were similar to baseline in both groups. Among those with schistosomiasis, IFN-y and IL-2 responses to CFP, and IL-2 and IL-4 responses to PHA declined but there was a sustained increase in cytokine responses to SWA following treatment. These data do not support the hypothesis that helminth infection exacerbates HIV infection. The possibility that chronic helminth infection may suppress HIV replication and that effects on HIV replication may vary during helminth infection and treatment should be considered.

The Journal of Immunology, 2004

Infection and Immunity, 2004

The human host is continuously exposed to the egg and the adult worm developmental stages of Schi... more The human host is continuously exposed to the egg and the adult worm developmental stages of Schistosoma mansoni during chronic infections with the parasite. To assess the cytokine responses induced by these different costimulating stages and how they are influenced by host age and infection intensity, whole blood samples from a cross-sectional cohort of 226 members of a Ugandan fishing community who had been resident in an area with high transmission of S. mansoni for the previous 10 years or from birth were stimulated with S. mansoni egg antigen (SEA) or worm antigen (SWA). SWA-specific gamma interferon (IFN-γ) production increased with age, and the levels of SWA- and SEA-specific interleukin 3 (IL-3) were weakly correlated with schistosome infection intensity. The production of most cytokines was little affected by age or infection intensity but was either SEA or SWA specific. One hundred thirty-two members of the cohort coproduced IL-5 and IL-13 specifically in response to SWA, ...

Clinical and Vaccine Immunology, 2006

Eosinophil activity in vivo and in vitro was studied in relation to infection intensities and pla... more Eosinophil activity in vivo and in vitro was studied in relation to infection intensities and plasma cytokine profiles of 51 Schistosoma mansoni -infected Ugandan fishermen before treatment and 24 h and 3 weeks posttreatment. Blood eosinophil numbers significantly declined 24 h posttreatment, but significant eosinophilia had developed by 3 weeks posttreatment. Cellular eosinophil cationic protein (ECP) content increased significantly during the transient eosinopenia but was significantly reduced 3 weeks later. No similar reduction in cellular eosinophil protein X (EPX) content was seen. Before treatment, S. mansoni infection intensity was positively correlated with 24-h boosts in plasma interleukin-5 (IL-5) and IL-6 levels, which were in turn negatively correlated with the posttreatment fall in eosinophil numbers. Significant correlations were observed between pretreatment infection intensities and plasma IL-10 and eotaxin levels. Treatment induced significant fluctuations in plasma...

F1000 - Post-publication peer review of the biomedical literature, 2009

The immunologic basis for the potential enhanced HIV-1 acquisition in Ad5 seropositive individual... more The immunologic basis for the potential enhanced HIV-1 acquisition in Ad5 seropositive individuals who received the Merck rAd5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5 seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5 seronegative subjects following vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study. In the phase 2b efficacy study (the STEP study) evaluating the Merck recombinant adenovirus serotype 5 (rAd5) vector-based HIV-1 vaccine, vaccinees with baseline Ad5specific neutralizing antibodies (NAbs) exhibited a 2.3-fold increased rate of HIV-1 acquisition as compared with controls1,2. This potential increased HIV-1 susceptibility appeared to be durable for >52 weeks of follow-up and remains unexplained. These findings largely paralyzed the HIV-1 vaccine field and emphasized the importance of evaluating vector-specific immunity in the context of HIV-1 vaccine studies. A hypothesis has been proposed in which baseline Ad5-specific NAbs may have been surrogate markers for Ad5specific T lymphocyte responses, and anamnestic Ad5-specific CD4 + T lymphocytes following vaccination in Ad5 seropositive subjects may have served as increased targets for HIV-1 infection. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is co... more Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is common in communities along the shore of Lake Albert. In this study, we have identified cellular immune responses associated with fibrosis. A cohort of 199 individuals aged 6-50, resident in the village for at least 10 years or since birth, were examined for evidence of periportal fibrosis by ultrasound using the Niamey protocol. Whole-blood samples were assayed for levels of nine cellular immune molecules (IL-3, IL-4, IL-5, IL-10, IL-13, TNF-␣, IFN-␥, IL-1␤, and RANTES) in the absence of in vitro Ag stimulation, and after stimulation with egg and worm Ags. A lack of Ag specificity allowed the number of variables in the analysis to be reduced by factor analysis. The resulting factor scores were then entered into a risk analysis using a classification tree algorithm. Children, adult males, and adult females had different factors associated with fibrosis. Most cases of fibrosis in children (eight of nine) were associated with low (<47th percentile) IL-10 factor scores. Adult females at lowest risk had relatively high IFN-␥ factor scores (>83rd percentile), whereas those at highest risk had a combination of intermediate (32nd to 83rd percentile) IFN-␥ and relatively high (>60th percentile) TNF-␣ factor scores. Adult males at lowest risk of fibrosis had moderate TNF-␣ factor scores (55th to 82nd percentile), and a high risk was associated with either high TNF-␣ factor scores (>82nd percentile), or intermediate TNF-␣ combined with low RANTES factor scores (<58th percentile). These results demonstrate that periportal fibrosis is associated with cytokine production profiles that vary with both age and gender.

PLOS ONE

Background We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given... more Background We evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given with/without intradermal electroporation (EP) as prime and (ii) the impact of boosting with modified vaccinia virus Ankara (HIV-MVA) administered with or without subtype C CN54rgp140 envelope protein adjuvanted with Glucopyranosyl Lipid A (GLA-AF) in volunteers from Tanzania and Mozambique. Methods Healthy HIV-uninfected adults (N = 191) were randomized twice; first to one of three HIV-DNA intradermal priming regimens by needle-free ZetaJet device at weeks 0, 4 and 12 (Group I: 2x0.1mL [3mg/mL], Group II: 2x0.1mL [3mg/mL] plus EP, Group III: 1x0.1mL

Scientific Reports

In cross-sectional studies increased vaginal bacterial diversity has been associated with vaginal... more In cross-sectional studies increased vaginal bacterial diversity has been associated with vaginal inflammation which can be detrimental for health. We describe longitudinal changes at 5 visits over 8 weeks in vaginal microbiota and immune mediators in African women. Women (N = 40) with a normal Nugent score at all visits had a stable lactobacilli dominated microbiota with prevailing Lactobacillus iners. Presence of prostate-specific antigen (proxy for recent sex) and being amenorrhoeic (due to progestin-injectable use), but not recent vaginal cleansing, were significantly associated with microbiota diversity and inflammation (controlled for menstrual cycle and other confounders). Women (N = 40) with incident bacterial vaginosis (Nugent 7-10) had significantly lower concentrations of lactobacilli and higher concentrations of Gardnerella vaginalis, Atopobium vaginae, and Prevotella bivia, at the incident visit and when concentrations of proinflammatory cytokines (IL-1β, IL-12p70) were increased and IP-10 and elafin were decreased. A higher 'composite-qPCR vaginal-health-score' was directly associated with decreased concentrations of proinflammatory cytokines (IL-1α, IL-8, IL-12(p70)) and increased IP-10. This longitudinal study confirms the inflammatory nature of vaginal dysbiosis and its association with recent vaginal sex and progestin-injectable use. A potential role for proinflammatory mediators and IP-10 in combination with the vaginal-health-score as predictive biomarkers for vaginal dysbiosis merits further investigation.

Frontiers in immunology, 2017

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvan... more There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization...

Journal of Virology, 2016

ABSTRACTInterleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates H... more ABSTRACTInterleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replicationin vitroand facilitates homeostatic proliferation of CD25+FoxP3+CD4+T cells. CD25+FoxP3+CD4+T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25+FoxP3+CD4+T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV+and HIV−study volunteers. Different memory CD4+T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV+subjects, 51% (median) of CD25+FoxP3+CD4+T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67+cells were detected in CD25+FoxP3+memory CD4+T cells (median, 27.6%) in comparison to CD25−FoxP3−memory CD4+T cells (median, 4.1%;P< 0.0001). HIV DNA content was 15-fold higher in CD25...

Journal of Immunology, Mar 1, 2008

The immune response to vaccination with Bacillus Calmette-Guerin (BCG), the only tuberculosis vac... more The immune response to vaccination with Bacillus Calmette-Guerin (BCG), the only tuberculosis vaccine available, has not been fully characterized. We used multiparameter flow cytometry to examine specific T cell cytokine production and phenotypic profiles in blood from 10-week old infants, routinely vaccinated with BCG at birth. Ex vivo stimulation of whole blood with BCG for 12 hours induced expression of predominantly IFN-γ, IL-2 and TNF-α in CD4+ T cells, in 7 distinct cytokine combinations. IL-4 and IL-10 expression were detected in CD4+ T cells at low frequencies, and only in cells that did not co-express Type 1 cytokines. Specific CD8+ T cells were less frequent than CD4+ T cells, and produced mainly IFN-γ and/or IL-2, and less TNF-α, IL-4 and IL-10. Importantly, many mycobacteria-specific CD4+ and CD8+ T cells did not produce IFN-γ. The predominant phenotype of BCG-specific Type 1 T cells was that of effector cells, i.e., CD45RA–CCR7–CD27+, which may reflect persistence of M. bovis BCG in infants until 10 weeks of age. Among 5 phenotypic patterns of CD4+ T cells, central memory cells were more likely to be IL-2+, and effector cells more likely to be IFN-γ+. We concluded that neonatal vaccination with BCG induces T cells with a complex pattern of cytokine expression and phenotypes. Measuring IFN-γ production alone underestimates the magnitude and complexity of the host cytokine response to BCG vaccination, and may not be an optimal readout in studies of BCG and novel tuberculosis vaccination.

PloS one, 2016

A vaccine against HIV is widely considered the most effective and sustainable way of reducing new... more A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA). Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart. The vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding ...

PLOS ONE, 2016

Background Defining optimal routes for induction of mucosal immunity represents an important rese... more Background Defining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.

F1000 - Post-publication peer review of the biomedical literature, 2009

Virus-specific CD8 + T cells probably mediate control over HIV replication in rare individuals, t... more Virus-specific CD8 + T cells probably mediate control over HIV replication in rare individuals, termed long-term nonprogressors (LTNPs) or elite controllers. Despite extensive investigation, the mechanisms responsible for this control remain incompletely understood. We observed that HIVspecific CD8 + T cells of LTNPs persisted at higher frequencies than those of treated progressors with equally low amounts of HIV. Measured on a per-cell basis, HIV-specific CD8 + T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4 + T cells. This function required lytic granule loading of effectors and delivery of granzyme B to target cells. Defective cytotoxicity of progressor effectors could be restored after treatment with phorbol ester and calcium ionophore. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. They also demonstrate that lytic granule contents of memory cells are a critical determinant of cytotoxicity that must be induced for maximal per-cell killing capacity.

Clinical and Vaccine Immunology, 2015

Data on immune mediators in the genital tract and the factors that modulate them in sub-Saharan w... more Data on immune mediators in the genital tract and the factors that modulate them in sub-Saharan women are limited. Cervicovaginal lavage (CVL) samples from 430 sexually active women from Kenya, South Africa, and Rwanda were analyzed for 12 soluble immune mediators using Bio-Plex and Meso Scale Discovery multiplex platforms, as well as single enzyme-linked immunosorbent assays. Ten bacterial species were quantified in vaginal swab samples. Bacterial vaginosis (BV) was defined by Nugent scoring. CVL samples from HIV-infected women showed a clear-cut proinflammatory profile. Pregnant women, adolescents, and women engaging in traditional vaginal practices differed in specific soluble markers compared to reference groups of adult HIV-negative women. Cervical mucus, cervical ectopy, abnormal vaginal discharge, and having multiple sex partners were each associated with an increase in inflammatory mediators. The levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-12(p70), and IL-8 were elevat...

BMC immunology, Jan 21, 2004

Parasite-specific IgE levels correlate with human resistance to reinfection with Schistosoma spp.... more Parasite-specific IgE levels correlate with human resistance to reinfection with Schistosoma spp. after chemotherapy. Although the role of eosinophils in schistosomiasis has been the focus of a great deal of important research, the involvement of other Fcepsilon receptor-bearing cells, such as mast cells and basophils, has not been investigated in relation to human immunity to schistosomes. Chemotherapy with praziquantel (PZQ) kills schistosomes living in an in vivo blood environment rich in IgE, eosinophils and basophils. This releases parasite Ags that have the potential to cross-link cell-bound IgE. However, systemic hypersensitivity reactions are not induced by treatment. Here, we describe the effects of schistosomiasis, and its treatment, on human basophil function by following changes in total cellular histamine and in vitro histamine-release induced by schistosome Ags or anti-IgE, in blood samples from infected Ugandan fishermen, who are continuously exposed to S. mansoni inf...

Genital Tract Immunological Markers in Sub-Saharan African Women with Relevance to HIV Risk and Prevention

AIDS Research and Human Retroviruses, 2014

Bacterial Vaginosis and HIV: An Analysis of the MDP301 Trial

AIDS Research and Human Retroviruses, 2014

Immune Responses after Two Immunizations with rgp140/GLA Following Priming with HIV-DNA and HIV-MVA in Healthy Tanzanian Volunteers

AIDS Research and Human Retroviruses, 2014

Transactions of the Royal Society of Tropical Medicine and Hygiene, 2003

It has been proposed that helminth infection may exacerbate HIV progression by promoting activati... more It has been proposed that helminth infection may exacerbate HIV progression by promoting activation of 'type 2' immune responses. To examine this hypothesis, we investigated helminth infection in a cohort of HIV-l-seropositive adults in Entebbe, Uganda, during November 1999 to January 2000. Individuals with helminths were treated. At enrolment, after 5 weeks and after 4 months, CD4 + and CD8 + T cell counts and viral load were measured. Cytokine responses (interferon [IFN]-y, interleukin [ILl-2, IL-4 and IL-5) to Schiswsoma mansoni adult worm antigen (SWA), Mycobacterium tuberculosis culture filtrate proteins (CFPs) and phytohaemagglutinin (PHA) were measured in a whole blood assay. At baseline, CD4 + T cell counts and CD4+:CD8 + ratios were higher in individuals with helminths than in those without (median CD4 + T cell counts 467/pL and 268/pL, respectively, P = 0.005). Viral load was lower among those with helminths but this was not statistically significant. During follow-up, CD4 ÷ T cell counts and cytokine responses to PHA fell among individuals without helminths. Among those treated for helminths, CD4 ÷ counts remained stable. Viral loads showed a transient increase at 5 weeks, which was more marked among those treated for helminths, but the levels at 4 months were similar to baseline in both groups. Among those with schistosomiasis, IFN-y and IL-2 responses to CFP, and IL-2 and IL-4 responses to PHA declined but there was a sustained increase in cytokine responses to SWA following treatment. These data do not support the hypothesis that helminth infection exacerbates HIV infection. The possibility that chronic helminth infection may suppress HIV replication and that effects on HIV replication may vary during helminth infection and treatment should be considered.