Circulating CD14brightCD16+ 'intermediate' monocytes exhibit enhanced parasite pattern recognition in human helminth infection.

Circulating monocyte sub-sets have recently emerged as mediators of divergent immune functions during infectious disease but their role in helminth infection has not been investigated. In this study we evaluated whether 'classical' (CD14brightCD16-), 'intermediate' (CD14brightCD16+), and 'non-classical' (CD14dimCD16+) monocyte sub-sets from peripheral blood mononuclear cells varied in both abundance and ability to bind antigenic material amongst individuals living in a region of Northern Senegal which is co-endemic for Schistosoma mansoni and S. haematobium. Monocyte recognition of excretory/secretory (E/S) products released by skin-invasive cercariae, or eggs, of S. mansoni was assessed by flow cytometry and compared between S. mansoni mono-infected, S. mansoni and S. haematobium co-infected, and uninfected participants. Each of the three monocyte sub-sets in the different infection groups bound schistosome E/S material. However, 'intermediate' CD14brightCD16+ monocytes had a significantly enhanced ability to bind cercarial and egg E/S. Moreover, this elevation of ligand binding was particularly evident in co-infected participants. This is the first demonstration of modulated parasite pattern recognition in CD14brightCD16+ intermediate monocytes during helminth infection, which may have functional consequences for the ability of infected individuals to respond immunologically to infection

Enhanced Pro-Inflammatory Cytokine Responses following Toll-Like-Receptor Ligation in Schistosoma haematobium-Infected Schoolchildren from Rural Gabon

BACKGROUND: Schistosoma infection is thought to lead to down-regulation of the host's immune response. This has been shown for adaptive immune responses, but the effect on innate immunity, that initiates and shapes the adaptive response, has not been extensively studied. In a first study to characterize these responses, we investigated the effect of Schistosoma haematobium infection on cytokine responses of Gabonese schoolchildren to a number of Toll-like receptor (TLR) ligands. METHODOLOGY: Peripheral blood mononuclear cells (PBMCs) were collected from S. haematobium-infected and uninfected schoolchildren from the rural area of Zile in Gabon. PBMCs were incubated for 24 h and 72 h with various TLR ligands, as well as schistosomal egg antigen (SEA) and adult worm antigen (AWA). Pro-inflammatory TNF-alpha and anti-inflammatory/regulatory IL-10 cytokine concentrations were determined in culture supernatants. PRINCIPAL FINDINGS: Infected children produced higher adaptive IL-10 responses than uninfected children against schistosomal antigens (72 h incubation). On the other hand, infected children had higher TNF-alpha responses than uninfected children and significantly higher TNF-alpha to IL-10 ratios in response to FSL-1 and Pam3, ligands of TLR2/6 and TLR2/1 respectively. A similar trend was observed for the TLR4 ligand LPS while Poly(I:C) (Mda5/TLR3 ligand) did not induce substantial cytokine responses (24 h incubation). CONCLUSIONS: This pilot study shows that Schistosoma-infected children develop a more pro-inflammatory TLR2-mediated response in the face of a more anti-inflammatory adaptive immune response. This suggests that S. haematobium infection does not suppress the host's innate immune system in the context of single TLR ligation

Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial

SummaryBackgroundHIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189.FindingsBetween Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3).InterpretationMVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both.FundingEuropean & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium

Chapter 14 SUMMARY AND CONCLUSIONS

Climate variability is a reality that is affecting rural livelihoods in West Africa today and presenting a growing challenge in the region, as in many other parts of the African continent and elsewhere. Climate change will have far-reaching consequences for the poor and marginalized groups among which the majority depend on agriculture for their livelihoods and have a lower capacity to adapt. Weather-related crop failures, fishery collapses, and livestock deaths in addition to losses of property are already causing economic losses and undermining food security in West Africa. This situation is likely to become more desperate and to threaten the survival of the majority of poor farmers as global warming continues. Feeding the increasing populations in a subregion with one of the highest rates of population growth in the world requires radical transformation of a largely underdeveloped agriculture over the next four decades. A major challenge is increasing agricultural production among resource-poor farmers without exacerbating environmental problems and simultaneously coping with climate change

Safety and immunogenicity of a heterologous prime-boost Ebola virus vaccine regimen in healthy adults in the United Kingdom and Senegal

Background The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. Methods We undertook two Phase I studies assessing safety and immunogenicity of the viral vector MVA-EBO-Z, manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with ChAd3-EBO-Z followed by MVA-EBO-Z. Adult volunteers in the UK (n = 38) and Senegal (n=40) were vaccinated and an accelerated one week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. Results The standard and accelerated heterologous prime-boost regimes were well-tolerated and elicited potent cellular and humoral immunogenicity in the UK and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. Conclusions MVA biomanufactured on an immortalised duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in Phase II studies with the one week prime-boost interval regimen appearing particularly suitable for outbreak control

Safety and immunogenicity of a heterologous prime-boost Ebola virus vaccine regimen in healthy adults in the United Kingdom and Senegal

Background The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. Methods We undertook two Phase I studies assessing safety and immunogenicity of the viral vector MVA-EBO-Z, manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with ChAd3-EBO-Z followed by MVA-EBO-Z. Adult volunteers in the UK (n = 38) and Senegal (n=40) were vaccinated and an accelerated one week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. Results The standard and accelerated heterologous prime-boost regimes were well-tolerated and elicited potent cellular and humoral immunogenicity in the UK and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. Conclusions MVA biomanufactured on an immortalised duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in Phase II studies with the one week prime-boost interval regimen appearing particularly suitable for outbreak control

Safety and immunogenicity of a heterologous prime-boost Ebola virus vaccine regimen in healthy adults in the United Kingdom and Senegal

Background The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. Methods We undertook two Phase I studies assessing safety and immunogenicity of the viral vector MVA-EBO-Z, manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with ChAd3-EBO-Z followed by MVA-EBO-Z. Adult volunteers in the UK (n = 38) and Senegal (n=40) were vaccinated and an accelerated one week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. Results The standard and accelerated heterologous prime-boost regimes were well-tolerated and elicited potent cellular and humoral immunogenicity in the UK and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. Conclusions MVA biomanufactured on an immortalised duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in Phase II studies with the one week prime-boost interval regimen appearing particularly suitable for outbreak control