The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)(+) interleukin-2 (IL-2)(-) CD8(+) T cells (r = -0.6, P = 0.004). Within this functional CD8(+)IFN-γ(+)IL-2(-) population, cells with the CD45RA(+) chemokine (C-C) receptor 7 (CCR7)(-) phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8(+) T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development.

CYD-TDV protected against severe VCD and hospitalization for VCD for 5 years in persons who had exposure to dengue before vaccination, and there was evidence of a higher risk of these outcomes in vaccinated persons who had not been exposed to dengue. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530 , NCT01983553 , NCT01373281 , and NCT01374516 .).

Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children.Design Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. Setting Community congregate settings and households.Inclusion criteria Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays. Data extractionStudy results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. ResultsThe primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). Conclusions BCG protects against M tuberculosis infection as well as progression from infection to disease.Trial registration PROSPERO registration No CRD42011001698 (www. crd.york.ac.uk/prospero/). IntroductionBCG vaccine has been the subject of numerous efficacy trials and epidemiological studies conducted over several decades. These trials indicate that BCG has 60-80% protective efficacy against severe forms of tuberculosis in children, particularly meningitis, 1 2 and its efficacy against pulmonary diseases varies geographically.3-5 BCG does not seem to protect against disease when it is given to people already infected or sensitised to environmental mycobacteria, which could explain the geographical variation.6-8 Until recently it was not possible to establish whether the protective effect of BCG vaccination against disease was from its action in preventing acquisition of infection or limited to prevention of progression from infection to clinical disease.The scarcity of evidence on whether the vaccine is effective against Mycobacterium tuberculosis infection was because of limitations of the tuberculin skin test. This test cannot distinguish a positive response caused by M tuberculosis infection from that caused by BCG vaccination or non-tuberculous In this systematic review we examined the evidence for the protective effect of BCG against M tuberculosis infection, as opposed to against disease, in settings where children can be presumed to have been exposed to M tu...

Influenza is a major respiratory pathogen causing annual outbreaks and occasional pandemics. Influenza vaccination is the major method of prophylaxis. Currently annual influenza vaccination is recommended for groups at high risk of complications from influenza infection such as pregnant women, young children, people with underlying disease and the elderly, along with occupational groups such a healthcare workers and farm workers. There are two main types of vaccines available: the parenteral inactivated influenza vaccine and the intranasal live attenuated influenza vaccine. The inactivated vaccines are licensed from 6 months of age and have been used for more than 50 years with a good safety profile. Inactivated vaccines are standardized according to the presence of the viral major surface glycoprotein hemagglutinin and protection is mediated by the induction of vaccine strain specific antibody responses. In contrast, the live attenuated vaccines are licensed in Europe for children from 2–17 years of age and provide a multifaceted immune response with local and systemic antibody and T cell responses but with no clear correlate of protection. Here we discuss the immunological immune responses elicited by the two vaccines and discuss future work to better define correlates of protection.

BackgroundT-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults.MethodsWe conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46 years and 24 subjects aged 50 years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18 months.FindingsBoth vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP + M1 vaccination was significantly higher compared to ChAdOx1 NP + M1. In a mixed regression model, T-cell responses over 18 months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP + M1.InterpretationA two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A.Funding SourceMedical Research Council UK, NIHR BMRC Oxford.

SummaryBackgroundTackling tuberculosis requires testing and treatment of latent tuberculosis in high-risk groups. The aim of this study was to estimate the predictive values of the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs) for the development of active tuberculosis in high-risk groups—ie, people in recent contact with active tuberculosis cases and from high-burden countries.MethodIn this prospective cohort study, we recruited participants from 54 centres (eg, clinics, community settings) in London, Birmingham, and Leicester in the UK. Participants were eligible if they were aged 16 years or older and at high risk for latent tuberculosis infection (ie, recent contact with someone with active tuberculosis [contacts] or a migrant who had arrived in the UK in the past 5 years from—or who frequently travelled to—a country with a high burden of tuberculosis [migrants]). Exclusion criteria included prevalent cases of tuberculosis, and participants who were treated for latent tuberculosis after a positive test result in this study. Each participant received three tests (QuantiFERON-TB Gold-In Tube, T-SPOT.TB, and a Mantoux TST). A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in BCG-naive or 15 mm in BCG-vaccinated (TST-15) participants. Participants were followed up from recruitment to development of tuberculosis or censoring. Incident tuberculosis cases were identified by national tuberculosis databases, telephone interview, and review of medical notes. Our primary objective was to estimate the prognostic value of IGRAs compared with TST, assessed by the ratio of incidence rate ratios and predictive values for tuberculosis development. The study was registered with ClinicalTrials.gov, NCT01162265, and is now complete.FindingsBetween May 4, 2010, and June 1, 2015, 10 045 people were recruited, of whom 9610 were eligible for inclusion. Of this cohort, 4861 (50·6%) were contacts and 4749 (49·4%) were migrants. Participants were followed up for a median of 2·9 years (range 21 days to 5·9 years). 97 (1·0%) of 9610 participants developed active tuberculosis (77 [1·2%] of 6380 with results for all three tests). In all tests, annual incidence of tuberculosis was very low in those who tested negatively (ranging from 1·2 per 1000 person-years, 95% CI 0·6–2·0 for TST-5 to 1·9 per 1000 person-years, 95% CI 1·3–2·7, for QuantiFERON-TB Gold In-Tube). Annual incidence in participants who tested positively were highest for T-SPOT.TB (13·2 per 1000 person-years, 95% CI 9·9–17·4), TST-15 (11·1 per 1000 person-years, 8·3–14·6), and QuantiFERON-TB Gold In-Tube (10·1 per 1000 person-years, 7·4–13·4). Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5 (eg, ratio of test positivity rates in those progressing to tuberculosis compared with those not progressing T-SPOT.TB vs TST-5: 1·99, 95% CI 1·68–2·34; p<0·0001). However, TST-5 identified a higher proportion of participants who progressed to acti...

Despite recent advances in treatment and vector control, malaria is still a leading cause of death, emphasizing the need for an effective vaccine. The malaria life cycle can be subdivided into three stages: the invasion and growth within liver hepatocytes (pre-erythrocytic stage), the blood stage (erythrocytic stage), and, finally, the sexual stage (occurring within the mosquito vector). Antigen (Ag)-specific CD8+ T cells are effectively induced by heterologous prime-boost viral vector immunization and known to correlate with liver-stage protection. However, liver-stage malaria vaccines have struggled to generate and maintain the high numbers of Plasmodium-specific circulating T cells necessary to confer sterile protection. We describe an alternative “prime and target” vaccination strategy aimed specifically at inducing high numbers of tissue-resident memory T cells present in the liver at the time of hepatic infection. This approach bypasses the need for very high numbers of circulating T cells and markedly increases the efficacy of subunit immunization against liver-stage malaria with clinically relevant Ags and clinically tested viral vectors in murine challenge models. Translation to clinical use has begun, with encouraging results from a pilot safety and feasibility trial of intravenous chimpanzee adenovirus vaccination in humans. This work highlights the value of a prime-target approach for immunization against malaria and suggests that this strategy may represent a more general approach for prophylaxis or immunotherapy of other liver infections and diseases.

BackgroundIFN-γ and IL-2 cytokine-profiles define three functional T-cell subsets which may correlate with pathogen load in chronic intracellular infections. We therefore investigated the feasibility of the immunospot platform to rapidly enumerate T-cell subsets by single-cell IFN-γ/IL-2 cytokine-profiling and establish whether immunospot-based T-cell signatures distinguish different clinical stages of human tuberculosis infection.MethodsWe used fluorophore-labelled anti-IFN-γ and anti-IL-2 antibodies with digital overlay of spatially-mapped colour-filtered images to enumerate dual and single cytokine-secreting M. tuberculosis antigen-specific T-cells in tuberculosis patients and in latent tuberculosis infection (LTBI). We validated results against established measures of cytokine-secreting T-cells.ResultsFluorescence-immunospot correlated closely with single-cytokine enzyme-linked-immunospot for IFN-γ-secreting T-cells and IL-2-secreting T-cells and flow-cytometry-based detection of dual IFN-γ/IL-2-secreting T-cells. The untreated tuberculosis signature was dominated by IFN-γ-only-secreting T-cells which shifted consistently in longitudinally-followed patients during treatment to a signature dominated by dual IFN-γ/IL-2-secreting T-cells in treated patients. The LTBI signature differed from active tuberculosis, with higher proportions of IL-2-only and IFN-γ/IL-2-secreting T-cells and lower proportions of IFN-γ-only-secreting T-cells.ConclusionsFluorescence-immunospot is a quantitative, accurate measure of functional T-cell subsets; identification of cytokine-signatures of pathogen burden, distinct clinical stages of M. tuberculosis infection and long-term immune containment suggests application for treatment monitoring and vaccine evaluation.