Immunization with radiation-attenuated Plasmodium spp. sporozoites induces sterile protective immunity against parasite challenge. This immunity is targeted primarily against the intrahepatic parasite and appears to be sustained long term even in the absence of sporozoite exposure. It is mediated by multifactorial mechanisms, including T cells directed against parasite antigens expressed in the liver stage of the parasite life cycle and antibodies directed against sporozoite surface proteins. In rodent models, CD8+ T cells have been implicated as the principal effector cells, and IFN-gamma as a critical effector molecule. IL-4 secreting CD4+ T cells are required for induction of the CD8+ T cell responses, and Th1 CD4+ T cells provide help for optimal CD8+ T cell effector activity. Components of the innate immune system, including gamma-delta T cells, natural killer cells and natural killer T cells, also play a role. The precise nature of pre-erythrocytic stage immunity in humans, including the contribution of these immune responses to the age-dependent immunity naturally acquired by residents of malaria endemic areas, is still poorly defined. The importance of immune effector targets at the pre-erythrocytic stage of the parasite life cycle is highlighted by the fact that infection-blocking immunity in humans rarely, if ever, occurs under natural conditions. Herein, we review our current understanding of the molecular and cellular aspects of pre-erythrocytic stage immunity.

Data are lacking on the performance of interferon-c release assays (IGRAs) in children. Although IGRAs are recommended for screening for latent tuberculosis infection (LTBI), many clinicians wish to employ them as a diagnostic test for active tuberculosis (TB). The objective of the present study was to compare the performance of the two commercially available IGRAs and the tuberculin skin test (TST) side-by-side in children with active TB and LTBI.In a prospective study, 209 children were investigated for active (n591) or latent TB (n5118). TST, QuantiFERON-TB Gold In-tube (QFG-IT; Cellestis, Carnegie, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK) assays were simultaneously used.For culture-confirmed active TB, the sensitivity of the TST was 83%, compared with 80% for QFG-IT and 58% for T-SPOT.TB. IGRAs did not perform significantly better than TST, although QFG-IT was significantly better than T-SPOT.TB. The agreement between QFG-IT and T-SPOT.TB in culture-confirmed TB was poor at 66.7%. In LTBI, the agreement between QFG-IT and T-SPOT.TB was very good (92%) with moderate agreement between TST and T-SPOT.TB (75%) and QFG-IT and TST (77%).A negative interferon-c release assay should not dissuade paediatricians from diagnosing and treating presumed active tuberculosis. If used for diagnosis of latent tuberculosis infection, interferon-c release assays could significantly reduce the numbers of children receiving chemoprophylaxis. Very good concordance between both tests was found.

HPeV may cause severe disease and long-term neurological sequelae in young infants. HPeV should be considered in infants with clinical features of sepsis/meningitis with normal CSF microscopy. Prospective observational studies are warranted to better define the epidemiology of infection and thus inform future treatment trials.

Objectives: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. Trial design: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols.