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SummaryBackgroundCytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise.MethodsWe undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260.Findings67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p<0·0001) and seropositive (118 395; 64 503–217 272) versus 24 682 (17 909–34 017); p<0·0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0·0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0·0480) and number of days of ganciclovir treatment (p=0·0287) were reduced in vaccine recipients.InterpretationAlthough cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients.Funding, Grant R01AI051355 and , Grant 078332. Sponsor: University College London (UCL).

BackgroundVisceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.MethodsWe conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.FindingsChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.ConclusionThe results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.Trial registrationThis clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

Professional phagocytosis in mammals is considered to be performed exclusively by myeloid cell types. In this study, we demonstrate, for the first time, that a mammalian lymphocyte subset can operate as a professional phagocyte. By using confocal microscopy, transmission electron microscopy, and functional Ag presentation assays, we find that freshly isolated human peripheral blood γδ T cells can phagocytose Escherichia coli and 1 μm synthetic beads via Ab opsonization and CD16 (FcγRIII), leading to Ag processing and presentation on MHC class II. In contrast, other CD16+ lymphocytes, i.e., CD16+/CD56+ NK cells, were not capable of such functions. These findings of distinct myeloid characteristics in γδ T cells strongly support the suggestion that γδ T cells are evolutionarily ancient lymphocytes and have implications for our understanding of their role in transitional immunity and the control of infectious diseases and cancer.

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SUMMARYDendritic cells (DCs) have an essential role in the initiation of immune responses as they deliver antigen/epitope and the appropriate signals to activate naõ Ève T cells and thus start an immune response. In order to ful®l their function, DCs have to patrol different part of the body, thus migrating through the extracellular matrix to sample the local`antigenic' environment. In the present study, we have investigated which enzymes might be involved in this process using the Matrigel trans-well migration assay, an in vitro model of extracellular matrix migration. In this assay we analysed the migratory ability of interleukin-4 (IL-4)/ granulocyte macrophage±colony-stimulating factor (GM-CSF)-derived immature DCs as well as mature DCs, induced by tumour necrosis factor-a (TNF-a) and modi®ed vaccinia virus Ankara (MVA). The`mature' DCs showed an increased migration through Matrigel, which was signi®cantly inhibited by inhibitors of matrix metalloproteinases (MMP). We also observed that the dominant MMP involved in this process was MMP-9, and a concomitant decrease of the endogenous tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 was also observed. Collectively these data suggest that the balance between MMP/TIMP determines the net migratory capacity of human DCs. Surprisingly, TIMP-3 was signi®cantly increased in mature DC. Our data thus indicate that MMP and TIMP play a role in the migratory ability of human DCs. Our results also suggest that TIMP-3 expression might represent a new marker of maturation of human DCs.

As of May 17th 2020, the novel coronavirus disease 2019 (COVID-19) pandemic has caused 307,395 deaths worldwide, out of 3,917,366 cases reported to the World Health Organization. No specific treatments for reducing mortality or morbidity are yet available. Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and/or vaccines are found. In search of effective treatments, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 clinical trials on a range of antiviral drug regimens and repurposed drugs in various combinations. A paradigm shift is underway from the current focus of drug development targeting the pathogen, to advancing cellular Host-Directed Therapies (HDTs) for tackling the aberrant host immune and inflammatory responses which underlie the pathogenesis of SARS-CoV-2 and high COVID-19 mortality rates. We focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. Currently, the ClinicalTrials.gov and the WHO Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs or their products for treatment of COVID-19. MSCs should also be trialed for treatment of other circulating WHO priority Blueprint pathogens such as MERS-CoV which causes upto 34% mortality rates. It's about time funding agencies invested more into development MSCs per se, and also for a range of other HDTs, in combination with other therapeutic interventions. MSC therapy could turn out to be an important contribution to bringing an end to the high COVID-19 death rates and preventing long-term functional disability in those who survive disease.

Genetic factors such as the HLA type of patients may play a role in regard to disease severity and clinical outcome of patients with COVID-19. Taking the data deposited in the GISAID database, we made predictions using the IEDB analysis resource (TepiTool) to gauge how variants in the SARS-CoV-2 genome may change peptide binding to the most frequent MHC-class I and-II alleles in Africa, Asia and Europe. We caracterized how a single mutation in the wildtype sequence of of SARS-CoV-2 could influence the peptide binding of SARS-CoV-2 variants to MHC class II, but not to MHC class I alleles. Assuming the ORF8 (L84S) mutation is biologically significant, selective pressure from MHC class II alleles may select for viral varients and subsequently shape the quality and quantity of cellular immune responses aginast SARS-CoV-2. MHC 4-digit typing along with viral sequence analysis should be considered in studies examining clinical outcomes in patients with COVID-19.