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Background Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.Methods A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19 th June to 28 th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20).Findings 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1mg) to 61% (14/23; 10.0mg) in ELISA and 46% (18/39; 0.3mg) to 87% (20/23; 5.0mg and 10.0mg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1mg to 1023 (468-2236) ng/mL at 5.0mg (p<0.001) and was not higher at 10.0mg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1mg) to 48% (11/23; 5.0mg) depending on dose level received.Interpretation Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.

SummaryBackgroundThe cross-sectional HIV care continuum is widely used to assess the success of HIV care programmes among populations of people with HIV and the potential for ongoing transmission. We aimed to investigate whether a longitudinal continuum, which incorporates loss to follow-up and mortality, might provide further insights about the performance of care programmes.MethodsIn this longitudinal cohort study, we included individuals who entered the UK Collaborative HIV Cohort (CHIC) study between Jan 1, 2000, and Dec 31, 2004, and were linked to the national HIV cohort database (HIV and AIDS Reporting System). For each month during a 10 year follow up period, we classified individuals into one of ten distinct categories according to engagement in care, antiretroviral therapy (ART) use, viral suppression, loss to cohort follow-up and loss to care, and mortality, and assessed the proportion of person-months of follow-up spent in each stage of the continuum. 5 year longitudinal continuums were also constructed for three separate cohorts (baseline years of entry 2000–03, 2004–07, and 2008–09) to compare changes over time.FindingsWe included 12 811 people contributing 1 537 320 person-months in our analysis. During 10 years of follow-up, individuals spent 811 057 (52·8%) of 1 537 320 person-months on ART. Of the 811 057 person-months spent on ART, individuals had a viral load of 200 copies per mL or less for 607 185 (74·9%) person-months. 10 years after cohort entry, 3612 (28·1%) of 12 811 individuals were lost to follow-up, 954 (26·4%) of whom had transferred to a non-CHIC UK clinic for care. By 10 years, 759 (5·9%) of 12 811 participants who entered the cohort had died. Loss to follow-up decreased and the proportion of person-months that individuals spent virally suppressed increased over calendar time.InterpretationLoss to follow-up in HIV care programmes was high and rates of viral suppression were lower than previously reported. Complementary information provided by a longitudinal continuum might highlight areas for intervention along the HIV care pathway, however, transfers outside the cohort must be accounted for.FundingMedical Research Council, UK.