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1.
BMJ Open ; 12(6): e058195, 2022 06 16.
Article in English | MEDLINE | ID: covidwho-1909754

ABSTRACT

OBJECTIVES: Prevalence surveys remain the best way to assess the national tuberculosis (TB) burden in many countries. Challenges with using culture (the reference standard) for TB diagnosis in prevalence surveys have led to increasing use of molecular tests (Xpert assays), but discordance between these two tests has created problems for deciding which individuals have TB. We aimed to design an accurate diagnostic algorithm for TB prevalence surveys (TBPS) that limits the use of culture. DESIGN: TBPS in four communities, conducted during 2019. SETTING: Three Zambian communities and one South-African community included in the TBPS of the Tuberculosis Reduction through Expanded Anti-retroviral Treatment and Screening study. PARTICIPANTS: Randomly sampled individuals aged ≥15 years. Among those who screened positive on chest X-ray or symptoms, two sputum samples were collected for field Xpert-Ultra testing and a third for laboratory liquid-culture testing. Clinicians reviewed screening and test results; in Zambia, participants with Mycobacterium tuberculosis-positive results were followed up 6-13 months later. Among 10 984 participants, 2092 screened positive, 1852 provided two samples for Xpert-Ultra testing, and 1009 had valid culture results. OUTCOMES: Culture and Xpert-Ultra test results. RESULTS: Among 946 culture-negative individuals, 917 were Xpert-negative, 12 Xpert-trace-positive and 17 Xpert-positive (grade very low, low, medium or high), with Xpert categorised as the highest grade of the two sample results. Among 63 culture-positive individuals, 8 were Xpert-negative, 9 Xpert-trace-positive and 46 Xpert-positive. Counting trace-positive results as positive, the sensitivity of Xpert-Ultra compared with culture was 87% (95% CI 76% to 94%) using two samples compared with 76% (95% CI 64% to 86%) using one. Specificity was 97% when trace-positive results were counted as positive and 98% when trace-positive results were counted as negative. Most Xpert-Ultra-positive/culture-negative discordance was among individuals whose Xpert-positive results were trace-positive or very low grade or they reported previous TB treatment. Among individuals with both Xpert-Ultra results grade low or above, the positive-predictive-value was 90% (27/30); 3/30 were plausibly false-negative culture results. CONCLUSION: Using Xpert-Ultra as the primary diagnostic test in TBPS, with culture only for confirmatory testing, would identify a high proportion of TB cases while massively reducing survey culture requirements. TRIAL REGISTRATION NUMBER: NCT03739736.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Tuberculosis , Humans , Mycobacterium tuberculosis/genetics , Prevalence , Sensitivity and Specificity , South Africa/epidemiology , Sputum/microbiology , Tuberculosis/diagnosis , Tuberculosis/epidemiology , Tuberculosis, Pulmonary/diagnosis , Zambia/epidemiology
2.
BMC Health Serv Res ; 22(1): 503, 2022 Apr 14.
Article in English | MEDLINE | ID: covidwho-1793944

ABSTRACT

BACKGROUND: Across Sub-Saharan Africa, adolescents and young people (AYP) aged 15-24 have limited access to sexual and reproductive health (SRH) services, including HIV testing services (HTS). In response, the Yathu Yathu study was implemented in two high-density communities in Lusaka, Zambia. Yathu Yathu provides comprehensive, community-based, peer-led SRH services, including differentiated HTS (finger-prick and HIV self-testing) and comprehensive sexuality education (CSE). We describe adaptations to the Yathu Yathu intervention in response to the COVID-19 epidemic, and implications on uptake of HTS among AYP. METHODS: Yathu Yathu provides SRH services through community-based peer-led spaces. AYP in study communities were offered prevention points cards (PPC), which incentivizes and tracks service use. Social media (WhatsApp©/Facebook©) is used to engage and inform AYP about SRH. Due to COVID-19, hubs closed from April-June 2020. We describe adaptations in response to COVID-19 and, using routinely collected PPC data, describe uptake of HTS before (September 2019-March 2020) and after (July-December 2020) adaptations in response to COVID-19. We describe reach of the Yathu Yathu Facebook page and use qualitative data to describe AYP experiences of SRH service access. RESULTS: During hub closures, CSE was delivered via video on social media, resulting in an increase in Facebook page followers from 539(April) to 891(June). WhatsApp groups evolved as a platform to deliver CSE and COVID-19 information, with higher participation among young people aged 20-24. Key service delivery adaptations included: reducing the number of participants in hubs, mandatory handwashing before entry, use of personal protective equipment by staff and provision of facemasks to AYP. HTS were provided as normal. Adaptations led to fewer AYP attending hubs. Uptake of HTS among AYP visiting hubs for the first time after COVID-19-related closures was higher (73.2%) compared to uptake before adaptations (65.9%; adjOR=1.24 95%CI 0.99, 1.56, p=0.06). Despite disappointments with some aspects of service delivery, AYP expressed happiness that hubs had reopened. CONCLUSIONS: Social media can be a useful additional platform to reach AYP with HIV prevention information during COVID-19. With proper infection control in place, HTS can safely be provided to, accessed and accepted by AYP in community-based settings during COVID-19. TRIAL REGISTRATION: National Clinical Trials NCT04060420,19th August 2019. Current Controlled Trials ISRCTN75609016 , 14th September 2021, retrospectively registered.


Subject(s)
Acquired Immunodeficiency Syndrome , COVID-19 , HIV Infections , Reproductive Health Services , Adolescent , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , Community Health Services , HIV Infections/diagnosis , HIV Infections/epidemiology , HIV Infections/prevention & control , HIV Testing , Humans , Reproductive Health , Young Adult , Zambia/epidemiology
3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332827

ABSTRACT

SARS-CoV-2 infection, and resulting disease, COVID-19, has a high mortality amongst patients with haematological malignancies. Global vaccine rollouts have successfully reduced hospitalisations and deaths, but the efficacy of vaccination in patients with haematological malignancies is known to be reduced. The UK-strategy offered a third, mRNA-based, vaccine as an extension to the primary course in these patients. Here we quantify serological responses following these vaccines in a cohort of 381 patients with haematological malignancies attending routine haematology outpatient clinics. By comparison with healthy controls, we report suboptimal responses following two primary vaccines, with significantly enhanced responses following the third primary dose. These responses however are heterogeneous and determined by haematological malignancy sub-type and therapy. We identify a group of patients with continued sub-optimal vaccine responses who may benefit from additional doses, as well as early intervention with monoclonal therapies in the event of developing SARS-CoV-2 infection.

4.
Research Square ; 2022.
Article in English | EuropePMC | ID: covidwho-1786488

ABSTRACT

SARS-CoV-2 infection, and resulting disease, COVID-19, has a high mortality amongst patients with haematological malignancies. Global vaccine rollouts have successfully reduced hospitalisations and deaths, but the efficacy of vaccination in patients with haematological malignancies is known to be reduced. The UK-strategy offered a third, mRNA-based, vaccine as an extension to the primary course in these patients. Here we quantify serological responses following these vaccines in a cohort of 381 patients with haematological malignancies attending routine haematology outpatient clinics. By comparison with healthy controls, we report suboptimal responses following two primary vaccines, with significantly enhanced responses following the third primary dose. These responses however are heterogeneous and determined by haematological malignancy sub-type and therapy. We identify a group of patients with continued sub-optimal vaccine responses who may benefit from additional doses, as well as early intervention with monoclonal therapies in the event of developing SARS-CoV-2 infection.

5.
Trials ; 23(1): 263, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1779666

ABSTRACT

BACKGROUND: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. METHODS: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. DISCUSSION: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. TRIAL REGISTRATION: The protocol is registered on Clinical. TRIALS: gov and EudraCT and has approval from UK Ethics and MHRA.


Subject(s)
COVID-19 , HIV Infections , HIV-1 , Broadly Neutralizing Antibodies , Clinical Trials, Phase II as Topic , Community Participation , HIV Antibodies , HIV Infections/diagnosis , HIV Infections/drug therapy , Humans , Prospective Studies , Quality of Life , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
6.
HIV Med ; 23(8): 929-930, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1704453
7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319221

ABSTRACT

Summary: 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. 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.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% to 61% in ELISA and 46% to 87% in the immunoblot assay.Concurrent anti-S IgG ranged from GM concentration (95% CI) 74 (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 15-48% depending on dose level received.Interpretation: Encapsulated saRNA is safe for clinical development and is immunogenic at low dose levels. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.Trial Registration: (ISRCTN17072692, EudraCT 2020-001646-20)Funding Statement: Medical Research Council UKRI (MC_PC_19076 and MC_UU_12023/23), National Institute for Health Research, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust.Declaration of Interests: P.F.M. and R.J.S. are co-inventors on a patent application covering this SARS-CoV-2 saRNA vaccine. All other authors have nothing to declare. Ethics Approval Statement: This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency and the North East - York Research Ethics Committee (reference 20/SC/0145).

8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315019

ABSTRACT

• Background: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART, remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs);3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control.• Methods: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n=36);in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after re-starting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures.• Discussion: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV-control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. Trial registration : The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315017

ABSTRACT

Background: It is unclear from epidemiological data for COVID-19 infections, whether people living with HIV (PLWH) have a different outcomes compared to the general population. We conducted a multi-centre, retrospective matched cohort study of SARS-CoV-2 PCR-positive hospital inpatients analysed by HIV-status.Methods: HIV-negative patients were matched to PLWH admitted to hospital before 31 st May 2020, with a 3:1 ratio by: hospital site, SARS-CoV-2 test date +/- 7 days, age +/- 5 years, gender, and index of multiple deprivation decile (IMDD) +/- 1. The primary objective was clinical improvement (≥2-point improvement on a 7-point ordinal scale) or hospital discharge by day 28, whichever was earlier.Results: 68 PLWH and 181 HIV-negative comparators were included. After adjustment for ethnicity, frailty, baseline hypoxia, duration of symptoms prior to baseline, body mass index categories, and comorbidities (hypertension, chronic cardiac disease, chronic lung disease, active malignancy, diabetes, and chronic renal disease), the effect size of HIV status was not associated with time to clinical improvement or discharge from hospital (aHR 0.70, 95%CI 0.43, 1.17;p=0.18), despite unadjusted hazards of PLWH achieving the primary outcome being 43% lower (p=0.005). Baseline frailty (aHR=0.79;95%CI 0.65, 0.95;p=0.011), malignancy (aHR=0.37;95%CI 0.17, 0.82;p=0.014) remained associated with poorer outcomes. PLWH were more likely of black and minority ethnicities (75.0% vs 48.6%, p=0.0002), higher median clinical frailty score (3 IQR 2-5 vs 2 IQR 1-4, p=0.0069), higher proportion of active malignancy (14.4% vs 9.9%, p=0.29). Median body mass index (BMI) was lower amongst PLWH (27.7 IQR 23.9-32.3 vs 29.4 IQR 24.7-34.3, p=0.19). Median CD4 count of PLWH was 352cells/µL (IQR 235-619) and 95.7% had suppressed viral loads <200copies/mL, 63/68 (92.3%) were taking antiretroviral therapy.Conclusions: Differences in clinical outcomes of COVID-19 hospitalisations in PLWH may be due to other important factors including increased frailty and comorbidities such as malignancies, rather than HIV-status alone.Funding Statement: This study has not received any funding sources.Declaration of Interests: MJL has received grants and honoraria from Gilead Sciences and Viiv Healthcare not related to this work. SF has received research grants to her institution from NIH, MRC, BMGF. JT has received support for virtual conference registration from ViiV Healthcare and research grants from the Medical Research Council and the British HIV Association not related to this work. CvH has received educational grants, conference support and advisory board fees from ViiV Healthcare, Gilead Sciences, MSC not related to this work. MP reports grants and personal fees from Gilead Sciences and personal fees from QIAGEN, outside the submitted work. MP is supported by a NIHR Development and Skills Enhancement Award (NIHR301192) and in receipt of funding from UKRI / MRC (MR/V027549/1). He acknowledges the support from UKRI, the NIHR Leicester BRC and NIHR ARC East Midlands. No other competing interests, financial relationships with any organisations that might have an interest in the submitted work, or other relationships or activities that could appear to have influenced the submitted work have been reported by other authors.Ethics Approval Statement: Ethical approval was granted by the UK Health Research Authority (REC reference 20/HRA/2278).

10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310655

ABSTRACT

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine is immunogenic and protects against COVID-19. However, data on vaccine immunogenicity are needed for the 40 million people living with HIV (PWH), who may have less functional immunity and more associated co-morbidities than the general population. Methods: Between the 5th and 24th November 2020, 54 adults with HIV, aged 18-55 years, were enrolled into a single arm open label vaccination study within the protocol of the larger phase 2/3 COV002 trial. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses (5 × 1010 vp) was given 4-6 weeks apart. All participants were on antiretroviral therapy (ART) with undetectable plasma HIV viral loads and CD4+ T cell counts >350 cells/µl at enrolment. Data were captured on adverse events. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo interferon-γ enzyme-linked immunospot assay (ELISpot) and T cell proliferation. All outcomes were compared with a HIV uninfected group from the main COV002 study.Findings: 54 participants with HIV (median age 42.5 years (IQR 37.2-49.8)) received two doses of ChAdOx1 nCoV-19. Median CD4+ T cell count at enrolment was 694 cells/µl (IQR 562-864). Results are reported for 56 days of follow-up. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (49%), fatigue (47%), headache (47%), malaise (34%), chills (23%), and muscle or (36%) joint pain (9%), the frequencies of which were similar to the HIV-negative participants. There were no serious adverse events. Anti-spike IgG responses by ELISA peaked at Day 42 (median 1440 ELISA units, IQR 704-2728) and were sustained out to Day 56. There was no correlation with CD4+ T cell count or age and the magnitude of the anti-spike IgG response at Day 56 (P>0.05 for both). ELISpot and T cell proliferative responses peaked between Day 14 and 28 after prime and were sustained through to Day 56. When compared to participants without HIV there was no statistical difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (P>0.05 for all analyses).Interpretation: In this study of PWH, vaccination with ChAdOx1 nCoV-19 was well tolerated and there was no difference in humoral and cell-mediated immune responses compared to an adult cohort without HIV who received the same vaccination regime. Trial Registration: Trial Registration number is NCT04400838. Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). AstraZeneca reviewed the data from the study and the final manuscript before 474 submission, but the authors retained editorial control. SCG is cofounder of Vaccitech (a collaborator in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AVSH is a cofounder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/0004 7).Ethical Approval: Written informed consent was obtained from all participants, and the trial was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency (reference 21584/0424/001-0001) and the South Central Berkshire Research Ethics Committee (reference 20/SC/0145). Vaccine use was authorised by Genetically Modified Organisms Safety Committees at each participating site.

11.
J Int AIDS Soc ; 25(2): e25882, 2022 02.
Article in English | MEDLINE | ID: covidwho-1669512

ABSTRACT

INTRODUCTION: The International AIDS Society convened a multidisciplinary committee of experts in December 2020 to provide guidance and key considerations for the safe and ethical management of clinical trials involving people living with HIV (PLWH) during the SARS-CoV-2 pandemic. This consultation did not discuss guidance for the design of prevention studies for people at risk of HIV acquisition, nor for the programmatic delivery of antiretroviral therapy (ART). DISCUSSION: There is strong ambition to continue with HIV research from both PLWH and the research community despite the ongoing SARS-CoV-2 pandemic. How to do this safely and justly remains a critical debate. The SARS-CoV-2 pandemic continues to be highly dynamic. It is expected that with the emergence of effective SARS-CoV-2 prevention and treatment strategies, the risk to PLWH in clinical trials will decline over time. However, with the emergence of more contagious and potentially pathogenic SARS-CoV-2 variants, the effectiveness of current prevention and treatment strategies may be compromised. Uncertainty exists about how equally SARS-CoV-2 prevention and treatment strategies will be available globally, particularly for marginalized populations, many of whom are at high risk of reduced access to ART and/or HIV disease progression. All of these factors must be taken into account when deciding on the feasibility and safety of developing and implementing HIV research. CONCLUSIONS: It can be assumed for the foreseeable future that SARS-CoV-2 will persist and continue to pose challenges to conducting clinical research in PLWH. Guidelines regarding how best to implement HIV treatment studies will evolve accordingly. The risks and benefits of performing an HIV clinical trial must be carefully evaluated in the local context on an ongoing basis. With this document, we hope to provide a broad guidance that should remain viable and relevant even as the nature of the pandemic continues to develop.


Subject(s)
COVID-19 , HIV Infections , HIV Infections/drug therapy , HIV Infections/epidemiology , HIV Infections/prevention & control , Humans , Pandemics , SARS-CoV-2
12.
EClinicalMedicine ; 44: 101262, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1620636

ABSTRACT

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 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0µg, 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; 0.1µg) to 61% (14/23; 10.0µg) in ELISA and 46% (18/39; 0.3µg) to 87% (20/23; 5.0µg and 10.0µg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1µg to 1023 (468-2236) ng/mL at 5.0µg (p<0.001) and was not higher at 10.0µg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1µg) to 48% (11/23; 5.0µg) 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. FUNDING: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.

13.
HIV Med ; 23(2): 121-133, 2022 02.
Article in English | MEDLINE | ID: covidwho-1434702

ABSTRACT

BACKGROUND: The contribution of HIV to COVID-19 outcomes in hospitalized inpatients remains unclear. We conducted a multi-centre, retrospective matched cohort study of SARS-CoV-2 PCR-positive hospital inpatients analysed by HIV status. METHODS: HIV-negative patients were matched to people living with HIV (PLWH) admitted from 1 February 2020 to 31 May 2020 up to a 3:1 ratio by the following: hospital site, SARS-CoV-2 test date ± 7 days, age ± 5 years, gender, and index of multiple deprivation decile ± 1. The primary objective was clinical improvement (two-point improvement or better on a seven-point ordinal scale) or hospital discharge by day 28, whichever was earlier. RESULTS: A total of 68 PLWH and 181 HIV-negative comparators were included. In unadjusted analyses, PLWH had a reduced hazard of achieving clinical improvement or discharge [adjusted hazard ratio (aHR) = 0.57, 95% confidence interval (CI): 0.39-0.85, p = 0.005], but this association was ameliorated (aHR = 0.70, 95% CI: 0.43-1.17, p = 0.18) after additional adjustment for ethnicity, frailty, baseline hypoxaemia, duration of symptoms prior to baseline, body mass index (BMI) categories and comorbidities. Baseline frailty (aHR = 0.79, 95% CI: 0.65-0.95, p = 0.011), malignancy (aHR = 0.37, 95% CI 0.17, 0.82, p = 0.014) remained associated with poorer outcomes. The PLWH were more likely to be of black, Asian and minority ethnic background (75.0% vs 48.6%, p = 0.0002), higher median clinical frailty score [3 × interquartile range (IQR): 2-5 vs, 2 × IQR: 1-4, p = 0.0069), and to have a non-significantly higher proportion of active malignancy (14.4% vs 9.9%, p = 0.29). CONCLUSIONS: Adjusting for confounding comorbidities and demographics in a matched cohort ameliorated differences in outcomes of PLWH hospitalized with COVID-19, highlighting the importance of an appropriate comparison group when assessing outcomes of PLWH hospitalized with COVID-19.


Subject(s)
COVID-19 , HIV Infections , COVID-19/epidemiology , COVID-19/therapy , England/epidemiology , Female , HIV Infections/epidemiology , Hospitalization , Humans , Male , Pandemics , Retrospective Studies , Treatment Outcome
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