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1.
Cell Reports Medicine ; : 100510, 2022.
Article in English | ScienceDirect | ID: covidwho-1621096

ABSTRACT

Summary SARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with improved disease outcome and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta and Delta infection trigger responses with significantly improved Fc cross-reactivity against global VOCs compared to D614G-infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.

2.
J Int AIDS Soc ; 24(12): e25846, 2021 12.
Article in English | MEDLINE | ID: covidwho-1591262

ABSTRACT

INTRODUCTION: While pregnant people have been an important focus for HIV research, critical evidence gaps remain regarding prevention, co-infection, and safety and efficacy of new antiretroviral therapies in pregnancy. Such gaps can result in harm: without safety data, drugs used may carry unacceptable risks to the foetus or pregnant person; without pregnancy-specific dosing data, pregnant people face risks of both toxicity and undertreatment; and delays in gathering evidence can limit access to beneficial next-generation drugs. Despite recognition of the need, numerous barriers and ethical complexities have limited progress. We describe the process, ethical foundations, recommendations and applications of guidance for advancing responsible inclusion of pregnant people in HIV/co-infections research. DISCUSSION: The 26-member international and interdisciplinary Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Working Group was convened to develop ethics-centred guidance for advancing timely, responsible HIV/co-infections research with pregnant people. Deliberations over 3 years drew on extensive qualitative research, stakeholder engagement, expert consultation and a series of workshops. The guidance, initially issued in July 2020, highlights conceptual shifts needed in framing research with pregnant people, and articulates three ethical foundations to ground recommendations: equitable protection from drug-related risks, timely access to biomedical advances and equitable respect for pregnant people's health interests. The guidance advances 12 specific recommendations, actionable within the current regulatory environment, addressing multiple stakeholders across drug development and post-approval research, and organized around four themes: building capacity, supporting inclusion, achieving priority research and ensuring respect. The recommendations describe strategies towards ethically redressing the evidence gap for pregnant people around HIV and co-infections. The guidance has informed key efforts of leading organizations working to advance needed research, and identifies further opportunities for impact by a range of stakeholder groups. CONCLUSIONS: There are clear pathways towards ethical inclusion of pregnant people in the biomedical research agenda, and strong agreement across the HIV research community about the need for - and the promise of - advancing them. Those who fund, conduct, oversee and advocate for research can use the PHASES guidance to facilitate more, better and earlier evidence to optimize the health and wellbeing of pregnant people and their children.


Subject(s)
Acquired Immunodeficiency Syndrome , Biomedical Research , Coinfection , HIV Infections , Child , Female , HIV Infections/drug therapy , HIV Infections/prevention & control , Humans , Pregnancy , Stakeholder Participation
4.
Lancet Infect Dis ; 21(11): e342-e347, 2021 11.
Article in English | MEDLINE | ID: covidwho-1561809

ABSTRACT

Large-scale deployment of COVID-19 vaccines will seriously affect the ongoing phases 2 and 3 randomised placebo-controlled trials assessing SARS-CoV-2 vaccine candidates. The effect will be particularly acute in high-income countries where the entire adult or older population could be vaccinated by late 2021. Regrettably, only a small proportion of the population in many low-income and middle-income countries will have access to available vaccines. Sponsors of COVID-19 vaccine candidates currently in phase 2 or initiating phase 3 trials in 2021 should consider continuing the research in countries with limited affordability and availability of COVID-19 vaccines. Several ethical principles must be implemented to ensure the equitable, non-exploitative, and respectful conduct of trials in resource-poor settings. Once sufficient knowledge on the immunogenicity response to COVID-19 vaccines is acquired, non-inferiority immunogenicity trials-comparing the immune response of a vaccine candidate to that of an authorised vaccine-would probably be the most common trial design. Until then, placebo-controlled, double-blind, crossover trials will continue to play a role in the development of new vaccine candidates. WHO or the Council for International Organizations of Medical Sciences should define an ethical framework for the requirements and benefits for trial participants and host communities in resource-poor settings that should require commitment from all vaccine candidate sponsors from high-income countries.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Clinical Trials as Topic , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Double-Blind Method , Humans , Immunogenicity, Vaccine , Pandemics/prevention & control , SARS-CoV-2/immunology
5.
Preprint in English | Other preprints | ID: ppcovidwho-295924

ABSTRACT

Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The emergence of C.1.2, associated with a high substitution rate, includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 VOC/VOIs. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta showed high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2.

6.
Preprint in English | EuropePMC | ID: ppcovidwho-295139

ABSTRACT

Summary Background People living with HIV (PLWH) have been reported to have an increased risk of more severe COVID-19 disease outcome and an increased risk of death relative to HIV-uninfected individuals. Here we assessed the ability of the Johnson and Johnson Ad26.CoV2.S vaccine to elicit neutralizing antibodies to the Delta variant in PLWH relative to HIV-uninfected individuals. We also compared the neutralization after vaccination to neutralization elicited by SARS-CoV-2 infection only in HIV-uninfected, suppressed HIV PLWH, and PLWH with detectable HIV viremia. Methods We enrolled 26 PLWH and 73 HIV-uninfected participants from the SISONKE phase 3b open label South African clinical trial of the Ad26.CoV2.S vaccine in health care workers (HCW). Enrollment was a median 56 days (range 19-98 days) post-vaccination and PLWH in this group had well controlled HIV infection. We also enrolled unvaccinated participants previously infected with SARS-CoV-2. This group consisted of 34 PLWH and 28 HIV-uninfected individuals. 10 of the 34 (29%) SARS-CoV-2 infected only PLWH had detectable HIV viremia. We used records of a positive SARS-CoV-2 qPCR result, or when a positive result was absent, testing for SARS-CoV-2 nucleocapsid antibodies, to determine which vaccinated participants were SARS-CoV-2 infected prior to vaccination. Neutralization capacity was assessed using participant plasma in a live virus neutralization assay of the Delta SARS-CoV-2 variant currently dominating infections in South Africa. This study was approved by the Biomedical Research Ethics Committee at the University of KwaZulu–Natal (reference BREC/00001275/2020). Findings The majority (68%) of Ad26.CoV2.S vaccinated HCW were found to be previously infected with SARS-CoV-2. In this group, Delta variant neutralization was 9-fold higher compared to the infected only group (GMT=306 versus 36, p<0.0001) and 26-fold higher relative to the vaccinated only group (GMT=12, p<0.0001). No significant difference in Delta variant neutralization capacity was observed in vaccinated and previously SARS-CoV-2 infected PLWH relative to vaccinated and previously SARS-CoV-2 infected, HIV-uninfected participants (GMT=307 for HIV-uninfected, 300 for PLWH, p=0.95). SARS-CoV-2 infected, unvaccinated PLWH showed 7-fold reduced neutralization of the Delta variant relative to HIV-uninfected participants (GMT=105 for HIV-uninfected, 15 for PLWH, p=0.001). There was a higher frequency of non-responders in PLWH relative to HIV-uninfected participants in the SARS-CoV-2 infected unvaccinated group (27% versus 0%, p=0.0029) and 60% of HIV viremic versus 13% of HIV suppressed PLWH were non-responders (p=0.0088). In contrast, the frequency of non-responders was low in the vaccinated/infected group, and similar between HIV-uninfected and PLWH. Vaccinated only participants showed a low neutralization of the Delta variant, with a stronger response in PLWH (GMT=6 for HIV-uninfected, 73 for PLWH, p=0.02). Interpretation The neutralization response of the Delta variant following Ad26.CoV2.S vaccination in PLWH with well controlled HIV was not inferior to HIV-uninfected study participants. In SARS-CoV-2 infected and non-vaccinated participants, the presence of HIV infection reduced the neutralization response to SARS-CoV-2 infection, and this effect was strongest in PLWH with detectable HIV viremia Funding South African Medical Research Council, The Bill & Melinda Gates Foundation.

8.
Non-conventional in English | MEDLINE, Grey literature | ID: grc-750467

ABSTRACT

Background Healthcare resource constraints in low and middle-income countries necessitate selection of cost-effective public health interventions to address COVID-19. Methods We developed a dynamic COVID-19 microsimulation model to evaluate clinical and economic outcomes and cost-effectiveness of epidemic control strategies in KwaZulu-Natal, South Africa. Interventions assessed were Healthcare Testing (HT), where diagnostic testing is performed only for those presenting to healthcare centres;Contact Tracing (CT) in households of cases;Isolation Centres (IC), for cases not requiring hospitalisation;community health worker-led Mass Symptom Screening and diagnostic testing for symptomatic individuals (MS);and Quarantine Centres (QC), for contacts who test negative. Given uncertainties about epidemic dynamics in South Africa, we evaluated two main epidemic scenarios over 360 days, with effective reproduction numbers (R e ) of 1.5 and 1.2. We compared HT, HT+CT, HT+CT+IC, HT+CT+IC+MS, HT+CT+IC+QC, and HT+CT+IC+MS+QC, considering strategies with incremental cost-effectiveness ratio (ICER) <US$1,290/year-of-life saved (YLS) to be cost-effective. Findings With R e 1.5, HT resulted in the most COVID-19 deaths and lowest costs over 360 days. Compared with HT, HT+CT+IC+MS reduced mortality by 76%, increased costs by 16%, and was cost-effective (ICER $350/YLS). HT+CT+IC+MS+QC provided the greatest reduction in mortality, but increased costs by 95% compared with HT+CT+IC+MS and was not cost-effective (ICER $8,000/YLS). With R e 1.2, HT+CT+IC+MS was the least costly strategy, and HT+CT+IC+MS+QC was not cost-effective (ICER $294,320/YLS). Interpretation In South Africa, a strategy of household contact tracing, isolation, and mass symptom screening would substantially reduce COVID-19 mortality and be cost-effective. Adding quarantine centres for COVID-19 contacts is not cost-effective.

9.
AIDS Res Hum Retroviruses ; 2021 Nov 25.
Article in English | MEDLINE | ID: covidwho-1486408

ABSTRACT

The HIV Research for Prevention (HIVR4P) conference catalyzes knowledge sharing on biomedical HIV prevention interventions such as HIV vaccines, antibody infusions, pre-exposure prophylaxis, and microbicides in totality-from the molecular details and delivery formulations to the behavioral, social, and structural underpinnings. HIVR4P // Virtual was held over the course of 2 weeks on January 27-28 and February 3-4, 2021 as the COVID-19 pandemic continued to inflict unprecedented harm globally. The HIVR4P community came together with 1,802 researchers, care providers, policymakers, implementers, and advocates from 92 countries whose expertise spanned the breadth of the HIV prevention pipeline from preclinical to implementation. The program included 113 oral and 266 poster presentations. This article presents a brief summary of the conference highlights. Complete abstracts, webcasts, and daily rapporteur summaries may be found on the conference website (https://www.hivr4p.org/).

10.
Cell Host Microbe ; 29(11): 1611-1619.e5, 2021 11 10.
Article in English | MEDLINE | ID: covidwho-1466221

ABSTRACT

The Johnson and Johnson Ad26.COV2.S single-dose vaccine represents an attractive option for coronavirus disease 2019 (COVID-19) vaccination in countries with limited resources. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus or infected in the second wave when Beta predominated. Prior infection significantly boosts spike-binding antibodies, antibody-dependent cellular cytotoxicity, and neutralizing antibodies against D614G, Beta, and Delta; however, neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses are induced after vaccination, regardless of prior infection. T cell recognition of variants is largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination after infection could result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Vaccination , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Female , Humans , Male , Middle Aged , T-Lymphocytes/immunology
11.
J Int AIDS Soc ; 24(3): e25685, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1453605
12.
Lancet Glob Health ; 9(9): e1177-e1178, 2021 09.
Article in English | MEDLINE | ID: covidwho-1305337
17.
Lancet Glob Health ; 9(2): e120-e129, 2021 02.
Article in English | MEDLINE | ID: covidwho-922185

ABSTRACT

BACKGROUND: Health-care resource constraints in low-income and middle-income countries necessitate the identification of cost-effective public health interventions to address COVID-19. We aimed to develop a dynamic COVID-19 microsimulation model to assess clinical and economic outcomes and cost-effectiveness of epidemic control strategies in KwaZulu-Natal province, South Africa. METHODS: We compared different combinations of five public health interventions: health-care testing alone, where diagnostic testing is done only for individuals presenting to health-care centres; contact tracing in households of cases; isolation centres, for cases not requiring hospital admission; mass symptom screening and molecular testing for symptomatic individuals by community health-care workers; and quarantine centres, for household contacts who test negative. We calibrated infection transmission rates to match effective reproduction number (Re) estimates reported in South Africa. We assessed two main epidemic scenarios for a period of 360 days, with an Re of 1·5 and 1·2. Strategies with incremental cost-effectiveness ratio (ICER) of less than US$3250 per year of life saved were considered cost-effective. We also did sensitivity analyses by varying key parameters (Re values, molecular testing sensitivity, and efficacies and costs of interventions) to determine the effect on clinical and cost projections. FINDINGS: When Re was 1·5, health-care testing alone resulted in the highest number of COVID-19 deaths during the 360-day period. Compared with health-care testing alone, a combination of health-care testing, contact tracing, use of isolation centres, mass symptom screening, and use of quarantine centres reduced mortality by 94%, increased health-care costs by 33%, and was cost-effective (ICER $340 per year of life saved). In settings where quarantine centres were not feasible, a combination of health-care testing, contact tracing, use of isolation centres, and mass symptom screening was cost-effective compared with health-care testing alone (ICER $590 per year of life saved). When Re was 1·2, health-care testing, contact tracing, use of isolation centres, and use of quarantine centres was the least costly strategy, and no other strategies were cost-effective. In sensitivity analyses, a combination of health-care testing, contact tracing, use of isolation centres, mass symptom screening, and use of quarantine centres was generally cost-effective, with the exception of scenarios in which Re was 2·6 and when efficacies of isolation centres and quarantine centres for transmission reduction were reduced. INTERPRETATION: In South Africa, strategies involving household contact tracing, isolation, mass symptom screening, and quarantining household contacts who test negative would substantially reduce COVID-19 mortality and would be cost-effective. The optimal combination of interventions depends on epidemic growth characteristics and practical implementation considerations. FUNDING: US National Institutes of Health, Royal Society, Wellcome Trust.


Subject(s)
COVID-19/prevention & control , Epidemics/prevention & control , Public Health/economics , Adolescent , Adult , COVID-19/epidemiology , Child , Child, Preschool , Computer Simulation , Cost-Benefit Analysis , Humans , Infant , Infant, Newborn , Middle Aged , Models, Biological , Public Health/methods , South Africa/epidemiology , Young Adult
20.
medRxiv ; 2020 Oct 11.
Article in English | MEDLINE | ID: covidwho-636369

ABSTRACT

Background: Healthcare resource constraints in low and middle-income countries necessitate selection of cost-effective public health interventions to address COVID-19. Methods: We developed a dynamic COVID-19 microsimulation model to evaluate clinical and economic outcomes and cost-effectiveness of epidemic control strategies in KwaZulu-Natal, South Africa. Interventions assessed were Healthcare Testing (HT), where diagnostic testing is performed only for those presenting to healthcare centres; Contact Tracing (CT) in households of cases; Isolation Centres (IC), for cases not requiring hospitalisation; community health worker-led Mass Symptom Screening and molecular testing for symptomatic individuals (MS); and Quarantine Centres (QC), for household contacts who test negative. Given uncertainties about epidemic dynamics in South Africa, we evaluated two main epidemic scenarios over 360 days, with effective reproduction numbers (Re) of 1·5 and 1·2. We compared HT, HT+CT, HT+CT+IC, HT+CT+IC+MS, HT+CT+IC+QC, and HT+CT+IC+MS+QC, considering strategies with incremental cost-effectiveness ratio (ICER)

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