Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in people living with and without HIV in South Africa: an interim analysis of a randomised, double-blind, placebo-controlled, phase 1B/2A trial,The Lancet HIV

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Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in people living with and without HIV in South Africa: an interim analysis of a randomised, double-blind, placebo-controlled, phase 1B/2A trial
The Lancet HIV ( IF 16.1 ) Pub Date : 2021-08-17 , DOI: 10.1016/s2352-3018(21)00157-0
Shabir A Madhi ₁ , Anthonet L Koen ₂ , Alane Izu ₁ , Lee Fairlie ₃ , Clare L Cutland ₄ , Vicky Baillie ₂ , Sherman D Padayachee ₅ , Keertan Dheda ₆ , Shaun L Barnabas ₇ , Qasim Ebrahim Bhorat ₈ , Carmen Briner ₉ , Parvinder K Aley ₁₀ , Sutika Bhikha ₂ , Tandile Hermanus ₁₁ , Elizea Horne ₁₂ , Aylin Jose ₂ , Prudence Kgagudi ₁₁ , Teresa Lambe ₁₃ , Masebole Masenya ₁₂ , Mduduzi Masilela ₅ , Nonhlanhla Mkhize ₁₁ , Andrew Moultrie ₂ , Christian K Mukendi ₂ , Thandeka Moyo-Gwete ₁₁ , Amit J Nana ₂ , Ayanda Nzimande ₂ , Faeezah Patel ₁₂ , Sarah Rhead ₁₀ , Carol Taoushanis ₂ , Asha Thombrayil ₂ , Samuel van Eck ₁₂ , Merryn Voysey ₁₀ , Tonya L Villafana ₁₄ , Johan Vekemans ₁₄ , Sarah C Gilbert ₁₃ , Andrew J Pollard ₁₀ , Penny L Moore ₁₁ , Gaurav Kwatra ₁ ,

Affiliation

South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; African Leadership in Vaccinology Expertise, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
African Leadership in Vaccinology Expertise, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
African Leadership in Vaccinology Expertise, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Setshaba Research Centre, Tshwane, South Africa.
Division of Pulmonology, Groote Schuur Hospital and the University of Cape Town, Cape Town, South Africa; Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK.
Family Centre for Research With Ubuntu, Department of Paediatrics, University of Stellenbosch, Cape Town, South Africa.
Soweto Clinical Trials Centre, Soweto, South Africa.
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Oxford Vaccine Group, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
SAMRC Antibody Immunity Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; National Institute for Communicable Diseases Division of the National Health Laboratory Service, Johannesburg, South Africa.
Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Jenner Institute, Nuffield Department of Medicine, University of Oxford, UK.
AstraZeneca Biopharmaceuticals, Cambridge, UK.

Background

People living with HIV are at an increased risk of fatal outcome when admitted to hospital for severe COVID-19 compared with HIV-negative individuals. We aimed to assess safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV and HIV-negative individuals in South Africa.

Methods

In this ongoing, double-blind, placebo-controlled, phase 1B/2A trial (COV005), people with HIV and HIV-negative participants aged 18–65 years were enrolled at seven South African locations and were randomly allocated (1:1) with full allocation concealment to receive a prime-boost regimen of ChAdOx1 nCoV-19, with two doses given 28 days apart. Eligibility criteria for people with HIV included being on antiretroviral therapy for at least 3 months, with a plasma HIV viral load of less than 1000 copies per mL. In this interim analysis, safety and reactogenicity was assessed in all individuals who received at least one dose of ChAdOx1 nCov 19 between enrolment and Jan 15, 2021. Primary immunogenicity analyses included participants who received two doses of trial intervention and were SARS-CoV-2 seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.

Findings

Between June 24 and Nov 12, 2020, 104 people with HIV and 70 HIV-negative individuals were enrolled. 102 people with HIV (52 vaccine; 50 placebo) and 56 HIV-negative participants (28 vaccine; 28 placebo) received the priming dose, 100 people with HIV (51 vaccine; 49 placebo) and 46 HIV-negative participants (24 vaccine; 22 placebo) received two doses (priming and booster). In participants seronegative for SARS-CoV-2 at baseline, there were 164 adverse events in those with HIV (86 vaccine; 78 placebo) and 237 in HIV-negative participants (95 vaccine; 142 placebo). Of seven serious adverse events, one severe fever in a HIV-negative participant was definitely related to trial intervention and one severely elevated alanine aminotranferase in a participant with HIV was unlikely related; five others were deemed unrelated. One person with HIV died (unlikely related). People with HIV and HIV-negative participants showed vaccine-induced serum IgG responses against wild-type Wuhan-1 Asp614Gly (also known as D614G). For participants seronegative for SARS-CoV-2 antigens at baseline, full-length spike geometric mean concentration (GMC) at day 28 was 163·7 binding antibody units (BAU)/mL (95% CI 89·9–298·1) for people with HIV (n=36) and 112·3 BAU/mL (61·7–204·4) for HIV-negative participants (n=23), with a rising day 42 GMC booster response in both groups. Baseline SARS-CoV-2 seropositive people with HIV demonstrated higher antibody responses after each vaccine dose than did people with HIV who were seronegative at baseline. High-level binding antibody cross-reactivity for the full-length spike and receptor-binding domain of the beta variant (B.1.351) was seen regardless of HIV status. In people with HIV who developed high titre responses, predominantly those who were receptor-binding domain seropositive at enrolment, neutralising activity against beta was retained.

Interpretation

ChAdOx1 nCoV-19 was well tolerated, showing favourable safety and immunogenicity in people with HIV, including heightened immunogenicity in SARS-CoV-2 baseline-seropositive participants. People with HIV showed cross-reactive binding antibodies to the beta variant and Asp614Gly wild-type, and high responders retained neutralisation against beta.

Funding

The Bill & Melinda Gates Foundation, South African Medical Research Council, UK Research and Innovation, UK National Institute for Health Research, and the South African Medical Research Council.

中文翻译：

针对南非 HIV 感染者和未感染者的 SARS-CoV-2 ChAdOx1 nCoV-19 (AZD1222) 疫苗的安全性和免疫原性：随机、双盲、安慰剂对照 1B/2A 期试验的中期分析

背景

与 HIV 阴性者相比，HIV 感染者因重症 COVID-19 入院时死亡的风险更高。我们的目的是评估 ChAdOx1 nCoV-19 (AZD1222) 疫苗在南非 HIV 感染者和 HIV 阴性个体中的安全性和免疫原性。

方法

在这项正在进行的双盲、安慰剂对照 1B/2A 期试验 (COV005) 中，18-65 岁的艾滋病毒感染者和艾滋病毒阴性参与者在南非的七个地点进行了登记，并随机分配 (1:1)完全分配隐藏，接受 ChAdOx1 nCoV-19 的初免-加强方案，两次剂量间隔 28 天。HIV 感染者的资格标准包括接受抗逆转录病毒治疗至少 3 个月，且血浆 HIV 病毒载量低于每毫升 1000 个拷贝。在这项中期分析中，对从入组到 2021 年 1 月 15 日期间接受至少一剂 ChAdOx1 nCov 19 的所有个体的安全性和反应原性进行了评估。主要免疫原性分析包括接受两剂试验干预且患有 SARS-CoV-2 的参与者基线血清阴性。该试验已在 ClinicalTrials.gov（NCT04444674）和泛非临床试验注册中心（PACTR202006922165132）注册。

发现

2020 年 6 月 24 日至 11 月 12 日期间，共有 104 名艾滋病毒感染者和 70 名艾滋病毒阴性者入组。102 名 HIV 感染者（52 种疫苗；50 种安慰剂）和 56 名 HIV 阴性参与者（28 种疫苗；28 种安慰剂）接受了初免剂量，100 名 HIV 感染者（51 种疫苗；49 种安慰剂）和 46 名 HIV 阴性参与者（24 种疫苗；28 种安慰剂）接受了初免剂量。 22 安慰剂）接受两剂（初免剂和加强剂）。在基线时 SARS-CoV-2 血清阴性的参与者中，HIV 感染者发生了 164 起不良事件（86 起疫苗；78 起安慰剂），而 HIV 阴性参与者发生了 237 起不良事件（95 起疫苗；142 起安慰剂）。在七项严重不良事件中，艾滋病毒阴性参与者的严重发烧肯定与试验干预有关，而艾滋病毒参与者的丙氨酸氨基转移酶严重升高不太可能与试验干预有关；另外五人被认为无关。一名艾滋病毒感染者死亡（不太可能相关）。HIV 感染者和 HIV 阴性参与者表现出疫苗诱导的针对野生型 Wuuhan-1 Asp614Gly（也称为 D614G）的血清 IgG 反应。对于基线时 SARS-CoV-2 抗原血清阴性的参与者，第 28 天的全长尖峰几何平均浓度 (GMC) 为 163·7 结合抗体单位 (BAU)/mL (95% CI 89·9–298·1) HIV 感染者 (n=36) 和 HIV 阴性参与者 (n=23) 112·3 BAU/mL (61·7–204·4)，两组的第 42 天 GMC 加强反应均有所上升。基线 SARS-CoV-2 血清阳性 HIV 感染者在每次接种疫苗后表现出比基线血清阴性 HIV 感染者更高的抗体反应。无论 HIV 状态如何，β 变体 (B.1.351) 的全长刺突和受体结合结构域均出现高水平结合抗体交叉反应。在产生高滴度反应的艾滋病毒感染者中，主要是那些在入组时受体结合域血清呈阳性的人，针对β的中和活性得以保留。