Findings of a study in the Oxford AstraZeneca COVID-19 vaccine trial have been published. This is a landmark study in so far as being the first to raise the alarm that, despite early successes with COVID-19 vaccines, further research is warranted on a next generation of COVID-19 vaccines.
The results from this study, however, only indicate that the AstraZeneca vaccine does not have at least 60% efficacy against mild-moderate COVID-19 due to the B.1.351 (N501Y.V2) variant.
Based on a broader body of evidence, the World Health Organisation recommends that this vaccine still be deployed in countries where the B.1.351 variant circulates, as it likely still protects against severe infection, hospitalisation, and death caused by COVID-19.
Professor Shabir Madhi, executive director of the Vaccines and Infectious Diseases Analytics (VIDA) Research Unit at the University of the Witwatersrand, Johannesburg, led the trial in South Africa:
“Despite the disappointing finding that the AstraZeneca vaccine did not protect against mild COVID infection because of the B.1.351 variant first identified in South Africa, peer review and publication of our research validates the findings and makes a compelling case for the development of a second-generation vaccines worldwide,” says Madhi.
First-generation vaccines refer to those designed to respond to the original SARS-CoV-2 virus. Second-generation vaccines refer to technology and design innovations that can provide protections against the constantly evolving variants that cause COVID-19 disease.
The findings of this study were previously publicised as a preprint, and concluded that the ChAdOx1 nCoV-19 vaccine provided minimal protection against mild to moderate COVID-19 infection from the B.1.351 coronavirus variant first identified in South Africa in mid-November 2020.
Prior to the evolution of the B.1.351 and P.1 variants, the South African National Health Department had ordered and taken delivery of approximately one million doses of the Oxford AstraZeneca vaccine on 1 February 2021, after a published pooled analysis of this vaccine in December 2020 showed an overall vaccine efficacy of 66.7% in the UK and Brazil.
“We were in a state of euphoria about the high efficacy of several COVID-19 vaccines against the original virus, but then the AstraZeneca study threw us a curve-ball,” says Madhi. “In this study now published in NEJM, we found that two doses of ChAdOx1 nCoV19 had no efficacy against non-hospitalised mild to moderate COVID-19, mainly due to the B.1.351 variant.”
The randomised, multi-centre, double-blinded trial enrolled 2026 participants between 24 June and 9 November 2020. The trial was a phase 1b/11 trial that aimed to evaluate the safety, immunogenicity, and efficacy of the AstraZeneca vaccine ChAdOx1 nCoV19 in preventing symptomatic COVID-19. Immunogenicity refers to the ability of a foreign substance, such as an antigen, to provoke an immune response. Vaccine efficacy refers to the percentage reduction of a disease in a clinical trial.
“A trial enrolling just 2026 participants is considered small, while phase 3 trials enrol tens of thousands of participants,” says Madhi. “Yet the startling data that our small trial generated was irrefutable, and the implications profound.”
The majority of participants enrolled were relatively young (under 65-years-old), generally healthy, and HIV-negative. The median [middle] age of participants was 30 years old. More than half (56.5%) of the trial participants identified as male, 70.5% were Black Africans, 12.8% were white, and 14.9% identified as ‘mixed’ race.
“These demographics are important because they reflect characteristics of the overall population in South Africa. Conducting clinical trials in diverse settings like these is critical to understanding how vaccines work in local contexts,” says Madhi.
The primary objective of this trial was to establish this vaccine’s efficacy against all-severity COVID-19, irrespective of variants. A secondary objective was to evaluate the vaccine’s efficacy against the B.1.351 variant specifically.
“When this trial began in June 2020, we were testing a vaccine against SARS-COV-2,” says Madhi. “By January 2021, SARS-CoV-2 had spawned variants, including the B.1.351 first discovered in South Africa. As a secondary objective, we tested a hypothesis: would this vaccine prove at least 60% efficacious in preventing mild to moderate COVID-19 disease? It did not.”
The results showed that a two-dose regimen of ChAdOx1-nCov19 did not show protection against mild to moderate COVID-19 due to the B.1.351 variant.
Crucially, Madhi notes that, “This vaccine may still help protect high-risk individuals with co-morbidities from contracting severe COVID-19 disease, having to be hospitalised, mechanically ventilated, or dying. The AstraZeneca vaccine remains essential in the arsenal against this virus, particularly in Africa, which has already received 14 million doses of this vaccine as the COVID-19 immunisation programme starts in multiple countries.”
On 15 February 2021, the WHO recommended that the AstraZeneca vaccine still be rolled out, even in countries where the B.1.351 variant or other similar variants of concern are circulating.
A WHO news release says that the vaccine was reviewed on 8 February by the WHO Strategic Advisory Group of Experts on Immunization (SAGE), which makes recommendations for vaccines’ use in populations (recommended age groups, intervals between shots, advice for specific groups such as pregnant and lactating women). The SAGE recommended the vaccine for all age groups 18 years and above.
“While the AstraZeneca vaccine – like many other first-generation COVID-19 vaccines – is unlikely to interrupt transmission of SARS-CoV-2 or protect against mild infection from variants like B.1.351, these first-generation vaccines could still provide the only sustainable option to prevent flooding our hospitals with severe COVID-19 cases, and to mitigate Covid-19 deaths once the third wave hits,” says Madhi.
The development of an Oxford AstraZeneca and other COVID-19 vaccines targeting the B.1351 variant is currently underway.
The South African study increased awareness worldwide of the necessity of developing vaccines that target variants specifically – and even reimagining vaccines entirely.
Innovations in vaccine technologies, platforms and designs suggest exciting advances in this field.
“The finding of our [Oxford AstraZeneca COVID-19 vaccine] study are truly a turning point in COVID vaccine development – and a rude awakening,” says Madhi. “This one small South African study has alerted the world to the fact that second generation COVID-19 vaccines will be required to provide protection against inevitable and persistent SARS-COV-2 variants. If we had not conducted this trial in South Africa, the world would be none the wiser.”
Study details
Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant
Shabir A Madhi, Vicky Baillie, Clare L Cutland, Merryn Voysey, Anthonet L Koen, Lee Fairlie, Sherman D Padayachee, Keertan Dheda, Shaun L Barnabas, Qasim E Bhorat, Carmen Briner, Gaurav Kwatra, Khatija Ahmed, Parvinder Aley, Sutika Bhikha, Jinal N Bhiman, As’ad E Bhorat, Jeanine du Plessis, Aliasgar Esmail, Marisa Groenewald, Elizea Horne, Shi-Hsia Hwa, Aylin Jose, Teresa Lambe, Matt Laubscher, Mookho Malahleha,
Masebole Masenya, Mduduzi Masilela, Shakeel McKenzie, Kgaogelo Molapo,
Andrew Moultrie, Suzette Oelofse, Faeezah Patel, Sureshnee Pillay, Sarah Rhead, Hylton Rodel, Lindie Rossouw, Carol Taoushanis, Houriiyah Tegally, Asha Thombrayil, Samuel van Eck, Constantinos K Wibmer, Nicholas M Durham, Elizabeth J Kelly, Tonya L Villafana, Sarah Gilbert, Andrew J Pollard, Tulio de Oliveira, Penny L Moore, Alex Sigal, Alane Izu for the NGS-SA Group Wits–VIDA COVID Group
Published in the New England Journal of Medicine on 16 March 2021
Abstract
Background
Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa.
Methods
We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose.
Results
Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], −49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (92.9%) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, −76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups.
Conclusions
A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant.
[link url="https://www.wits.ac.za/covid19/covid19-news/latest/south-african-oxford-astrazeneca-covid-19-vaccine-study-a-global-game-changer.html"]University of the Witwatersrand material[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa2102214?query=featured_home"]New England Journal of Medicine study (Open access)[/link]