key: cord-0255236-x34ta15l
authors: Shabir A. Madhi, Vicky Baillie; Clare L. Cutland, Merryn Voysey; Anthonet L. Koen, Lee Fairlie; Sherman D. Padayachee, Keertan Dheda; Shaun L. Barnabas, Qasim Ebrahim Bhorat; Carmen Briner, Gaurav Kwatra; NGS-SA, Wits-VIDA COVID team; Khatija Ahmed, Parvinder Aley; Sutika Bhikha, Jinal N. Bhiman; As’ad Ebrahim 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, Sur
title: Safety and efficacy of the ChAdOx1 nCoV-19 (AZD1222) Covid-19 vaccine against the B.1.351 variant in South Africa
date: 2021-02-12
journal: nan
DOI: 10.1101/2021.02.10.21251247
sha: 4e4b33a476c520a0b660845abce11081e43d48b3
doc_id: 255236
cord_uid: x34ta15l

nan

The authors are grateful to the teams at Advent (Pomezia, Italy) and COBRA Biologicals (Keele, UK) for supply of vaccines.

SAM is a member of WHO's SAGE but does not participate in discussions on COVID-19 vaccines. SAM institution receive other grants related to Covid-19 research from BMGF and South African Medical Research Council.

Oxford University has entered into a partnership with Astra Zeneca for further development of ChAdOx1 nCoV-19. SCG is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines 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 a consultant to Vaccitech for an unrelated project. PMF is a consultant to Vaccitech. AJP is Chair of UK Dept. Health and Social Care's (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in discussions on COVID-19 vaccines, and is a member of the WHO's SAGE. AJP is an NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR or WHO.

NMD, EJK and TLV are employees of Astra Zeneca. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 12, 2021. ; https://doi.org/10.1101/2021.02. 10 .21251247 doi: medRxiv preprint

Assessing safety and efficacy of Covid-19 vaccines in different populations is essential, as is investigation of efficacy against emerging SARS-CoV-2 variants of concern including the B.1.351 (501Y.V2) variant first identified in South Africa.

We conducted a randomized multicentre, double blinded controlled trial on safety and efficacy of ChAdOx1-nCoV19 in HIV-uninfected people in South Africa. Participants age 18 to <65 years randomized (1:1) to two doses of vaccine containing 5x10 10 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

There has been unprecedented speed in developing vaccines for Covid-19, which is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), since being declared a pandemic by World Health Organization (WHO) on March 11, 2020. 1-4 ChAdOx1-nCoV19, a replication-deficient chimpanzee adenoviral vector containing the SARS-CoV-2 structural surface glycoprotein antigen, is one of six COVID-19 vaccines based on different platforms that have been authorized for emergency use, [5] [6] [7] [8] [9] [10] [11] with efficacy results of two further vaccines having recently been reported. 12,13 Thus far, excluding the South African components of the Novavax 12 and Jansen Covid-19 vaccine trials 13 and the inactivated whole virus vaccines, 10 preclinical and most clinical studies assessed protection against the prototype SARS-CoV-2 sequence (B.1) or the D614G variant. 5, 6, 8, 9 Recently, the SARS-CoV-2 spike genome has accumulated mutations, including within the receptor binding domain (RBD) and N-terminal domains (NTD). 14,15 These domains are major targets of the antibody response. The RBD mutations include the N501Y mutation which is associated with increased affinity for the angiotensin converting enzme-2 (ACE2). 16 In contrast, E484K and K417N RBD mutations and mutations in the NTD have been associated with neutralizing antibody escape. 17 The B.1.1.7 lineage, first identified in the United Kingdom (UK), includes the N501Y mutation which has been associated with 53% increased transmissibly. 18 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Here, we report on a multi-centred South African phase Ib/II trial evaluating the safety, immunogenicity and VE of ChAdOx1-nCoV19 in preventing symptomatic COVID-19. This interim analysis is limited to addressing co-primary safety analysis; and primary and key secondary VE objectives including efficacy specifically against B.1.351 variant. Furthermore, we report on immunogenicity of ChAdOx1-nCoV19, and post-hoc PSVNA and LVNA investigation of the sensitivity of the original D614G virus and the B.1.351 variant to vaccine-elicited antibodies.

In this randomized, double-blinded, placebo-controlled, multi-site trial conducted in South Africa, we assessed the safety and efficacy of two standard doses of ChAdOx1-nCoV19 administered 21-35 days apart, compared to saline (0.9% NaCl) placebo. Adults aged 18 to <65 years, with no or wellcontrolled chronic medical conditions, were eligible for participation. Key exclusion criteria included HIV positivity at screening (for the efficacy cohort), previous or current laboratory-confirmed Covid-19, history of anaphylaxis in relation to vaccination and morbid obesity (body mass index ≥40kg/m 2 ).

Detailed inclusion and exclusion criteria are found in Supplementary text 1.1. ChAdOx1-nCoV19 was developed at the University of Oxford, who sponsored the trial, with sources of study vaccine supply reported in Supplement text 1.2.

Trial data were available to all authors, who confirm its accuracy and completeness. An independent data and safety monitoring committee reviewed efficacy and unblinded safety data. A local trial is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 12, 2021. 

A cohort of 70 HIV-uninfected individuals were enrolled first (Group-1) for intensive safety and immunogenicity monitoring, followed by enrolment of another 1956 HIV-uninfected individuals, all (excluding five who were not vaccinated) were included in safety analysis and 1467 for the primary efficacy analysis (Fig. 1) . Details of study procedures are in the protocol (Appendix 1; pg 68-73). The study follow-up is ongoing.

Trial participants were randomized to receive either 0.33-0.5ml ChAdOx1-nCoV19 (lot dependent) or placebo intramuscularly into the deltoid muscle of the non-dominant arm on day of randomization and a booster 21-35 days later. Participants were observed for 30 minutes post vaccination for acute reactions. Study-injection preparation and vaccination were done by unblinded site staff who were not involved in any other study procedures. Trial participants and all other study staff remain blinded to treatment group.

The safety analysis evaluated occurrence of solicited local and systemic reactogenicity within 7 days following vaccination, unsolicited adverse events for 28 days following vaccination, changes in baseline safety laboratory measures (Group-1 only) and serious adverse events. Further details of . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 12, 2021. ; https://doi.org/10.1101/2021.02.10.21251247 doi: medRxiv preprint evaluating for safety and reactogenicity are detailed in Supplementary Text 1.3. Adverse event data reported up until January 15 th , 2021 are included in this report.

Testing for SARS-CoV-2 infection using a nucleic acid amplification test (NAAT) included sampling at routine scheduled visits detailed in the protocol (Appendix 1; pages 68-73); as well as when participants presented with any symptoms suggestive of Covid-19. Participants were advised at time of randomization as to which clinical symptoms suggestive of Covid-19 should trigger them to present to be investigated for SARS-CoV-2 infection (Table S1 ). Also, short message service was sent every two weeks as a reminder to present for investigation if symptomatic. Details of NAAT, whole genome sequencing and phylogenetic analysis are described in Supplementary Text 1.4.

SARS-CoV-2 serostatus at randomization was evaluated using an IgG assay to the nucleoprotein (N) as described. 8 For antibody neutralization studies, PSVA (methods in Supplementary 1.5) to prototype virus was performed on serum samples obtained two weeks after the 2 nd dose of vaccine in 107 randomly selected ChAdOx1-nCoV19 recipients who were seronegative for IgG N-protein at enrolment. In addition, we present post-hoc data on the comparative pseudoneutralization for vaccine recipients enrolled in the Brazil (n=226) and UK (n=326) ChAdOx1-nCoV19 studies.

To assess neutralization activity of vaccine-elicited antibodies against B.1.351, 25 serum samples from Group-1 participants who tested seronegative at enrolment but showed varying neutralizing antibody titers at 14 days post 2 nd dose of injection were assayed using PSVNA and LVNA before unblinding of study arm allocation. 14, 21 The PSVNA tested neutralization activity against the original is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 12, 2021. ; https://doi.org/10.1101/2021.02.10.21251247 doi: medRxiv preprint

Covid-19 cases were evaluated by at least two physicians who were independent of the study and masked to study-arm assignment, discordant assessments were evaluated by a third adjudicator.

Grading of severity was based on a pre-specified scoring system; Supplementary Table S1 and S2.

The primary endpoint was efficacy against NAAT-confirmed symptomatic Covid-19 occurring more than 14 days after the 2 nd injection in participants who were seronegative at randomization. VE against B.1.351 lineage was a pre-specified secondary objective.

Other secondary efficacy objectives included VE against Covid-19 for the overall population For the primary efficacy analyses, only per-protocol seronegative participants were included. VE was calculated as 1-the relative risk and 95% CI were calculated using the Clopper-Pearson exact method is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 12, 2021. ; https://doi.org/10.1101/2021.02.10.21251247 doi: medRxiv preprint are reported. A sensitivity analysis was conducted which includes modified intention-to-treat, seronegative participants irrespective of whether they received the vaccine or placebo.

We screened 3,022 individuals across seven sites, of whom 2,026 HIV-uninfected individuals were enrolled from June 24 th through to November 9 th , 2020. The initiation of enrolment coincided with the peak of the first Covid-19 wave in South Africa; Supplementary Figure S2 . Overall, 1,010 participants received vaccine and 1,011 received placebo (Fig. 1 ). There were 1,467 (750 vaccinees and 717 placebo) Covid-19-naïve participants eligible for the primary VE analysis, reason for exclusion indicated in Figure 1 .

The median age was Figure 131 years, 56.5% identified as male gender, and the racial distribution included 70.5% black-Africans, 12.8% whites and 14.9% identifying as "mixed" race. Nineteen percent of enrolees were obese (BMI≥30-40 kg/m 2 ), 42.0% were smokers, 2.8% had underlying hypertension and 3.1% had chronic respiratory conditions. The median duration between doses was 28 days; and the median duration of follow-up from enrolment and from 14 days after the second dose of injection were 156 and 121 days, respectively (as of January 15 th , 2021). Demographics of the baseline seronegative population was like the overall population; Table 1 .

Local and systemic reactogenicity data are presented in Supplementary Figures S3 and S4 which subsided within 24 hours, and in whom no reactogenicity was observed after the 2 nd dose. All other events were considered unrelated or unlikely to be related to injection received.

. CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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Humoral response to ChAdOx1-nCoV19 induced strong neutralising antibodies at 28 days after the first dose, which rose further after a second dose. The responses in ChAdOx1-nCoV19 recipients in our study was similar those from the UK and Brazil studies (Fig. 2a) .

On PSVNA testing, 9 (47%) out of the 19 seronegative vaccinees showed no neutralization activity against an RBD triple-mutant pseudovirus (containing K417N, E484K and N501Y), and 15/19 (79%) had no neutralization activity against B.1.351 pseudovirus (Fig. 2b) . Vaccinees with NAAT-confirmed illness (prior to emergence of B.1.351) showed similar results to those with no NAAT confirmed illness (Fig. 2b) . Samples from the SARS-CoV-2 infected placebo recipients showed similar reduction in neutralizing activity, with residual titers of <100 (or knockout) against the RBD triple-mutant and B.1.351 (Fig. 2b) .

LVNA showed lower neutralization overall relative to PSVNA (Fig. 2c) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Figure 7) .

All forty-two endpoint cases were graded either as mild (vaccinees=15; placebo-recipients=17) or moderate (vaccinees=4; placebo-recipients=6) with no cases of severe disease or hospitalisation in either arm. The incidence (per 1000 person-years) of Covid-19 more than 14 days after the 2nd dose among seronegative participants, and subsequent NAAT confirmed infection through to 14 days post second injection, was 93.6 and 73.1 in placebo and vaccine recipients, respectively; VE: 21.9% (95%CI: -49.9; 59.8); Table 2 . Similarly, inclusive of participants that were seropositive but had a nonreactive PCR before or at randomization, the incidence (per 1000 person-years) of Covid-19 >14 days post 2 nd injection did not differ between placebo (81. Table 2 . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint fold-increase following a booster dose does suggest heterogeneity in vaccine immunogenicity. [5] [6] [7] 9 The mRNA Covid-19 vaccines, although having modest neutralizing antibody after the first dose, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Another recent multi-national study inclusive of South Africa, evaluated efficacy of a single dose of the Janssen non-replicating adenovirus type 26 vaccine (Ad26-vaccine). Interim results from the South African arm reported VE of 54% against moderate-severe and 85% against severe Covid-19 mainly due to B.1.351 variant. 13 The Ad26-vaccine study, however, only submitted NAAT confirmed cases that had at least three symptoms for endpoint adjudication 28 and consequently the VE analyses likely excludes the majority of mild Covid-19 in the study. Notably, the immunogenicity of Ad26-vaccine is similar to that of ChAdOx1-nCoV19 following the first dose and after the second dose. 13, 29 The neutralizing antibody response induced by the Ad26-vaccine against the B.1.351 variant has not yet been reported on. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted February 12, 2021. ; https://doi.org/10.1101/2021.02.10.21251247 doi: medRxiv preprint While there is high correlation between antibody response and VE, suggesting that the neutralizing antibody response is important, it has been reported that T cell responses may contribute to protection from COVID-19 pathophysiology even in the presence of suboptimal neutralizing antibody titers. 30 In a post hoc inclusion in this manuscript, we report on T-helper immune responses induced by ChAdOx1-nCoV19 among vaccine recipients from the UK. In the Spike-Specific T cells that is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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Wibmer CK, Ayres F, Hermanus T, et al. New collaboration makes further 100 million doses of COVID-19 vaccine available to lowand middle-income countries. 2020. (Accessed February 5, 2021, at https://www.gavi.org/news/media-room/new-collaboration-makes-further-100-million-doses-covid-19-vaccine-available-low.) 32.

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The copyright holder for this this version posted February 12, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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Figure 2a: Pseuduoneutralization assay to original SARS-CoV-2 virus in ChAdOx1 nCoV-19 (AZD1222) recipients from the United Kingdom, Brazil and South Africa; Fig 2b: Pseduneutralization assay to original, triple recpetor-binding domain and B.1.351 variant; Fig 2c Live virus neutralization virus assay against original and B

Legend to Fig 2a: Vaccine serum from baseline seronegative 18-64 year old AZD1222 vaccinees receiving two standard doses in the United Kingdom

and South Africa (n=107) were evaluated in a validated pseudoneutralisation assay at baseline, 28 days after first dose and 28 days after second dose. Boxes show median (IQR)

The authors would like to thanks all the volunteers who participated in this study.The authors gratefully acknowledge the local safety physician, Guy Richards, for reviewing all SAEs.