Breakthrough SARS-CoV-2 Infections in the PROVENT Prevention Trial Were Not Associated With AZD7442 (Tixagevimab/Cilgavimab) Resistant Variants

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Abstract

Background

We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants identified from breakthrough infections in the PROVENT preexposure prophylaxis trial.

Methods

Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles.

Results

At completion of 6 months' follow-up, no AZD7442-resistant variants were observed in breakthrough coronavirus disease 2019 (COVID-19) cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and nonbreakthrough cases.

Conclusions

Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure.

Clinical Trials Registration

NCT04625725.

Abstract

Symptomatic COVID-19 breakthrough cases in the PROVENT preexposure prophylaxis trial were not due to resistance-associated substitutions in AZD7442 (tixagevimab/cilgavimab) binding sites or lack of AZD7442 exposure.

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Most cited references 14

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Potently neutralizing and protective human antibodies against SARS-CoV-2

Seth Zost, Pavlo Gilchuk, James Brett Case … (2020)

The COVID-19 pandemic is a major threat to global health 1 for which there are limited medical countermeasures 2,3 . Moreover, we currently lack a thorough understanding of mechanisms of humoral immunity 4 . From a larger panel of human monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein 5 , we identified several that exhibited potent neutralizing activity and fully blocked the receptor-binding domain of S (SRBD) from interacting with human ACE2 (hACE2). Competition-binding, structural, and functional studies allowed clustering of the mAbs into classes recognizing distinct epitopes on the SRBD as well as distinct conformational states of the S trimer. Potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two mouse models of SARS-CoV-2 infection, passive transfer of either COV2-2196 or COV2-2130 alone or a combination of both mAbs protected mice from weight loss and reduced viral burden and inflammation in the lung. In addition, passive transfer of each of two of the most potently ACE2 blocking mAbs (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutics.

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Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial

Peter Gilbert, David C. Montefiori, Adrian McDermott … (2021)

Symptomatic COVID-19 infection can be prevented by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. A “correlate of protection” is a molecular biomarker to measure how much immunity is needed to fight infection and is key for successful global immunization programs. Gilbert et al . determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna COVE phase 3 clinical trial (see the Perspective by Openshaw). By measuring binding and neutralizing antibodies against the viral spike protein, the authors found that the levels of both antibodies correlated with the degree of vaccine efficacy. The higher the antibody level, the greater the protection afforded by the messenger RNA (mRNA) vaccine. Antibody levels that predict mRNA vaccine efficacy can therefore be used to guide vaccine regimen modifications and support regulatory approvals for a broader spectrum of the population. —PNK SARS-CoV-2 binding and neutralizing antibodies correlate with the degree of vaccine efficacy and protection for the Moderna mRNA COVID-19 vaccine. In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.

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Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19

Myron Levin, Andrew Ustianowski, Stephane De Wit … (2022)

Abstract Background The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days. Methods In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase–polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183. Results A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group. Conclusions A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.)

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Author and article information

Contributors

Kevin M Tuffy

Bahar Ahani

Anastasia A Aksyuk

Miles Avila

Tyler Brady

Gustavo H Kijak

Gavin Koh

Myron J Levin

Tiffany L Roe

Nicolette Schuko

Jesse Thissen

Andrew Ustianowski

Tianhui Zhang

Elizabeth J Kelly

Katie Streicher

Journal

Journal ID (nlm-ta): J Infect Dis

Journal ID (iso-abbrev): J Infect Dis

Journal ID (publisher-id): jid

Title: The Journal of Infectious Diseases

Publisher: Oxford University Press

ISSN (Print): 0022-1899

ISSN (Electronic): 1537-6613

Publication date Collection: 15 October 2023

Publication date (Electronic): 06 June 2023

Publication date PMC-release: 06 June 2023

Volume: 228

Issue: 8

Pages: 1055-1059

Affiliations

Vaccines and Immune Therapies, BioPharmaceuticals Research and Development, AstraZeneca , Gaithersburg, Maryland, USA

Vaccines and Immune Therapies, BioPharmaceuticals Research and Development, AstraZeneca , Cambridge, United Kingdom

University of Colorado School of Medicine , Aurora, Colorado, USA

Vaccines and Immune Therapies, BioPharmaceuticals Research and Development, AstraZeneca , Gaithersburg, Maryland, USA

Vaccines and Immune Therapies, BioPharmaceuticals Research and Development, AstraZeneca , Cambridge, United Kingdom

North Manchester General Hospital , Manchester, United Kingdom

Discovery Sciences, BioPharmaceuticals Research and Development, AstraZeneca , Gaithersburg, Maryland, USA

Vaccines and Immune Therapies, BioPharmaceuticals Research and Development, AstraZeneca , Gaithersburg, Maryland, USA

Author notes

Correspondence: Elizabeth J. Kelly, PhD, Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals Research and Development, AstraZeneca, 1 MedImmune Way, Gaithersburg, MD 20878-2204 ( beth.kelly@ 123456astrazeneca.com ).

Potential conflicts of interest. M. J. L. reports research support from GSK, Johnson & Johnson, Moderna, and Novavax; consultancy for Dynavax, GSK, Merck & Co, Pfizer, Curevo, and Seqirus; and data safety monitoring board for GSK. A. U. reports honoraria/speaker fees from Sanofi, Merck, Janssen, GSK, and Gilead; and advisory boards for Gilead, Merck, and ViiV/GSK. All other authors are employees of, and hold or may hold stock in, AstraZeneca.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Article

Publisher ID: jiad210

DOI: 10.1093/infdis/jiad210

PMC ID: 10582904

PubMed ID: 37280116

SO-VID: 5e08cbaa-09a7-4213-a522-96de599d942d

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 06 January 2023

Date: 31 May 2023

Date accepted : 05 June 2023

Date: 20 June 2023

Page count

Pages: 5

Funding

Funded by: AstraZeneca, DOI 10.13039/100004325;

Funded by: United States Government;

Funded by: Department of Health and Human Services, DOI 10.13039/100012737;

Funded by: Department of Defense, DOI 10.13039/100000005;

Funded by: Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, DOI 10.13039/100017443;

Award ID: W911QY-21-9-0001

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Breakthrough SARS-CoV-2 Infections in the PROVENT Prevention Trial Were Not Associated With AZD7442 (Tixagevimab/Cilgavimab) Resistant Variants

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Abstract

Background

Methods

Results

Conclusions

Clinical Trials Registration

Abstract

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Novel Coronavirus Disease COVID-19

Most cited references 14

Potently neutralizing and protective human antibodies against SARS-CoV-2

Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial

Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19

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