ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques

Doremalen, Neeltje van; Lambe, Teresa; Spencer, Alexandra J.; Belij‐Rammerstorfer, Sandra; Purushotham, Jyothi N.; Port, Julia R; Avanzato, Victoria A.; Bushmaker, Trenton; Flaxman, Amy; Ulaszewska, Marta; Feldmann, Friederike; Allen, Elizabeth; Sharpe, Hannah; Schulz, Jonathan; Holbrook, Myndi G.; Okumura, Atsushi; Meade-White, Kimberly; Pérez-Pérez, Lizzette; Edwards, Nick J.; Wright, Daniel; Bissett, Cameron; Gilbride, Ciaran; Williamson, Brandi N.; Rosenke, Rebecca; Long, Dan; Ishwarbhai, Alka; Kailath, Reshma; Rose, Louisa; Morris, Susan; Powers, Claire; Lovaglio, Jamie; Hanley, Patrick W.; Scott, Dana; Saturday, Greg; Wit, Emmie de; Gilbert, Sarah C.; Munster, Vincent J.

doi:10.1038/s41586-020-2608-y

Cited by 857 publications

(834 citation statements)

References 19 publications

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“…Although non-human primates represent an attractive model for SARS-CoV-2 vaccine development [2][3][4][5] , multiple studies [26][27][28] including our own suggest that the Syrian hamster provides an effective animal model to evaluate SARS-CoV-2 vaccine e cacy for the following reasons: 1) low dose (i.e. 10 2 -10 3 TCID 50 ) i.n.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the humoral immune response, type 1 biased S-speci c T cell immunity likely contributes to protection in convalescent COVID-19 patients 25 . Broadly-reactive and/or type 1 cytokine producing T cell responses are also characteristic of DNA, Adenovirus serotype 26 and chimpanzee Adenovirus vaccines that protected non-human primates against SARS-CoV-2 challenge and are in clinical development 2,4,5 . In vivo and in vitro T cell analyses in our study demonstrated that MF59C.1-adjuvanted Sclamp vaccination elicited a robust, broad and type 1 biased polyfunctional T cell response in mice, consistent with features of a T cell response that could contribute to protection against SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

“…The scienti c community, including critical industry and academic partnerships, have embarked on an unprecedented race to develop and produce effective COVID-19 vaccine(s) for global use 1 . Several recent reports validate the SARS-CoV-2 Spike (S) protein as a promising target for COVID-19 vaccine development [2][3][4][5] . However, these approaches utilise platforms based on nucleic acids, viral vectors or insect cell production systems which could face challenges during large-scale manufacture and distribution.…”

Section: Introductionmentioning

confidence: 94%

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Molecular clamp stabilised Spike protein for protection against SARS-CoV-2

Watterson

Wijesundara

Modhiran

et al. 2020

Preprint

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Efforts to develop and deploy effective vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continue at pace with more than 30 candidate vaccines now in clinical evaluation. Here we describe the preclinical development of an adjuvanted, prefusion-stabilised Spike (S) protein “Sclamp” subunit vaccine, from rational antigen design through to assessing manufacturability and vaccine efficacy. In mice, the vaccine candidate elicits high levels of neutralising antibodies to epitopes both within and outside the receptor binding domain (RBD) of S, as well as broadly reactive and polyfunctional S-specific CD4+ and cytotoxic CD8+ T cells. We also show protection in Syrian hamsters, which has emerged as a robust animal model for pulmonary SARS-CoV-2 infection. No evidence of vaccine enhanced disease was observed in animal challenge studies and pre-clinical safety was further demonstrated in a GLP toxicology study in rats. The Sclamp vaccine candidate is currently progressing rapidly through clinical evaluation in parallel with large-scale manufacture for pivotal efficacy trials and potential widespread distribution.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Molecular clamp stabilised Spike protein for protection against SARS-CoV-2

Watterson

Wijesundara

Modhiran

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…With extensive pulmonary surface area exposed to SARS- Consequently, in parallel to the in vivo studies described above, antibody engineering of clone AvGn-B has been performed and a panel of more potent variants has now been isolated. As shown in Table 2 Future studies will explore the efficacy of the AvGn-B and/or its variants in non-human primate models, several of which have been described for use in SARS-CoV-2 pathogenesis and countermeasure development studies 40,60,61 . Larger studies will also be conducted to examine whether AvGn-B and/or its variants by reducing viral load and accumulation of macrophages within the lung will prevent downstream inflammatory and coagulation sequalae of SARS-CoV-2 infection within other parenchymatous organs, particularly heart, kidneys and liver.…”

Section: Analysis Of Macrophage Infiltration In Lung Tissue Of Animalmentioning

confidence: 99%

A potent SARS-CoV-2 neutralizing human monoclonal antibody that reduces viral burden and disease severity in Syrian hamsters

Fagre

Manhard

Adams

et al. 2020

Preprint

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The emergence of COVID-19 has led to a pandemic that has caused millions of cases of disease, variable morbidity and hundreds of thousands of deaths. Currently, only remdesivir and dexamethasone have demonstrated limited efficacy, only slightly reducing disease burden, thus novel approaches for clinical management of COVID-19 are needed. We identified a panel of human monoclonal antibody clones from a yeast display library with specificity to the SARS-CoV-2 spike protein receptor binding domain that neutralized the virus in vitro. Administration of the lead antibody clone to Syrian hamsters challenged with SARS-CoV-2 significantly reduced viral load and histopathology score in the lungs. Moreover, the antibody interrupted monocyte infiltration into the lungs, which may have contributed to the reduction of disease severity by limiting immunopathological exacerbation. The use of this antibody could provide an important therapy for treatment of COVID-19 patients.

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“…and is more distantly related to the human infectious alphacoronaviruses HCoV 229E and HCoV NL63 (6). Finding ways to control and prevent further infection are top priorities which include the targeted discovery of drugs that impair viral mechanisms (7)(8)(9) and antigenic epitopes through which vaccines raise immunity (10)(11)(12). This study addresses both by utilizing evolutionary information from SARS-CoV-2 sequence and structural data to search for actionable functional sites for each protein in the SARS-CoV-2 genome.…”

Section: Introductionmentioning

confidence: 99%

Identification of evolutionarily stable sites across the SARS-CoV-2 proteome

Wang

Konecki

Marciano

et al. 2020

Preprint

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Since the first recognized case of COVID-19, more than 30 million people have been infected worldwide. Despite global efforts in drug and vaccine development to fight the disease, there is currently no vaccine or drug cure for COVID-19, though some drugs reduce severity and hasten recovery. Here we interrogate the evolutionary history of the entire SARS-CoV-2 proteome to identify functional sites that can inform the search for treatments. Combining this information with the mutations observed in the current COVID-19 outbreak, we systematically and comprehensively define evolutionarily stable sites that are useful drug targets. Several experimentally-validated effective drugs interact with these proposed target sites. In addition, the same evolutionary information can prioritize cross reactive antigens that are useful in directing multi-epitope vaccine strategies to illicit broadly neutralizing immune responses to the betacoronavirus family. Although the results are focused on SARS-CoV-2, these approaches are based upon evolutionary principles and are agnostic to organism or infective agent.

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ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques

Cited by 857 publications

References 19 publications

Molecular clamp stabilised Spike protein for protection against SARS-CoV-2

Molecular clamp stabilised Spike protein for protection against SARS-CoV-2

A potent SARS-CoV-2 neutralizing human monoclonal antibody that reduces viral burden and disease severity in Syrian hamsters

Identification of evolutionarily stable sites across the SARS-CoV-2 proteome

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