ChAdOx1 nCoV-19 (AZD1222) vaccine candidate significantly reduces SARS-CoV-2 shedding in ferrets

Marsh, Glenn A.; McAuley, Alexander J.; Au, Gough G.; Riddell, Sarah; Layton, Daniel S.; Singanallur, Nagendrakumar Balasubramanian; Layton, Rachel; Payne, Jean; Durr, Peter A.; Bender, Hannah; Barr, Jennifer; Bingham, John; Boyd, Victoria; Brown, Sheree; Bruce, Matthew P.; Burkett, Kathie; Eastwood, Teresa; Edwards, Sarah; Gough, Tamara J.; Halpin, Kim; Harper, Jenni; Holmes, Clare; Horman, William S J; Vuren, Petrus Jansen van; Lowther, Sue; Maynard, Kate; McAuley, Kristen D.; Neave, Matthew J.; Poole, Timothy; Rootes, Christina L.; Rowe, Brenton; Soldani, Elisha; Stevens, Vittoria; Stewart, Cameron R.; Suen, Willy W.; Tachedjian, Mary; Todd, Shawn; Trinidad, Lee; Walter, Duane; Watson, Naomi; Drew, Trevor W.; Gilbert, Sarah C.; Lambe, Teresa; Vasan, Seshadri S.

doi:10.1038/s41541-021-00315-6

Cited by 50 publications

(43 citation statements)

References 23 publications

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“…Similar to recent ferret studies involving two other vaccines, [72][73][74] microneutralisation assays employing the full length replicative viruses for the four current VOC (alpha, beta, gamma, and delta) were performed with each of the five samples from mice vaccinated with hCMP-mRBD, hCMP-mRBD (CHO) and mRBD-Gly IZ (Figure 3j-3l;, note that the sera used for neutralization studies with full length virus were after three immunizations because all the available sera after two immunizations had been used up in the pseudoviral assays). Negative control (unvaccinated mice sera) and positive control (terminal pooled ferret sera from Marsh et al 73 ) were included for comparison; the assays were performed in duplicates as the volumes of mice sera were limited, however these replicate titers were frequently identical or at most within 2-fold of one another. 50% neutralization titers were calculated for each serum/variant combination on the duplicate values using the method of Spearman and Karber (Figure 3j-3l) 75,76 .…”

Section: Trimeric Mrbd Elicits High Titers Of Neutralizing Antibodies In Mice and Guinea Pigs And Protects Hamsters From Viral Challengesupporting

confidence: 63%

“…However, multicomponent as well as Spy-tagged nanoparticles do have the potential advantage of modularity and being able to display two or more antigens simultaneously. Trimeric RBD elicited sera neutralized B.1.351 pseudovirus with only a relatively small drop in neutralization titer compared to that seen for B.1 virus(Figure 3f-3i Comparison with live virus neutralisation demonstrates that while the two values are correlated, pseudovirus neutralisation titers are frequently 10-to-100-fold higher, therefore where feasible, it is useful to also employ live, infectious virus when assessing the neutralisation efficacy of vaccine-induced antibodies [72][73][74] . In the present case, very encouragingly, the trimeric RBD elicited sera were able to neutralize all four current variants of concern equivalently.…”

Section: Discussionmentioning

confidence: 99%

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Immunogenicity and protective efficacy of a highly thermotolerant, trimeric SARS-CoV-2 receptor binding domain derivative

Malladi

Patel

Rajmani

et al. 2021

Preprint

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The Receptor Binding Domain of SARS-CoV-2 is the primary target of neutralizing antibodies. We fused our previously described, highly thermotolerant glycan engineered monomeric RBD to a heterologous non-immunogenic trimerization domain derived from cartilage matrix protein. The protein was expressed at a good yield of ∼80-100 mg/liter in Expi293 cells, as well as in both CHO and HEK293 stable cell lines. The designed trimeric RBD was observed to form homogeneous disulfide-linked trimers. When lyophilized, the trimer possessed remarkable functional stability to transient thermal stress of upto 100 °C and was stable to long term storage of over 4 weeks at 37 °C. Two immunizations with an AddaVax adjuvanted formulation elicited antibodies with high endpoint neutralizing titers against replicative virus with geometric mean titers of ∼1114 and 1940 in guinea pigs and mice respectively. In pseudoviral assays, corresponding titers were ∼3600 and ∼16050, while the corresponding value for human convalescent sera was 137. Similar results were obtained with an Alhydrogel, CpG combination adjuvant. The same immunogen was expressed in Pichia pastoris, but this formed high molecular weight aggregates and elicited much lower ACE2 competing antibodies than mammalian cell expressed protein. The excellent thermotolerance, high yield, and robust immunogenicity of such trimeric RBD immunogens suggest that they are a promising modality to combat COVID-19.ImportanceSARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic. The viral surface exposed Spike glycoprotein is the target of neutralizing antibodies of which a major fraction targets the receptor binding domain (RBD). Thus RBD derived immunogens are attractive vaccine candidates. Monomeric, mammalian cell expressed RBD protein elicits low to moderate titers of neutralizing antibodies. We designed a highly expressed, trimeric RBD derivative with a non-immunogenic trimerization domain. In guinea pigs and mice respectively, this derivative induces 20-300 fold higher neutralizing antibody titers relative to convalescent human sera, while remaining conformationally intact after incubation for over four weeks at 37 °C and for ninety minutes at 100 °C when lyophilized. Such trimeric RBD formulations should not require a cold chain. Additionally, the high titers of neutralizing antibodies should buffer against viral sequence variation. These are both highly desirable attributes for a COVID-19 vaccine, especially in resource limited settings.

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Section: Trimeric Mrbd Elicits High Titers Of Neutralizing Antibodies In Mice and Guinea Pigs And Protects Hamsters From Viral Challengesupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Immunogenicity and protective efficacy of a highly thermotolerant, trimeric SARS-CoV-2 receptor binding domain derivative

Malladi

Patel

Rajmani

et al. 2021

Preprint

Self Cite

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“…The vaccine generated nAb titers of 320, and resulted in 15‐fold reduction of viral RNA titers in nasal washes. [ 177 ]…”

Section: Vaccine Developmentmentioning

confidence: 99%

“…To date, only two SARS‐2 infection challenge studies have utilized ferrets for the purpose of examining vaccine efficacy. [ 177 , 247 ] In contrast, Syrian hamsters have been recently employed as a suitable infection challenge animal model for SARS‐2; this model is susceptible to infection using relatively low SARS‐2 dose (10 3.5 PFU). [ 248 , 249 ] Importantly, viral RNA titers are detectable, days 2–7 post‐infection, in nasal turbinates, duodenum, feces, brain, and kidneys.…”

Section: Animal Models For Vaccines Against Sars‐2: Efficacy and Safety Evaluationmentioning

confidence: 99%

Key Considerations for the Development of Safe and Effective SARS‐CoV‐2 Subunit Vaccine: A Peptide‐Based Vaccine Alternative

et al. 2021

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COVID‐19 is disastrous to global health and the economy. SARS‐CoV‐2 infection exhibits similar clinical symptoms and immunopathological sequelae to SARS‐CoV infection. Therefore, much of the developmental progress on SARS‐CoV vaccines can be utilized for the development of SARS‐CoV‐2 vaccines. Careful antigen selection during development is always of utmost importance for the production of effective vaccines that do not compromise recipient safety. This holds especially true for SARS‐CoV vaccines, as several immunopathological disorders are associated with the activity of structural and nonstructural proteins encoded in the virus's genetic material. Whole viral protein and RNA‐encoding full‐length proteins contain both protective and “dangerous” sequences, unless pathological fragments are deleted. In light of recent advances, peptide vaccines may present a very safe and effective alternative. Peptide vaccines can avoid immunopathological pro‐inflammatory sequences, focus immune responses on neutralizing immunogenic epitopes, avoid off‐target antigen loss, combine antigens with different protective roles or mechanisms, even from different viral proteins, and avoid mutant escape by employing highly conserved cryptic epitopes. In this review, an attempt is made to exploit the similarities between SARS‐CoV and SARS‐CoV‐2 in vaccine antigen screening, with particular attention to the pathological and immunogenic properties of SARS proteins.

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“…15 The ChAdOx1 vaccine is a chimpanzee adenoviral vector vaccine, whereas the Ad26.COV2.S vaccine is a human adenoviral vector vaccine. 16,17 The clinical syndrome seen after both of these vaccines appears similar; however, the extent to which these cases represent the same pathophysiologic syndrome is still unclear, and the syndrome seems to occur at a 4-fold higher frequency with ChAdOx1. 15 In contrast, with the Pfizer-BioNTech messenger RNA (mRNA) vaccine (BNT162b2), there have been no reports of CVST following a large number of doses administered.…”

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confidence: 99%

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine–Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis

et al. 2021

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IMPORTANCEThe COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST.OBSERVATIONS VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk.CONCLUSIONS AND RELEVANCE Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

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ChAdOx1 nCoV-19 (AZD1222) vaccine candidate significantly reduces SARS-CoV-2 shedding in ferrets

Cited by 50 publications

References 23 publications

Immunogenicity and protective efficacy of a highly thermotolerant, trimeric SARS-CoV-2 receptor binding domain derivative

Immunogenicity and protective efficacy of a highly thermotolerant, trimeric SARS-CoV-2 receptor binding domain derivative

Key Considerations for the Development of Safe and Effective SARS‐CoV‐2 Subunit Vaccine: A Peptide‐Based Vaccine Alternative

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine–Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis

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