Safety, mucosal and systemic immunopotency of an aerosolized adenovirus-vectored vaccine against SARS-CoV-2 in rhesus macaques

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ABSTRACT

Mucosal immunity provides a potential for preventing initial infection and stopping subsequent transmission of SARS-CoV-2. Here, we examined the safety and immunogenicity of a replication-defective adenovirus type-5 vectored vaccine (Ad5-nCov) encoding SARS-CoV-2 spike protein delivered by nebulization inhalation in rhesus macaques. The vaccine-associated clinical pathology and toxicity were not observed in the NHP model. The extensive safety study indicated that Ad5-nCoV was mainly confined to the organs related to respiratory system and was rapidly cleared away from the system. Our results showed that Ad5-nCoV delivered by inhalation robustly elicited both systematic and mucosal immune responses against SARS-nCoV-2 and variants. Thus, Ad5-nCoV inhalation may provide an effective, safe and non-invasive vaccination strategy for the control of SARS-CoV-2.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

Feng-Cai Zhu, Yu-Hua Li, Xu-Hua Guan … (2020)

Summary Background A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Methods We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127. Findings Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination. Interpretation The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation. Funding National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.

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Establishment and validation of a pseudovirus neutralization assay for SARS-CoV-2

Jianhui Nie, Qianqian Li, Jiajing Wu … (2020)

ABSTRACT Pseudoviruses are useful virological tools because of their safety and versatility, especially for emerging and re-emerging viruses. Due to its high pathogenicity and infectivity and the lack of effective vaccines and therapeutics, live SARS-CoV-2 has to be handled under biosafety level 3 conditions, which has hindered the development of vaccines and therapeutics. Based on a VSV pseudovirus production system, a pseudovirus-based neutralization assay has been developed for evaluating neutralizing antibodies against SARS-CoV-2 in biosafety level 2 facilities. The key parameters for this assay were optimized, including cell types, cell numbers, virus inoculum. When tested against the SARS-CoV-2 pseudovirus, SARS-CoV-2 convalescent patient sera showed high neutralizing potency, which underscore its potential as therapeutics. The limit of detection for this assay was determined as 22.1 and 43.2 for human and mouse serum samples respectively using a panel of 120 negative samples. The cutoff values were set as 30 and 50 for human and mouse serum samples, respectively. This assay showed relatively low coefficient of variations with 15.9% and 16.2% for the intra- and inter-assay analyses respectively. Taken together, we established a robust pseudovirus-based neutralization assay for SARS-CoV-2 and are glad to share pseudoviruses and related protocols with the developers of vaccines or therapeutics to fight against this lethal virus.

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Journal

Journal ID (nlm-ta): Emerg Microbes Infect

Journal ID (iso-abbrev): Emerg Microbes Infect

Title: Emerging Microbes & Infections

Publisher: Taylor & Francis

ISSN (Electronic): 2222-1751

Publication date (Electronic, pub): 29 January 2022

Publication date (Electronic, collection): 2022

Publication date PMC-release: 29 January 2022

Volume: 11

Issue: 1

Pages: 438-441

Affiliations

[a ]CanSino Biologics , Tianjin, People’s Republic of China

[b ]Institute of Biotechnology, Academy of Military Medical Sciences , Beijing, People’s Republic of China

Author notes

[CONTACT ] Tao Zhu tao.zhu@ 123456cansinotech.com CanSino Biologics , Tianjin 300457, People’s Republic of China

[*]

Contributed equally.

Supplemental data for this article can be accessed https://doi.org/10.1080/22221751.2022.2030199.

Article

Publisher ID: 2030199

DOI: 10.1080/22221751.2022.2030199

PMC ID: 8803102

PubMed ID: 35094672

SO-VID: f1e83feb-fa90-49d8-834b-b28130110256

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Safety, mucosal and systemic immunopotency of an aerosolized adenovirus-vectored vaccine against SARS-CoV-2 in rhesus macaques

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Novel Coronavirus Disease COVID-19

Most cited references 10

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

Establishment and validation of a pseudovirus neutralization assay for SARS-CoV-2

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