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Authors: Neeltje van Doremalen, Teresa Lambe, Alexandra Spencer, Sandra Belij-Rammerstorfer, Jyothi N. Purushotham, Julia R. Port, Victoria Avanzato, Trenton Bushmaker, Amy Flaxman, Marta Ulaszewska, Friederike Feldmann, Elizabeth R. Allen, Hannah Sharpe, Jonathan Schulz, Myndi Holbrook, Atsushi Okumura, Kimberly Meade-White1, Lizzette Pérez-Pérez1, Cameron Bissett2, Ciaran Gilbride2, Brandi N. Williamson1, Rebecca Rosenke, Dan Long, Alka Ishwarbhai, Reshma Kailath, Louisa Rose, Susan Morris, Claire Powers, Jamie Lovaglio, Patrick W. Hanley, Dana Scott, Greg Saturda3, Emmie de Wit, Sarah C. Gilbert, Vincent J. Munster.

Link to paper: https://doi.org/10.1101/2020.05.13.093195

Journal/ Pre-Print: bioRxiv

Tags: Immunology/Immunity, Therapeutics, Vaccines, Virology

Research Highlights 

1. Single injection of adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2 reduced pneumonia in virus-challenged macaques

2. Vaccinated macaques showed somewhat improved clinical scores after inoculation with SARS-CoV-2 compared to controls

3. Vaccinated macaques showed increased IFNy response in PBMCs subjected to antigen recall with SARS-CoV-2 spike protein compared to controls, but maintained viral genomic RNA in upper respiratory tracts although at lower levels than controls

Summary

Non-human primates were immunized with a single injection of adenovirus-vectored vaccine (ChAd-Ox1 nCov-19). They reported antibody development by day 14 post vaccination and weak neutralizing antibody responses in all vaccinated animals. A SARS-CoV-2 challenge 28 days post vaccination led to clinical symptoms in 5 out of 6 vaccinated animals but improved disease progression compared to non-vaccinated animals. Vaccinated animals showed virus depletion in the lower respiratory tracts in the majority of lung samples but upper respiratory tracts continued to show genomic viral RNA. No increase of pro-inflammatory cytokines or immune enhancement of disease was observed.

Impact for SARS-CoV2/COVID19 research efforts

· Understand the immune response to SARS-CoV2/COVID19

· Understand the virology and/or cell biology of SARS-CoV2/COVID19

· Clinical symptoms and pathogenesis of SARS-Cov2/COVID19

· Develop a vaccine for SARS-CoV2/COVID19

Study Type

· In vivo study (mouse + Non-human primates/macaques)

Strengths and limitations of the paper

Novelty: First in-vivo study in macaques & mice with the newly developed ChAd-Ox1 nCov-19 vaccine that is currently in clinical trials

Standing in the field: Translatability

Appropriate statistics: Mann Whitney U for macaque clinical and virological outcomes, no statistical tests shown for mouse or macaque immunological outcomes.

Viral model used: Infection of rhesus macaques or mice (BALB/c & outbred CD1) with SARS-Cov2 spike protein vaccine or GFP control vaccine

Translatability: Non-human primates are one of the closest species to humans for experimental models. A recent publication showed development of COVID-19 symptoms in an experimental model in macaques (https://doi.org/10.1038/s41586-020-2324-7). However, with decreased severity compared to humans. One of the strengths of this vaccine is that no antibody dependent enhancement (ADE) was documented (one of main obstacles to SARS-CoV vaccine and dengue virus), reassuring for evaluation of the ChAdOx1 nCoV-19 vaccine in human clinical trials. Previous studies on animal models vaccinated with SARS-Cov showed induction of ADE or eosinophil mediated pathology. (Bolles, M. et al. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J. Virol. 85, 12201–12215 (2011). Liu, L. et al. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight 4, e123158 (2019). Yang, Z.-y. et al. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc. Natl Acad. Sci. USA 102, 797 (2005)).

Main limitations:

· Number of animals used is small (6 with ChAd-Ox1 nCov-19, 3 with control vaccine)

· Low IFNg response in S antigen-restimulated PBMCs with 1/6 stronger responders

· Viral neutralisation titers low in vaccinated animals on day of challenge at 28 days post inoculation (between 1:20-1:40, median <1/20)

· Macaques are not very susceptible to severe disease

· Macaques were protected from developing pneumonia but retained viral genomic RNA in the upper respiratory tract. Therefore, vaccinated subjects might still transmit the virus. However, monkeys were challenged with a high viral titer (2.6 x 106 TCID50).