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[Preprint]. 2020 May 13:2020.05.13.093195.
doi: 10.1101/2020.05.13.093195.

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

Neeltje van Doremalen  1 , Teresa Lambe  2 , Alexandra Spencer  2 , Sandra Belij-Rammerstorfer  2 , Jyothi N Purushotham  1   2 , Julia R Port  1 , Victoria Avanzato  1 , Trenton Bushmaker  1 , Amy Flaxman  2 , Marta Ulaszewska  2 , Friederike Feldmann  3 , Elizabeth R Allen  2 , Hannah Sharpe  2 , Jonathan Schulz  1 , Myndi Holbrook  1 , Atsushi Okumura  1 , Kimberly Meade-White  1 , Lizzette Pérez-Pérez  1 , Cameron Bissett  2 , Ciaran Gilbride  2 , Brandi N Williamson  1 , Rebecca Rosenke  3 , Dan Long  3 , Alka Ishwarbhai  2 , Reshma Kailath  2 , Louisa Rose  2 , Susan Morris  2 , Claire Powers  2 , Jamie Lovaglio  3 , Patrick W Hanley  3 , Dana Scott  3 , Greg Saturday  3 , Emmie de Wit  1 , Sarah C Gilbert  2 , Vincent J Munster  1
Affiliations

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

Neeltje van Doremalen et al. bioRxiv. .

Update in

  • ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques.
    van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, Avanzato VA, Bushmaker T, Flaxman A, Ulaszewska M, Feldmann F, Allen ER, Sharpe H, Schulz J, Holbrook M, Okumura A, Meade-White K, Pérez-Pérez L, Edwards NJ, Wright D, Bissett C, Gilbride C, Williamson BN, Rosenke R, Long D, Ishwarbhai A, Kailath R, Rose L, Morris S, Powers C, Lovaglio J, Hanley PW, Scott D, Saturday G, de Wit E, Gilbert SC, Munster VJ. van Doremalen N, et al. Nature. 2020 Oct;586(7830):578-582. doi: 10.1038/s41586-020-2608-y. Epub 2020 Jul 30. Nature. 2020. PMID: 32731258 Free PMC article.

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was not Th2 dominated, as demonstrated by IgG subclass and cytokine expression profiling. A single vaccination with ChAdOx1 nCoV-19 induced a humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. ChAdOx1 nCoV-19 is currently under investigation in a phase I clinical trial. Safety, immunogenicity and efficacy against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.

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Conflict of interest statement

Competing interests SCG is a board member of Vaccitech and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering a SARS-CoV-2 (nCoV-19) vaccine. Teresa Lambe is named as an inventor on a patent application covering a SARS-CoV-2 (nCoV-19) vaccine. The remaining authors declare no competing interests.

Figures

Extended Data Figure 1.
Extended Data Figure 1.. Antigen specific responses following ChAdOx1 nCov19 vaccination.
a. IgG subclass antibodies detected against S1 or S2 protein in sera of BALB/c or CD1 mice. b. Frequency of cytokine positive CD4+ or CD8+ T cells following stimulation of splenocytes with S1 pool (dark) or S2 pool (transparent) peptides in BALB/c (red) and CD1 (blue) mice. d. Log10 fold change in cytokine levels in supernatant from S1 (dark) and S2 (transparent) stimulated splenocytes when compared to corresponding unstimulated splenocyte sample for BALB/c and CD1 mice.
Extended Data Figure 2.
Extended Data Figure 2.. Serum cytokines in rhesus macaques challenged with SARS-CoV-2.
Fold increase in cytokines in serum compared to 0 DPI values.
Extended Data Figure 3.
Extended Data Figure 3.. Viral load in rhesus macaques challenged with SARS-CoV-2
Viral genomic RNA in respiratory tissues excluding lung tissue (left panel) and other tissues (right panel). A two-tailed Mann-Whitney’s rank test was performed to investigate statistical significance. Bonferroni correction was applied, and thus statistical significance was reached at p>0.0125.
Figure 1:
Figure 1:. Humoral and cellular immune responses to ChAdOx1 nCoV-19 vaccination in mice.
a. End point titer of serum IgG detected against S1 or S2 protein. Control mice were below the limit of detection. b. Virus neutralizing titer in serum. c. Summed IFN-γ ELISpot responses in splenocytes toward peptides spanning the spike protein. Control mice had low (<100 SFU) or no detectable response. d. Summed frequency of spike-specific cytokine positive CD4+ or CD8+ T cells. BALB/c = red; CD1 = blue; vaccinated = circle; control = square; dotted line = limit of detection; line = mean; SFU = spot-forming units.
Figure 2.
Figure 2.. Humoral and cellular immune responses to ChAdOx1 nCoV-19 vaccination in rhesus macaques.
a. Study schedule for NHPs. V = vaccination with ChAdOx1 nCoV-19; G = vaccination with ChAdOx1 GFP; E = exam; N = exam and necropsy. b. Virus neutralizing titer in serum. d. Summed IFN-γ ELISpot responses in PBMCs toward peptides spanning the spike protein Vaccinated animals = red circles; control animals = blue squares; dotted line = limit of detection; line - median; SFU = spot-forming units.
Figure 3.
Figure 3.. Clinical signs and viral load in rhesus macaques inoculated with SARS-CoV-2 after vaccination with ChAdOx1 nCoV-19.
a. Mean clinical score with standard deviation in NHPs. Any scoring associated with food was removed from final score. b. Viral load in BAL fluid obtained from rhesus macaques, bar at geometric mean. *=p-value<0.0166. c. Viral load in nose swabs obtained from rhesus macaques, bar at geometric mean. d. Viral load in tissues at 7 DPI. Pictured are individual values with geometric mean bars (left panels) and geometric mean of all lung lobes per group (right panel). ***=p-value<0.001; ****=p-value<0.0001. Vaccinated animals = red circles; control animals = blue squares; dotted line = limit of detection.
Figure 4.
Figure 4.. Histological changes in lungs of rhesus macaques on 7 dpi.
a) Focal interstitial pneumonia in lungs of a control animal (blue box). The area in the black box is magnified in panel b. b) Interstitial pneumonia with edema (asterisk), type II pneumocyte hyperplasia (arrowhead) and syncytial cells (arrow) in control animals. c) SARS-CoV-2 antigen (visible as red-brown staining) was detected by immunohistochemistry in type I and type II pneumocytes in the lungs of control animals. d) No histological changes were observed in the lungs of ChadOx1 nCoV-19-vaccinated animals. e) Higher magnification of lung tissue in panel d. No evidence of pneumonia or immune-enhanced inflammation is observed. f) No SARS-CoV-2 antigen was detected by immunohistochemistry in the lungs of vaccinated animals. Magnification: panels a, d 40x; panels b, c, e, f 400x.
See this image and copyright information in PMC

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