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Authors: Shipo Wu et al. 

Journal/ Pre-Print:Research Square 

Tags: Immunology/Immunity, Animal Model 

Research Highlights

  • Immunisation of BALB/c mice with Ad5-nCoV2 via the mucosal route elicits higher neutralising Ab response whereas the muscular route supports a stronger cellular response 

  • Challenge of immunised BALB/c mice with a mouse-adapted SARS-CoV2 (HRB26M) shows protective efficacy of Ad5-nCoV2 

  • Vaccination of ferrets with Ad5-nCoV2 results in neutralising Ab production and challenge with SARS-CoV2 shows protective efficacy of Ad5-nCoV2 

Summary 

This works tests the pre-clinical immunogenicity and efficacy of an adenovirus-vectored vaccine encoding the Spike protein of SARS-CoV-2 Wuhan-Hu-1 strainCompared to mice immunised intramuscularly (IM), mice vaccinated intranasally (IN) developed neutralising antibody titers higher and persisting 4 times longer (for up to 8 weeks post-vaccination (pv)) when the highest dose of the Ad5-nCoV was used (5×10viral particles (vp))S-specific IgA was found only in the IN groups at week 10 pv. Furthermore, by 2 weeks pv significant Th1-like CD8+ and CD4+ T cell responses were found in IM and IN vaccinated animals, even when middle doses were used (5×108 vp). The elicited cellular response was stronger in IM immunised animals. Following challenge using a mouse-adapted SARS-CoV2 at week 10 pv, no virus was detected in the lungs by day 3 and 5 post-challenge. Using a similar experimental design, the authors tested the immunogenicity and protective capacity of Ad5-nCoV (at the dose of 5×1010 vp ) in ferrets. IN and IM vaccinations elicited comparable IgG titers and replicated the induction of cellular immune responses, being higher in IM-vaccinated ferrets. The IN-immunization, however, prevented the replication of SARSC-CoV-2 in the upper respiratory tract, which was not detected by PFU determination nor qRT-PCR measurements starting between days 2-8. This works demonstrates the development of mucosal immunity capable of halting virus replication in the upper and lower respiratory tract, with important implications in vaccination policies aimed at slowing the rate of virus dissemination and severity of disease in susceptible individuals.      

Impact for SARS-CoV2/COVID19 research efforts  

Develop a vaccine for SARS-CoV2/COVID19 

Characterise safety and mucosal immunogenicity of a replication deficient Adenovirus-vectored vaccine (Ad5-nCoV) 

Study Type  

  • In vivo study (BALB/c mice and ferrets) 

Strengths and limitations of the paper 

Novelty: Demonstration that a single administration of a viral vectored vaccine promotes protective mucosal immunity and prevent virus shedding from the upper respiratory tract in two animal models, suggesting its potential use for the prevention of SARS-CoV-2 disease and dissemination.  

Standing in the field: Titration of vectored vaccine (5×107-9 vpand comparison of IM and IN routes of administration demonstrates a superior immunogenicity of mucosal immunization (IN) over IM when high doses of the vaccine are used (5×109)These findings suggest the potential use of IN administration to facilitate and reduce the costs of vaccination strategies.  

Appropriate statistics: Yes. (Not clear in Figure 3a which type of statistic was used) 

Viral model used: 

  • spike (S) protein was selected based on the Wuhan-Hu-1 strain (YP_009724390) 

  • Mouse-adapted SARS-CoV2/HRB26/human/2020/CHN (HRB26M, GISAID access no. EPI_ISL_459910) was generated using the human patient isolate SARS-CoV-2/HRB26/human/2020/CHN (HRB26, GISAID access no. EPI_ISL_459909)  

  • SARS-CoV-2/human/CHN/Beijing_IME-BJ01/2020 (Genbank No. MT291831) 

  • SARS-CoV-2/HRB25/human/2020/CHN (HRB25, GISAID access no. EPI_ISL_467430)  

Translatability: Phase I clinical trial performed and Phase II under development (https://clinicaltrials.gov/ct2/show/NCT04341389). 

Main limitations:  

  • Dose of Ad expressed in vp not pfu 

  • AdHu5 use could lead to antivector immunity from previous infections in humans as AdHu5 prevalence is high in the human populations (around 80%). This vector has been dropped from CTs since a failed HIV (STEP) trial. The authors do not address this  

  • Fig 1c: text states that ELISA S IgG titres peaked at day 28 in the IM groups, but it appears they already peaked at day 14 

  • Figure 1d, e, g, h: ctrl Ad5 vector not depicted in the graphs 

  • Suggestion for Figure 1 i,j : make it more clear that it is antigen specific immune response to SARS-CoV2 peptides, also in the main text 

  • Suggestion for Fig 3c: better labelling of the graph, not clear it’s an IFNg ELIspot 

  • Study presents data of one animal experiment both for the mice and the ferret study, should be repeated to assure reproducibility