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Authors: Chandrashekar et al.,

Link to paper: https://science.sciencemag.org/content/early/2020/05/19/science.abc4776

Journal/ Pre-Print: Science

Tags: Immunology/Immunity, Vaccines, Virology

Research Highlights

1. SARSCoV2 infection in rhesus macaques induced protective humoral and cellular immunity against re-exposure, which has implications for vaccine development, epidemiological modelling for herd immunity and antibody-based therapeutics.

2. SARSCoV2 infected pneumocytes and ciliated bronchial epithelial cells in rhesus macaques, inducing multifocal areas of acute inflammation and viral pneumonia.

3. Protection against re-challenge with SARSCoV2 seems to be largely independent of initial inoculant titre during primary challenge.

Summary

Rhesus macaques (n=9) were infected and re-challenged (day 35) with 1.1 x104-6 PFU SARSCoV2 to assess natural immunity upon re-exposure. Following primary infection, antibodies to SARSCoV2 proteins (receptor binding domain, nucleocapsid, and in particular the prefusion S ectodomain) were detected and capable of triggering complement deposition, NK cell degranulation and IFNγ secretion. CD4+ and CD8+ T cell responses to the prefusion S ectodomain were also detected. Upon re-challenge, viral load in the bronchoalveolar lavage was reduced 5xlog(10) as were symptoms. These effects are hypothesised to be due to the enhanced neutralising antibody titres detected. Independently infected animals sacrificed on days 2 and 4 showed infected pneumocytes and ciliated bronchial epithelial cells, and adjacent multifocal regions of inflammatory infiltrates (neutrophils, macrophages, T cells). Further work is required to assess the duration of protection, prove what is functionally mediating any protection and identify if this is true in humans.

Impact for SARS-CoV2/COVID19 research efforts

· Understand the immune response to SARS-CoV2/COVID19 and importantly, viral re-challenge

· Clinical symptoms and pathogenesis of SARS-Cov2/COVID19, with a focus on lung pathology

· Informative data for vaccine development to SARS-CoV2/COVID19: These data show a capacity to generate protective immunity and the type of antigens that elicitstrong antibody-dependent processes

Study Type

· In vivo study (rhesus macaque) primary and repeat (35 days later) infection with SARSCoV2

Strengths and limitations of the paper

Novelty: Showed that SARSCoV2 infection in rhesus macaques protects against re-challenge, an effect that is thought to be due to the humoral and cellular immune responses induced by primary infection. This study also performs more detailed in situ analysis of inflammatory cells and viral RNA in the lungs.

Standing in the field: Expands previous rhesus macaques COVID19 studies to look at immune responses in the lungs after infection and consequences for re-infection

Appropriate statistics: Numbers are understandably low but statistics seem appropriate and control group infected only at re-challenge is included for comparison.

Viral model used: Rhesus macaques infected with SARSCoV2 intra-tracheally and intra-nasally. A dose of 1.1 x104 PFU - 1.1 x106 PFU was administered

Translatability: Evidence that SARSCoV2 infection protects against re-challenge, potentially via protective humoral and/or cellular immunity has implications with for vaccine development, epidemiological modelling and public health approaches

Main limitations:

· Discussed in the paper but worth of consideration:

o Animals do not develop respiratory symptoms like humans so ideally need a better in vivo model still (e.g. only group 1 showed clear neutro- and lymphopenia)

o Only correlate anamnestic antibody responses with reduced symptoms but don’t show causal protection

o Nearly all animals were protected from re-challenge so couldn’t look at correlates with, for example, antibodies to see what might be driving protection

· It would have been nice to compare matched animals after primary infection and re-challenge, and also include a non-infected group for all analyses not just the pathology

· Likely outside of the scope of this study, but it misses out to address issue of long-term protection (after initial B cell response has weaned off and antibody titres are reduced again after primary infection à re-infection 5 weeks post-initial inoculant)

· No representative plots e.g. for IFNg staining

· No quantification of in situ staining