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Reinfection could not occur in SARS-CoV-2 infected rhesus macaques

Authors: Bao L. et al

Link to paper: https://www.biorxiv.org/content/10.1101/2020.03.13.990226v1.full

Journal/ Pre-Print: bioRxiv

Key Words: Immunity; Non-human primates

Research Highlights 

1. Immunity to SARS-CoV-2 achieved in non-human primates following primary infection.

Summary

Bao et al show that non-human primates (NHPs) are protected from SARS-CoV-2 re-challenge 28 days after the primary infection. Prior to reinfection authors confirmed that NHPs fulfilled the same criteria applied for human hospital discharge. Protection was determined on the basis of absence of viral RNA in various tissues, pulmonary pathology and clinical manifestations. These results suggest that 1) a competent humoral immunity is generated following primary infection with SARS-CoV-2 and that 2) the phenomena of clinical recurrence may be due to other factors such as “false-negative” qPCR results leading to discharge or the reactivation of latent viral infection.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19

The paper specifically aims to understand the susceptibility to reinfection of NHP. The analysis of the immune response to SARS-CoV-2 infection is limited to that of spike protein-specific and SARS-Cov-2 neutralizing antibody levels. Considering the variability of some metrics, the number of animals is insufficient to get an accurate view of the adaptive immunity to primary and secondary infections.

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

Detection of viral RNA in several organs and tissues including bladder, heart, skeletal muscle and spinal cord provides further evidence of the potential tropism of SARS-CoV-2. The methods used are unable to determine whether SARS-Cov-2 establishes latency in infected tissues.

Develop a vaccine for SARS-CoV2/COVID19

Enumeration of antibody titres which neutralise SARS-Cov-2 infection in vitro provides a reference for antibody readouts generated during vaccine trials.

Study Type

· In vivo study (NHP)

Strengths and limitations of the paper

Novelty: The idea that immunity is generated following infection with SARS-CoV-2 and confirmed pantropism of the virus in an NHP model.

Standing in the field: Immunity to reinfection indicates that human cases of recurrence of SARS-CoV-2 positivity following hospital discharge might be due to other causes such as “false-negative” qPCR results or the reactivation of latent viral infection, which remains to be elucidated. This former is supported by published data in which qPCR results for viral RNA fluctuate over time between negative and positive in sputum, throat swab and stool samples (Wolfel et al, 2020 - https://www.nature.com/articles/s41586-020-2196-x_reference.pdf).

Appropriate statistics: No. Statistical tests are not used for the majority of data due to NHPs being dealt with on a case by case basis, thus n = 1. In addition, there is no true control group as there were no mock-infected animals. For these reasons it is not appropriate to have statistical tests in fig 1g.

Viral model used: SARS-CoV-2

Translatability: Although the paper demonstrates that anti-S titers associate with resistance to reinfection and the progressive decay of viral RNA in infected tissues, the association between seroconversion and viral clearance seems to be delayed in humans (Wolfel et al, 2020 - https://www.nature.com/articles/s41586-020-2196-x_reference.pdf). In addition, protective titers in NHPs are not comparable to those reported in humans (Wu et al, 2020 - https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v1.full.pdf).

Main limitations: Small sample size (n=4) and one independent experiment. Only one timepoint of reinfection assessed (28 dpi). A later re-exposure time point may be more relevant considering re-exposure more likely to occur following relaxation of lockdown rules. This will also assess if immunity is transient or long-lasting.