Pre-clinical models to define correlates of protection for SARS-CoV-2

Abstract

A defined immune profile that predicts protection against a pathogen-of-interest, is referred to as a correlate of protection (CoP). A validated SARS-CoV-2 CoP has yet to be defined, however considerable insights have been provided by pre-clinical vaccine and animal rechallenge studies which have fewer associated limitations than equivalent studies in human vaccinees or convalescents, respectively. This literature review focuses on the advantages of the use of animal models for the definition of CoPs, with particular attention on their application in the search for SARS-CoV-2 CoPs. We address the conditions and interventions required for the identification and validation of a CoP, which are often only made possible with the use of appropriate in vivo models.

Keywords: SARS-CoV-2; animal models; correlates of protection (CoP); immunity; vaccines.

Figure 1

SARS-CoV-2 animal model development overview demonstrating the preferred SARS-CoV-2 animal models on the left, and inadequate/impractical COVID-19 models with defined limitations on the right, and the processes by which animal models are identified in the central column. Created with BioRender.com.

Figure 2

An overview of immunological assays and analysis that can be performed on animal samples. MNA, microneutralisation assay; ELISA, enzyme-linked immunosorbent assay; ADNP, antibody-dependent neutrophil phagocytosis; ADMP, antibody-dependent macrophage phagocytosis; FcyRs, fragment crystallisable of antibody receptor; ADCC, antibody-dependent cellular cytotoxicity; ADNK, antibody-dependent NK cell activation; PBMC, peripheral blood mononuclear cells; RNAseq, RNA sequencing. Created with BioRender.com.

Figure 3

A vaccine development pipeline highlighting the stages where candidate CoPs can be identified and confirmed. Created with BioRender.com.

Figure 4

Schematic of the scope to manipulate the immunological response by I) administering the candidate CoP to the challenge model (at top in blue) via i) adoptive transfer of T cells from a convalescent individual or ii) passive immunisation with convalescent serum or a therapeutic mAb or II), removing candidate CoP from challenge model (at bottom in red) via i) T cell depletion or ii) use of an immunodeficient animal model. Challenging the animal with virus and ascertaining the effects of removal/addition of these immune features on virology and pathology, can provide evidence for/against the candidate CoPs. Created with BioRender.com.

Figure 5

Schematic representing the scope to identify CoPs by investigating a range of a) vaccine candidate platforms, b) number of vaccine doses, and c) vaccine dosing regimens to give a range of outcomes in order to identify the immune profile that differentiates protected from unprotected animals. Created with BioRender.

Figure 6

Graphical summary of CoPs proposed in the referenced literature following computational analysis of preclinical study datasets, involving a) macaques, b) Syrian golden hamsters, and c) mice. ADCP, antibody-dependent cellular phagocytosis; ADCC, antibody-dependent cellular cytotoxicity; ADCD, antibody-dependent complement; Ab, antibody. Created with BioRender.com.