SARS-CoV-2 Variants, Vaccines, and Host Immunity

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta coronavirus that emerged at the end of 2019 in the Hubei province of China. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Herd or community immunity has been proposed as a strategy to protect the vulnerable, and can be established through immunity from past infection or vaccination. Whether SARS-CoV-2 infection results in the development of a reservoir of resilient memory cells is under investigation. Vaccines have been developed at an unprecedented rate and 7 408 870 760 vaccine doses have been administered worldwide. Recently emerged SARS-CoV-2 variants are more transmissible with a reduced sensitivity to immune mechanisms. This is due to the presence of amino acid substitutions in the spike protein, which confer a selective advantage. The emergence of variants therefore poses a risk for vaccine effectiveness and long-term immunity, and it is crucial therefore to determine the effectiveness of vaccines against currently circulating variants. Here we review both SARS-CoV-2-induced host immune activation and vaccine-induced immune responses, highlighting the responses of immune memory cells that are key indicators of host immunity. We further discuss how variants emerge and the currently circulating variants of concern (VOC), with particular focus on implications for vaccine effectiveness. Finally, we describe new antibody treatments and future vaccine approaches that will be important as we navigate through the COVID-19 pandemic.

Keywords: SARS-CoV-2; coronavirus; immunity; spike protein; vaccines; variants of concern.

Figure 1

Summary of the two branches of the immune system activated during viral infection, followed by the development of viral immunity. (A) The innate immune response is activated within hours of viral exposure as the body’s first line of defense that releases a series of anti-viral molecules at the site of infection. (B) An adaptive immune response is initiated after being primed by components of the innate immune system to initiate pathogen-specific cellular and humoral immune responses days after infection. Primed immune memory cells remain following viral clearance, constituting the presence of immunity. (STAT, signal transducer and activator of transcription; JAK, Janus kinase; CD, cluster of differentiation; MHC, major histocompatibility complex; TCR, T-cell receptor). Image created by PM using BioRender (https://biorender.com/).

Figure 2

Schematic representation of the SARS-CoV-2 virion and the domain structure of its spike protein. Furin cleavage sites are as indicated, and numbers represent amino acid positions within the protein. (S1&S2, subunit 1 & 2; NTD, N-terminal domain; RBM, receptor binding motif; RBD, receptor binding domain; CTD1&CTD2, C-terminal domain; FP, furin peptide; HR1&HR2, heptad repeats; CH, central helix; CD, connector domain; TM, transmembrane domain; CT, cytoplasmic tail). Image created by PM using BioRender (https://biorender.com/).

Figure 3

Schematic representation of the different conformational states of the SARS-CoV-2 spike protein. When in the closed conformation, the receptor binding domain (RBD) and its epitopes are hidden thereby contributing to immune evasion. In contrast, when subunit 1 (S1) dissociates from subunit 2 (S2) an open conformation is achieved that exposes the spike protein RBD and allows interaction with the host angiotensin-converting enzyme 2 (ACE2) to facilitate viral entry. Image created by PM using BioRender (https://biorender.com/).

Figure 4

Molecular mechanisms introducing genomic alterations into the SARS-CoV-2 genome. Nucleotide changes can emerge naturally in the viral genome through the various replication errors shown. Apart from replication errors, host-derived RNA editing enzymes apolipoprotein B mRNA editing catalytic polypeptide-like enzyme (APOBEC) and adenosine deaminase RNA specific 1 enzyme (ADAR1) can introduce signature point substitutions [cytosine (C) to uracil (U) and adenosine (A) to inosine (I)] into the viral genome. Lastly, if two viral variants co-infect the same cell recombination can occur whereby the genetic material of the two variants are packages into a single virion. Image created by PM using BioRender (https://biorender.com/).

Figure 5

Currently circulating SARS-CoV-2 variants of concern and their receptor binding domain (RBD) amino acid substitutions of interest to virulence and immune evasion. The N501Y substitution is common to the Alpha, Beta, Gamma and Omicron variant strains. The E484K/Q/A and K417T/N substitutions are present in the Beta, Gamma and Omicron strains, while the L452R substitution is unique to the Delta variant. Image created by PM using BioRender (https://biorender.com/).