The Immune Response to SARS-CoV-2 and Variants of Concern

Abstract

At the end of 2019 a newly emerged betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of severe pneumonia, subsequently termed COVID-19, in a number of patients in Wuhan, China. Subsequently, SARS-CoV-2 rapidly spread globally, resulting in a pandemic that has to date infected over 200 million individuals and resulted in more than 4.3 million deaths. While SARS-CoV-2 results in severe disease in 13.8%, with increasing frequency of severe disease with age, over 80% of infections are asymptomatic or mild. The immune response is an important determinant of outcome following SARS-CoV-2 infection. While B cell and T cell responses are associated with control of infection and protection against subsequent challenge with SARS-CoV-2, failure to control viral replication and the resulting hyperinflammation are associated with severe COVID-19. Towards the end of 2020, several variants of concern emerged that demonstrate increased transmissibility and/or evasion of immune responses from prior SARS-CoV-2 infection. This article reviews what is known about the humoral and cellular immune responses to SARS-CoV-2 and how mutation and structural/functional changes in the emerging variants of concern impact upon the immune protection from prior infection or vaccination.

Keywords: COVID-19; SARS-CoV-2; immune response; pandemic; vaccine; variants of concern.

Figure 1

The genomic structure of SARS-CoV-2. The genome encodes two large open reading frames (ORFs), ORF1a and ORF1b, which encode 16 non-structural proteins (NSP1-NSP16). The structural genes encode the structural proteins, spike (S), envelope (E), membrane (M), and nucleocapsid (N), and the accessory genes (3a, 3b, 6, 7a, 7b, 8, 9 and 10) (Created with Biorender.com accessed on 9 September 2021).

Figure 2

The emergence of new variants over time. The colours represent the ancestral clade. The variants of concern and variants of interest are shown on the graph. The image was taken from www.nextstrain.org under a CC-BY-4.0 license and is unchanged (accessed on 15 July 2021).

Figure 3

The mutations in the spike protein of four variants of concern. The schematic design of the spike protein is shown on the left. The mutations in 4 variants of concern are shown in the table on the right.

Figure 4

Structural comparison of the spike proteins of the variants of concern and the ancestral variant. (A) A ribbon diagram of the prefusion conformation of SARS-CoV-2 S protein trimer (PDB ID: 7DDN) (Ancestral variant). (B) SARS-CoV-2 spike protein trimer structure space filling model (B.1) (trimer). (C) Ribbon diagram of the monomer of the SARS CoV-2 spike protein (B1.). Spike protein monomer ribbon structures from (D) B.1.1.7 (UK variant/Alpha) spike structure in monomer, (E) P.1 (Brazil variant/Gamma) spike structure in monomer, (F) B.1.357 (South African variant/Beta) spike structure in monomer, and (G) B.1.617.2 (Indian variant/Delta) spike structure in monomer. In D to G, the spike protein monomer ribbon structures are superimposed on a faint transparent van der Waals surface The NTD site is shown in pink, the RBD is shown in blue, the mutations in the spike (compared to 19A) are shown as orange spheres, and the glycans are shown in light green. Images were made using PyMOL version 2.3.2.