SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates

Abstract

Understanding immune responses to severe acute respiratory syndrome coronavirus 2 is crucial to understanding disease pathogenesis and the usefulness of bridge therapies, such as hyperimmune globulin and convalescent human plasma, and to developing vaccines, antivirals, and monoclonal antibodies. A mere 11 months ago, the canvas we call COVID-19 was blank. Scientists around the world have worked collaboratively to fill in this blank canvas. In this Review, we discuss what is currently known about human humoral and cellular immune responses to severe acute respiratory syndrome coronavirus 2 and relate this knowledge to the COVID-19 vaccines currently in phase 3 clinical trials.

Figure 1

The structure of the SARS-CoV-2 virion SARS-CoV-2 is a spherical, enveloped virus, with three structural proteins present in the lipid bilayer: the spike glycoprotein, the membrane protein, and the envelope protein. The nucleocapsid protein is associated with the membrane protein and is complexed with the viral RNA genome. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

Figure 2

SARS-CoV-2 infection and the development of immunity The illustration depicts the major steps in the viral lifecycle and in the development of immune responses. (1) Attachment of the SARS-CoV-2 virion to the cell surface via interactions with the ACE2 cellular receptor. (2) Entry into the cell. Viral proteins can be recognised by pattern recognition receptors (eg, TLR3, TLR4, and TLR7), leading to the release of danger-associated molecular patterns, the inflammatory response, and the activation of innate anti-viral pathways. (3) Membrane fusion and release of RNA into the cell. (4) RNA translation to produce viral proteins. (5) RNA genome is copied and attached to the nucleocapsid protein. (6) Assembly of daughter SARS-CoV-2 virions. (7) Recognition of the spike glycoprotein and nucleocapsid protein (structural proteins) by the B-cell receptor. (8) B cell produces spike glycoprotein-binding antibodies and neutralising antibodies targeting the RBD region of the spike glycoprotein. (9) Viral uptake by APCs. (10) Presentation of antigens, including epitopes from structural and non-structural proteins, to T cells. (11) Activation of Th cells. (12) Activation of CTLs. (13) Th cells produce cytokines (mainly IFNγ, IL-2, and TNFα). (14) CTL recognition and killing of infected cells. ACE2=angiotensin-converting enzyme 2. APC=antigen-presenting cell. CTL=cytotoxic T lymphocyte. RBD=receptor-binding domain. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. Th=T-helper. TLR=toll-like receptor. TNF=tumour necrosis factor.

Figure 3

SARS-CoV-2 proteins targeted by adaptive immune responses The four structural proteins are shown in the red boxes. Non-structural proteins and accessory factors are shown in the blue boxes. Arrows link antibodies to the viral proteins they target and identify viral proteins shown to contain epitopes targeted by CD4⁺ T cells or CD8⁺ T cells. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.