Correlates of Vaccine-Induced Protection against SARS-CoV-2

Abstract

We are in the midst of a pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). SARS-CoV-2 has caused more than two million deaths after one year of the pandemic. The world is experiencing a deep economic recession. Safe and effective vaccines are needed to prevent further morbidity and mortality. Vaccine candidates against COVID-19 have been developed at an unprecedented speed, with more than 200 vaccine candidates currently under investigation. Among those, 20 candidates have entered the clinical Phase 3 to evaluate efficacy, and three have been approved by the European Medicines Agency. The aim of immunization is to act against infection, disease and/or transmission. However, the measurement of vaccine efficacy is challenging, as efficacy trials need to include large cohorts with verum and placebo cohorts. In the future, this will be even more challenging as further vaccine candidates will receive approval, an increasing number of humans will receive vaccinations and incidence might decrease. To evaluate novel and second-generation vaccine candidates, randomized placebo-controlled trials might not be appropriate anymore. Correlates of protection (CoP) could be an important tool to evaluate novel vaccine candidates, but vaccine-induced CoP have not been clearly defined for SARS-CoV-2 vaccines. In this review, we report on immunogenicity against natural SARS-CoV-2 infection, vaccine-induced immune responses and discuss immunological markers that can be linked to protection. By discussing the immunogenicity and efficacy of forerunner vaccines, we aim to give a comprehensive overview of possible efficacy measures and CoP.

Keywords: COVID-19; SARS-CoV-2; correlates of protection; immunogenicity; pandemic; vaccine.

Figure 1

Immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). (1) attachment of SARS-CoV-2 virus to host cell via angiotensin-converting enzyme 2 (ACE2)-receptor. (2) cell-entry. (3) membrane fusion and RNA-release into host cell. (4a) presentation of RNA and viral proteins to Toll-like receptor (TLR) and activation of innate immune response. (4b) assembly of virions. (5) uptake of virus by antigen presenting cell (APC). (6) presentation of antigens, including epitopes, to B-cell receptor (BCR). (7) production of binding and neutralizing antibodies by B-cells that, ideally, (8) neutralize the virus. (9) presentation of antigens, including epitopes, to T-cell receptor (TCR). (10) Activation of T helper (Th) cells and production of cytokines, that, recognized by (11) cytotoxic T-cells, (12) kill the virus. Graphic created at biorender.com.

Figure 2

Kinetics of immune response to SARS-CoV-2 infection.

Figure 3

Possible correlates of protection against SARS-CoV-2. Different isotypes of antibodies can be identified after vaccination or infection. Immunoglobulin (Ig)G and IgM are found in serum, while secretory IgA in its dimeric form is found on mucous membranes (A). Antibodies can target either the spike or other viral proteins, e.g., the nucleoprotein (B). Effect of antibodies can either be direct, mediated through the fragment antigen binding (Fab) part of the antibody (C) or indirect, mediated by the fragment crystallizable (Fc) part (D). The latter includes complement-dependent cytotoxicity (CDC), antibody dependent cell-mediated cytotoxicity antibodies (ADCC) and antibody-dependent phagocytosis (ADP). Cellular immune responses can be divided in CD4+ and CD8+ T-cell responses (E). Correlates of protection may differ in infection and vaccination, maybe even between different types of vaccines. Graphic created at biorender.com including adapted template from Daniela Rothschild Rodriguez.