Theoretical Explanation for the Rarity of Antibody-Dependent Enhancement of Infection (ADE) in COVID-19

Abstract

Global vaccination against the SARS-CoV-2 virus has proved to be highly effective. However, the possibility of antibody-dependent enhancement of infection (ADE) upon vaccination remains underinvestigated. Here, we aimed to theoretically determine conditions for the occurrence of ADE in COVID-19. We developed a series of mathematical models of antibody response: model Ab—a model of antibody formation; model Cv—a model of infection spread in the body; and a complete model, which combines the two others. The models describe experimental data on SARS-CoV and SARS-CoV-2 infections in humans and cell cultures, including viral load dynamics, seroconversion times and antibody concentration kinetics. The modelling revealed that a significant proportion of macrophages can become infected only if they bind antibodies with high probability. Thus, a high probability of macrophage infection and a sufficient amount of pre-existing antibodies are necessary for the development of ADE in SARS-CoV-2 infection. However, from the point of view of the dynamics of pneumocyte infection, the two cases where the body has a high concentration of preexisting antibodies and a high probability of macrophage infection and where there is a low concentration of antibodies in the body and no macrophage infection are indistinguishable. This conclusion could explain the lack of confirmed ADE cases for COVID-19.

Transfusion reactions associated with COVID‐19 convalescent plasma in outpatient clinical trials

“…SARS‐CoV‐2 vaccines that elicit antibody responses to SARS‐CoV‐2 have also not enhanced disease 24 . Our studies indicate that antibody disease enhancement is not a clinically relevant phenomenon with passive SARS‐CoV‐2 antibody therapy, which supports other observations on a population scale which also did not evidence enhancement of clinical disease progression 25,26 …”

“…24 Our studies indicate that antibody disease enhancement is not a clinically relevant phenomenon with passive SARS-CoV-2 antibody therapy, which supports other observations on a population scale which also did not evidence enhancement of clinical disease progression. 25,26 We noted no difference in adverse reactions between those receiving CCP and control plasma. This observation is reassuring since the administration of CCP to SARS-CoV-2 infected individuals has the potential to form antigen-antibody complexes that can trigger type III hypersensitivity reactions through crosslinking and engaging Fc receptors.…”

Pathways to altered virulence of SARS-CoV-2

“…Further, a broad meta-analysis of clinical reports of post-immune infection points to a lack of population-level ADE effects for SARS-CoV-2 vaccinal and natural immunity (120). As ADE effects in some cases may be observed only under very specific circumstances (e.g., with particular concentrations of antibodies (121) or a narrow range of binding potencies (122)) the lack of an observed ADE effect at present does not definitively preclude ADE in subpopulations or for future variants of the virus. This is particularly noteworthy in the context of recent findings that show that the viral spike protein is undergoing strong natural selection for the evasion of antibody neutralization activity, but not binding (123,124).…”