Vaccine-Associated Enhanced Disease and Pathogenic Human Coronaviruses

Abstract

Vaccine-associated enhanced disease (VAED) is a difficult phenomenon to define and can be confused with vaccine failure. Using studies on respiratory syncytial virus (RSV) vaccination and dengue virus infection, we highlight known and theoretical mechanisms of VAED, including antibody-dependent enhancement (ADE), antibody-enhanced disease (AED) and Th2-mediated pathology. We also critically review the literature surrounding this phenomenon in pathogenic human coronaviruses, including MERS-CoV, SARS-CoV-1 and SARS-CoV-2. Poor quality histopathological data and a lack of consistency in defining severe pathology and VAED in preclinical studies of MERS-CoV and SARS-CoV-1 vaccines in particular make it difficult to interrogate potential cases of VAED. Fortuitously, there have been only few reports of mild VAED in SARS-CoV-2 vaccination in preclinical models and no observations in their clinical use. We describe the problem areas and discuss methods to improve the characterisation of VAED in the future.

Keywords: COVID-19; SARS-CoV-2; coronavirus; enhancement; safety; vaccine; vaccine-associated enhanced disease.

Figure 1

Mechanisms of vaccine-associated enhanced disease. (A) Antibody-dependent enhancement (ADE) occurs when antibodies increase the ability of a virus to infect cells (also see Figure 2 ). (B) Antibody-enhanced disease (AED) occurs when antibodies exacerbate inflammation, resulting in pathology (also see Figure 2 ). (C) Th2-skewed responses can be pathogenic for some infections and so vaccines that induce Th2 responses in this case can cause pathology. Usually Th2 pathology is associated with eosinophil infiltration. (D) Components of vaccine formulations such as bovine serum albumin (BSA) and cellular debris can mediate pathogenic cellular responses to these components when encountered again as contaminants in the challenge material. While these components are normally removed during vaccine preparation, some preclinical studies have not included appropriate washing and centrifugation steps to facilitate this. (E) Immune complexes between viral proteins, antibodies and/or complement can lead to a build-up of deposits in blood vessels and organs or facilitate enhanced uptake of virus through myeloid cells, causing ADE. Both of these outcomes can enhance pathology. Made with BioRender.com.

Figure 2

Overview of antibody-dependent enhancement (ADE) and antibody-enhanced disease (AED). (A) Non-neutralising antibodies or sub-neutralising antibody concentrations bind to viruses and interact with Fc receptors on myeloid cells. This facilitates the internalisation of viruses. Viruses that can productively infect myeloid cells can proliferate and spread following their uptake, enhancing infection. This is a form of ADE. (B) Cross-reactive antibodies bind to both virus and host cell components, bringing viruses in close contact with their receptor. Receptor-mediated uptake and enhanced infection follows. This is another form of ADE. (C) Antibodies against a particular epitope drive a conformational change in a viral protein which enhances infection through improved binding to the host cell receptor. This is another form of ADE. (D) Antibodies bound to virus interact with Fc receptors on myeloid cells and either activate immunoreceptor tyrosine-based activation motifs (ITAMs) associated with these receptors, or facilitate viral uptake and subsequent activation of endosomal toll-like receptors (TLRs). Through either of these mechanisms, inflammatory cytokines and chemokines are produced, exacerbating inflammation to a pathogenic extent and polarising myeloid cells towards more inflammatory phenotypes. These are forms of AED. Productive infection of myeloid cells is not required for this mechanism. Created with BioRender.com.

Figure 3

How modification of the spike protein could impact neutralising activity. (A) Native spike: Antibodies are generated against a neutralising epitope on the vaccine-derived spike protein, which closely represents the neutralising epitope found on circulating virus. As a result, neutralising activity against the vaccine-derived spike corresponds to neutralisation of circulating virus. (B) Modified spike: Antibody responses may be generated against a modified epitope, which no longer represents a neutralising epitope on circulating virus. As a result, antibodies produced in response to native spike may be sub-neutralising or non-neutralising and may contribute to VAED. Spike protein structure accessed through Protein Data Bank, PBD entry 6VXX (120). Created with BioRender.com.