key: cord-0861026-0k0en86w
authors: Coish, Jeremia M.; MacNeil, Adam J.
title: Out of the frying pan and into the fire? Due diligence warranted for ADE in COVID-19
date: 2020-06-24
journal: Microbes Infect
DOI: 10.1016/j.micinf.2020.06.006
sha: eaccd317803b2b6f978e7f8cf360e1b0fd7b1ee8
doc_id: 861026
cord_uid: 0k0en86w

Antibody-dependent enhancement (ADE) is an atypical immunological paradox commonly associated with dengue virus re-infection. However, various research models have demonstrated this phenomenon with other viral families, including Coronaviridae. Recently, ADE in SARS-CoV-2 has emerged as one hypothesis to explain severe clinical manifestations. Whether SARS-CoV-2 is augmented by ADE remains undetermined and has therefore garnered criticism for the improper attribution of the phenomenon to the pandemic. Thus, critical evaluation of ADE in SARS-CoV-2 vaccine development will be indispensable to avoid a global setback and the erosion of public trust.

CoV-2 has emerged as one hypothesis to explain severe clinical manifestations. Whether SARS-11

CoV-2 is augmented by ADE remains undetermined and has therefore garnered criticism for the 12 improper attribution of the phenomenon to the pandemic. Thus, critical evaluation of ADE in 13 SARS-CoV-2 vaccine development will be indispensable to avoid a global setback and the 14 erosion of public trust. appropriate concern that spans all in vitro research. However, in vitro research is a fundamental 39 pre-requisite for animal models and an ethical checkpoint. In fact, without cell culture 40 experiments exploring ADE in arboviruses, we would lack a critical understanding of the 41 fundamental molecular interactions contributing to ADE. Additionally, in vivo evidence for ADE 42

is not limited to flaviviruses and has been demonstrated in coronavirus animal models as well. 43

New Zealand white rabbits exposed to a primary single intranasal MERS-CoV infection lacked 44 neutralizing antibodies, were not protected from re-infection, and showed enhanced pulmonary 45

inflammation [16] . The investigators concluded that people exposed to MERS-CoV who fail to 46 develop neutralizing antibodies may be at an increased risk for severe lung disease. Feline infectious peritonitis, a disease caused by coronaviruses, has also been enhanced by vaccines that 48 fail to induce a robust level of protective antibodies [17] [18] [19] . ADE of SARS-CoV has also been 49 described through a novel FcγRII-dependent and ACE2-independent cell entry mechanism [20] . 50

The authors state that this warrants concern in the safety evaluation of any candidate human 51 vaccines against SARS-CoV, though their intervention did offer protection. This also illustrates 52 that ADE is not always indicative of disease pathology but raises concern for the 53 immunocompromised. It should also raise concern for the improper attribution of ADE in the 54 absence of robust demonstration in animal models, as clearly articulated by Sharma recently in, 55 "It is too soon to attribute ADE to COVID-19" [15] , which could certainly hinder the 56 development and/or uptake of any SARS vaccine. However, a double-inactivated SARS-CoV 57 vaccine has also been shown to provide incomplete protection in aged mice and induce an 58 increased eosinophilic pro-inflammatory pulmonary response [21] . A clear demonstration of the 59 importance for critically evaluating safety across demographics. 60 61 Immunization is arguably the greatest medical advance in the history of civilization. In the face 62 of the COVID-19 pandemic, a vaccine that elicits robust SARS-CoV-2-specific neutralizing 63 antibodies will be the most effective way to produce herd immunity, minimizing COVID-19-64 related deaths. We agree with Sharma [15] that improper attribution of ADE in the absence of a 65 robust demonstration in animal models would undoubtedly slow progress in the development and 66 implementation of effective vaccines against SARS-CoV-2. However, we caution that 67 fundamental cellular and molecular mechanisms are ascertained through in vitro research and 68

should not be considered extraneous to our understanding of COVID-19, but rather leveraged appropriately and in context. If there is any reason to suspect ADE from a COVID-19 vaccine, it 70 should be met with a critical eye rather than irrational exuberance for a fast-tracked vaccine 71 rollout. Dengvaxia, the first live-attenuated vaccine for DENV, was shown to protect previously 72 infected DENV children, but put DENV-naïve individuals at risk for disease [22, 23] . This later 73 

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