Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies

The emergence and rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in substantial global morbidity and mortality along with widespread social and economic disruption. SARS-CoV-2 is a betacoronavirus closely related to SARS-CoV (with ~80% sequence identity), which caused the SARS outbreak in 2002. Its next closest human coronavirus relative is Middle East respiratory syndrome-related coronavirus (MERS-CoV; ~54% sequence identity), which caused Middle East respiratory syndrome in 2012 (refs. ^1,2). SARS-CoV-2 is also genetically related to other endemic human coronaviruses that cause milder infections: HCoV-HKU1 (~52% sequence identity), HCoV-OC43 (~51%), HCoV-NL63 (~49%) and HCoV-229E (~48%)¹. SARS-CoV-2 is even more closely related to coronaviruses identified in horseshoe bats, suggesting that horseshoe bats are the primary animal reservoir with a possible intermediate transmission event in pangolins³.

Cellular entry of SARS-CoV-2 is mediated by the binding of the viral spike (S) protein to its cellular receptor, angiotensin-converting enzyme 2 (ACE2)^4,5. Other host entry factors have been identified, including neuropilin-1 (refs. ^6,7) and TMPRSS2, a transmembrane serine protease involved in S protein maturation⁴. The SARS-CoV-2 S protein consists of the S1 subunit, which contains the receptor binding domain (RBD), and the S2 subunit, which mediates membrane fusion for viral entry⁸. A major goal of vaccine and therapeutic development is to generate antibodies that prevent the entry of SARS-CoV-2 into cells by blocking either ACE2–RBD binding interactions or S-mediated membrane fusion.

One potential hurdle for antibody-based vaccines and therapeutics is the risk of exacerbating COVID-19 severity via antibody-dependent enhancement (ADE). ADE can increase the severity of multiple viral infections, including other respiratory viruses such as respiratory syncytial virus (RSV)^9,10 and measles^11,12. ADE in respiratory infections is included in a broader category named enhanced respiratory disease (ERD), which also includes non-antibody-based mechanisms such as cytokine cascades and cell-mediated immunopathology (Box 1). ADE caused by enhanced viral replication has been observed for other viruses that infect macrophages, including dengue virus^13,14 and feline infectious peritonitis virus (FIPV)¹⁵. Furthermore, ADE and ERD has been reported for SARS-CoV and MERS-CoV both in vitro and in vivo. The extent to which ADE contributes to COVID-19 immunopathology is being actively investigated.

In this Perspective, we discuss the possible mechanisms of ADE in SARS-CoV-2 and outline several risk mitigation principles for vaccines and therapeutics. We also highlight which types of studies are likely to reveal the relevance of ADE in COVID-19 disease pathology and examine how the emerging data might influence clinical interventions. Read More » “Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies”