The recent outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), previously known by the provisional name 2019 novel coronavirus (2019‐nCoV), in the city of Wuhan in China's Hubei province in 2019–2020 has been causing significant numbers of mortality and morbility in humans with the coronavirus infection diseases (COVID‐19) with fever, severe respiratory illness, and pneumonia.^[1-3^] Till April 8, 2020, there have been over 1 431 973 confirmed cases globally, leading to at least 82 085 deaths. These SARS‐CoV‐2 isolates belong to the Betacoronavirus genus of the Coronaviradae family which is an enveloped single‐stranded RNA virus containing a 30 kb genome with 14 open reading frames including four major viral structure proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins.^[4-7^] The S gene sequences of SARS‐CoV‐2 isolates have a 93.1% nucleotide sequence identity to the Rhinolophus affinis bat coronavirus RaTG13, but only less than 75% nucleotide sequence identity to the severe acute respiratory syndrome coronavirus (SARS‐CoV). The viral S sequences of SARS‐CoV‐2 compared to SARS‐CoV have three additional short insertions in the N‐terminal domain, and four out of five key residues changes in the receptor‐binding motif of S protein receptor binding domain (RBD).^[6, 7^] Although both SARS‐CoV‐2 and SARS‐CoV share the same human cellular receptor‐angiotensin converting enzyme II, SARS‐CoV‐2 appears to be more readily transmitted from human to human.^[1, 8, 9^]

The S protein is the major target for COVID‐19 vaccine development, mainly based on the elicitation of virus neutralizing antibodies as the immune correlates to vaccine protection. The current status of COVID‐19 vaccine development includes, i) three phase I vaccine candidates, ii) 11 preclinical vaccine candidates, and iii) 26 research‐stage vaccine candidates (Table  1; [https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker?feed=Regulatory-Focus?utm_source=Facebook&utm_medium=social&utm_campaign=Regulatory-Focus]). Most of these vaccine candidates are based on the S antigen either as inactivated vaccines, subunit vaccines, viral vectored vaccines, and nucleic acid‐based DNA or mRNA vaccines. Among these vaccine candidates, the Coalition for Epidemic Preparedness Innovations (CEPI) has provided funding to develop COVID‐19 vaccines using the following platform technology: a) Curevac Inc. (mRNA), b) Inovio Pharmaceuticals Inc. (DNA), c) Moderna, Inc. (mRNA), d) University of Queensland (molecular clam), e) Novavax (nanoparticles), f) University of Oxford (adenovirus vector), g) University of Hong Kong (live‐attenuated influenza virus), and h) Institute of Pasteur (measles vector) to accelerate the development of vaccines and enable equitable access to these vaccines for people during outbreaks [https://cepi.net/covid-19/].

To date, many previous studies of SARS‐CoV, Middle East respiratory syndrome‐related coronavirus (MERS‐CoV), and other coronavirus vaccines revealed several safety concerns associated with the use of coronavirus S‐based vaccines, including inflammatory and immunopathological effects such as pulmonary eosinophilic infiltration and antibody‐dependent disease enhancement (ADE) following subsequent viral challenge of vaccinated animals.^[10-21^] The anti‐S antibodies for ADE may facilitate uptake by macrophage expressing FcR, leading to macrophage stimulation and the production of proinflammatory cytokines (IL‐6, IL‐8, and MCP1) and loss of tissue‐repaired cytokine (TGFβ).^[22^] Moreover, the Th2‐associated immunopathology has been documented for the inactivated vaccines of respiratory syncytial virus after viral challenge^[23-25^] and the inactivated vaccines of MERS‐CoV after virus challenge.^[20^] Thus, the safety and the potentially harmful responses in vaccines to develop ADE antibodies against any coronaviruses should be carefully assessed in human trials.^[26^] It has been proposed that the neutralizing epitope‐rich S1 region, or the RBD region, instead of the entire full‐length S protein as an alternative target for MERS‐CoV vaccine development.^[27^] Whether the use of S1 or RBD antigen of SARS‐CoV‐2, or the selection of Th1‐skewed adjuvants rather than alum adjuvant, can avoid the inflammatory, immunopathological, and ADE effects, requires further studies from animal models and human trials. These findings are particularly important for developing a safe and effective COVID‐19 vaccine.

Suh‐Chin Wu