Progress and Concept for COVID‐19 Vaccine Development

Abstract

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 , 2 , 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 , 5 , 6 , 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/]. Table 1 The current status of COVID‐19 vaccine development Company Vaccine candidates Status Moderna mRNA‐1273 Phase I NCT04283461 CanSino Biologics Ad5‐nCoV Phase I ChiCTR2000030906 Inovio INO‐4800 (DNA) Phase I NCT04336410 Pfizer and BioNTech BNT162 (mRNA) Pre‐clinical Novavax Recombinant nanoparticle vaccine Pre‐clinical CureVac mRNA‐based vaccine Pre‐clinical Generex Ii‐Key peptide vaccine Pre‐clinical Vaxart Oral recombinant vaccine Pre‐clinical Imperial College London Self‐amplifying RNA vaccine Pre‐clinical Medicago Plant‐based vaccine (VLP) Pre‐clinical Takis Biotech DNA‐based vaccine Pre‐clinical J&J and BARDA AdVac and PER.C6 systems Pre‐clinical Altimmune Intranasal vaccine Pre‐clinical University of Saskatchewan Not revealed Pre‐clinical Clover and GSK S‐Trimer Research Heat Biologics gp96‐based vaccine Research CSL and University of Queensland Molecular clamp vaccine Research Sanofi Not revealed Research iBio Plant‐based vaccine Research ExpreS2ion Biotechnologies Not revealed Research EpiVax Ii‐Key peptide vaccine Research Codagenix Live attenuated vaccine Research Zydus Cadila DNA and/or live attenuated recombinant vaccine candidate Research Sinovac Formalin‐inactivated and alum‐adjuvanted candidate vaccine Research Geovax and Bravovax Modified Vaccinia Ankara virus like particles (MVA‐VLP) vaccine Research University of Oxford Chimpanzee adenovirus vaccine vector (ChAdOx1) Research Greffex Adenovirus‐based vector vaccine Research Walter Reed and USAMARIID Not revealed Research MIGAL Modified avian coronavirus vaccine Research Vaxil Bio Protein subunit COVID‐19 vaccine candidate Research AJVaccines Not revealed Research Baylor Re‐purposed SARS vaccine; S1 or RBD protein vaccine Research Institut Pasteur Not revealed Research Tonix Pharmaceuticals and Southern Research Horsepox vaccine with percutaneous administration Research Fudan University, Shanghai Jiao Tong University, and RNACure Biopharma mRNA‐based vaccine Research Arcturus Therapeutics and Duke‐NUS Self‐replicating RNA and nanoparticle non‐viral delivery system Research University of Pittsburgh Not revealed Research ImmunoPrecise Not revealed Research Peter Doherty Institute for Infection and Immunity Not revealed Research Tulane University Not revealed Research John Wiley & Sons, Ltd. This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. 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 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 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 , 24 , 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 Conflict of Interest The author declares no conflict of interest.