Abstract
Novel corona virus caused pneumonia first reported in December, 2019 in Wuhan, China was later named COVID-19. Due to its special pathogenicity, COVID-19 transmitted with high speed beyond borders and has significantly affected normal life. Currently, no specific drugs, treatment or vaccines are available. Vaccine development for COVID-19 is a highly complex process involving viral genomic studies, identification of target for vaccine, vaccine design, manufacturing, storage and distribution, preclinical and clinical safety and efficacy studies. The high levels of efforts and global collaboration at this scale is unprecedented. The World Health Organization (WHO) has documented 160 different COVID-19 vaccine candidates as of July 13, 2020 with 26 currently on clinical evaluation while 137 vaccines on preclinical evaluation. COVID-19 vaccine efforts mark the first use of mRNA-type vaccines ever evaluated. Numerous research organizations have successfully initiated clinical evaluation of COVID-19 vaccines. This review aims to summarize the advances and challenges for COVID-19 vaccines development.
Keywords: COVID-19, Vaccine development, RNA and DNA vaccine
To the editor,
On December 31, 2019, novel corona virus caused pneumonia was first reported in Wuhan, China. The pathogen was soon identified as a novel corona virus from unknown origin and then was named as “corona virus of 2019” or “COVID-19”. With a rapid spread of the virus, WHO declared a global pandemic on March 11, 2020. According to WHO, as of July 14, 2020, almost all countries in the world have been affected with 12,768,307 confirmed cases and 566,654 confirmed deaths due to COVID-19 (https://covid19.who.int/). Its highly infectious and asymptomatic transmission characteristics have made it to a pandemic in a short time [1]. Vaccines are an essential countermeasure urgently needed to control the pandemic.
2-dimension and 3-dimension studies demonstrated COVID-19 virus as RNA stranded virus, surrounded by membrane (M) protein, envelope (E) protein, and the spike (S) structural protein. Genome of virus is highly packed inside nucleocapsid (N) protein which is enveloped by M, E and S protein [2]. Five nonstructural proteins including ORF1ab, ORF3a, ORF7, ORF8, ORF9 and ORF10 play a critical rule in adhesion of virus to host cell and can compromise vaccine efficacy [3]. SARS-CoV-2 shares genetic homology with other coronaviruses found in bats and its closest related human virus, SARS-CoV-1. The spike protein of SARS-CoV-2 has high identity with that of SARS and MERS, which might indicate the similarity of immune evasion mechanism. After publication of the full RNA genetic sequence of COVID-19 from infected patients by Chinese researchers on January 10, 2020 [2], many organizations around the world started to develop vaccines, based on knowledge obtained from SARS and MERS vaccine development, by different means including inactivated whole COVID-19 virus [4–6], live attenuated virus, adenovirus-based recombinant vector RNA and DNA vaccines [Fig. 1]. As of August 24, 2020, WHO documented a total of 160 vaccine candidates against COVID-19, with 26 vaccines currently in clinical evaluation (Table 1) and 137 under pre-clinical evaluation [7]. In order to get herd immunity, an estimated 67% of population needs to be vaccinated to stop the virus spreading [8]. A vaccine targeting the Spike protein receptor-binding domain (S-RBD) of SARS-CoV-2 induces protective immunity [9] in phase II/III human evaluation, after safety and efficacy results in rhesus macaque [10]. Meanwhile, the Ad5 vectored COVID-19 vaccine targeting the spike glycoprotein showed tolerability and immunogenicity at 28 days post-vaccination (NCT04313127) [11]. A few recent studies demonstrated promising results. The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles was safe, and induced significant immune responses in the majority of recipients after a single immunization (NCT04341389) [12]. Analysis of 2 randomized phase 1 and phase 2 clinical trials of inactivated vaccine showed that patients had a low rate of adverse reactions and demonstrated immunogenicity (ChiCTR2000031809) [13]. Phase 1/2 single-blind, randomised controlled trial with adenovirus vaccine that expresses the spike protein of SARS-CoV-2 in chimpanzee (ChAdOx1 nCoV-19) showed an acceptable safety profile, and homologous boosting increased antibody responses [14]. Meanwhile clinical trial of mRNA-1273 vaccine results showed vaccination of nonhuman primates induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung [15, 16]. Another mRNA-based vaccine BNT162 was initiated phase I/II trial in China (ChiCTR2000034825).
Fig. 1.
Distribution of COVID-19 vaccine types under development.
Data modified from the WHO website: https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf
Table 1.
26 candidate vaccines in clinical evaluation
| Platform | Type of candidate vaccine | Developer | Coronavirus target | Current stage of clinical evaluation/regulatory status coronavirus candidate | Estimated enrollment | Same platform for non-Coronavirus candidates | Trial start date | Estimated completion date |
|---|---|---|---|---|---|---|---|---|
| DNA | DNA plasmid vaccine with electroporation | Inovio Pharmaceuticals | INO-4800, Spike glycoprotein of SARS-CoV-2 |
Phase 1/2 |
160 120 |
multiple candidates |
June 22, 2020 April 3, 2020 |
February 22, 2022 July 2021 |
| DNA | DNA plasmid vaccine + Adjuvant | Osaka University/ AnGes/ Takara Bio | DNA vaccine (AG0301-COVID19) | Phase 1/2 NCT04463472 | 30 | June 29, 2020 | July 31, 2021 | |
| DNA | DNA plasmid vaccine | Cadila Healthcare Limited | DNA COVID-19 | Phase 1/2 CTRI/2020/07/026352 | 1048 | July 1, 2020 | N/A | |
| DNA | DNA Vaccine (GX-19) | Genexine Consortium | DNA COVID-19 | Phase 1 NCT04445389 | 210 | June 17, 2020 | June 17, 2022 | |
| Inactivated | Inactivated + alum | Sinovac | Inactivated COVID-19 virus |
Phase 3 NCT04456595 Phase 1/2 |
8870 422 744 |
SARS |
July 2020 May 20, 2020 April 16, 2020 |
October 2021 July 20, 2020 December 13, 2020 |
| Inactivated | Inactivated | Wuhan institute of Biological Products/Sinopharm | Inactivated COVID-19 virus | Phase 1/2 ChiCTR2000031809 | 1456 | April 11, 2020 | November 10, 2021 | |
| Inactivated | Inactivated | Beijing Institute of Biological Products/Sinopharm | Inactivated COVID-19 virus | Phase 1/2 ChiCTR2000032459 | 1456 | April 28, 2020 | November 28, 2021 | |
| Inactivated | Whole-Virion Inactivated | Bharat Biotech | Inactivated COVID-19 virus | Phase 1/2 CTRI/2020/07/026300 | 1125 | |||
| Inactivated | Inactivated | Institute of Medical Biology, Chinese Academy of Medical Sciences | Inactivated COVID-19 | Phase 1 NCT04412538 | 942 | May 15, 2020 | September, 2021 | |
| NonReplicating Viral Vector | ChAdOx1 | University of Oxford/AstraZeneca/Serum Institute of India | Recombinant COVID-19 (chimpanzee adenovirus vector ChAdOx1) |
Phase 3 ISRCTN89951424 Phase2b/3 EUCTR2020-001228–32-GB Phase 1/2 PACTR2020069221 |
2000 12,330 2000 |
MERS, influenza, TB, Chikungunya, Zika, MenB, plague | May 01, 2020 June 24, 2020 | July 31, 2021 December 30, 2021 |
| NonReplicating Viral Vector | Adenovirus Type 5 Vector | CanSino Biological Inc./Beijing Institute of Biotechnology | Recombinant COVID-19 (Adenovirus Vector) |
Phase 2 ChiCTR2000031781 Phase 1 ChiCTR2000030906 |
500 108 |
Ebola |
April 12, 2020 March 16, 2020 |
January 31, 2021 December 31, 2020 |
| NonReplicating Viral Vector | Adeno-based | Gamaleya Research Institute | Recombinant COVID-19 adenovirus vector |
Phase 1 |
38 38 |
June 17, 2020 | August 15, 2020 | |
| Protein | Recombinant Novel Coronavirus Vaccine (Adenovirus Vector) | Hubei Provincial CDC | Recombinant COVID-19 (Adenovirus Vector) | Phase II NCT04341389 | 508 | April 12, 2020 | January 31, 2021 | |
| Protein | Adenovirus Type 5 Vector | Hubei Provincial CDC | Recombinant COVID-19 (Adenovirus Type 5 Vector) | Phase I NCT04313127 | 108 | March 15, 2020 | December 30, 2020 | |
| Protein Subunit | Full length recombinant SARs CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M | Novavax | SARS-CoV-2 rS (COVID-19) nanoparticle | Phase 1/2 NCT04368988 | 131 | RSV; CCHF, HPV, VZV, EBOV | May 25, 2020 | July 31, 2021 |
| Protein Subunit | Native like Trimeric subunit Spike Protein vaccine | Clover Biopharmaceuticals Inc./GSK/Dynavax | Recombinant SARS-CoV-2 trimeric s protein subunit vaccine for COVID-19 | Phase 1 NCT04405908 | 150 | HIV, REV Influenza | June 19, 2020 | March 30, 2021 |
| Protein Subunit | Adjuvanted recombinant protein (RBDDimer) | Anhui Zhifei Longcom Biopharmaceutical/ Institute of Microbiology, Chinese Academy of Sciences | Adjuvanted recombinant protein (RBDDimer) (CHO Cells) | Phase 1 NCT04445194 | 50 | MERS | June 22, 2020 | September 20, 2021 |
| Protein Subunit | Recombinant spike protein with Advax™ adjuvant | Vaxine Pty Ltd/Medytox | Recombinant spike protein | Phase 1 NCT04453852 | 40 | June 30, 2020 | July 1, 2021 | |
| Protein Subunit | Molecular clamp stabilized Spike protein | University of Queensland/GSK/Dynavax | Molecular clamp stabilized Spike protein | Phase 1 ACTRN12620000674932p | 120 | Nipah, influenza, Ebola, Lassa | ||
| RNA | LNP-encapsulated mRNA | Moderna NIAID | mRNA-1273 COVID-19 |
Phase 2 NCT04405076 Phase 1 NCT04283461 |
600 120 |
multiple candidates | May 29, 2020 March 16, 2020 |
August, 2021 November 22, 2021 |
| RNA | 3 LNP-mRNAs | biotech/Fosum Pharma/Pfizer | RNA COVID-19 | Phase ½ EUCTR2020-001038–36-DE NCT04368728 |
444 32,000 |
April 20, 2020 April 29, 2020 |
January 23, 2023 | |
| RNA | LNP-nCoVsaRNA | Imperial College London | LNP-nCoVsaRNA | Phase 1 ISRCTN17072692 | 320 | EBOV; LASV, MARV, Inf (H7N9), RABV | April, 2020 | July, 2021 |
| RNA | mRNA | Curevac | mRNA Vaccine CVnCoV | Phase 1 NCT04449276 | 168 | RABV, LASV, YFV; MERS, InfA, ZIKV, DENV, NIPV | June 18, 2020 | August, 2021 |
| RNA | mRNA | People's Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech | mRNA COVID-19 | Phase 1 ChiCTR2000034112 | 168 | June 25, 2020 | December 31, 2021 | |
| RNA | mRNA | Jiangsu Provincial CDC | SARS-CoV-2 mRNA vaccine (BNT162b1) | Phase I ChiCTR2000034825 | 144 | July 20, 2020 | December 31, 2020 | |
| VLP | Plant-derived VLP adjuvanted with GSK or Dynavax adjs | Medicago Inc | Coronavirus-like particle COVID-19 | Phase 1 NCT04450004 | 180 | Flu, Rotavirus, Norovirus, West Nile virus, Cancer | July 10, 2020 | April 30, 2021 |
Data modified from the WHO website: https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf
Both live-attenuated vaccines and inactivated vaccines are highly established in product development and manufacturing process but require handling live virus. Meanwhile recombinant protein-based and vector-based vaccines are safe but require epitope selection, antigen design, and vehicle development. Some new-generation vaccine types were not produced on large scale before. RNA and DNA vaccines are two new vaccine technologies currently in focus for COVID-19 vaccine development.
Vaccine development for COVID-19 is a highly complex process involving viral genomic studies, identification of target for vaccine, vaccine design, manufacturing, storage and distribution, preclinical and clinical safety and efficacy studies. The high levels of efforts and global collaboration at this scale is unprecedented. Due to the special nature of this novel virus, vaccine development for COVID-19 seems to be very challenging. However, with the accumulation of more knowledge about the virus and the efforts of global scientific cooperation, the covid-19 vaccine will be successfully developed, and the COVID-19 pandemic will eventually be controlled.
Acknowledgements
Not Applicable
Abbreviations
- COVID-19
Corona virus 2019
- WHO
World health organization
- SARS
Severe acute respiratory syndrome
- MERS
Middle East Respiratory Syndrome
Authors’ contributions
All authors contributed to drafting and revising the article and agree to be accountable for all aspects of the work. JY approved the final manuscript. All authors read and approved the final manuscript.
Funding
This study was funded by the Key Scientific Research Project of Henan Provincial Education Department (20A320062) and Special Talents Project Fund of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. The funding bodies did not participate in study design, in data collection, analysis, and interpretation, and in writing the manuscript.
Availability of data and materials
Not Applicable.
Ethics approval and consent to participate
Not Applicable.
Consent for publication
Not Applicable.
Competing interests
The authors declare that they have no competing interests.
Footnotes
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Contributor Information
Jifeng Yu, Email: Yujifengzzu@163.com.
Jiancheng Guo, Email: gjc@zzu.edu.cn.
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Not Applicable.