MINIREVIEW: Overview of Candidate Vaccines Against Covid-19

Author: Mariateresa Coppola; Reviewers: Silvia Licciulli, Alessandro Fracassi

To date, there is no licensed vaccine against SARS-CoV-2, the virus causing the respiratory disease Covid-19 (1). Therefore, the development of SARS-CoV-2 vaccines is urgently needed. Prioritizing criteria include (2): low number of doses required to achieve immunization; potential to induce high level of neutralizing antibodies and cytotoxic cell-mediated responses; previous proven success of the strategy against other diseases; low risk of infection enhancement (caution has been raised by the immunopathology observed with SARS-CoV and MERS-CoV inactivated candidate vaccines (3-4)); fast development and capability to produce large quantities of vaccine; duration of immunity; vaccine stability (i.e. not prone to mutation); low cost per dose.
According to the most recent WHO report (5), 67 potential candidates are in a pre-clinical stage. Among the various platform technologies in the pipeline are: vaccines based on viral vectors (non-replicating viruses, n = 9, and replicating, n = 6); protein subunits (n = 24); virus-like particles (VLP, n = 3); inactivated virus (n = 3) and live attenuated virus (n = 2); nucleic acids: DNA (n = 6) and mRNA (n = 11) (5). All these approaches have advantages and disadvantages.
Viral vector-based vaccines are able to induce potent immune responses against the encoded target antigen. However, pre-existing immunity against the vector (e.g. due to repeated vaccination) could hamper immune responses (as seen for Ad5 vectors) (6). In addition, residual viral replication raises safety concerns due to the risk of adverse events (6). Although subunit proteins vaccines are generally safer, they require repeated administrations to induce long-lasting immunity (7), which together with the high production costs, hamper their transition to the clinic.
DNA and RNA-based vaccines allow a relatively simple, fully synthetic production process (6). Yet, the potential for long term persistence and genomic integration, as well as the dependence on injection devices or electroporation, represent major disadvantages of the DNA technology (6). The recently developed RNA-based vaccines, although safer due to their inability of genomic integration, are less well characterized in humans than other platforms (6).
It has recently been shown that the spike (S) protein mediates host cell invasion by both SARS-CoV and SARS-CoV-2 via binding to a receptor protein called angiotensin-converting enzyme 2 (ACE2) located on the surface membrane of host cells (8). Unsurprisingly, most of the vaccines for Covid-19 are designed to target the spike (S) protein of SARS-CoV-2 (5).

A number of clinical studies are ongoing or about to start (9). The first vaccine to enter clinical testing (mRNA-1273) was developed by the U.S. pharmaceutical company Moderna and is based on the novel lipid nanoparticle (LNP)-encapsulated mRNA technology (10). This vaccine is being tested in an open-label, dose-ranging study. Forty-five healthy volunteers will receive two intramuscular injections of the mRNA-1273 28 days apart and will be followed for up to 12 months after the second vaccination. Safety and reactogenicity are the primary endpoints, whereas immunogenicity, as measured by IgG ELISA to the 2019-nCoV S protein following the 2-dose vaccination, is the secondary objective. The end of data collection and the release of primary outcomes is scheduled for June 1st, 2021.

The second vaccine (Ad5-nCoV) was developed by the Chinese pharmaceutical company CanSino Biologics and is based on a replication-defective adenovirus. This vaccine is being evaluated in an open-label dose-escalation trial testing safety, tolerance and both humoral and cell-mediated immunogenicity in 108 healthy adults (11). Results will be shared six months after the trial is completed.

After the release of the latest WHO report, more studies evaluating different Covid-19 vaccine candidates have been registered in clinicaltrials.gov. Two of these clinical trials, sponsored and run by the Shenzhen Geno-Immune Medical Institute in China, are investigating the safety and efficacy of artificial antigen presenting cells (aAPC) (12) and dendritic cells (DCs) (13) modified by lentiviral viral vectors expressing SARS-CoV-2 viral proteins and immune modulatory genes. The primary end-results assessed in 100 healthy volunteers are expected in July 2023.

A phase I/II multicenter study, sponsored by the University of Oxford, will soon begin recruitment of 510 healthy adult volunteers (14). This clinical trial aims to determine the efficacy, safety and immunogenicity of the candidate vaccine ChAdOx1 nCoV-19 based on an adenovirus vaccine vector. The vaccine will be administered in single or double doses intramuscularly. Results of this study are expected by May 2021.

A phase I clinical study dosed the first patient at the beginning of April to test safety and immunogenicity of a synthetic DNA vaccine developed by Inovio Pharmaceuticals in collaboration with The Wistar Institute in Philadelphia (15). The study, conducted by the University of Pennsylvania, will enrol up to 40 healthy volunteers who will receive two doses of the vaccine four weeks apart. Results are expected by late summer.

Symvivo Corporation developed an oral Covid-19 vaccine approach based on delivery of genetically modified probiotic bacteria that, after colonizing the gut, secrete and deliver to intestinal epithelial cells plasmid DNA encoding for SARS-CoV-2 spike protein. This vaccine is being tested on 84 healthy participants in a Phase I trial to evaluate safety and immunogenicity (16). Results are expected by August 2021.

Although no existing vaccines, including those against other coronaviruses, can be repurposed in the context of the Covid-19 global outbreak (17), there are currently two registered clinical trials, one in the Netherlands conducted on 1500 volunteers (18) and one in Australia conducted on 4170 volunteers (19), evaluating the efficacy of Bacillus Calmette-Guérin (BCG) vaccination in protecting healthcare workers against Covid-19. The primary end-results will be released in October 2020.

Based on this preliminary overview, it is clear that the preclinical vaccine portfolio against Covid-19 is highly rich, heterogeneous and dynamic. More of these candidates will enter clinical trials in late spring/summer. Therefore, as soon as the results of these studies will be available, we should gain crucial insights on which of these candidates will be safe and effective at inducing protection against Covid-19.

Bibliography:

WHO R&D Blueprint – novel Coronavirus(nCov), Vaccine prioritization for clinical trials. Appropriate WHO Confidentiality Undertakings were signed and submitted to WHO by all participating experts. Consultation date : January 30, 2020

2019 Novel Coronavirus Global Research and Innovation Forum: Towards a Research Roadmap – Pr. Yazdan Yazdanpanah, Chair of GloPIDR

Bolles M, Deming D, Long K, Agnihothram S, Whitmore A, Ferris M, Funkhouser W, Gralinski L, Totura A, Heise M, Baric RS. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol. 2011 Dec;85(23):12201-15.

Agrawal AS, Tao X, Algaissi A, Garron T, Narayanan K, Peng BH, Couch RB, Tseng CT. Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus. Hum Vaccin Immunother. 2016 Sep;12(9):2351-6.

WHO DRAFT landscape of COVID-19 candidate vaccines – 11April2020

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Shang W, Yang Y, Rao Y, Rao X. The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines. NPJ Vaccines. 2020 Mar 6;5:18.

Liu, C.; Zhou, Q.; Li, Y.; Garner, L. V.; Watkins, S. P.; Carter, L. J.; Smoot, J.; Gregg, A. C.; Daniels, A. D.; Jervey, S.; Albaiu, D. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci. 2020, 6 (3), 315-331.

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National Institute of Allergy and Infectious Diseases (NIAID) – Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis SARS CoV-2 Infection (COVID-19) – ClinicalTrials.org

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Safety and Immunity of Covid-19 aAPC Vaccine – ClinicalTrials.gov

Immunity and Safety of Covid-19 Synthetic Minigene Vaccine – ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04276896

A Study of a Candidate COVID-19 Vaccine (COV001) – ClinicalTrials.gov

Safety, Tolerability and Immunogenicity of INO-4800 for COVID-19 in Healthy Volunteers – ClinicalTrials.gov

Evaluating the Safety, Tolerability and Immunogenicity of bacTRL-Spike Vaccine for Prevention of COVID-19 – ClinicalTrials.gov

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Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine – ClinicalTrials.gov

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