Authored by: OrthoEvidence

“I think there will be vaccine that will initially be available some time between November and December, but very limited supply, and it will have to be prioritized. … If you’re asking me when is it going to be generally available to the American public so we can begin to take advantage of vaccine to get back to our regular life, I think we’re probably looking at late second quarter, third quarter 2021.”

 — Dr. Robert Redfield, Director of the Centers for Disease Control and Prevention (CDC) —

Almost 10 months have passed since the initial outbreak of COVID-19 and people around the world are still suffering from the health and financial burden. Some people once put their hopes on herd immunity achieved by natural infection, but emerging evidence shows this may be a dead end (see our previous OE Original: The Sobering Story of SARS-CoV-2 Seroprevalence: What You May Have Heard About Herd Immunity). As a result, people are turning their attention to vaccines for SARS-CoV-2, which seems like the only option to reach herd immunity. 

In the United States, there are usually 6 stages in the development, testing and approval of new vaccines, including the exploratory stage, pre-clinical stage, clinical development, regulatory review and approval, manufacturing, and quality control (CDC, 2014). Vaccine development starts in the lab, which is followed by testing in animals if the lab tests show potential benefits of the vaccine. If the vaccine is found to be safe in animals and studies also predict it is safe in humans, the clinical development stage involving clinical trials with volunteers are conducted next (Food and Drug Administration (FDA), 2011).

As is the case for any drug or biologic, clinical trials for vaccines are typically done in three phases (CDC, 2014; FDA, 2018):

  • Phase I clinical trials: Usually involve 20 to 100 healthy volunteers and determine whether the vaccine is safe, whether it seems to work, whether there are serious adverse events, and doses that are safe.
  • Phase II clinical trials: Usually test vaccines on hundreds of volunteers and aim to determine the most frequent short-term adverse effects and how subjects’ immune systems respond to the vaccine.
  • Phase III clinical trials: Involve thousands of participants and focus on the efficacy and safety of the vaccine. 

The results obtained from phase III trials, together with the evidence from the phase I and II trials, will be considered by the regulatory bodies (e.g., FDA) for clinical or public health use. When the regulatory body is convinced that the vaccine is efficacious and safe, and that the benefits outweigh the harms or risks, it will approve and license the vaccine. Many vaccines will also undergo phase IV studies after approval, which mainly aim to monitor the safety of the vaccine in large populations and determine the effectiveness of the vaccine in real world settings (as opposed to a clinical trial setting) (Smith et al., 2015).

Generally speaking, the development, testing, and approval process of new vaccines can take years and this process comes without the guarantee of success. However, due to the urgent need, there is now growing advocacy for rapid or fast-track development, testing, and approval of a vaccine for COVID-19. On August 31, 2020, the director of the FDA said he was willing to fast-track the normal approval process to authorize the use of a COVID-19 vaccine as soon as possible. To be specific, the FDA would consider the authorization of a vaccine before the completion of phase III clinical trials as long as they believe the benefits outweigh the risks (Source: Financial Times). On September 16, when testified before a Senate Appropriations subcommittee, Dr. Robert Redfield, the director of the CDC, was also optimistic about identifying an effective vaccine by the end of 2020. However, he predicted that such vaccines would not be available to general public until “late second quarter, third quarter 2021.”

In this OE Original, we will review the development and testing of COVID-19 vaccines and follow some high-profile vaccines that are currently being tested in phase III trials. 

COVID-19 Vaccines at the Stage of Phase III Trials by Vaccine Type

Vaccines can be classified into 6 types: nucleic acid-based vaccines, recombinant viral-vectored vaccines, inactivated virus, live attenuated virus, protein subunit, and virus-like particles (Jeyanathan et al., 2020). In this section, we provide information about vaccines against COVID-19 which have entered phase III clinical trials by their types. Currently, no COVID-19 vaccines based on protein subunit or virus-like particles have been investigated in phase III trials. 

1. Nucleic acid-based vaccines (mRNA vaccines)

An mRNA vaccine is a type of nucleic acid-based vaccine which is synthesized by in vitro transcription without involving any microbial molecules. It is non-infectious compared to other types of vaccines that contain viral components such as live attenuated and inactivated viral vaccines (Pardi et al., 2018). Different from DNA vaccines, which have been explored for years, mRNA vaccines have been gaining our attention only in recent years, despite the fact that no mRNA vaccines have been licensed for use in humans (Jeyanathan et al., 2020). However, in animal models, mRNA vaccines against pathogens such as influenza and Zika virus have shown beneficial effects (Chahal et al., 2017; Petsch et al., 2012).

1.1 BNT162b2

BNT162b, sponsored by BioNTech, Pfizer, and Fosun Pharma, belongs to the mRNA vaccine class. It consists of 2 candidates: BNT162b1 and 2. BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor-binding domain and has completed testing in mice (Laczko et al., 2020) and initial testing in humans (Mulligan et al., 2020). Results from the human trial showed that BNT162b1 was safe and could yield high neutralizing antibody titers (Mulligan et al., 2020). 

However, BNT162b2, which encodes a prefusion stabilized membrane-anchored SARS-CoV-2 full-length spike, showed significantly less systemic reactogenicity, such as fevers and fatigue, compared to BNT162b1 (Walsh et al., 2020). Therefore, BNT162b2 has been selected for phase III trials (NCT Identifier: NCT04368728). The results could be available as soon as October 2020, according to Pfizer (Source: New York Times).

1.2 mRNA-1273

Another mRNA vaccine is sponsored by Moderna Therapeutics and the National Institutes of Health (NIH). Results from phase I trials have shown that the mRNA-1273 vaccine could induce anti-SARS-CoV-2 immune responses with no trial-limiting safety concerns (Jackson et al., 2020). mRNA-1273 is currently being investigated in phase II (NCT Identifier: NCT04405076) and III trials (NCT Identifier: NCT04470427). 

2. Recombinant viral-vectored vaccines

Recombinant viral-vectored vaccines, bioengineered to express antigens of the target pathogen, are built on either an attenuated replication-competent viral backbone or a replication-deficient viral backbone (Jeyanathan et al., 2020). A number of recombinant viral-vectored vaccines have been explored in order to prevent infection caused by pathogens like Ebola virus (Humphreys et al., 2018). 

2.1 ChAdOx1 nCoV-19 (AZD-1222)

ChAdOx1 nCoV-19 is sponsored by AstraZeneca and the University of Oxford. The vaccine was built using the backbone of chimpanzee-derived adenovirus. It is so far the most clinically advanced vaccine candidate against COVID-19 in terms of clinical development (Jeyanathan et al., 2020). The phase I/II study showed that ChAdOx1 nCoV-19 induced neutralizing antibodies in over 90% of the research participants (Folegatti et al., 2020). However, a serious adverse event (transverse myelitis) was found in one volunteer which led to the pause of global trials on September 6. Shortly after on September 12, the British and Brazilian trials resumed (Identifier: EudraCT 2020-001228-32). 

2.2 Ad5-nCoV 

Sponsored by CanSino Biologics, Ad5-nCoV is a recombinant viral-vectored vaccine built on the backbone of Ad5, a human serotype 5 adenovirus. The phase II trial revealed that Ad5-nCoV is safe and could induce significant neutralising antibody responses in the majority of volunteers after a single immunisation (Zhu et al., 2020). A global phase III clinical trial to evaluate the efficacy and safety of Ad5-nCoV is ongoing (NCT Identifier: NCT04526990).

3. Live attenuated viral vaccines

Live attenuated viral vaccines are obtained from attenuated virus strains by mutating or deleting virulence genes, which allows the mutant to replicate to a limited extent without causing disease in hosts (Plotkin, 2014). Live attenuated vaccines can be applied to coronaviruses, which have genes that can be deleted, leading to attenuation. It is possible however, that the attenuated viruses can revert themselves genetically and regain their ability to cause disease (Jeyanathan et al., 2020). The risk that coronaviruses might recombine with wild strains to generate a pathogenic strain exists (Tao et al., 2017).

3.1 The Bacillus Calmette-Guerin (BCG) vaccine

BCG, based on the attenuated strains of the actual pathogen, is currently used for the prevention of tuberculosis (Plotkin, 2014). BCG has been shown to reduce the incidence of respiratory syncytial virus infection (Ohrui et al., 2005; Stensballe et al., 2005). It has been proposed that the induction of the non-specific immunity by BCG may have a protective effect against COVID-19 (O’Neill et al., 2020). Several phase III clinical trials have been ongoing, for example, NCT04328441NCT04327206, and EudraCT 2020-001783-28.

4. Inactivated vaccines

Inactivated vaccines, derived from physically or chemically inactivated viruses, have the potential of being rapidly generated and scaled up in a pandemic situation with the existing technology and infrastructure used for viruses like the influenza virus (Wood et al., 2004). Compared to live attenuated viral vaccines, inactivated vaccines have fewer safety concerns.

4.1 PiCoVacc

PiCoVacc, also called Corona Vac, is sponsored by Sinovac Biotech. The vaccine was first tested in mice, rats, and nonhuman primates and induced SARS-CoV-2-specific neutralizing antibodies (Gao et al., 2020). Results from the phase II trial showed that PiCoVacc was safe and could induce immune responses in more than 90% of the participants (Zhang et al., 2020). The phase III trials have been approved in countries such as Brazil and Indonesia (NCT Identifier: NCT04456595).

4.2 BBIBP-CorV

BBIBP-CorV is developed by Sinopharma. Phase I/II trials showed that BBIBP-CorV was well tolerated and induced neutralizing antibodies in volunteers (Xia et al., 2020). The phase III trials have been initiated in countries like Morocco, Peru, and the United Arab Emirates (Identifier: ChiCTR2000034780). Sinopharma is also developing a second COVID-19 inactivated vaccine, which has been under phase III trials in China and the United Arab Emirates.


Compared to the conventional vaccine development, which usually follows a linear sequence of steps and takes 10 to 15 years, vaccine development amid a pandemic requires us to significantly compress the time frame, with preclinical, clinical, and manufacturing processes overlapping and happening in parallel (Lurie et al., 2020). It took about 5 years for the first Ebola vaccine to be qualified by the World Health Organization (WHO) (Le et al., 2020). However, it is proposed that COVID-19 vaccines should be available for emergency use in early 2021 (Source: U.S. Department of Health & Human Services), which only leaves us several months to qualify a vaccine. To meet this expectation, fundamental changes have to be made to the development, testing, and approval process of COVID-19 vaccines. We must be cautious about sacrificing safety for speed as mass vaccination with an unsafe vaccine could result in a public health disaster. 

Currently, researchers and industries have developed over 150 vaccine candidates of various vaccine types, and about 8 of them have been tested in phase III clinical trials. These vaccine types have their own immunological advantages and disadvantages. For instance, mRNA vaccines are considered safer for patients relative to vaccines derived from live attenuated viruses because mRNA vaccines do not involve any viral molecules during synthesis. However, mRNA vaccines require repeated vaccination in order to induce the immune response, while live attenuated viral vaccines only need single delivery (Jeyanathan et al., 2020). 

It is far from certain which type of vaccines or which vaccine strategy will eventually succeed in the prevention of COVID-19. We should be aware that the vaccine development for COVID-19 is an evolving process that will continue for years to come. It is necessary and essential for us to explore each and every possibility, stay up to date with new, fast accumulating knowledge on COVID-19, and prioritize the vaccine strategy of greatest promise in future. 

Even if a vaccine is proven to be efficacious and safe, there are still many challenges that lie ahead such as large-scale production and who can access the vaccine. As stated in Bill Gates’ recent report, the pandemic won’t stop unless we deliver vaccines “equitably to those who need them most, no matter where they live or how much money they have”.


Centers for Disease Control and Prevention (CDC). (2014). Vaccine Testing and the Approval Process.   Retrieved from

Chahal, J. S., et al. (2017). An RNA nanoparticle vaccine against Zika virus elicits antibody and CD8+ T cell responses in a mouse model. Sci Rep, 7(1), 252. doi:10.1038/s41598-017-00193-w

Folegatti, P. M., et al. (2020). Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. The Lancet, 396(10249), 467-478. doi:10.1016/S0140-6736(20)31604-4

Food and Drug Administration (FDA). (2011). Ensuring the Safety of Vaccines in the United States.   Retrieved from,%20blood%20&%20biologics/published/Ensuring-the-Safety-of-Vaccines-in-the-United-States.pdf

Food and Drug Administration (FDA). (2018). Vaccine Product Approval Process.   Retrieved from

Gao, Q., et al. (2020). Development of an inactivated vaccine candidate for SARS-CoV-2. Science, 369(6499), 77. doi:10.1126/science.abc1932

Hobernik, D., et al. (2018). DNA Vaccines-How Far From Clinical Use? International journal of molecular sciences, 19(11), 3605. doi:10.3390/ijms19113605

Humphreys, I. R., et al. (2018). Novel viral vectors in infectious diseases. Immunology, 153(1), 1-9. doi:10.1111/imm.12829

Jackson, L. A., et al. (2020). An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. New England Journal of Medicine. doi:10.1056/NEJMoa2022483

Jeyanathan, M., et al. (2020). Immunological considerations for COVID-19 vaccine strategies. Nature Reviews Immunology. doi:10.1038/s41577-020-00434-6

Laczko, D., et al. (2020). A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice. Immunity. doi:10.1016/j.immuni.2020.07.019

Le, T. T., et al. (2020). Evolution of the COVID-19 vaccine development landscape. Nat Rev Drug Discov. doi:10.1038/d41573-020-00151-8

Lurie, N., et al. (2020). Developing Covid-19 Vaccines at Pandemic Speed. New England Journal of Medicine, 382(21), 1969-1973. doi:10.1056/NEJMp2005630

Mulligan, M. J., et al. (2020). Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. doi:10.1038/s41586-020-2639-4

O’Neill, L. A. J., et al. (2020). BCG-induced trained immunity: can it offer protection against COVID-19? Nature Reviews Immunology, 20(6), 335-337. doi:10.1038/s41577-020-0337-y

Ohrui, T., et al. (2005). [Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations]. Nihon Ronen Igakkai Zasshi, 42(1), 34-36. doi:10.3143/geriatrics.42.34

Pardi, N., et al. (2018). mRNA vaccines – a new era in vaccinology. Nat Rev Drug Discov, 17(4), 261-279. doi:10.1038/nrd.2017.243

Petsch, B., et al. (2012). Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol, 30(12), 1210-1216. doi:10.1038/nbt.2436

Plotkin, S. (2014). History of vaccination. Proceedings of the National Academy of Sciences of the United States of America, 111(34), 12283-12287. doi:10.1073/pnas.1400472111

Smith, P., et al. (2015). Chapter 22, Phase IV studies Field Trials of Health Interventions: A Toolbox, 3rd edition. Oxford (UK): OUP Oxford.

Stensballe, L. G., et al. (2005). Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls community based case-control study. Vaccine, 23(10), 1251-1257. doi:10.1016/j.vaccine.2004.09.006

Tao, Y., et al. (2017). Surveillance of Bat Coronaviruses in Kenya Identifies Relatives of Human Coronaviruses NL63 and 229E and Their Recombination History. Journal of virology, 91(5), e01953-01916. doi:10.1128/JVI.01953-16

Walsh, E. E., et al. (2020). RNA-Based COVID-19 Vaccine BNT162b2 Selected for a Pivotal Efficacy Study. medRxiv, 2020.2008.2017.20176651. doi:10.1101/2020.08.17.20176651

Wood, J. M., et al. (2004). From lethal virus to life-saving vaccine: developing inactivated vaccines for pandemic influenza. Nature Reviews Microbiology, 2(10), 842-847. doi:10.1038/nrmicro979

Xia, S., et al. (2020). Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA, 324(10), 951-960. doi:10.1001/jama.2020.15543

Zhang, Y.-J., et al. (2020). Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine in Healthy Adults Aged 18-59 years: Report of the Randomized, Double-blind, and Placebo-controlled Phase 2 Clinical Trial. medRxiv, 2020.2007.2031.20161216. doi:10.1101/2020.07.31.20161216

Zhu, F.-C., et al. (2020). Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet, 396(10249), 479-488. doi:10.1016/S0140-6736(20)31605-6