Coronavirus disease 2019 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first reported in December 2019, in Wuhan, province of Hubei in China. Since then, it has become one of the world’s toughest health problems. The World Health Organization (WHO) announced on January 30, 2020 that the COVID-19 epidemic was a public health emergency of international concern and on March 20, 2020, that it was a pandemic.1 As of January 24, 2021, more than 97 million cases of COVID-19 have been reported worldwide, causing more than 2 million deaths.2 In just a few months, huge efforts have been made and several vaccines are in development.
This review summarizes COVID-19 vaccines clinical trials in phase III and IV and all published clinical trials’ results.
A review of the scientific literature was conducted with the aim to study the therapeutic trials of vaccines against the coronavirus disease 2019 (COVID-19). To this end, as of January 24, 2021 a search for articles published on PubMed using the Mesh word “COVID-19 Vaccine”, as well as a search for protocols registered on ClinicalTrials.gov by combining the words “COVID-19”, “SARS-CoV-2” and “Vaccine” was made. The published WHO reports on candidate COVID-19 vaccines were reviewed. At first, citations that were not in French or in English and not a clinical trial or randomized controlled trial were excluded. Then, those with irrelevant information or subject and studies with focus other than COVID-19 vaccine development or clinical trial were excluded. For registered protocols, those in relation with drugs were excluded.
Included citations in the COVID-19 vaccine therapeutic trials review
On PubMed, 1227 articles were initially found, out of which 16 articles were selected. In the end, 14 articles were selected. On ClinicalTrials.gov, as of January 24, 2021, 72 phase III or IV, clinical trial protocols, encompassing vaccines and treatments have been identified initially, of which 66 for COVID-19 vaccines have been selected (Figure 1).
WHO COVID-19 vaccine report as of January 24, 2021
According to the WHO COVID-19 vaccine report of January 22, 2021, there were 237 vaccines. More specifically, 64 vaccines were in clinical evaluation (16 in phase III, 6 in phase II / III, 5 in phase II, 19 in phase I / II and 18 in phase I) and 173 vaccines were in preclinical evaluation.3
Phase III and IV clinical trials
New COVID-19 Vaccines
Most of the candidate COVID-19 vaccines are based on the S antigen in the form of inactivated vaccines, subunit vaccines, viral vector vaccines, and DNA or mRNA 3 nucleic acid vaccines.5
In this review, the focus will be on clinical trials for vaccines in phase III and above.
For the new candidates COVID-19 vaccines, there were 37 clinical trials on Phase III, of which one clinical trial was simultaneously in phase I/II/III and eight in phase II/III. Eleven (30%) clinical trials concerned inactivated vaccines and 30 (81%) clinical trials used two doses. Six clinical trials were active and not recruiting while 23 were still recruiting participants. The number of participants to be recruited varied from 100 to 60,000 (Table 1).
Other vaccines to fight COVID-19
With the hypothesis that the measles vaccine could reduce the incidence of COVID-19, as of January 24, 2021, there were three clinical trials, in phase III, using this vaccine in the fight against infection with SARS-CoV-2:
An international clinical trial (NCT04333732), randomized, double-blind, placebo-controlled, in healthcare workers at risk of contracting COVID-19 (N = 30 000) and aged 18 years and older. These are randomly assigned to cohorts of placebo vaccine and MMR or MR vaccine. The estimated end of study date is August 2021.43
A randomized, single-blinded, placebo-controlled clinical trial in New Orleans (NCT04475081), recruiting healthy healthcare workers (N=60) aged 18 to 70 years. They are randomly assigned to cohorts of placebo vaccine and MMR vaccine. The estimated end of study date is December 1st, 2021.44
A randomized clinical trial in Egypt (NCT04357028), single-blind, placebo-controlled, recruiting healthy healthcare workers (N = 200) and aged between 18 and 50 years. Participants are randomly assigned to cohorts of placebo vaccine and MMR vaccine. The estimated end of study date was November 1st, 2020, but the clinical trial was suspended due to failure of subject recruitment.45
Both polio and coronavirus are positive strand RNA viruses, it is likely that they can induce common innate immune mechanisms. There were three clinical trials:
A randomized clinical trial in Guinea-Bissau (NCT04445428), double-blind and in phase IV, evaluating the effect of the administration of the oral polio vaccine (OPV) compared to the absence of vaccine in 3400 people, aged over 50 years and recruited by invitation. The objective of the trial is to test the hypothesis that OPV reduces the combined risk of admission or death from morbidity by at least 28% over the next six months. The estimated end of this study date is December 2021.46
A Phase IV clinical trial in United States (NCT04639375), evaluating whether an immune response to SARS-CoV 2 RdRp is induced in adults after receiving a booster inoculation of IPV. The number of participants is estimated at 25 healthy volunteers aged between 18 and 80 years old. All participants will receive one IPV by injection. The estimated end of this study date is January 15, 2021.47
A randomized, multi-center, phase III, clinical trial in the United States and New Zealand (NCT04540185), evaluating the safety and efficacy of OPV with and without NA-831 versus to placebo. The number of participants is estimated at 3600, aged over 18 years, in good health and recruited by invitation.48
Hypotheses have been made that the tuberculosis vaccine (BCG) may induce partial protection against the severity of infection with SARS-CoV-2. In this context, as of January 24, 2021, there were 23 clinical trials using the BCG vaccine, including six in phase IV.49–54 Four (17%) clinical trials were active and not recruiting,49,55–57 while the Colombian clinical trial was withdrawn due to the lack of sponsorship.58 The number of recruits ranged from 59 to 10 078 (Table 2).
Published clinical trials’ results
As of January 24, 2021, there was 13 clinical trials’ published results in different phases, of which six were in phase I/II59–64 and four had a number of participants less than 100.60,64–66 Only two clinical trials had a non-randomized trial.60,67 All studies concerned healthy adults aged 18 years and over. In general, local and systemic reactions if present, were described as mild to moderate and consisted in injection site pain, fever, myalgia, headache and fatigue (Table 3).
At this time, there is no determination as to whether a vaccine candidate will be universal or indicated for specific populations, or how many doses will be needed, or the likely presentations.68
Since the emergence of SARS-CoV-2, the scientific community has been committed to identifying a therapeutic approach as well as a vaccine that is both effective and safe to achieve the goal of reducing morbidity and mortality attributable to COVID-19.
This review is a recent synthesis of clinical trials and published protocols regarding COVID-19 vaccination.
In total, as of January 24, 2021, there were 37 phase III clinical trials involving new candidates for the COVID-19 vaccine. The number of subjects required to be included in these trials varied between 100 and 60 000. The criteria for non-inclusion and exclusion in these phase clinical trials III were mainly children and pregnant women: none of the protocols of these trials concerned pregnant women and almost all of them didn’t include persons aged less than 18 years, except for the multinational BioNTech SE/Pfizer’s clinical trial where they included healthy individuals aged 12 years and over for their phase II/III.6 and ModernaTX’s clinical trial including healthy adolescents aged 12 to 17 years.30 AstraZenaca’s clinical trial in Russia was suspended due the occurrence of suspected unexpected serious adverse reaction at University of Oxford sponsored study, and will continue to be on hold until the approval on the Russian Ministry of health.42
Under the hypothesis that certain other vaccines can strengthen innate immunity, thus making it possible to induce a decrease in infection by SARS CoV2, several other phase III and IV clinical trials have been launched such as BCG vaccine (n=23), measles vaccines (n=3) and polio vaccines (n=3). At the time of writing this review, there was no publication of the results of these clinical trials.
All published clinical trials’ results concerning the safety and immunogenicity of the vaccine were phases I/II and II/III with promising results concerning these two criteria. Having multiples vaccines candidates could be an advantage. In fact, in case one of them fails, there is still others under development. However, the majority of the published clinical trials’ results involved a small proportion of participants, in addition to the accelerated process of COVID-19 vaccines development, these could mask some side-effects. Moreover, this rush in the manufacturing process might lead to the production of a vaccine with limited effectiveness and therefore provide immunity, complete or incomplete, only to some vaccinated individuals.87 Furthermore, published clinical trials’ results involved only healthy individuals and few elderly. Even though the more vulnerable individuals, such as the elderly and those with co-morbidities would have priority for vaccines, the vaccine effectiveness and side effects are unknow in this group.87
Despite the progress made and the promising results of clinical trials of candidate vaccines, many obstacles and difficulties must be considered, in particular the logistical difficulties surrounding the mass production and the delivery of millions or even billions of doses to the world population, which will represent probably the biggest current challenge. Note that other constraints related to certain types of vaccines, such as mRNAs which are quite unstable at room temperature, requiring storage in freezers.88 Indeed almost all the new COVID-19 vaccines mentioned require cold storage with different requirements. The distribution of these vaccines then assumes a need for the cooperation of government and companies for cold storage and global transport. The Pfizer vaccine should be stored at a temperature of minus 70 °C ± 10 °C,89,90 the frozen Gam-COVID- vaccine (Sputnik V) requires a storage temperature of minus 18 °C, while its lyophilized formulation should be stored at a temperature of 2 to 8 °C.60 Furthermore, despite the rapid development and production of vaccines, their distribution to the most vulnerable and deprived populations and in the poorest countries remains the major issue requiring to help these groups and countries in order to benefit from the necessary and efficient logistics allowing to end this pandemic.
COVID-19 vaccine development continues at unprecedented speed, but it’s uncertain that there would be enough production in 2021. New waves of SARS-CoV-2 infections are likely to occur, therefore, we will have to continue preventive measures such as social distancing, mask wearing and hand hygiene.
We would like to thank WHO Tunisia Office for their financial support to the open access fees of this article.
MO performed the literature search and drafted the manuscript.
MS was responsible for the redaction and revision of the manuscript, and developed the methodology with MO.
AH and HL selected the clinical trials for new candidates COVID-19 vaccines and summarized it.
SDe and HBS were responsible for the other COVID-19 vaccine part, while SDh and CH were responsible for the published clinical trials’ results.
LB, SB and NBAB critically revised the manuscript.
All authors approved the final version of the manuscript.
The authors completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request from the corresponding author), and declare no conflicts of interest.
Molka Osman, National Observatory of New and Emerging Diseases, Tunisia, [email protected]