6. Vaccines under advanced stage of clinical development
According to the WHO, up to December 10th 2020, 52 candidate vaccines are under clinical evaluation and 162 under preclinical evaluation (World Health Organization, 2020b). Specifically, 13 vaccines are already in advanced stage of clinical development, being evaluated in phase 3 clinical trials.
In table 1 an overview of these vaccines is reported. For some of these products, many clinical studies are currently undergoing but others have already provided preliminary results. Among these 13 vaccines, four are currently undervaluation by the EMA: ChAdOx1-S (AZD1222, Astrazeneca), LNP-encapsulated mRNA (mRNA-1273, Moderna), 3 LNP-mRNAs (BNT162b2, Pfizer), and Adenovirus Type 26 vector (Ad26.COV2.S, Janssen). Hereafter the preliminary efficacy and safety results for those vaccines are reported.
Indeed, on December 8th, the preliminary results of a phase 3 trials of the COVID-19 vaccine developed by AstraZeneca and Oxford University (ChAdOx1 nCoV-19 vaccine) were published in the Lancet journal. This vaccine was developed using a chimpanzee adenovirus viral vector that triggers the expression of the spike protein of SARS-CoV-2. Once injected, the human cells produce the protein and train the immune system to antibodies and T-cells against it. The published preliminary results refer to data from 4 ongoing randomised, controlled trials which are currently underway across the UK, Brazil, and South Africa (studies ISRCTN89951424, NCT04324606, NCT04400838, and NCT04444674). Adult participants were randomized to receive two doses of the vaccine [(both containing 5×10¹⁰ viral particles – standard dose cohort (SD) or a low dose as first dose and a standard dose as second dose (LD/SD cohort)] or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). From April until November 2020, 23,848 participants were enrolled. Of these, 11,636 participants were included in the interim primary efficacy analysis. In SD and LD/SD cohort, the vaccine efficacy was 62,1% and 90%, respectively. Starting from 21 days after the first dose, ten cases hospitalised for COVID-19 all in the control arm occurred. One hundred and seventy-five severe adverse events occurred, of which 84 in the ChAdOx1 nCoV-19 group and 91 in the control group. Among serious adverse events, there were cases of haemolytic anaemia and transverse myelitis. Authors concluded that the new vaccine is efficacious and it could contribute to control of the disease in this pandemic (Voysey et al., 2020). The British and Indian regulatory agencies recently granted the marketing approval for the Oxford University/AstraZeneca vaccine. Indeed, the UK MHRA provided authorization for emergency supply of this vaccine for the active immunization of subjects 18 years or older (AstraZeneca, 2020).
Pfizer developed a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein, BNT162b2, whose efficacy and safety were recently published on the NEJM (Polack et al., 2020). Specifically, a multinational, placebo-controlled, pivotal efficacy trial, which is still ongoing, enrolled 43,548 patients aged > 16 years of age and who were randomized to receive two doses, 21 days apart, of placebo or the BNT162b2 vaccine (30 μg per dose). A total of 43,448 received injections: 21,720 with the vaccine and 21,728 with placebo. Study’s results revealed for the vaccine an efficacy in preventing COVID-19 equal to 95% (95% credible interval, 90.3 to 97.6); indeed, after the second dose, 8 cases of Covid-19 were detected among subjects who received BNT162b2 vs. 162 among those assigned to placebo. Similar results were found across subjects’ subgroups by age, sex, race, ethnicity, baseline body-mass index, and the comorbidities. After the first dose, 9 cases of severe COVID-19 were detected among subjects receiving placebo vs. 1 case in those receiving BNT162b2. BNT162b2 demonstrated a good safety profile, being associated with short-term, mild-to-moderate injection site reactions, fatigue, and headache and no difference were detected between groups in term of serious adverse events (Polack et al., 2020). This vaccine was firstly approved in the UK with its administration started in December 2020, then it was authorized, during the same month, by the FDA for emergency use in subjects 16 years of age and older. Finally, on December 21st, 2020 the EMA has granted a conditional marketing authorisation for this vaccine to prevent COVID-19 in people from 16 years of age.
Moderna also developed a RNA-vaccine and recently shared data on the achievement of its study’s primary efficacy endpoints. Indeed, on November 30th 2020, Moderna announced the results related to primary efficacy analysis of the COVE study (NCT04470427), a phase 3, randomized, placebo-controlled study, which is investigating the efficacy, safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine in 30,000 adult subjects in the U.S (Moderna, 2020). The results of this trial, which were recently published on the NEJM, demonstrated that the mRNA-1273 vaccine has 94.1% efficacy at preventing Covid-19. Thirty subjects, all receiving placebo, developed severe Covid-19. Local and systemic reactions occurred in subjects who received the vaccine, but no safety concerns were identified. Serious adverse events were rare, and no differences were found between the placebo and the vaccine groups (Baden et al., 2020). On December 18th, 2020, the U.S. FDA issued an emergency use authorization for the second vaccine to prevent COVID-19 in individuals 18 years of age and older.
Lastly, the efficacy and safety of Adenovirus Type 26 vector (Ad26.COV2.S, Janssen – Johnson & Johnson) is currently evaluated in phase 3 ENSEMBLE and ENSEMBLE 2, randomized, double-blind, placebo-controlled clinical trials (both studies will enroll approximately 90,000 subjects). On November 15th 2020, preliminary results from a phase 1/2a clinical study were published, showing that, after a single-dose among adult and elderly subjects, the vaccine induced a prompt and robust immune response (Janssen, 2020).
Lastly, many other vaccines are under evaluation in phase 1-2 clinical trials. Some of them are facing delays in achieving study’s outcomes. For instance, Sanofi and GSK announced a delay in their adjuvanted recombinant protein-based COVID-19 vaccine program due to a low immune response in adults aged > 49 years for an insufficient antigen concentration. The pharmaceutical companies state that they will carry out a Phase 2b study with an improved antigen formulation (Sanofi, 2020a).
In conclusion, vaccination has already started in some countries with the Pfizer’s vaccine administered in UK and US since December 2020, the Oxford University/AstraZeneca vaccine which was administered for the first time in the UK on January 4th 2021, the Chine’s vaccine (CoronaVac) administered to Chinese since July, or the Gamaleya Research Institute’s vaccine (Sputnik V) approved in Russia for emergency use since august 2020. Therefore, preliminary efficacy and safety data from real life will be soon available.