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.