ChAdOx1 nCoV-19 vaccine clinical trials
A vaccine is a special drug that people do not take every day but only
once or a few times. It primes the immune system to fight off an
infection; however, like any drug, vaccines can vary in probability of
both effectiveness and side effects; benefits and risks that can differ
depending on age, comorbidities and other genetic and/or environmental
factors. The widespread mortality and morbidity associated with the
COVID-19 pandemic has induced the development of several vaccines
(1 ), some of which have recently received emergency use
authorisation. Among them, ChAdOx1 nCoV-19 vaccine was authorised with a
regimen of two standard doses given with an interval of 4–12 weeks on
the basis of the interim analysis data (2 ). Following
regulatory approval, the optimal dose interval was assessed in a recent
report through post-hoc exploratory analyses (3 ). The ChAdOx1
nCoV-19 vaccine consists of a replication-deficient chimpanzee
adenoviral vector containing the full-length SARS-CoV-2 spike
glycoprotein gene, which was tested across different studies
(2,4,5 ). Based on previous experience with ChAdOx1 MERS (a
chimpanzee adenovirus-vectored vaccine encoding the spike protein of
Middle East respiratory syndrome coronavirus, 7 ), the
vaccination studies (COV001-UK, COV002-UK, and COV003-Brazil,
COV005-South Africa) were initially designed to assess a single-dose (5
× 1010 particles) of ChAdOx1 nCoV-19 (2,4,5 ),
although other vaccination protocols consist of first (i.e., prime) and
second (i.e., boost) doses. Differently from vectors derived from human
viruses for which pre-existing immunity can reduce the vaccine
immunogenicity (because of the possibility of anti-vector immunity), a
chimpanzee adenovirus-vectored vaccine can bypass this possibility;
however, after the prime dose there is the possibility to develop an
anti-vector immunity, which could inhibit the potency of the booster
effect of a second dose. Preliminary data showed that vaccination of
rhesus macaques with a single dose of ChAdOx1 nCoV-19 was able to
protect from SARS-CoV-2 infection, indicating the efficacy of the
single-dose strategy (6 ). However, once the studies were
underway, analysis of immune responses and other factors justified for
amendments to the trials including groups receiving different
vaccination protocols in the analysis. Induction of both spike-specific
neutralising antibody titres and T-cell responses has been shown to
provide protection against viral infections in animal models
(6,7 ) and the immunogenicity data from phase 1 (COV001-UK,
begun on April 23, 2020) showed a substantial increase in SARS-CoV-2
spike neutralising antibodies (but not in interferon-γ ELISpot T cell
response to SARS-CoV-2 spike peptides) with a second dose of vaccine
given after 28 days (4 ). Based on this observation, the trial
protocol was modified to a regime of two doses administered 28 days
apart (4 ). A second study (COV002-UK) included participants who
received a low dose (LD) of the vaccine (2.2 × 10¹⁰ viral particles) as
their first dose and were boosted with a standard dose (SD, 3.5-6.5 ×
10¹⁰ virus particles), called LD/SD group, and subsequently participants
who were vaccinated with two standard-dose vaccines (SD/SD group).
Initial low dosing of viral particles in COV002 was due to an inaccurate
quantification of viral particles by spectrophotometric method and
further doses were adjusted to the standard dose (5 × 10¹° viral
particles) using a more accurate qPCR assay (2 ). The trial
protocol was amended on June 5, 2020, resulting in enrolment of two
distinct groups with different dosing regimens. The LD/SD cohort was
enrolled between May 31 and June 10, 2020, while the SD/SD cohort (aged
18–55 years) was enrolled later from June 9 to July 20, 2020
(2 ). Older age cohorts began subsequently in August, all of
whom were assigned to two standard dose (SD/SD) cohort. However,
participants who received the prime vaccination of low-dose ChAdOx1
nCoV-19 had similar anti-spike antibody titres by day 28 after both
their prime and booster vaccination as those who received a standard
dose and were higher than for those who did not receive a booster
vaccine, suggesting that immune responses elicited by LD/SD and SD/SD
were similar and confirming that prime-boost regimen (28 days apart)
could give a higher protection (5 ). Nevertheless, as for
previous observations (4 ), IFN-γ ELISpot T cell responses
against SARS-CoV-2 spike peptides peaked 14 days after the prime
vaccination and did not increase significantly after the booster
vaccination (5 ). Based on the above observations, it was
offered a second booster dose to the participants who received a low
prime dose (originally planned as single-dose cohort) and it produced
the LD/SD cohort (protocol modified on July 20, 2020); however, some
participants chose not to receive the second dose and constituted a
cohort of low single-dose recipients (2,3 ). On the other hand,
most participants in the LD/SD group (COV002) received a second dose
around 12 weeks after the first, while the interval between doses for
the SD/SD group (COV002) was both lower and more heterogeneous
(2 ). Boosting began on Aug 3, 2020, resulting in a longer gap
between prime and booster vaccines in LD/SD cohort (median 84 days,
interquartile range, IQR, 77—91) than for those in SD/SD cohorts
(median 69 days, IQR 50–86) (2 ). Moreover, in UK the large
number of participants who received the two-dose schedule delayed the
administration of the second dose (target 28 days) because of an
insufficient production of the vaccine (2 ). Differently, a
trial in Brazil (COV003), which began on June 23, 2020, included a two
standard dose (SD/SD) group with the majority of participants receiving
a second dose within 6 weeks of the first (median 36 days) (2 ).
These situations provide the opportunity to analyse the vaccine efficacy
of a single dose, and the effect of different dose interval.
Unfortunately, there was no overlap in enrolment of participants in
these cohorts and participants of LD/SD cohort and single LD cohort were
vaccinated (prime dose) before those of SD/SD cohort (2 ).