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 ).