Possible influence of anti-vector immunity on efficacy of ChAdOx1 nCoV-19 vaccine
Interestingly, vaccine efficacy against symptomatic or asymptomatic disease in participants (COV002-UK) who received a low dose as their first dose of vaccine (LD/SD) was significantly higher than that of participants who received two standard-dose (SD/SD) vaccines (2,3 ). Indeed, vaccine efficacies in LD/SD group was 90.0% (95% CI 67.4–97.0) and 58.9% (95% CI 1.0–82.9) against symptomatic and asymptomatic (evaluated by mean of weekly self-swab) disease, respectively, whereas they were respectively 60.3% (95% CI 28.0–78.2) and 3.8% (95% CI -72.4–46.3) in SD/SD group (data cutoff on Nov 4, 2020) (2 ), indicating that the two trial protocols produced significantly different protection from SARS-CoV-2 symptomatic and asymptomatic disease and transmission. Moreover, the SD/SD cohort in Brazil displayed a relatively low protection, 64,2% (95% CI 30.7–81.5), which was similar to vaccine efficacy of SD/SD UK cohort (60.3%). These surprising data might suggest that low prime dose would induce a longer and/or a higher SARS-CoV-2 immune protection; however, others factors such as dose interval might be involved in determining the significant differences between LD/SD and SD/SD cohorts. In this regard, both the UK (COV002) and Brazil (COV003) SD/SD cohorts, which displayed relatively low vaccine efficacies against primary symptomatic COVID-19, had shorter dose intervals than LD/SD cohort (data cutoff on Nov 4, 2020) (2 ), suggesting that the longer dose intervals of LD/SD group might give higher protection. Indeed, exploratory subgroup analyses of SD/SD cohorts from both UK and Brazil showed a trend (although not significant) of increase in vaccine efficacy when comparing those with short interval between doses (<6 weeks, 53.4%) and those with longer interval (≥6 weeks 65.4%) (data cutoff on Nov 4, 2020) (2 ). Notably, a subsequent analysis (data cutoff on Dec 7, 2020) (3 ) revealed that when SD/SD group was restricted to those who received their vaccines more than 84 days (12 weeks) between the two doses (a dose interval similar to LD/SD group), vaccine efficacy of SD/SD cohort (81.3% [95% CI 60.3–91.2]) was similar to that of LD/SD cohort (80.7%, [95% CI 62.1–90.2]) (3 ). Moreover, ChAdOx1 nCoV-19 vaccine had a higher efficacy in those with a longer prime-boost interval (vaccine efficacy 81.3% [95% CI 60.3–91.2] at ≥84 days) than in those with a short interval (vaccine efficacy 55.1% [95% CI 33.0–69.9] at <42 days), further suggesting that long (≥84 days) dose intervals give higher protection. However, 84 days of dose interval might increase the probability of infection between the two doses. In this regard, although anti-SARS-CoV-2 spike IgG responses after a single standard dose of ChAdOx1 nCoV-19 vaccine showed a decrease from the peak at day 28 (median 5496 AU/ml [IQR 2548-12061] for participants aged 56–69 years and 9807 AU/ml [IQR 5847-17220] for participants aged 18–55 years) of 34% by day 90 (geometric mean ratio [GMR] 0.66 [95% CI 0.59–0.74]), a single standard dose was efficacious (76.0% [95% CI 59.3–85.9]) against primary symptomatic (but not against asymptomatic) SARS-CoV-2 infection in the first 90 days after vaccination, with no significant waning of protection during this period, thus supporting the approach to delay second doses (3 ). As indicated in the report, participants were censored in the analysis of single-dose efficacy at the time of their booster dose (3 ); however, most participants in the single dose analysis received a second dose within 90 days after the first dose. That means that the data analysed for participants from 22 to 90 days since first dose were collected before the data cutoff date indicated in the report (December 7, 2020), possibly between June and October. Instead, the group of participants reaching 91 and 120 days since first dose likely represents people who never received a second dose, for which vaccine efficacy was assessed at the data cutoff date (December 7, 2020). During this last period (the time between the beginning of November and the beginning of December), the vaccine efficacy of single dose appeared to wane, reaching only 31.6% protection (95% CI -141.8–80.7). This is possibly due to a progressive decrease of anti-SARS-CoV-2 spike IgG responses (64% by day 180, GMR 0.36 [0.27–0.47]) from the peak at day 28 and/or other factors (e.g. SARS-CoV-2 variants emerging during the month of November, see later). Altogether the data suggested that a 3-month dose interval provided better protection after a second dose without compromising protection in the period before the booster dose is administered. This conclusion was supported by immunogenicity data that showed that in both LD/SD and SD/SD cohorts, participants who received a second standard vaccine more than 84 days after the first had anti-SARS-CoV-2 spike IgG titres more than two-fold higher than those who received the second dose within 42 days of their initial vaccination. Assuming there is a relationship between the humoral immune response and vaccine efficacy, this evidence suggested that long (≥84 days) dose intervals were more efficacious than shorter dose intervals and could induce a long protection from SARS-CoV-2 (3 ). These data were recently discussed in a report (3 ); however, a possible hypothesis underlying this observation was not discussed. In this regard, it has already been highlighted that there is the possibility to develop an anti-vector immunity on homologous boosting and this eventuality could be on the origin of the reduced potency of the booster effect when the second dose was administered earlier than 84 days. Indeed, it is likely that immunity against the antigenic proteins of simian adenovirus vector tends to wane during the time (as well as that against spike proteins), providing a rational explanation to the increased anti-SARS-CoV-2 spike IgG responses and vaccine efficacy produced by delayed boosting.