Individual results for IgG binding to S-protein from the original strain and Alpha variant expressed as BAU/mL for all five cohorts are shown in Fig. 1. The GMC (95% CI) of Clover vaccine recipients following two doses for original spike was 1010 BAU/ml [752–1355] as compared to GMC following two doses for mRNA-1273 (5530 BAU/mL [4007–7633]), BNT162b2 (2653 BAU/mL [2071–3399]), ChAdOx1 nCoV-19 (196 BAU/mL [140–273] and after one dose of Ad.26COV2.s (61 BAU/ml [37–101]). The Clover vaccine recipients GMC was significantly higher to both original and Alpha variant than ChadOx1nCoV-19 vaccine cohort (p < 0.0001) and Ad.26COVV2.s vaccine cohort (P < 0.0001) and significantly lower when compared to Pfizer and Moderna (P < 0.0001). Responses to the RBD for original and Alpha variant showed similar results with Clover GMC significantly higher for ChadOxInCoV-19 (p = 0.0009 for original and p = 0.0013 for alpha) and Ad.26COVV2.s cohorts (p < 0.0001 for both). Of note, the younger Clover adults generally displayed higher response against S-protein and RBD for original prototype and Alpha variant compared to the older adults (Table 1). However, the older adults had a GMC that was still higher than GMC for both the ChAdOx1nCoV-19 and Ad.26COV2.S entire vaccine cohorts which each contained older adults (5).
Table 1
Age specific Geometric Mean Concentrations (GMC) of IgG Binding Antibody Units (BAU/mL) assessed by ELISA against S-protein and RBD of the original prototype SARS-CoV-2 and of the Alpha variant (B.1.1.7) in participants vaccinated with SCB-2019
| | Virus and Antigen |
| | Original prototype | Alpha variant |
Age | | S-protein | RBD | S-protein | RBD |
18–60 years | n | 90 | 90 | 90 | 90 |
GMC (BAU/mL) | 1097 | 1217 | 700 | 1259 |
[95% CI] | [802–1502] | [889–1666] | [511–961] | [933–1699] |
≥ 60 years | n | 10 | 10 | 10 | 10 |
GMC (BAU/mL) | 477 | 430 | 345 | 481 |
[95% CI] | [215–1057] | [135–1365] | [153–779] | [150–1542] |
Major issue for licensure of new COVID-19 vaccines is twofold: Firstly, the conduct of controlled field efficacy trials is hampered by the fact that placebo control is at this stage deemed unethical by most ethical review boards whilst the comparison of a new candidate to an approved vaccine is operationally problematic because of the limited access of approved Covid-19 vaccines for clinical trials. Secondly, assessing clinical efficacy against an evolving background of disease incidence due to new variants replacing the original prototype Wuhan-Hu-1 virus. At the time of this report, COVID-19 in most of the world is caused predominantly by VOC including the Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Gamma (P.1), Mu (B.1.621) and other variants. Many of the variants have reduced sensitivity to antibody compared to original and alpha and currently approved vaccines are showing lower efficacy/effectiveness against VOCs than original virus (8–10). As it is no longer feasible to evaluate or compare clinical efficacy of new vaccines to approved vaccines against the original strain, it has become critically important to compare new vaccines to the approved vaccines based on immunogenicity to the original strain and VOC rather than clinical efficacy. As noted, our group previously reported that binding antibody was correlated to efficacy and also highly correlated with neutralization antibody. We and others also suggest that binding antibody comparisons may be superior choice due technical simplicity, lower variability, easier standardization and ability to assess neutralizing as well non-neutralizing antibody activities. (4,11).
For the four approved vaccines compared in this report, efficacies were 94.1% (95% CI: 89.3–96.8) [12], 94.6% (89.9–97.3) [13] and 80.7% (66.5–88.9) [14] against symptomatic disease of original virus after two doses for mRNA-1273, BNT162b2 and ChAdOx1 nCoV-19, respectively, and 72.0% (58.2–81.7) after one dose of Ad26.COV2.S [15]. The binding antibody response for SCB-2019 + CpG/alum to the original virus predicts an efficacy rate in a range of 81–94%. Furthermore, GMCs of binding antibody to Alpha variant compared favorably to the approved vaccine responses, and thus acceptable efficacy against Alpha variant is predicted within the on-going trial by Clover. However other VOC with lower levels of cross reactivity with the original strains are expected to be predominant in this trial and thus overall efficacy is predicted to be lower than for the original strain.
We therefore suggest that immunogenicity comparisons need to be considered for authorization of new vaccines because the predominance of VOC in ongoing trials will make current efficacy guidelines based on the original strain challenging or impossible to achieve. We further propose an approach to conduct such comparisons that would require co-operation among multiple stakeholders: namely to assemble adequately sized banks of post immunization sera from licensed vaccines to support direct comparisons with responses to new vaccines for non-inferiority. The comparisons could be done in an independent blinded manner against the original strain and VOCs. We suggest that binding antibody may be best suited for these comparisons provided that a strong correlations between binding and neutralization for original strain and VOCs have been established. Utilizing an established serum bank would avoid the requirement of securing comparator vaccines by all developers in many different locations and avoid lengthy head-to-head non-inferiority trials which would delay timely availability of much needed safe and effective additional vaccines.