Towards a population-based threshold of protection for COVID-19 vaccines

Abstract

Correlates of protection for COVID-19 vaccines are urgently needed to license additional vaccines. We measured immune responses to four COVID-19 vaccines of proven efficacy using a single serological platform. IgG anti-Spike antibodies were highly correlated with ID50 neutralization in a validated pseudoviral assay and correlated significantly with efficacies for protection against infection with wild-type, alpha and delta variant SARS-CoV-2 virus. The protective threshold for each vaccine was calculated for IgG anti-Spike antibody. The mean protective threshold for all vaccine studies for WT virus was 154 BAU/ml (95 %CI 42-559), and for studies with antibody distributions that enabled precise estimation of thresholds (i.e. leaving out 2-dose mRNA regimens) was 60 BAU/ml (95 %CI 35-102). We propose that the proportion of individuals with responses above the appropriate protective threshold together with the geometric mean concentration can be used in comparative non-inferiority studies with licensed vaccines to ensure that new vaccines will be efficacious.

Keywords: COVID vaccines; COVID-19; Correlates of protection; SARS-CoV-2.

Fig. 1

Spike IgG antibody to original wild type (WT) virus, alpha and delta variant. IgG Concentrations, GMCs and 95% CI (BAU/ml) to Spike derived from WT as well as the B.1.1.7 (alpha variant) and B.617.2 (delta variant), following complete courses of four different SARS CoV 2 vaccines administered to naïve recipients. Concentrations are expressed in standardised binding antibody units (BAU)/ml calibrated against the WHO international standard, and GMC are displayed by text above the bars with 95% CI represented by whiskers.

Fig. 2

Pseudovirus neutralization of wild type and delta virus for the fully immunized cohorts. ID50 neutralisation geometric mean titres (GMT) for a lenti-pseudovirus Wuhan-1 spike containing D614G (WT) or B.1.617.2 (AY.3) (delta variant) in sera of vaccinees following complete courses of four different SARS CoV 2 vaccines administered to naïve recipients. Neutralization titers shown are the inhibitory dilution (ID) of serum samples at which relative luminescence units (RLU) were reduced by 50% (ID50) compared to virus control wells after subtraction of background RLUs (see methods for details). The cohorts were compared by pairwise rank sum test adjusted for multiple comparisons and significance determined as follows: p < 0.0001 for all except Moderna vs Pfizer for delta (p < 0.05), and AZ compared to J&J was not significant for WT or delta.

Fig. 3

Correlation of Spike IgG binding antibody with vaccine efficacy for wild type, alpha and delta variants. Vaccine efficacy/effectiveness (VE) and SARS-CoV-2 spike binding IgG GMC, against Original (WT), alpha and delta variants. Data included in correlation analyses are described in Table 2 and Table S2. Superscript 1 or 2 indicates the number of doses for the vaccine regimen. The y-axis is estimated log risk-ratio reported on the vaccine efficacy scale. The x-axis is the geometric mean concentration (GMC) of spike-specific IgG antibody binding measured by MSD and calibrated to the WHO standard (binding antibody units per mL). Error bars indicate 95% confidence intervals for either the GMC IgG level (x-axis) or VE (y-axis). Weighted least-squares linear regression fit using inverse variance weighting on VE estimates (dashed line black for WT, dashed line blue for alpha variant). Rank correlation coefficient, variance explained by the model, and mean squared error (MSE) are indicated for the WT, and alpha variant models. An overall model rank correlation includes Delta variant in Fig. 3B. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Distribution of spike-specific binding antibody vaccine responses and determination of a vaccine-specific protective threshold. Reverse cumulative distribution functions (RCDs) were estimated from spike-specific IgG vaccine responses measured in cohorts of individuals who received: one or two doses of the Pfizer or Moderna mRNA-based vaccines, one or two doses of the Oxford/AstraZeneca vaccine, and one dose of the J + J vaccine. Panel A, B, C for original virus, Panel D, E, F for alpha variant, and Panel G, H for delta variant. Each RCD along the y-axis represents the estimated proportion of participants who responded with at least as high a response as indicated along the x-axis. Shaded region indicates a point-wise 95% confidence interval (CI; see Methods for details). For each vaccine regimen, a published estimate of vaccine efficacy or effectiveness was used to compute a protective threshold by finding the VE^th percentile of the RCD (solid horizontal line at VE^th percentile). The protective threshold is shown (vertical sold line) with a 95% CI (dashed vertical line) that takes into account uncertainty in estimation of both the RCD and VE (see Methods for details).

Fig. 5

Summary of protective antibody binding thresholds derived for each vaccine. A protective threshold (BAU/ml) for each vaccine regimen is displayed with 95% confidence interval (circle symbols). Thresholds were computed for original (WT, black), alpha (blue), and delta (orange) spike-specific responses paired with WT, alpha or delta variant specific estimates of vaccine efficacy. An average overall protective threshold was computed for WT and alpha independently (triangle symbols) using a random effects meta-analytic approach (see Methods for details). Separately an average was computed for WT excluding the two-dose mRNA vaccine regimens. The protective threshold and 95% CI are annotated along the right y-axis. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)