Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis

Abstract

Background: Several SARS-CoV-2 variants of concern have been identified that partly escape serum neutralisation elicited by current vaccines. Studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. We explored whether in-vitro neutralisation titres remain predictive of vaccine protection from infection with SARS-CoV-2 variants.

Methods: In this meta-analysis, we analysed published data from 24 identified studies on in-vitro neutralisation and clinical protection to understand the loss of neutralisation to existing SARS-CoV-2 variants of concern. We integrated the results of this analysis into our existing statistical model relating in-vitro neutralisation to protection (parameterised on data from ancestral virus infection) to estimate vaccine efficacy against SARS-CoV-2 variants. We also analysed data on boosting of vaccine responses and use the model to predict the impact of booster vaccination on protection against SARS-CoV-2 variants.

Findings: The neutralising activity against the ancestral SARS-CoV-2 was highly predictive of neutralisation of variants of concern. Decreases in neutralisation titre to the alpha (1·6-fold), beta (8·8-fold), gamma (3·5-fold), and delta (3·9-fold) variants (compared to the ancestral virus) were not significantly different between different vaccines. Neutralisation remained strongly correlated with protection from symptomatic infection with SARS-CoV-2 variants of concern (r _S=0·81, p=0·0005) and the existing model remained predictive of vaccine efficacy against variants of concern once decreases in neutralisation to the variants of concern were incorporated. Modelling of predicted vaccine efficacy against variants over time suggested that protection against symptomatic infection might decrease below 50% within the first year after vaccination for some vaccines. Boosting of previously infected individuals with existing vaccines (which target ancestral virus) is predicted to provide a higher degree of protection from infection with variants of concern than primary vaccination schedules alone.

Interpretation: In-vitro neutralisation titres remain a correlate of protection from SARS-CoV-2 variants and modelling of the effects of waning immunity predicts a loss of protection to the variants after vaccination. However, booster vaccination with current vaccines should enable higher neutralisation to SARS-CoV-2 variants than is achieved with primary vaccination, which is predicted to provide robust protection from severe infection outcomes with the current SARS-CoV-2 variants of concern, at least in the medium term.

Funding: The National Health and Medical Research Council (Australia), the Medical Research Future Fund (Australia), and the Victorian Government.

Figure 1

In-vitro neutralisation of SARS-CoV-2 variants of concern (A) The change in neutralisation titre between the ancestral virus and different SARS-CoV-2 variants for either convalescent individuals (left) or those immunised with different vaccines is shown. Individual colours reflect different studies or laboratories (appendix pp 15–16). Solid dots indicate where titres were measurable for both ancestral and variant neutralisation. Crosses indicate where one titre fell below the limit of detection for that assay. Different studies estimate different changes in neutralisation titre even for the same vaccine or variant combination. The dashed horizonal line indicates the censored mean decrease in titre for a given variant (across all vaccine and convalescent samples), and blue horizontal bars indicate the censored mean titre for a given vaccine or variant combination. The boxes extend between the first and third quartiles, and the whiskers extend to 1·5 times the IQR. (B) The correlation between the mean neutralisation titre against the ancestral virus (x-axis) and mean neutralisation titre against the variants of concern (y-axis) is shown. The predicted line for a 1:1 association is indicated (dashed blue line). The observed mean decrease in neutralisation titre across all vaccines and convalescent individuals is indicated by an arrow (with the length of the arrow representing the decrease in neutralisation titre) and the predicted variant neutralisation is indicated by a dashed red line (shading indicates the 95% CI). Tints indicate the mean neutralisation for a given vaccine or variant combination, averaging across available studies (number of studies indicated).

Figure 2

Predicting vaccine efficacy against SARS-CoV-2 variants The association between mean neutralisation of ancestral SARS-CoV-2 and protection against symptomatic (A) and severe infection (B) with different variants is shown. The line indicates the model prediction of efficacy for a given neutralisation against ancestral virus. Shading indicates 95% CI based on uncertainties in measuring mean neutralisation titre against ancestral virus, the loss of neutralisation against each variant and in model parameters. Individual points shown represent results of different studies of vaccine efficacy against ancestral virus (black) or SARS-CoV-2 variants. Details of studies of ancestral virus are outlined in Khoury et al (all of which are randomised controlled trials), and studies of variants of concern are outlined in the appendix (p 17).

Figure 3

Predicted effect of a booster dose on neutralising antibody responses The normalised neutralisation titres (ie, neutralisation titres divided by the geometric mean of a convalescent cohort) against ancestral virus observed following initial vaccination (vertical grey lines) and the effects of vaccination of previously infected individuals (vertical orange lines) are shown. Results for individual studies are indicated as vertical lines, and symbols above the lines indicate the vaccine(s) used and infection history. The geometric mean of boosting seen in previously infected individuals (from all studies) is shown as a dashed red line. Shaded areas indicate the range of mean neutralisation observed following vaccination of naive (grey) or previously infected (orange) individuals. Two studies of a third booster dose in previously vaccinated individuals are shown as vertical blue lines (and the vaccines used are indicated with symbols above the lines). The modelled association between neutralisation and protection from ancestral (black) or variants of concern are shown as coloured curves for either any symptomatic SARS-CoV-2 infection (A) or severe infection (B).

Figure 4

Predicted protection from SARS-CoV-2 infection and the effect of an additional booster dose at 6 months The predicted protection over time is shown for four hypothetical vaccines that initially provide 95%, 90%, 80%, or 70% protection against symptomatic infection with the ancestral virus. It is assumed that neutralisation decays with a half-life of 108 days and variant neutralisation decreases as estimated (appendix p 23). Solid lines are mean model predictions, and shading indicates the lower bound of the 95% CI (indicating the minimal predicted efficacy). The dashed line indicates the predicted effect of boosting previously infected individuals with BNT162b2 or mRNA-1273 6 months after their primary infection (geometric mean of all boosting studies; appendix p 24) and assumes decay after boosting is the same as after initial infection or primary vaccination.

Figure 5

Predicting protective efficacy for new vaccines or new variants (A) The association between neutralisation and protection can be used for immunobridging to predict vaccine efficacy from in-vitro neutralisation titres. The geometric mean neutralisation titre from 20–30 individuals around 2 weeks after vaccination needs to be measured. These neutralisation titres can then be normalised against sera from convalescent individuals (1–3 months after infection with ancestral SARS-CoV-2 strain), serum from individuals recently vaccinated with common vaccines, and the international standards. This neutralisation (vertical dashed blue line) can then be used to predict efficacy against the ancestral virus (black curve and grey 95% CI). (B) To predict efficacy against a new variant, we need to first estimate the difference in neutralisation titre between the ancestral and new variant SARS-CoV-2 (ideally averaging the decrease measured in different assays across four or more laboratories). This difference in titre can then be used to shift the curve of efficacy against the variant (red arrow, red curve, and pink shaded 95% CI) to the right. The predicted efficacy and 95% CI of the new vaccine against the new variant (purple hexagon and whiskers) can then be ascertained.