Neutralising antibodies predict protection from severe COVID-19

ABSTRACT

BackgroundVaccine protection from COVID-19 has been shown to decline with time-since-vaccination and against SARS-CoV-2 variants. Protection against severe COVID-19 is higher than against symptomatic infection, and also appears relatively preserved over time and against variants. Although protection from symptomatic SARS-CoV-2 infection is strongly correlated with neutralising antibody titres, this relationship has been less well described for severe COVID-19. Here we analyse whether neutralising antibody titre remains predictive of protection against severe COVID-19 in the face of waning neutralising antibody levels and emerging variants. MethodsWe extracted data from 15 studies reporting on protection against a range of SARS-CoV-2 clinical endpoints ( any infection, symptomatic infection and severe COVID-19). We then estimated the concurrent neutralising antibody titres using existing parameters on vaccine potency, neutralising antibody decay, and loss of recognition of variants and investigated the relationship between neutralising antibody titre and vaccine effectiveness against severe COVID-19. FindingsPredicted neutralising antibody titres are strongly correlated with vaccine effectiveness against symptomatic and severe COVID-19 (Spearman{rho} = 0.94 and 0.63 respectively, p<.001 for both). The relationship between neutralisation titre and protection is consistent with previous estimates, with 76% (127 of 167) of reported values of protection against severe COVID-19 across a range of vaccines and variants lie within the 95% confidence intervals of the previously published model. InterpretationNeutralising antibody titres are predictive of vaccine effectiveness against severe COVID-19 including in the presence of waning immunity and viral variants. FundingNational Health and Medical Research Council (Australia), Medical Research Future Fund (Australia). O_TEXTBOXEvidence before this study COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infection has been shown to be strongly predicted by neutralising antibody titres. However, there has not been sufficient data on vaccine efficacy against severe disease to determine whether the correlation between neutralising antibody titres and protection is maintained for severe COVID-19. Indeed, the apparent faster waning of vaccine efficacy against symptomatic (compared to severe) COVID-19 has led some to hypothesise about a decoupling of protection from symptomatic and severe disease. It is therefore important to identify whether neutralising antibody titre remains a correlate of protection against severe COVID-19 in real-world scenarios of waning immunity and SARS-CoV-2 variants. We searched PubMed between inception and March 2, 2022 for studies (Key search terms (SARS-CoV-2 OR COVID-19) AND (followup OR waning OR duration OR durable) AND (protection OR efficacy OR effectiveness)) and also monitored other public sources of information such as Twitter. We identified 15 studies that reported data on vaccine effectiveness against (i) a defined clinical endpoint (ii) for an identifiable variant, (ii) for a single vaccine (or vaccine type), (iii) over an identified time since vaccination, and (iv) for which data was either provided in or readily extractable from the original publication. Added value of this study Previous work has identified that neutralising antibodies correlate strongly with protection from symptomatic COVID-19 disease for both ancestral virus and for variants of concern. Here we examine published data on vaccine effectiveness to determine if this correlation remains valid for predicting protection against severe COVID-19. Our work shows that vaccine effectiveness against severe COVID-19 is strongly correlated with neutralising antibody titres for different vaccines, variants, and over the first six months after vaccination. The relationship between vaccine effectiveness and protection against severe COVID-19 is consistent with a previously published analysis and indicates that the 50% protective titre for protection against severe COVID-19 is lower than that associated with protection from symptomatic infection. Implications of all of the available evidence In the face of increased exposure and immunity to numerous SARS-CoV-2 variants it is becoming increasingly important to be able to predict not only protection against symptomatic infection, but also protection against severe COVID-19. Here we show that neutralising antibody titres remain predictive of vaccine effectiveness against severe COVID-19 in the face of waning immunity and SARS-CoV-2 variants. This is consistent with a low level of neutralising antibodies being associated with protection from severe COVID-19. This work will be of use in providing early estimates of protection against severe COVID-19 for new SARS-CoV-2 antigenic variants, informing optimal booster timing, and will support future vaccine development by allowing prediction of vaccine protection conferred against severe outcomes. C_TEXTBOX