Determinants of passive antibody efficacy in SARS-CoV-2 infection

Abstract

Neutralising antibodies are an important correlate of protection from SARS-CoV-2 infection. Multiple studies have investigated the effectiveness of passively administered antibodies (either monoclonal antibodies, convalescent plasma or hyperimmune immunoglobulin) in preventing acquisition of or improving the outcome of infection. Comparing the results between studies is challenging due to different study characteristics including disease stage, trial enrolment and outcome criteria, and different product factors, including administration of polyclonal or monoclonal antibody, and antibody targets and doses. Here we integrate data from 37 randomised controlled trials to investigate how the timing and dose of passive antibodies predicts protection from SARS-CoV-2 infection. We find that both prophylactic and early therapeutic administration (to symptomatic ambulant subjects) have significant efficacy in preventing infection or progression to hospitalisation respectively. However, we find that effectiveness of passive antibody therapy in preventing clinical progression is significantly reduced with administration at later clinical stages (p<0.0001). To compare the dose-response relationship between different treatments, we normalise the administered antibody dose to the predicted neutralisation titre (after dilution) compared to the mean titre observed in early convalescent subjects. We use a logistic model to analyse the dose-response curve of passive antibody administration in preventing progression from symptomatic infection to hospitalisation. We estimate a maximal protection from progression to hospitalisation of 70.2% (95% CI: 62.1 - 78.3%). The dose required to achieve 50% of the maximal effect (EC-50) for prevention of progression to hospitalisation was 0.19-fold (95% CI: 0.087 - 0.395) of the mean early convalescent titre. This suggests that for current monoclonal antibody regimes, doses between 7- and >1000-fold lower than currently used could still achieve around 90% of the current effectiveness (depending on the variant) and allow much more widespread use at lower cost. For convalescent plasma, most current doses are lower than required for high levels of protection. This work provides a framework for the rational design of future passive antibody prophylaxis and treatment strategies for COVID-19.

Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial

“…These data suggest that despite half-lives of only approximately 30 days, 16 a single 1200 mg dose provided sufficient drug exposure concentrations, above those required to effectively neutralise the virus in target tissues for 5 months. This observation is consistent with a 2022 meta-analysis, 22 which also suggests that many SARS-CoV-2 antibodies have been administered at doses much higher than needed to achieve sufficient neutralisation for efficacy in prevention or treatment settings.…”

Neutralising antibodies predict protection from severe COVID-19

“…That antibodies are capable of reducing the risk of severe COVID-19 is perhaps not surprising, since monoclonal antibody therapy administered in the first five days after symptom onset has been shown to reduce the risk of hospitalisation for severe SARS-CoV-2 by up to 85%, when administered in doses comparable to the neutralisation titres achieved in individuals vaccinated with an mRNA vaccine and/or booster (i.e. 7-fold the neutralisation titre found in the average convalescent individual) 24,25 . Indeed, some studies suggest that passive antibody administration may remain effective even later in infection when administered to seronegative subjects 26 .…”

Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection

“…Studies of passive administration of neutralizing monoclonal antibodies in animals and humans support that this is a mechanistic correlate of protection ( 21-23 ). Indeed, a recent study comparing protective titers in prophylactic and therapeutic studies suggests that the protective titers may be very similar ( 24 ). Neutralizing antibody levels are also correlated with protection from severe SARS-CoV-2 infection ( 2 ).…”