How timing and dose of different types of passive antibody treatments predict protection against SARS-CoV-2 infection

Scientists have said levels of neutralizing antibodies are strongly correlated with prevention of symptomatic and severe coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) . Several products, such as convalescent plasma (CP), hyperimmune immunoglobulin (hIVIG), and monoclonal antibodies (mAb) neutralizing SARS-CoV-2, have been used in the passive delivery of neutralizing antibodies for SARS- CoV-2.

Study: Determinants of passive antibody efficacy in SARS-CoV-2 infection. Image credit: LuXiFeR Bowlo/Shutterstock

context

Among passive antibodies, PC was relatively more available at the start of the pandemic. However, due to its limited availability, it was primarily used to treat severely infected COVID-19 patients who required hospitalization. The development of hIVIGs requires a large amount of plasma; it is a more standardized product and contains a larger volume of antibody titers. This is why hIVIGs are more efficient than PCs. Many studies have shown that the SARS-CoV-2 neutralizing mAb is more potent and can be given at a higher dose.

However, one of the disadvantages of monoclonal antibodies is that they only target a single epitope of SARS-CoV-2, which makes them vulnerable to immune evasion of SARS-CoV-2 variants. The three passive antibody treatments gave variable results.

Clinical trials associated with the evaluation of high-titer convalescent plasma have shown no improvement in the death rate or condition of severely infected COVID-19 patients who required hospitalization and intensive care treatment. In contrast, treating outpatients, with mild to moderate disease, with mAbs showed a significant reduction in COVID-19-related hospitalizations. Scientists have noted large differences in antibody-based therapies for the prevention and treatment of SARS-CoV-2 infection, with respect to the administration of the intervention, in particular, the timing at which passive antibody treatments are administered, the doses of antibodies used and the results of the treatments.

A new study

A new study published on the medRxivThe preprint server* focused on performing a systematic search of the literature and aggregated data associated with randomized controlled trials of passive antibody therapy. This would allow researchers to study how the timing and dose of administration of different types of passive antibody treatments help prevent or protect individuals from SARS-CoV-2 infection. In this study, researchers assessed the efficacy of different doses of neutralizing antibodies, from pre-existing studies, by assessing the mean neutralizing serum titer of individuals recovering from COVID-19.

Main conclusions

In this study, scientists determined the effective dose of neutralizing antibodies by sifting through different studies on CP and Mabs related to outpatient treatment. They found a strong correlation between higher efficacy and treatment in the early phase of the disease, for both CP and mAb treatments. Importantly, the authors stated that a dose of mAb significantly lower than those typically used in many current treatment regimens could be effective in achieving maximum protection against symptomatic infection and hospitalization.

This means that the administration of a lower dose of mAb is useful for the treatment of COVID-19, which would significantly reduce the cost of treatment. These studies also indicated that higher doses of convalescent plasma could provide several benefits if administered to ambulant subjects. This strategy is more effective in treating patients infected with SARS-CoV-2 variants.

The researchers also pointed out that the timing of antibody administration is one of the key factors in determining treatment success. For example, single doses of antibodies showed 92.4% protection against infection when given prophylactically, 73.5% protection for outpatients with COVID-19, and provided no protection in hospitalized patients.

One of the reasons for the reduced effectiveness when given at an advanced stage of the disease could be that the exact need is much higher at this stage than when given. This study found that neutralizing antibody titer for 50% of maximal protection could prevent acquisition of infection as well as disease progression from outpatient COVID-19 to hospitalization.

Additionally, the researchers highlighted an efficacy ‘ceiling’ for the therapeutic treatment of COVID-19, where peak efficacy was reduced at a particularly late stage. The ceiling effect of passive antibodies could be due to endogenous antibody responses.

The scientists revealed that the level of antibodies required to achieve 90% protection against SARS-CoV-2 is approximately 0.90 times the average recovery titer. This implies that the continued increase in endogenous antibody responses during infection can reach levels of protection where the further addition of passive antibodies would not provide more protection. The authors said further studies are needed to determine the optimal timing of passive antibody therapy in individuals with symptoms of COVID-19.

Main limitations

The current study has several limitations, including the aggregation of studies that used different therapeutic approaches with different recruitment and outcome criteria. Another limitation is that it equated administered doses of convalescent plasma and monoclonal antibodies based on a single study. Additionally, the researchers considered the dose administered, whereas the majority of studies did not measure plasma neutralization titers in recipients after administration.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health behavior, or be treated as established information.

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