Levels of virus-neutralizing antibodies
Tixagevimab/Cilgavimab, ground-glass opacities
DISEASE, VIRUS, SECONDARY
The study was conducted during the surge of the SARS-CoV-2 Omicron BA.5 sublineage. Genetic analyses of the patients’ nasopharyngeal swabs by real-time PCR confirmed that all swabs contained SARS-CoV-2 Omicron sublineage BA.5 RNA.We determined the levels of nAbs to the initial SARS-CoV-2 variant (Wuhan D614G) and to the Omicron sublineages BA.1, BA.2 and BA.5 in the blood serum of the patients to identify the neutralization activity of nAbs. In the IV treatment groups (Tixagevimab/Cilgavimab 300 mg, Tixagevimab/Cilgavimab 600 mg and Regdanvimab groups), we observed a strong increase in nAbs to the Wuhan variant immediately after the drug administration (Titers mAbs to different SARS-CoV-2 variants.IV, intravenously; IM, intramuscularly; mg, milligram, kg, kilogram; GMT, geometric mean titer; CI, confidence interval.Interestingly, in the Tixagevimab/Cilgavimab IM 300 mg group the levels of nAbs to the Omicron sublineages reached its maximum by Day 4 of the study, with values significantly higher than those in the Regdanvimab group (also on Day 4). It is important to note that the levels of nAbs to different Omicron sublineages did not differ significantly on Day 4 between the groups of IV and IM administration of Tixagevimab/Cilgavimab at a dose of 300 mg.Analysis of the nAb levels to different SARS-CoV-2 sublineages over time within each group revealed the following patterns:Tixagevimab/Cilgavimab IV administration groups: a significant increase in the levels of nAbs to the Wuhan and Omicron BA.1 and BA.2 sublineages was detected immediately after the drug administration, the nAb levels remained stable for 4 days; a significant increase in the levels of nAbs to the Omicron BA.5 sublineage was detected immediately after drug administration, and then the nAb levels increased over time and reached their maximum on Day 4 of the study, which indicated the development of the host immune response.Tixagevimab/Cilgavimab IM administration group: the highest nAb levels were detected on Day 4 of the study. At the same time, the levels of nAbs to the Omicron sublineages on Day 4 of the study did not differ between the groups of IV and IM administration.Regdanvimab IV administration group: a significant increase in the levels of nAbs to the Wuhan variant was detected immediately after administration, while there was no increase in nAbs to different sublineages of the Omicron variant. On Day 4 of the study, a decrease in nAbs to the Wuhan variant was detected, indicating the removal of nAbs from the systemic circulation. The increase in nAbs to the Omicron sublineages on day 4 of the study indicates the development of immune response.In the groups that received Tixagevimab/Cilgavimab the levels of nAbs to the Omicron sublineage BA.5 on Day 4 of the study were significantly higher (about 10 times) than in the Regdanvimab group.The levels of nAbs to the Omicron BA.1, BA.2 and BA.5 sublineages in the intravenous Tixagevimab/Cilgavimab group were significantly higher than those in the Regdanvimab group. A robust increase in nAbs to the Wuhan variant of SARS-CoV-2 virus was detected in patients who received Regdanvimab immediately after administration, while no increase of nAb levels to the Omicron BA.1, BA.2 and BA.5 sublineages was seen (Comparison of nAbs levels in the IV Tixagevimab/Cilgavimab and IV Regdanvimab patient groups. T/C, Tixagevimab/Cilgavimab; Regda, Regdanvimab. The levels of nAbs to the Omicron BA.1, BA.2 and BA.5 sublineages in the intravenous Tixagevimab/Cilgavimab group were significantly higher than those in the Regdanvimab group. A robust increase in nAbs to the Wuhan variant of SARS-CoV-2 virus was detected in patients who received Regdanvimab immediately after administration, while no increase of nAb levels to the Omicron BA.1, BA.2 and BA.5 sublineages was seen.The nAb titer for the Wuhan variant in patients who received Tixagevimab/Cilgavimab IV exceeded 10,000; the nAb titer for the Omicron BA.5 sublineage Tixagevimab/Cilgavimab group on Day 4 of the study was 450, with a greater than 22-fold decrease in the neutralization activity when compared to the Wuhan variant. The levels of nAbs to Omicron BA.2 and BA.5 sublineages in the Tixagevimab/Cilgavimab IM group were significantly higher by Day 4 than in the Regdanvimab group (Comparison of nAbs levels in IM Tixagevimab/Cilgavimab and Regdanvimab patient groups. T/C, Tixagevimab/Cilgavimab; Regda, Regdanvimab; IM, intramuscularly. The levels of nAbs to Omicron BA.2 and BA.5 sublineages in the Tixagevimab/Cilgavimab IM group were significantly higher by Day 4 than in the Regdanvimab group.The increase in the nAb titer in the blood serum of patients who received Tixagevimab/Cilgavimab IM occurred with a delay (compared to IV administration). However, by Day 4 of observation the levels of nAbs to Omicron BA.1, BA.2, BA.5 sublineages did not differ from the Tixagevimab/Cilgavimab IV group (Comparison of nAbs levels in IV and IM Tixagevimab/Cilgavimab patient groups. IM, intamuscularly, IV, intravenously. The increase in the nAb titer in the blood serum of patients who received Tixagevimab/Cilgavimab IM occurred with a delay (compared to IV administration). By Day 4 of observation the levels of nAbs to Omicron BA.1, BA.2, BA.5 sublineages did not differ from the Tixagevimab/Cilgavimab IV group.
Geometric mean of nAbs titers to different variants of SARS-CoV-2. In the Regdanvimab group, the geometric mean of nAb titers to the Wuhan variant was higher than that in the Tixagevimab/Cilgavimab groups, both one hour after administration and on Day 4 (p<0.001), while an inverse effect was observed for the concentrations of nAbs against Omicron sublineages (p<0.001).When analyzing the outcome of the disease as a secondary endpoint, 100% recovery was observed in the Tixagevimab/Cilgavimab groups regardless of the route of administration. In the Regdanvimab group, 2 patients (8.3%) were transferred from the day patient facility to the hospital inpatient department due to the appearance of new foci of ground-glass opacities seen on chest CT, as well as the absence of positive laboratory dynamics. However, the difference between the groups was not statistically significant (p =0,209) (Outcomes of the disease.IM, intamuscularly; IV, intravenously; mg, milligram; kg, kilogram.The study of laboratory parameters over time showed that the lymphocyte levels did not differ significantly between patients, while the levels of CRP and D-Dimer were significantly lower in the Tixagevimab/Cilgavimab 300 + 300 mg IV group by Day 4 of the observation than in the other groups regardless of the ongoing concomitant anti-inflammation therapy (Laboratory parameters over time. CRP, C-reactive protein; IM, intamuscularly, IV, intravenously, mg, milligram, kg, kilogram; Regd, Regdanvimab. The lymphocyte levels did not differ significantly between patients, while the levels of CRP and D-Dimer were significantly lower in the Tixagevimab/Cilgavimab 300 + 300 mg IV group by Day 4 of the observation than in the other groups regardless of the ongoing concomitant anti-inflammation therapy.