The real-world effectiveness of an intranasal spray A8G6 antibody cocktail in the post-exposure prophylaxis of COVID-19 (preprint)

ABSTRACT

BackgroundDue to the continuous appearance of novel SARS-CoV-2 variants that are resistant to approved antibodies and leading to the epidemic rebound, several approved neutralizing antibodies have been paused for their usage against COVID-19. Previously, we identified A8G6, an antibody combination of two synergic SARS-CoV-2 neutralizing antibodies 55A8 and 58G6, that showed broad neutralizing activities against Omicron variants. When administrated by the nasal spray delivery system, A8G6 showed promising efficacy in COVID-19 animal models and also showed favorable safety profile in preclinical models as well as in a first-in-human trial. The aim of this study is to evaluate the real-world efficacy of A8G6 neutralizing antibody nasal spray in post-exposure prevention of COVID-19. MethodsFrom November 27, 2022 to January 31, 2023, an open-label, non-randomized, two-arm, blank-controlled, investigator-initiated trial was conducted in Chongqing, China. High-risk healthy participants (18-65 years) within 72 hours after close contact to SARS-CoV-2 infected individuals were recruited and received a three-dose (1.4 mg/dose) A8G6 nasal spray treatment daily or no treatment (blank control) for 7 consecutive days. The primary end points were 1) the occurrence of positive SARS-CoV-2 RT-PCR cases in A8G6 treated group vs blank control group at the end of day 7; 2) time to SARS-CoV-2 positive conversion at the end of day 7. The secondary end points were 1) viral load of SARS-CoV-2 when participants became SARS-CoV-2 positive; 2) the time from SARS-CoV-2 infection to negative COVID-19 conversion. Safety end point of the nasal spray AG86 was analyzed by recording adverse events during the whole course of this trial. This study was registered with Chictr.org (ChiCTR2200066416). FindingsOf 513 enrolled participants, 173 in the A8G6 treatment group and 340 in the blank-control group were included in the analysis. SARS-CoV-2 infection occurred in 151/340 (44.4%) subjects in the blank control group and 12/173 (6.9%) subjects with the A8G6 treatment group. The result indicates that the intranasal spray A8G6 reduces the risk of SARS-CoV-2 infection (HR=0.12, 95% CI, 0.07-0.22; p<0.001). The prevention efficacy of the A8G6 treatment within 72-hours exposure was calculated to be 84.4% (95% CI 74.4%-90.4%). Moreover, compared to the blank-control group, the time from the SARS-CoV-2 negative to the positive COVID-19 conversion was significantly longer in the AG86 treatment group (mean time 3.4 days in the A8G6 treatment group vs 2.6 days in the control group, p=0.019). In the secondary end-point analysis, the A8G6 nasal treatment had no effects on the viral load at baseline SARS-CoV-2 RT-PCR positivity and the time of the negative COVID-19 conversion (viral clearance). Finally, 5 participants (3.1%) in the treatment group reported general adverse effects. We did not observe any severe adverse effects related to the A8G6 treatment in this study. InterpretationIn this study, the intranasal spray AG86 antibody cocktail showed potent efficacy for prevention of SARS-CoV-2 infection in close contacts of COVID-19 patients. FundingChongqing Biomedical R&D Major Special Project, Project (No. CSTB2022TIAD-STX0013), Chongqing Science and Health Joint Medical High-end Talent Project (No. 2022GDRC012), Science and Technology Research Program of Chongqing Municipal Education Commission (No. KJZD-K202100402), CQMU Program for Youth Innovation in Future Medicine (No. W0073). Research in contextO_ST_ABSEvidence before the studyC_ST_ABSTwo potent neutralizing antibodies 55A8 and 58G6 against SARS-CoV-2 were identified from the plasma of COVID-19 convalescent patients. In our previous studies, the synergetic neutralization of the antibody combination of 55A8 and 58G6 (A8G6) had been shown in structural mechanism, as well as in vitro and in vivo. Pre-clinical evaluation of A8G6 nasal spray showed promising efficacy against Omicron BA.4/5 infection in golden syrian hamsters challenged with live virus. In a first-in-human trial, A8G6 also showed favorable safety profile and nasal concentration over IC90 of neutralization activity against Omicron BA.4/5. The preliminary data showed that the intranasal spray A8G6 had the excellent efficacy, safety and druggability to protect against COVID-19. Added value of this studyThis is the first human trial showing that a nasal spray of neutralizing antibody cocktail is efficacious in preventing SARS-CoV-2 infection but is not efficacious in the post-infection treatment of COVID-19. In the Omicron wave of the COVID-19 pandemic in China in November, 2022, COVID-19 close contacts receiving the A8G6 treatment in the designated quarantine hotels showed a significantly lower incidence of SARS-CoV-2 infection. Additionally, the A8G6 treatment delayed time from exposure to the diagnosis of the COVID-19 positivity (median time 3.4 days in the treatment group vs 2.6 days in the control group). Furthermore, we analyzed the effects of the A8G6 treatment on the clinical status of close contacts who became infected with SARS-CoV-2. Results suggests that there were no significant differences in viral load of SARS-CoV-2 at the beginning of positive infection and the time of the viral clearance between A8G6 treatment and blank control groups. Overall, the trial result is consistent with the mechanism of action of nasal spray antibody cocktail for the prevention of SARS-CoV-2 infection. Finally, low safety risk of the nasal spray A8G6 was also shown in the trial. Implications of all the available evidenceWe observed the use of A8G6 to reduce the risk of SARS-CoV-2 infection. This study provided supporting evidences for the real-world effectiveness and safety of the nasal spray A8G6 among high-risk close contacts in the post-exposure prevention of COVID-19 during the Omicron BA.5.2 wave in China. This is the first proof of concept of using nasal spray neutralizing antibody for the prevention of viral infection. It implicates that the promising efficacy of the nasal spray A8G6 makes it possible for the fast-acting prevention in future COVID-19 waves.