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.
Subject(s)
Severe Acute Respiratory Syndrome , Virus Diseases , COVID-19ABSTRACT
With the development of COVID-19, even though increased global vaccination coverage, a super variant of SARS-CoV-2, Omicron, carrying a great number of mutations, has been verified its strong capacity of immune escape. An increased risk of SARS-CoV-2 reinfection or breakthrough infection should be concerned. We analyzed the humoral immune response of Omicron breakthrough infection and found its cross-neutralization against VOCs. We established mouse models to verify whether Omicron-specific RBD subunit boost immune response by immunizing Omicron-RBD recombinant proteins. The results suggest that an additional boost vaccination with Omicron-RBD protein could increase humoral immune response against both WT and current VOCs.
Subject(s)
COVID-19 , Breakthrough PainABSTRACT
A new detected SARS-CoV-2 variant Omicron (B.1.1.529) had reported from more than 80 countries. In the past few weeks, a new wave of infection driven by Omicron is in progress. Omicron Spike (S) protein pseudotyped virus was used to determine the effect of S mutations on its capacity of infectivity and immune evasion. Our results showed the lower entry efficiency and less cleavage ability of Omicron than D614G variant. Pseudotype-based neutralizing assay was performed to analyze neutralizing antibodies elicited by previously infection or the RBD-based protein subunit vaccine ZF2001 against the Omicron variant. Sera sampled at around one month after symptom onset from 12 convalescents who were previously infected by SARS-CoV-2 original strain shows a more than 20-fold decrease of neutralizing activity against Omicron variant, when compared to D614G variant. Among 12 individuals vaccinated by RBD subunit vaccine, 58.3% (7/12) sera sampled at 15-60 days after 3rd-dose vaccination did not neutralize Omicron. Geometric mean titers (GMTs, 50% inhibitory dose [ID50]) of these sera against Omicron were 9.4-fold lower than against D614G. These results suggested a higher risk of Omicron breakthrough infections and reduced efficiency of the protective immunity elicited by existing vaccines. There are important implications about the modification and optimization of the current epidemic prevention and control including vaccine strategies and therapeutic antibodies against Omicron variant.
Subject(s)
Breakthrough PainABSTRACT
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Spike protein that mediates coronavirus entry into host cells is a major target for COVID-19 vaccines and antibody therapeutics. However, multiple variants of SARS-CoV-2 have emerged, which may potentially compromise vaccine effectiveness. Using a pseudovirus-based assay, we evaluated SARS-CoV-2 cell entry mediated by the viral Spike B.1.617 and B.1.1.7 variants. We also compared the neutralization ability of monoclonal antibodies from convalescent sera and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine) and ZF2001 (RBD-subunit vaccine) against B.1.617 and B.1.1.7 variants. Our results showed that, compared to D614G and B.1.1.7 variants, B.1.617 shows enhanced viral entry and membrane fusion, as well as more resistant to antibody neutralization. These findings have important implications for understanding viral infectivity and for immunization policy against SARS-CoV-2 variants.
Subject(s)
Coronavirus Infections , COVID-19ABSTRACT
SARS-CoV-2 Spike-specific antibodies contribute the majority of the neutralizing activity in most convalescent human sera. Two SARS-CoV-2 variants, N501Y.V1 (also known as B.1.1.7 lineage or VOC-202012/01) and N501Y.V2 (B.1.351 lineage), reported from the United Kingdom and South Africa, contain several mutations in the receptor binding domain of Spike and are of particular concern. To address the infectivity and neutralization escape phenotypes potentially caused by these mutations, we used SARS-CoV-2 pseudovirus system to compare the viral infectivity, as well as the neutralization activities of convalescent sera and monoclonal antibodies (mAbs) against SARS-CoV-2 variants. Our results showed that N501Y Variant 1 and Variant 2 increase viral infectivity compared to the reference strain (wild-type, WT) in vitro. At 8 months after symptom onset, 17 serum samples of 20 participants (85%) retaining titers of ID50 >40 against WT pseudovirus, whereas the NAb titers of 8 samples (40%) and 18 samples (90%) decreased below the threshold against N501Y.V1 and N501Y.V2, respectively. In addition, both N501Y Variant 1 and Variant 2 reduced neutralization sensitivity to most (6/8) mAbs tested, while N501Y.V2 even abrogated neutralizing activity of two mAbs. Taken together the results suggest that N501Y.V1 and N501Y.V2 reduce neutralization sensitivity to some convalescent sera and mAbs.
ABSTRACT
Many countries around the world have all seen a sharp rise in COVID-19 cases as the second wave since the beginning of October 2020. Decline of antibodies response to severe acute respiratory syndrome coronavirus (SARS-CoV-2) that was reported exclusively in the early month increases the risk of reinfection for convalescent individuals. There is a current need to follow the maintenance of special antibodies against SARS-CoV-2. Here, we reported changes of antibodies against SARS-CoV-2 in convalescent patients over 8 months. Antibodies of all 20 participants targeting SARS-CoV-2 spike receptor binding-domain (RBD) had decreased from a mean OD450 value 1.78 to 0.38 over 8 months. The neutralizing antibody (NAb) titers decreased from the mean ID50 value 836 to 170. The NAb titers were significantly correlated with IgG level during 8 months (P<0.001). Furthermore, while RBD-specific IgG existence of 25% (5/20) convalescent plasma was undetectable, the NAb titers of 15% (3/20) convalescent plasma decreased below the threshold. In addition, compared to wild-type SARS-CoV-2 (S-D614), lower titers of neutralizing antibodies against its G614 variant were shown at 8 months after symptom onset. This study has important implications when considering antibody protection against SARS-CoV-2 reinfection.