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•SYN023-004: a large, one-year, randomized, double blind, controlled, rabies PEP study in Category III patients.•SYN023 is comprised of two humanized monoclonals against non-overlapping rabies virus epitopes.•SYN023 produces rapid and higher RVNA during the 2-week period after administration.•SYN023 safety profile appears similar to human rabies immunoglobulin. SYN023 is an anti-rabies monoclonal antibody mixture administered as part of post-exposure prophylaxis regimens. The rabies virus neutralizing antibody (RVNA) concentration generally accepted as an adequate immune response to vaccination is ≥ 0.5 IU/mL. Within 54 h of potential rabies exposure, 448 patients in two risk substrata of WHO Category III exposure were randomized to receive either 0.3 mg/kg SYN023 or 0.133 mL/kg human rabies immunoglobulin (HRIG) injected in and around the wound site(s) plus a course of rabies vaccination. Patients were followed for safety and absence of rabies for ≥ 365 days. GMT RVNA was higher with SYN023 throughout the 2-week post-treatment period. In the primary analysis group (n = 368), 99.4 % of SYN023 recipients versus 4.5 % of HRIG recipients had protective RVNA levels on Day 4. On Day 8, 98.1 % SYN023 versus 12.2 % HRIG recipients were protected. The SYN023:HRIG ratio of geometric mean titer of RVNA (RVNA GMTs) on Day 8 (19.42) exceeded the 10 % superiority margin (P < 0.0001) indicating higher Day 8 RVNA with SYN023. On Day 99, the SYN023:HRIG RVNA GMT ratio (0.66) was below the non-inferiority margin of 20 % (P = 0.9485) suggesting some moderation of vaccine immune response by SYN023 relative to HRIG. The ratio of percent SYN023:HRIG recipients achieving RVNA ≥ 0.5 IU/mL on Day 99 (0.98) met the non-inferiority margin of 20 % (P = 0.013) indicating anti-rabies immune response with SYN023 was non-inferior to HRIG despite this effect. There were no probable/confirmed rabies cases in any patient. Study regimens were well tolerated. SYN023 provided higher RVNA than HRIG soon after rabies exposure. By Day 99 post-treatment, GM RVNA with SYN023 was lower than HRIG, however, the percent of SYN023 recipients with a protective response was not inferior at this time point. No rabies cases were reported in the study. The SYN023 safety profile was acceptable. ClinicalTrials.gov ID: NCT03961555.

Since the beginning of the 2021 year, all the main six vaccines against COVID-19 have been used in mass vaccination companies around the world. Virus neutralization and epidemiological efficacy drop obtained for several vaccines against the B.1.1.7, B.1.351 P.1, and B.1.617 genotypes are of concern. There is a growing number of reports on mutations in receptor-binding domain (RBD) increasing the transmissibility of the virus and escaping the neutralizing effect of antibodies. The Sputnik V vaccine is currently approved for use in more than 66 countries but its activity against variants of concern (VOC) is not extensively studied yet. Virus-neutralizing activity (VNA) of sera obtained from people vaccinated with Sputnik V in relation to internationally relevant genetic lineages B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3 and Moscow endemic variants B.1.1.141 (T385I) and B.1.1.317 (S477N, A522S) with mutations in the RBD domain has been assessed. The data obtained indicate no significant differences in VNA against B.1.1.7, B.1.617.3 and local genetic lineages B.1.1.141 (T385I), B.1.1.317 (S477N, A522S) with RBD mutations. For the B.1.351, P.1, and B.1.617.2 statistically significant 3.1-, 2.8-, and 2.5-fold, respectively, VNA reduction was observed. Notably, this decrease is lower than that reported in publications for other vaccines. However, a direct comparative study is necessary for a conclusion. Thus, sera from “Sputnik V”-vaccinated retain neutralizing activity against VOC B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3 as well as local genetic lineages B.1.1.141 and B.1.1.317 circulating in Moscow.

We investigated the effectiveness of different COVID-19 vaccinations administered in Pakistan by studying the effect of inactivated virus, mRNA and vector formulations. This study in 916 participants was conducted between October 2021 and July 2022. Subjects receiving inactivated (A), mRNA (B), one-dose vector (C), and two-dose vector (D) vaccines were sampled at baseline, 6, 12, and 24 weeks. Serum IgG antibodies to wildtype Spike and its receptor binding domain (RBD) were measured. Pseudovirus particle-based neutralizing assays against wildtype, Delta, and JN.1 variants were performed. T cell IFN-γ responses to SARS-CoV-2 antigens were measured. Participants were aged 37.05 ± 14.44 years and comprised 48.6 % females. Baseline Spike seropositivity rose from 90 % to 96 % by 24 weeks; and 40 % to 90 % against RBD. Group B participants had the highest anti-RBD levels which peaked by 6 weeks. IgG RBD in group A and C increased up until 24 weeks. Anti-RBD levels were reduced in those over 50 years. At baseline neutralizing titers were present at 38.5 % against wildtype and in 34.2 % against Delta variants. Titers doubled in vaccine groups A-C by 12 weeks, with highest titers in B and lowest in group C participants. At baseline, neutralizing titers against the JN.1 variant were absent but low titers were evident in 10 % of participants after 12 weeks. T cell reactivity to SARS-CoV-2 increased from 31 % at baseline to 50 % in group A and 73 % in group B participants by 6 weeks after vaccination. Presence of immunity against wildtype and Delta variants in one-third of participants at baseline could be due to sub-clinical infections. Increase in humoral and cellular immunity was greater after mRNA as compared with inactivated vaccinations. As COVID-19 morbidity in the population remained low, our data supports effectiveness of multiple vaccine formulations in protecting against severe COVID-19 in this high transmission population.

The SYN023–006 study was conducted in WHO Category III rabies-exposed patient populations to assess the safety and efficacy of post-exposure prophylaxis that included either the monoclonal antibody mixture SYN023 or human rabies immunoglobulin (HRIG). This phase 3, double-blind, randomized, controlled trial was conducted at multiple clinical disease control sites in China. Patients were randomized 3:1 (stratified by study site) to wound infiltration with 0.3 mg/kg SYN023 or 20 IU/kg HRIG. All patients received thorough wound washing and 5 doses intramuscular Vero cell rabies vaccine. The composite primary study objective was to demonstrate: 1) superiority of Day 8 geometric mean (GM) concentration of serum rabies virus neutralizing antibodies (RVNA) with SYN023 versus HRIG (protocol-defined superiority margin: GM RVNA ratio 95 % confidence interval [CI] lower limit >1.2) and 2) no rabies in SYN023 recipients. Efficacy was evaluated in the Per-Protocol population. Safety endpoints included solicited and unsolicited adverse events (AEs) analyzed in all patients receiving any study treatment. Trial registration: ClinicalTrials.govNCT04644484. From 23 September 2020 to 26 June 2021, 537 male and 463 female patients were randomized (n = 750 SYN023, n = 250 HRIG). Day 8 GM RVNA was 4.339 IU/mL (standard error [SE]: 1.035) with SYN023 and 0.232 IU/mL (SE: 1.060) with HRIG. The SYN023:HRIG GM RVNA ratio was 18.695 (95 % CI: 16.440, 21.260) indicating superior RVNA with SYN023. No suspected rabies cases or deaths occurred. AEs were generally similar between treatment groups except greater local solicited AEs frequencies with HRIG (SYN023: 165/750 patients [22.0 %]; HRIG: 97/250 [38.8 %]). This study indicates that SYN023, a monoclonal antibody product, may be used as part of rabies post-exposure prophylaxis and provides superior protection sooner after exposure than HRIG.

•RSV F-specific antibodies did not correlate with protection against life-threatening RSV disease in infants.•Pre-existing acute RSV neutralizing antibodies did not correlate with protection against life-threatening RSV disease.•Acute RSV F-specific antibodies negatively correlated with patient age.•Convalescent RSV F-specific antibodies positively correlated with patient age for children over 2 months of age.•Acute RSV antibody titers showed no association with nasal RSV load. Humoral immune response against the pre-fusion (pre-F) conformation of respiratory syncytial virus (RSV) F protein has been proposed to play a protective role against infection. An RSV pre-F maternal vaccine has been recently approved in several countries to protect young infants against RSV. We aimed to assess serum IgG titers against the pre-F and post-F conformations of RSV F protein and their association with life-threatening RSV disease (LTD) in previously healthy infants. A prospective cohort study including hospitalized infants <12 months with a first RSV infection was conducted during 2017–2019. Patients with LTD required intensive care and mechanical respiratory assistance. RSV pre-F exclusive and post-F antibody responses were determined by post-F competition and non-competition immunoassays, respectively, and neutralizing activity was measured by plaque reduction neutralization test. Fifty-eight patients were included; the median age was 3.5 months and 41 % were females. Fifteen patients developed LTD. RSV F-specific antibody titers positively correlated with neutralizing antibody titers in acute and convalescent phases but, importantly, they did not associate with LTD. Acute RSV pre-F exclusive and post-F IgG titers negatively correlated with patient age (P = 0.0007 and P < 0.0001), while a positive correlation was observed between the fold changes in RSV F-specific antibody titers between convalescent and acute phase and patient age (P = 0.0014 and P < 0.0001). Infants ≤2 months exhibited significantly lower fold-changes in RSV F-specific and neutralizing antibody titers between convalescence and acute phase than older infants. Additionally, acute RSV antibody titers showed no correlation with nasal RSV load and, furthermore, nasal viral load was not associated with the development of LTD. This study highlights that protection against life-threatening RSV disease is not necessarily antibody-dependent. Further characterization of the immune response against RSV and its role in protection against severe disease is important for the development of the safest possible preventive strategies.

•Ormutivimab is the third recombinant human anti-rabies monoclonal antibody marketed in the world. In China, it is the first.•The study reported in this paper is the first phase IIb clinical study carried out in China. It further evaluates the activity, safety and immunogenicity of Ormutivimab combined with rabies vaccine, and recommends a reasonable dosage for phase III confirmatory clinical study.•In this study, the activity and safety of Ormutivimab combined with rabies vaccine were compared with that of commercial HRIG combined with vaccine and vaccinated alone.•In this study, the effects of different doses of Ormutivimab on active immunization of rabies vaccine were evaluated and compared with that of commercially available HRIG.•This study evaluated the dose correlation of Ormutivimab immunogenicity (anti-antibody) and the effect of anti-antibody on the activity. This study was a randomized, double-blind, parallel-controlled trail to evaluate the rabies virus neutralizing activity（RVNA）, safety and immunogenicity of Ormutivimab + rabies vaccine in Chinese healthy adults. Subjects were randomly and equally assigned to 4 groups (20 IU/kg Omtv + vaccine, 40 IU/kg Omtv + vaccine, 20 IU/kg HRIG + vaccine, and placebo + vaccine). Subjects received vaccine as the WHO Essen regime combined with Omutivimab、HRIG or placebo on Day 0. The study lasted for 43 days. A total of 240 subjects were simultaneously assigned to both FAS and SS. Fifty subjects with baseline RVNA > 0.05 IU/ml (detection limit) were excluded, 190 were included into mITT. All the subjects from 40 IU/kg Omtv + vaccine group had a protection level of RNVA (≥0.5 IU/ml, WHO) on Day 14, and those in 20 IU/kg Omtv + vaccine group and placebo + vaccine group converted positive 100 % on Day 28. In contrast to 20 IU/kg HRIG + vaccine and placebo + vaccine, Ormutivimab + vaccine provided a higher RVNA during Days 0 to 7. And RVNA in 40 IU/kg Omtv + vaccine and 20 IU/kg Omtv + vaccine groups were always higher than 20 IU/kg HRIG + vaccine group during the whole study. Although anti-Omtv antibody were detected in some subjects, it did not influence the RVNA. The incidence of adverse reactions was significantly lower in 20 IU/kg Omtv + vaccine group (17.2 %) than in 40 IU/kg Omtv + vaccine (36.7 %) and 20 IU/kg HRIG + vaccine groups (40.3 %). Compared with HRIG + vaccine and placebo + vaccine, Omtv + vaccine provided higher RNVA for earlier immune protection. The interference of Ormutivimab on the long-term immune protection induced by rabies vaccine is weaker than HRIG. At the same dose, the adverse reactions of Omtv + vaccine group were less than HRIG + vaccine group. Registration:ClinicalTrials.gov #NCT02559921.

•Protection appears earlier with SYN023 vs serum-derived immunoglobulin regimen.•SYN023 associated with limited suppression of vaccine response.•Safety profile of SYN023 post-exposure prophylaxis regimens is mild and manageable. SYN023-002 is a randomized, blinded, controlled study comparing rabies virus neutralizing activity (RVNA) and safety of SYN023, a monoclonal anti-rabies antibody mixture, to human-serum derived anti-rabies immunoglobulin (RIG) when administered with commercially available vaccines to healthy adult volunteers. Participants were randomized among 4 treatment groups (SYN023 + Imovax, SYN023 + RabAvert, HyperRab + Imovax, HyperRab + RabAvert). On Day 0, subjects received 1 dose of RIG (0.3 mg/kg SYN023 or 20 IU/mL HyperRab) and their first of 5 vaccine doses. The primary objective was to compare cumulative RVNA between SYN023 and HyperRab recipients. Secondary objectives were to compare safety and to assess SYN023 pharmacokinetics and immunogenicity. All 164 randomized subjects initiated treatment and were included in safety analyses. At least 34 subjects/treatment group received all treatment and had complete RVNA results, thus were included in the primary endpoint analysis. Mean RVNAs were approximately ten-fold higher in SYN023 recipients compared to HyperRab recipients until Day 14. From Day 14 onwards, mean RVNA was lower in SYN023 recipients, but remained above the RVNA level widely considered adequate (≥0.5 IU/mL) through Day 112 (study end). The point estimate of the cumulative RVNA (83.22% SYN023/HyperRab), but not the lower CI bound (90% CI: 66.06%, 104.83%), fell within the protocol-defined similarity margin. Each RIG + vaccine regimen appeared safe with mostly mild AEs and no serious or severe related events observed. Except injection site pain (22% HyperRab recipients vs. 6% SYN023 recipients), treatment-related AEs incidences were similar between RIGs. Anti-SYN023 antibodies were observed but had no apparent effects on PK or safety. SYN023 administered with commercially available vaccines provides adequate antibody coverage beginning earlier than other commercially available RIGs with an acceptable safety profile. Some suppression of vaccine response occurred, but RVNA levels ≥ 0.5 IU/mL were maintained throughout the relevant period. ClinicalTrials.gov #NCT02956746. Synermore biologics.

•Humoral immunity after SARS-CoV-2 Omicron breakthrough infections (BTI) was characterized using neutralizing and variant-specific antibody measurements.•Omicron-BTI patients showed robust neutralizing activity to all the WT, Delta, and Omicron strains in the convalescent phase.•The humoral characteristics of Omicron-BTI patients were between unvaccinated Omicron patients and uninfected vaccinees.•Our study suggests that cross-reactive vaccine-induced immunity was intensively stimulated after Omicron-BTI, which contributed to Omicron neutralization.•Measuring SARS-CoV-2 variant-specific antibody levels, as well as neutralizing activity, is useful for evaluating humoral immunity after breakthrough infection. SARS-CoV-2 Omicron breakthrough infection (Omicron-BTI) after vaccination has been frequently observed. A more detailed understanding of the humoral immunity against Omicron-BTI is required. We measured strain-specific live-virus based neutralizing activity, anti-spike IgG, and anti-receptor-binding domain (RBD) IgG titers in individuals with Omicron/BA.1-BTI and directly compared them with controls with diverse combinations of wild-type (WT) mRNA vaccination and infection history. Omicron-BTI individuals showed markedly higher neutralizing titers against all the WT, Delta, and Omicron strains in convalescent sera, compared with unvaccinated Omicron-infection individuals with only Omicron neutralizing activity. Similar tendencies were found in strain-specific anti-spike and anti-RBD IgG titers. The Omicron-specificity (BA.1/WT neutralizing ratio), Omicron-neutralizing efficiency per antibody unit, and anti-Omicron RBD-directivity of anti-spike antibodies in Omicron-BTI individuals were all significantly lower than those in unvaccinated Omicron-infection individuals, but they were equivalent to or higher than those in uninfected vaccinees. The induction of Omicron-specific neutralizing activity after Omicron-BTI was not weakened for eight months from the last vaccination. These findings suggest that cross-reactive vaccine-induced immunity was intensively stimulated following Omicron breakthrough infection, which contributed to Omicron neutralization. Measuring SARS-CoV-2 variant-specific antibody levels as well as neutralizing activity is useful for evaluating humoral immunity after breakthrough infection in the current situation of antigenic gaps between vaccinated and epidemic (Omicron sub-lineages) strains.

Coronavirus disease-2019 (COVID-19) remains a critical global health concern. We developed a fully automated, high-throughput competition immunoassay to elucidate how epitope recognition on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) correlates with neutralizing activity. Analysis of clinical samples from both SARS-CoV-2-infected and vaccinated individuals revealed that vaccination elicits significantly higher antibody titers across multiple S1 subunit epitopes compared to natural infection. Notably, median antibody levels against the receptor-binding motif (RBM) exceeded 50% in both cohorts, highlighting the RBM as a key target for antibody induction irrespective of immune origin. Furthermore, the strongest correlation with neutralizing activity was observed for antibodies directed against the broader S1 subunit, indicating that epitopes outside the RBM also contribute to neutralization. These findings underscore the importance of both RBM- and non-RBM-directed antibodies in effective immune defense against SARS-CoV-2. Our assay enables large-scale, reliable quantification of neutralizing antibodies and provides critical insights for developing improved diagnostic antigens and vaccine strategies aimed at eliciting robust, multi-epitope immune responses.

The emergence and rapid spread of the B.1.1.7 lineage (VOC-202012/01) SARS-CoV-2 variant has aroused global concern. The N501Y substitution is the only mutation in the interface between the RBD of B.1.1.7 and ACE2, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we assessed the neutralizing activity and binding affinity of a panel of 12 monoclonal antibodies against the wild type and N501Y mutant SARS-CoV-2 pseudovirus and RBD protein, respectively. We found that the neutralization activity and binding affinity of most detected antibodies (10 out of 12) were unaffected, although the N501Y substitution decreased the neutralizing and binding activities of CB6 and increased that of BD-23. These findings could be of value in the development of therapeutic antibodies.