The pharmacokinetics and safety comparison of Zamerovimab and Mazorelvimab monoclonal antibodies vs. HRIG in category III rabies post-exposure prophylaxis: a stratified analysis by wound characteristics.

The efficacy and safety of SYN023 (Zamerovimab and Mazorelvimab injection), the recombinant humanized anti-rabies virus monoclonal antibody mixture, combined with rabies vaccine in a WHO category III rabies post-exposure population: A randomized, double-blind, positive control, phase III clinical trial.

A phase 2b, Randomized, double blinded comparison of the safety and efficacy of the monoclonal antibody mixture SYN023 and human rabies immune globulin in patients exposed to rabies

Objective To investigate the early immune effects of rabies vaccine combined with human rabies immunoglobulin (HRIG). Methods Rapid fluorescent focus inhibition test (RFFIT) was used to test the titers of rabies virus neutralizing antibodies (RVNA). The titers of RVNA of persons who had exposed to rabies at degree III on day 0, day 1, day 7, day 14 and day 45 were compared. The dynamic curves and seroconversion rates (SCR) of RVNA in persons of different genders, age and vaccine regimens (Essen and Zagreb) groups were analyzed. Results No significant differences of SCR among different genders, age and vaccine regimens groups were observed on the same day. SCR could be 100% on day14 in different groups. The dynamic curves of RVNA within the first 14 days showed the models of gradual rise, rapid rise and rapid decline. Conclusions The dynamic curves of RVNA within the first 14 days varied when rabies vaccines were used in combination with HRIG, and not all subjects were proved to be protected based on the RVNA detection within this period. Key words: Rabies vaccine; Human rabies immunoglobulin; Rabies virus neutralizing antibody; Rapid fluorescent focus inhibition test

BackgroundA next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman–Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®).MethodsThis dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >−5% at D28. Safety was assessed up to 6 months after the last injection.ResultsNon-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines.ConclusionsIn a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines.Clinical Trials RegistrationNCT03965962.

Rabies Virus Neutralizing Activity, Safety, and Immunogenicity of Recombinant Human Rabies Antibody Compared with Human Rabies Immunoglobulin in Healthy Adults

BackgroundThis phase III clinical trial compared the immunogenicity and safety of a purified chick-embryo cell rabies vaccine (PCECV) administered according to a shortened post-exposure prophylaxis (PEP) 4-site/1-week intradermal regimen, compared with the currently recommended 2-site/Thai Red Cross (TRC) regimen.Methodology/Principal findingsThis controlled, open-label, multi-center study (NCT02177032) enrolled healthy individuals ≥1 year of age, randomized into 4 groups to receive intradermal PCECV according to one of the 2 regimens, with or without human rabies immunoglobulin (HRIG) administration at first visit (in adults only). Rabies virus neutralizing antibody (RVNA) concentrations and percentages of participants with RVNA concentrations ≥0.5 IU/mL (considered as adequate concentrations following PEP) were assessed up to day (D) 365 post-first vaccination. Non-inferiority of the 4-site/1-week regimen to the 2-site/TRC regimen was demonstrated if at D49, the lower limit of the 95% confidence interval (CI) for the difference between groups in the percentage of participants with adequate RVNA concentrations was >-5%. Of the 443 participants receiving the 4-site/1-week regimen, 88 adults received HRIG; 442 participants received the 2-site/TRC regimen (88 with HRIG). All participants achieved adequate RVNA concentrations by D14. At D49, the difference in percentage of participants with adequate RVNA concentrations between the 4-site/1-week and the 2-site/TRC groups was -1 (95%CI: -2.4–0.0); thus, non-inferiority was concluded. RVNA geometric mean concentrations were 18 IU/mL in 4-site/1-week groups and 12 IU/mL in 2-site/TRC groups at D14, and subsequently declined in all groups. RVNA concentrations were consistently lower in adults with HRIG administration than in those without. The 2 regimens had similar safety profiles. Of the 15 serious adverse events reported in 4-site/1-week groups and 19 in 2-site/TRC groups, none were vaccination-related.SignificanceThe data suggest that the 4-site/1-week regimen might be an alternative to current recommendations, with potential benefits in terms of improved cost-efficiency and compliance to vaccination.

It has not been reported that administration of combining rabies vaccines and immunoglobulin resulted in acute disseminated encephalomyelitis (ADEM) yet. This report described that an old man acquired ADEM after being administrated with purified Vero cell rabies vaccine (PVRV) and Human Rabies Immunoglobulin (HRIG). Then he was given intravenous and oral glucocorticoids. Simultaneously, rabies vaccination was continued with purified Chick embryo cell vaccines (PCECV) instead of PVRV. Furthermore, we analyzed the rabies virus neutralizing antibodies (RVNA) levels in the patient's blood at different time points after rabies vaccination. Collectively, we observed that PCECV vaccination did not affect the prognosis of ADEM, and glucocorticoid was crucial and effective, which had no significant influence on efficacy of PCECV.

Comparative Safety of Atorvastatin 80 mg Versus 10 mg Derived from Analysis of 49 Completed Trials in 14,236 Patients

BackgroundA serum-free, highly purified Vero rabies vaccine–next generation (PVRV-NG2) is under development. We conducted a phase III trial to describe the safety and immunogenicity profile of PVRV-NG2 compared with those of licensed purified Vero rabies vaccine (PVRV) in a simulated rabies postexposure prophylaxis (PEP) Zagreb regimen in Thailand.MethodsHealthy adults aged ≥18 years (n = 201) were randomized in a 2:1 ratio to receive PVRV-NG2 or PVRV in a rabies PEP Zagreb (days 0, 7, 21 [2-1-1]) regimen, with concomitant human rabies immunoglobulin (HRIG) at day 0. Immunogenicity end points included the proportion of participants with rabies virus–neutralizing antibody (RVNA) titers ≥0.5 IU/mL at days 0, 14, and 35. Safety outcomes were also assessed.ResultsA total of 199 participants completed the study (PVRV-NG2 n = 133, PVRV n = 66). In the PVRV-NG2 group and PVRV group, respectively, 91.0% (95% CI, 84.1%–95.6%) and 94.6% (95% CI, 85.1%–98.9%) had RVNA titers ≥0.5 IU/mL at day 14, increasing to 100% (95% CI, 96.8%–100%) and 100% (95% CI, 93.5%–100%) by day 35. The vaccines had similar safety profiles, and there were no safety concerns.ConclusionsPVRV-NG2 showed acceptable safety and immunogenicity profiles when co-administered with HRIG in a simulated PEP Zagreb regimen in healthy adults in Thailand.

Aim: The aims of the study were to evaluate the non-inferiority of the safety and immunogenicity of a new trial purified vero cell-cultured rabies vaccine (trial vaccine) in healthy subjects comparing with the control purified vero cell-cultured rabies vaccine (control vaccine) following Essen regimen and to evaluate the non-inferiority of the safety and immunogenicity of the trial vaccine following two intramuscular regimens, between Zagreb and Essen regimen. Methods: Serum samples were collected before vaccination and on d 7, 14, 35/42 post vaccination. Adverse events (AEs) were recorded for 30 d following each vaccination. This study was registered in the Chinese Clinical Trial Registry (ChiCTR-PPR-15007057). Results: There was no significant difference in the incidence of AEs, local and systemic reactions, among Zagreb group, Essen group, and control group. But the incidence of solicited AEs was a significant difference among the three groups (p = 0.0498). The incidence of solicited AEs was higher in Essen group than that in control group and Zagreb group (p = 0.0278, p = 0.0248). In the subjects whose antibodies were seronegative before vaccination, the seroconversion rates of antibodies among three groups were all 100.0% on d 14 and d 35/42. The Essen group was not inferior to the control group, and the Zagreb group was not inferior to the Essen group on d 14. On d 14 and d 35/42, the geometric mean concentration of the three groups was much higher than the immune protection level of 0.5 IU/ml. Conclusions: The trial vaccine had good safety and immunogenicity, and the trial vaccine is not inferior to the control vaccine. Abbreviations: PVRV: purified vero cell-cultured rabies vaccine; AE: adverse event; CI: confidence interval; GMC: geometric mean concentration; IM: intramuscular; NIFDC: National Institutes for Food and Drug Control; PPS: per-protocol set; SS: safety set; REFIT: Rapid Fluorescent Focus Inhibition Test; RVNA: rabies virus neutralizing antibody; WHO: World Health Organization.

Lack of access to rabies immunoglobulin (RIG) contributes to high rabies mortality. A recombinant human monoclonal antibody (SII RMAb) was tested in a postexposure prophylaxis (PEP) regimen in comparison with a human RIG (HRIG)-containing PEP regimen. This was a phase 2/3, randomized, single-blind, noninferiority study conducted in 200 participants with World Health Organization category III suspected rabies exposures. Participants received either SII RMAb or HRIG (1:1 ratio) in wounds and, if required, intramuscularly on day 0, along with 5 doses of rabies vaccine intramuscualarly on days 0, 3, 7, 14 and 28. The primary endpoint was the ratio of the day 14 geometric mean concentration (GMC) of rabies virus neutralizing activity (RVNA) as measured by rapid fluorescent focus inhibition test for SII RMAb recipients relative to HRIG recipients. One hundred ninety-nine participants received SII RMAb (n = 101) or HRIG (n = 98) and at least 1 dose of vaccine. The day 14 GMC ratio of RVNA for the SII RMAb group relative to the HRIG group was 4.23 (96.9018% confidence interval [CI], 2.59-6.94) with a GMC of of 24.90 IU/mL (95% CI, 18.94-32.74) for SII RMAb recipients and 5.88 IU/mL (95% CI, 4.11-8.41) for HRIG recipients. The majority of local injection site and systemic adverse reactions reported from both groups were mild to moderate in severity. A PEP regimen containing SII RMAb was safe and demonstrated noninferiority to HRIG PEP in RVNA production. The novel monoclonal potentially offers a safe and potent alternative for the passive component of PEP and could significantly improve the management of bites from suspected rabid animals. CTRI/2012/05/002709.

Bali Low.

BackgroundWe conducted an open-label trial using inactivated rabies vaccine (Imovax) as a neoantigen challenge after CAR-T therapy to assess predictors of vaccine response, the utility of a fractional escalating dose prime, and Imovax as a tool to assess ‘vaccine readiness’, even in patients receiving IVIG given that IVIG typically contains no rabies antibodies.Figure 1.Study designBlood was collected prior to and at 1, 2, and 4 weeks after completion of primary immunization and boost, and 26 weeks post-primary immunization. Rabies virus neutralizing antibodies (RVNA) were measured at each timepoint. Seroprotective response was defined as RVNA ≥ 0.5 IU/mL at week 4 post-boost, as defined by the World Health Organization (WHO).Figure 2.Rabies virus neutralizing antibody (RVNA) kinetics stratified by cohortA-B. RVNA kinetics in 10 healthy volunteers compared to BCMA (panel A) and CD19/CD20-CAR-T recipients (panel B) receiving a bolus prime versus fractional prime. The fractional prime was given as 6 escalating doses over 17 days. The horizontal dashed line indicates the World Health Organization (WHO) threshold for RVNA seroprotection (≥ 0.5 IU/mL).MethodsWe enrolled adults ≥ 6 months post–BCMA or CD19/CD20-CAR-T and healthy controls. Participants received a primary Imovax immunization, as a bolus dose or a fractional series of 6 escalating doses, followed by a bolus boost 6-10 weeks later (Fig 1). Rabies virus neutralizing antibodies (RVNA) were measured before and at 1, 2, and 4 weeks after prime and boost, and 26 weeks post-prime (week 4 post-boost RVNA ≥ 0.5 IU/mL = seroprotective response).Figure 3.Forest plot of univariate logistic regression model for predictors of rabies virus neutralizing antibody (RVNA) responseRVNA response was defined as RVNA ≥ 0.5 IU/mL at 4 weeks post-boost with the inactivated rabies vaccine (Imovax). Odds ratios and confidence intervals > 1 indicate specified predictors are associated with a greater likelihood of RVNA response. Predictor variables were measured at the time of first Imovax dose.ResultsWe enrolled 10 controls, 8 BCMA and 19 CD19/CD20-CAR-T recipients in the bolus prime arm, and 2 BCMA and 5 CD19/CD20-CAR-T recipients in the fractional prime arm. The median time from CAR-T to first vaccine was 10 months (IQR, 8-13). Seroprotective responses were observed in all controls, 4/8 (50%) BCMA and 3/19 (16%) CD19/CD20-CAR-T recipients in the bolus prime arm; and in 1/2 (50%) BCMA and 0/5 (0%) CD19/CD20-CAR-T recipients in the fractional prime arm (Fig 2). The RVNA kinetics of the responder in the fractional prime arm appeared similar to healthy controls, with an earlier and higher magnitude response than all other CAR-T recipients. BCMA-CAR-T, B cell count ≥ 20/uL, and higher switched memory B cell count were associated with higher odds of response (Fig 3). RVNA response had a positive predictive value (PPV) of 0.63 and a negative predictive value (NPV) of 0.74 for predicting responses to routine vaccines (Table 1). There were no serious related adverse events, and all participants completed the fractional prime.ConclusionWe used the rabies vaccine as an in vivo immune challenge to interrogate humoral immunocompetence after CAR-T. BCMA-CAR-T recipients were more likely to respond to Imovax than CD19/CD20-CAR-T recipients. A fractional prime could not rescue non-responders but may boost immunogenicity in responders. RVNA response had a moderate PPV and high NPV for predicting responses to routine vaccines and may be a valuable tool for determining vaccine readiness after CAR-T.DisclosuresJoshua A. Hill, MD, AlloVir: Advisor/Consultant|AlloVir: Grant/Research Support|Century Therapeutics: Advisor/Consultant|CSL Behring: Advisor/Consultant|ExeVir Bio: Advisor/Consultant|GeoVax: Advisor/Consultant|GeoVax: Grant/Research Support|Gilead Australia: Honoraria|Grifols: Advisor/Consultant|Karius: Advisor/Consultant|Karius: Travel|Medscape: Advisor/Consultant|Merck: Grant/Research Support|Moderna, Inc.: Board Member|Modulus: Advisor/Consultant|Oxford immunotec: Grant/Research Support|Sanofi Pasteur Inc.: Advisor/Consultant|Senti BioSciences, Inc: Advisor/Consultant|SymBio: Advisor/Consultant|Takeda: Grant/Research Support|Takeda Netherlands: Honoraria|UpToDate: Royalties

Monoclonal antibodies are successful biologics in treating a variety of diseases, including the prevention or treatment of viral infections. CL184 is a 1:1 combination of two human monoclonal IgG1 antibodies (CR57 and CR4098) against rabies virus, produced in the PER.C6 human cell line. The two antibodies are developed as replacements of human rabies immune globulin (HRIG) and equine rabies immune globulin (ERIG) in postexposure prophylaxis (PEP). The rapid fluorescent focus inhibition test (RFFIT) is a cell-based virus neutralization assay which is usually performed to determine the biological potency of a vaccine and to measure the levels of protection against rabies in humans and animals. In order to confirm the suitability of this assay as a pharmacodynamic assay, we conducted a validation using both HRIG- and CL184-spiked serum samples and sera from vaccinated donors. The validation results met all analytical acceptance criteria and showed that HRIG and CL184 serum concentrations can be compared. Stability experiments showed that serum samples were stable in various suboptimal conditions but that rabies virus should be handled swiftly once thawed. We concluded that the assay is suitable for the measurement of polyclonal and monoclonal rabies neutralizing antibodies in clinical serum samples.

The currently recommended intradermal regimen for post-exposure prophylaxis spreads over a month period which many times lead to low compliance from the patients. There is a need to introduce and evaluate short course regimens to overcome this problem. This study was conducted to evaluate the immunogenicity and safety of a “new one week intradermal regimen” for rabies post-exposure prophylaxis. A total of 80 healthy adult volunteers were enrolled and allocated randomly either to purified chick embryo cell (PCECV) rabies vaccine or purified verocell rabies vaccine (PVRV), 40 in each group. Each subject received intradermally one of the vaccines, using the one week regimen (4–4-4). Blood samples were collected on Days 0, 7, 14, 28,180 and 365 for estimation of rabies virus neutralizing antibody (RVNA) concentration. The sera samples were analyzed by rapid fluorescent focus inhibition test (RFFIT). All subjects in both the groups had adequate RVNA concentration of ≥ 0.5 IU/mL from day 14 to till day 180 and the difference of geometric mean concentrations between the two groups was not significant (p > 0.606). Further to assess the immunological memory produced by this new regimen, a “single visit four site” intradermal booster vaccination was given to those who did not have adequate RVNA concentration on day 365. This resulted in a quick and enhanced RVNA concentration in these subjects thus denoting a successful anamnestic response. The incidence of adverse events was 8.3% in PCECV group and 1.6% in PVRV group (p = 0.001) and the regimen was well tolerated without any dropouts. In conclusion, the new “one week intradermal regimen” is immunogenic and safe for rabies post-exposure prophylaxis and needs to be further evaluated in persons exposed to rabies.