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Read about French chemis and microbiologist Louis Pasteur, one of the first scientists to understand the importance of microorganisms both good and bad.

Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development. Optimized srRNA vaccines generate protective immunity (according to the WHO defined thresholds) at doses up to 1,000,000-fold lower than mRNA in female mouse models of influenza and rabies. Clinically, safety and immunogenicity of RBI-4000, an srRNA vector encoding the rabies glycoprotein, was evaluated in a Phase I study (NCT06048770). RBI-4000 was able to elicit de novo protective immunity in the majority of healthy participants when administered at a dose of 0.1, 1, or 10 microgram (71%, 94%, 100%, respectively) in a prime-boost schedule. Similarly, we observe immunity above the WHO benchmark of protection following a single administration in most participants at both 1 and 10 microgram doses. There are no serious adverse events reported across all cohorts. These data establish the high therapeutic index of optimized srRNA vectors, demonstrating feasibility of both low dose and single dose approaches for vaccine applications. Here the authors report an optimized self-replicating RNA (srRNA) vaccine approach that generates protective immunity at much lower doses than mRNA vaccines in mice. In a Phase 1 study using rabies glycoprotein as antigen, they show robust immune responses at doses as low as 0.1 µg, with a favorable safety profile.

Rabies is a zoonotic viral encephalitis that is endemic in many countries and confers a high mortality. Licensed vaccines require several doses to ensure efficacy. To investigate a logistically favorable approach, we assessed the safety and immunogenicity of ChAd155-RG, a novel investigational rabies vaccine using a replication-defective chimpanzee adenovirus vector. We conducted a first-in-human, phase 1, randomized, double-blind, dose-escalation trial comparing ChAd155-RG with a licensed inactivated vaccine (RabAvert) in healthy adults. Participants received either RabAvert at standard dosing or ChAd155-RG at a low dose for one immunization or a high dose for one or two immunizations. To assess safety, we evaluated reactogenicity, unsolicited adverse events, and thrombotic events. To measure immunogenicity, we measured rabies viral neutralizing antibody (VNA) titers and anti-ChAd155 neutralizing antibodies. Mild to moderate systemic reactogenicity and transient lymphopenia and neutropenia were more common among recipients of ChAd155-RG compared with those who received RabAvert. No thrombotic events or serious adverse events were reported. Only the groups receiving RabAvert or two doses of high-dose ChAd155-RG achieved 100 % seroconversion, and seroprotection was most durable in the RabAvert group. Most participants had preexisting anti-vector antibodies, which were boosted by ChAd155-RG. Baseline and post-vaccination anti-vector antibody titers were negatively associated with post-vaccination rabies VNA titers. In this phase 1 clinical trial, a novel rabies vaccine using a simian adenovirus vector was safe and tolerable, but generated lower, less durable rabies VNA titers than a standard inactivated rabies virus vaccine, which may be due to preexisting, anti-vector immunity.

•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.

Rabies is almost invariably fatal. A rabies monoclonal antibody (RmAb) was approved in India in 2016 for passive prophylaxis. This post-marketing study aimed to evaluate the long-term safety, immunogenicity, and efficacy of a post-exposure prophylaxis (PEP) regimen containing RmAb. This phase 4, open-label, randomised, active-controlled study was conducted at 15 tertiary care hospitals in India. Patients aged 2 years or older with WHO category 3 rabies exposure by a suspected rabid animal were eligible if the exposure occurred less than 72 h before enrolment, or less than 24 h before enrolment for exposures to the face, neck, hand, or fingers. Participants were randomly assigned (3:1) to receive either RmAb (Rabishield; Serum Institute of India, Pune, India) plus a purified Vero cell rabies vaccine (PVRV; Rabivax-S) or equine rabies immunoglobulin (ERIG; Equirab) plus PVRV as PEP. In each treatment group, patients were further randomly assigned (1:1) to receive PVRV either intradermally or intramuscularly. Study group allocation was done using a permuted block design with random block sizes of eight. A central randomisation list was generated before the study start and randomisation was performed with an interactive web response system. Participants and site personnel were not masked to group assignment. RmAb (3·33 IU/kg) and ERIG (40 IU/kg) were infiltrated into and around the wounds only on day 0 as per WHO 2018 recommendations. PVRV was administered 1·0 mL intramuscularly (days 0, 3, 7, 14, and 28) or 0·1 mL plus 0·1 mL intradermally (days 0, 3, 7, and 28). The primary outcome was treatment-related serious adverse events up to 365 days after immunisation, analysed in the safety analysis set (all participants who received at least one dose of vaccine with treatment). Geometric mean concentrations of rabies virus neutralising antibody were measured in a subset of patients. This study is registered with Clinical Trial Registry–India (CTRI/2019/06/019622) and is completed. 4059 participants were enrolled between Aug 21, 2019, and March 31, 2022, and randomly assigned. A total of 3994 participants (3001 male, 993 female) were treated (2996 RmAb plus PVRV, 998 ERIG plus PVRV), of which 3622 (90·7%) participants completed the 1-year follow-up. 11 adverse events were considered causally related to RmAb plus PVRV and 17 were considered causally related to the ERIG plus PVRV regimen. Most adverse events were mild and transient. Seven serious adverse events occurred in the RmAb group and all were causally unrelated. One causally related serious adverse event was reported in the ERIG group. On day 14, the geometric mean concentrations increased to 16·05 IU/mL (95% CI 13·25–19·44) in the RmAb group and 13·48 IU/mL (9·51–19·11) in the ERIG group (point estimate 1·19 [95% CI 0·82–1·72]). No patient developed rabies during the 1-year follow-up period. RmAb was safe and well tolerated and showed protective efficacy against rabies. A PEP regimen containing RmAb plus PVRV was immunogenic with long-term persistence of immune response. Serum Institute of India.

The aim of this study is to demonstrate that the freeze-dried human rabies vaccine (Vero cell), administered in a four-dose schedule (2-1-1) to the 10–60 years old population, has immunogenicity that is not inferior to the approved five-dose schedule and similar vaccines with a four-dose schedule, and to evaluate its safety. A total of 1800 individuals were enrolled and divided into three groups: four-dose test group, four-dose control group, and five-dose control group. The rabies virus neutralizing antibodies were measured using the Rapid Fluorescent Focus Inhibition Test to assess immunogenicity, and the incidence of adverse events and serious adverse events were statistically analyzed. The seroconversion rates 14 days after the first dose and 14 days after the complete course of vaccination were 100% in all three groups. The antibody GMC of the four-dose test group was higher than that of the five-dose control group, but slightly lower than the four-dose control group. Seven days after the first dose, both four-dose regimen groups showed higher seroconversion rates and antibody GMCs compared to the five-dose regimen group, proving that the immunogenic effect of the four-dose regimen seven days post-first vaccination is superior to the five-dose regimen. The overall incidence of adverse events showed no significant difference between the four-dose test group and the five-dose control group, but was significantly lower in the four-dose test group compared to the four-dose control group. The vaccine in the four-dose test group is equivalent in immunogenic effect to the four-dose control group vaccine and superior to the five-dose control group vaccine; the safety of the vaccine in the four-dose test group is equivalent to the five-dose control group vaccine and superior to the four-dose control group vaccine. clinicaltrials.gov number: NCT05549908.

To evaluate the safety, immunogenicity and immune persistence of a lyophilized purified human diploid cells rabies vaccine in healthy and previously unvaccinated people in a simulated rabies post-exposure prophylaxis, by traditional 5-dose Essen regimen and abbreviated 4-dose Zagreb regimen. A cohort of 1800 healthy participants aged 10–60 years old were randomized into three groups: 5-dose test group (T5, Essen regimen), 5-dose control group (C5, Essen regimen) and 4-dose test group (T4, Zagreb regimen) according to the ratio of 1:1:1, and inoculated with trial vaccine or control vaccine separately to analyze the safety of vaccine as well as rabies antibody levels before and after vaccination. Adverse reactions (AEs) mainly occurred after the initial dose of immunization, which were mostly mild (grade 1) in severity. The incidence of total AEs in T4 (38 %) was lower than that in C5 (45 %) (P = 0.02) from the initial dose to 28 days after the final dose; fever rate in T5 (12 %, P = 0.01) and T4 (13 %, P = 0.03) was lower than that in C5 (17 %). No vaccine-related serious AEs (SAEs) were observed. Seroconversion rates reached 100 % in all three groups 14 days following the first dose. Moreover, the seroconversion rate was 98 %, 96 % and 98 % 12 months following the first dose in T5, C5 and T4, respectively. Both T5 and T4 displayed higher neutralizing antibodies geometric mean concentration (GMC) and geometric mean increase (GMI) compared to those in C5 on day 7, day 14, and 12 months after the first dose, as well as on day 14 after the last dose. There were no significant differences in the incidence of AEs, seroconversion rate, GMC and GMI between T5 and T4. The trial vaccine administered following both Essen regimen and Zagreb regimen shows good safety, immunogenicity and immune persistence, and the trial vaccine is not inferior to the control vaccine. Clinical Trials Registration:NCT03971370.

The Zagreb and Essen regimens are comparable in terms of immunogenicity; however, how these regimens impact the immunogenicity of booster vaccination remains unknown. We conducted a clinical trial to assess the immunogenicity of booster vaccination with a purified Vero cell rabies vaccine after primary vaccination with the Zagreb or Essen regimens. This randomized, open-label, controlled, phase 3 trial, conducted in Shangyu City and Shengzhou City, Zhejiang Province, China, was divided into the primary and booster vaccination phases. After screening, all eligible participants were allocated to groups A, B, C, D, E, or F. Groups A, B, and C received the Zagreb regimen as the primary vaccine, while groups D, E, and F received the Essen regimen. The booster vaccination was conducted 6 months after the primary vaccination. Groups B and E received one dose of the booster, while groups C and F received two doses. Blood samples were collected before the booster, at 14 days after the booster, and at approximately 6 months after the booster. Safety was assessed from the first booster dose to 6 months after the final dose. A total of 718 participants completed the booster vaccination. The antibody positive rate (APR) of groups B, C, E, and F after the booster was 100%. The antibody titer rose significantly even after one booster, and was much higher in groups B (48.80 IU/ml) and C (64.38 IU/ml) (receiving Zagreb) than in groups E (34.25 IU/ml) and F (42.89 IU/ml) (receiving Essen). Although the incidence of ARs was higher in groups B (11.22%) and C (15.79%) than in groups E (3.68%) and F (10.87%), they were all mild and short-lived. No serious adverse events (SAEs) associated with vaccination were reported. The immunogenicity of booster vaccination after the Zagreb regimen was significantly higher than that after the Essen regimen. One booster may be sufficient to raise the antibody titer above the 0.5 IU/mL target. Clinical trial registration: This trial is registered at http://www.chinadrugtrials.org.cn/index.html under the registration number CTR20210426 at 08/03/2021.

Vaccines based on mRNA coding for antigens have been shown to be safe and immunogenic in preclinical models. We aimed to report results of the first-in-human proof-of-concept clinical trial in healthy adults of a prophylactic mRNA-based vaccine encoding rabies virus glycoprotein (CV7201). We did an open-label, uncontrolled, prospective, phase 1 clinical trial at one centre in Munich, Germany. Healthy male and female volunteers (aged 18–40 years) with no history of rabies vaccination were sequentially enrolled. They received three doses of CV7201 intradermally or intramuscularly by needle-syringe or one of three needle-free devices. Escalating doses were given to subsequent cohorts, and one cohort received a booster dose after 1 year. The primary endpoint was safety and tolerability. The secondary endpoint was to determine the lowest dose of CV7201 to elicit rabies virus neutralising titres equal to or greater than the WHO-specified protective antibody titre of 0·5 IU/mL. The study is continuing for long-term safety and immunogenicity follow-up. This trial is registered with ClinicalTrials.gov, number NCT02241135. Between Oct 21, 2013, and Jan 11, 2016, we enrolled and vaccinated 101 participants with 306 doses of mRNA (80–640 μg) by needle-syringe (18 intradermally and 24 intramuscularly) or needle-free devices (46 intradermally and 13 intramuscularly). In the 7 days post vaccination, 60 (94%) of 64 intradermally vaccinated participants and 36 (97%) of 37 intramuscularly vaccinated participants reported solicited injection site reactions, and 50 (78%) of 64 intradermally vaccinated participants and 29 (78%) of 37 intramuscularly vaccinated participants reported solicited systemic adverse events, including ten grade 3 events. One unexpected, possibly related, serious adverse reaction that occurred 7 days after a 640 μg intramuscular dose resolved without sequelae. mRNA vaccination by needle-free intradermal or intramuscular device injection induced virus neutralising antibody titres of 0·5 IU/mL or more across dose levels and schedules in 32 (71%) of 45 participants given 80 μg or 160 μg CV7201 doses intradermally and six (46%) of 13 participants given 200 μg or 400 μg CV7201 doses intramuscularly. 1 year later, eight (57%) of 14 participants boosted with an 80 μg needle-free intradermal dose of CV7201 achieved titres of 0·5 IU/mL or more. Conversely, intradermal or intramuscular needle-syringe injection was ineffective, with only one participant (who received 320 μg intradermally) showing a detectable immune response. This first-ever demonstration in human beings shows that a prophylactic mRNA-based candidate vaccine can induce boostable functional antibodies against a viral antigen when administered with a needle-free device, although not when injected by a needle-syringe. The vaccine was generally safe with a reasonable tolerability profile. CureVac AG.

In healthy adults, intradermal (ID) administration of a double dose of 0.1 mL of human diploid cell culture rabies vaccine over 2 visits (days 0 and 7) was safe and not inferior to the single-dose 3-visit ID schedule. Abstract Background The existing 4-week preexposure rabies vaccination schedule is costly and often not practicable. Shorter effective schedules would result in wider acceptance. Methods We conducted a noninferiority trial in 500 healthy adults comparing the safety and immunogenicity of a 2-visit (days 0 and 7) intradermal (ID) primary vaccination (2 doses of 0.1 mL ID of the human diploid cell culture rabies vaccine [HDCV] at days 0 and 7) vs a standard 3-visit schedule (single dose of 0.1 mL ID at days 0, 7, and 28). One year to 3 years after primary vaccination, a single booster dose of 0.1 mL ID of HDCV was given to evaluate the anamnestic rabies antibody response. The primary endpoint for immunogenicity was the percentage of subjects with an adequate antibody level >0.5 IU/mL 7 days after the booster injection. The safety endpoint was the proportion of participants developing adverse reactions following the primary vaccination and/or booster dose. Results All subjects in both study groups possessed a rabies antibody titer >0.5 IU/mL on day 7 following the booster dose. Following the booster dose, subjects exposed to the double-dose 2-visit ID schedule had a geometric mean titer of 37 IU/mL, compared with 25 IU/mL for the single-dose 3-visit schedule (P < .001). Local reactions at the injection site following primary vaccination were mild and transient. Conclusions In healthy adults, ID administration of a double dose of 0.1 mL of HDCV over 2 visits (days 0 and 7) was safe and not inferior to the single-dose 3-visit schedule. Clinical Trials Registration NCT01388985, EudraCT 2011-001612-62.