Purified Vero Cell Rabies Vaccine Research Articles

Safety and immunogenicity of a serum-free purified Vero rabies vaccine in comparison with the rabies human diploid cell vaccine (HDCV; Imovax® Rabies) administered in a simulated rabies post-exposure regimen in healthy adults

A new generation, serum-free, antibiotic-free, purified Vero rabies vaccine (PVRV-NG; Sanofi) has been developed based on the same Pitman-Moore viral strain used for the currently licensed purified Vero cell rabies vaccine (PVRV; Verorab®, Sanofi) and human diploid cell vaccine (HDCV; Imovax® Rabies, Sanofi). PVRV-NG has demonstrated a satisfactory safety profile and induces robust immune responses, with non-inferiority demonstrated versus PVRV when given as a three-dose pre-exposure prophylaxis (PrEP) regimen in healthy children and adults. Here, we evaluated the safety and immunogenic non-inferiority of PVRV-NG compared to HDCV when administered as simulated post-exposure prophylaxis (PEP), with concomitant administration of human rabies immunoglobulin (HRIG), in healthy adults in the USA. Participants were vaccinated according to the 5-dose Essen intramuscular regimen (4-week, 1-injection site regimen, with a single dose given on days 0, 3, 7, 14 and 28) for PEP, with concomitant HRIG administered on day 0. Rabies virus neutralising antibodies (RVNA) were evaluated on days 0, 14, 28 and 42. Non-inferiority of PVRV-NG compared with HDCV was shown if the lower limit of the 95 % confidence interval (CI) for the difference in seroconversion rates (RVNA titers ≥ 0.5 IU/mL on day 14) between PVRV-NG and HDCV was above the non-inferiority margin of –5 %. Safety was evaluated after each vaccination and monitored throughout the study. The difference in seroconversion rate between the PVRV-NG and HDCV groups was –2.8 % (95 % CI, –8.08 to 4.20), indicating that non-inferiority was not demonstrated. The seroconversion rate was < 99 % in both study groups on day 14. There were no major safety concerns identified, and PVRV-NG demonstrated a similar safety profile to HDCV.

Safety of purified Vero cell rabies vaccine manufactured in Pakistan: A comparative analysis of intradermal and intramuscular routes

Background Rabies vaccines are conventionally given via the intramuscular (IM) route; however, switching the route of administration from IM to intradermal (ID) without affecting efficacy can be advantageous in terms of cost, dosing, and time. Hence, it is indispensable to evaluate its safety along different routes. This study was carried out to ascertain the frequency of adverse drug events (ADEs) and associated factors, as well as to compare safety based on the IM and ID routes. Methods A prospective observational study was carried out on 184 individuals with rabies exposure. The vaccination schedules for post-exposure prophylaxis (PEP) included 0.2 milliliter (ml) of purified Vero cell rabies vaccine (PVRV) administered ID at two different sites with 0.1ml each on days 0, 3, and 7 in first group (3-dose regimen ID) and 0.5 ml administered IM on days 0, 3, 7, 14, and 28 in the second group (5-dose regimen IM). The safety of the vaccines was determined by reviewing ADEs during physical examinations and follow-up. ADEs were characterized by local and systemic effects. Results Of the total, 99 (53.80%) patients reported ADEs. Those who reported local and systemic ADEs were 80 (43.48%) and 59 (32.06%), respectively, while simultaneous occurrence was reported in 40 (40.40%) patients. The most frequent local ADE 76 (41.30%) reported was pain followed by erythema 18 (9.78%). Additionally, fever was in highest proportion 25 (13.59%) for systemic effects, followed by headache 15 (8.15%). The patients reported with ADEs by the IM and ID routes was comparable (p > 0.05). Similarly, both local and systemic effects were also comparable (p > 0.05). Conclusion Half of the study participants reported ADEs. Almost similar proportions of local and systemic effects were observed. Likewise, the ADEs recorded were comparable for both routes. PVRV carries very low safety concerns with either route for administration.

Safety and immunogenicity of a serum-free purified Vero rabies vaccine in healthy adults: A randomised phase II pre-exposure prophylaxis study

A serum-free, highly purified Vero cell rabies vaccine (PVRV-NG) is under development. We previously demonstrated that pre-exposure prophylaxis (PrEP) with PVRV-NG had a satisfactory safety profile and was immunogenically non-inferior to the licensed purified Vero cell rabies vaccine in adults. Here, we evaluated the safety and immunogenic non-inferiority of PrEP with PVRV-NG compared to the licensed human diploid cell vaccine (HDCV) in healthy adults (NCT01784874). Participants received three vaccinations (days 0, 7, and 28) as PrEP with or without a booster injection after 12 months. Rabies virus neutralising antibodies (RVNA) were evaluated on days 0, 28 (subgroup only), and 42, and Months 6, 12, and 12 + 14 days (booster group only). Non-inferiority (first primary objective) was based on the proportion of participants with RVNA titres ≥ 0.5 IU/mL (World Health Organization criteria for seroconversion) on day 42, expected to be ≥ 99% (second primary objective). Safety was evaluated after each dose and monitored throughout the study. At day 42, PVRV-NG was non-inferior to HDCV and the first primary objective was met; seroconversion was observed for 98.3% of PVRV-NG recipients and 99.1% of HDCV recipients. As < 99% of participants in the PVRV-NG group had RVNA titres ≥ 0.5 IU/mL, the second primary objective was not met. Booster vaccination produced a strong increase in RVNA titres for all groups, primed with PVRV-NG or HDCV. RVNA geometric mean titres tended to be higher for HDCV than PVRV-NG primary vaccine recipients. In a complementary evaluation using alternative criteria for seroconversion (complete virus neutralization at 1:5 serum dilution), 99.6% and 100% of participants in the PVRV-NG and HDCV groups, respectively, achieved seroconversion across the vaccine groups. No major safety concerns were observed during the study. PVRV-NG was well tolerated, with a similar safety profile to HDCV in terms of incidence, duration, and severity of adverse events after primary and booster vaccinations.ClinicalTrials.gov number: NCT01784874.

Post-Exposure Prophylactic Vaccination against Rabies: A Systematic Review.

Post-exposure prophylaxis (PEP) is an effective method for preventing rabies, a highly fatal infection in exposed persons. Malaysia is currently using the purified Vero cell rabies vaccine (PVRV). Nonetheless, there are other commercially available vaccine types and regimens. This systematic review aimed at comparing the effectiveness of the different PEP vaccines, regimens and routes of administration among Asian populations. We systematically reviewed the PubMed and Web of Science databases for articles reporting on the effectiveness of PEP vaccination against rabies among Asian populations between 2015 and 2019. Our search identified 11 relevant studies. Majority of study either used PCECV or PVRV type of vaccine, with different regimes and method. All are non-inferior to the other. Most of the studies recorded adequate response by Day 14 of vaccination. Nonetheless, the intradermal (ID) vaccination used minimal volume of vaccine used in all settings, thus cost less and the concurrent administration of RIG to the wound(s) doesn't affect the RVNA GMT response. PCECV, using either the Essen or Zagreb regimen, might be a useful alternative for the healthy population in the context of PVRV shortage, especially during an outbreak. Use of the Zagreb or Thai Red Cross (TRC) regimens can be considered (either PVRV or PCECV), as both demonstrate good immunogenic outcomes in Asian populations.

Inhibitory effect of concomitantly administered rabies immunoglobulins on the immunogenicity of commercial and candidate human rabies vaccines in hamsters

The World Health Organization protocol for rabies post-exposure prophylaxis (PEP) recommends extensive wound washing, immediate vaccination, and administration of rabies immunoglobulin (RIG) in severe category III exposures. Some studies have shown that RIG can interfere with rabies vaccine immunogenicity to some extent. We investigated the interference of RIG on a next generation highly purified Vero cell rabies vaccine candidate (PVRV-NG) versus standard-of-care vaccines in a previously described hamster model. The interference of either human (h) or equine (e) RIG on the immune response elicited by PVRV-NG, Verorab® (purified Vero cell rabies vaccine, PVRV), and Imovax® Rabies (human diploid cell rabies vaccine; HDCV) was evaluated using the 4-dose Essen PEP regimen. The anti-rabies seroneutralizing titers and specific serum IgM titers were measured by fluorescent antibody virus neutralization test and enzyme-linked immunosorbent assay, respectively, for the vaccines administered with or without RIG. The RIG interference on PVRV-NG, observed transiently at Day 7, was similar to that on PVRV and tended to be lower than that on HDCV using both read-outs. In summary, the results generated in the hamster model showed that RIG induced similar or less interference on PVRV-NG than the standard-of-care vaccines.

Guillain-barré syndrome after purified vero cell rabies vaccination: An unusual case report

Guillain-Barré syndrome (GBS) can be described as a collection of clinical syndromes that manifests as an acute inflammatory polyradiculoneuropathy with resultant weakness and diminished reflexes. Regarding pathophysiology of GBS, it is believed that autoimmunity- molecular mimicry plays a role in its pathogenesis. As the vaccines have an effect on the immune system it is reasonable that immunizations may be associated with subsequent GBS. Although rabies vaccines containing neural elements are very well known cause for GBS, no such positive correlation has been proven after newer formulations of rabies vaccine, derived from chick embryo cells. Here we report a case of GBS which developed after 5 weeks of anti-rabies vaccination (Purified Vero cell rabies vaccine) which was given after dog bite.

Purified Vero cell rabies vaccine (PVRV, Verorab): A review of intradermal use between 1985 and 2019

Background: Worldwide, rabies continues to kill roughly 59,000 individuals per year. Rabies vaccine types and regimens have changed over time, including the recent World Health Organization (WHO) update to include intradermal (ID) administration for rabies post-exposure prophylaxis (PEP). A trend has developed in the rabies field in which both the dose number and dose volume is reduced to accommodate patients and vaccine supply constraints, especially in underserved endemic regions. Methods & Materials: In light of this critical health issue and an evolving environment of vaccination, we sought to perform a full literature review of PEP and pre-exposure prophylaxis (PrEP) PVRV vaccination via ID administration. The ID route endorsed by WHO was already included in Verorab product insert since 1996 in several Asian countries, whereas the intramuscular (IM) route was first registered worldwide over 30 years ago. The review searched 7 databases (including the terms: rabies vaccine, PrEP, PEP, and ID) and was enriched with non-published data, thus covering a variety of schedules including company-sponsored or externally-conducted studies. Results: A total of 34 studies out of 136 original references were identified, including over 3000 subjects and related to no less than 10 PrEP and 17 PEP regimens, including booster administration. In all studies, seroconversion rate (SCR) was assessed by the proportion (%) of vaccines with RVNA titers ≥0.5 IU/mL. SCR was assessed from day (D) 0 to Year (Y) 5, including in general D14, D28 and Y1 and Y1 + D7 and/or D14 data for schedules with booster. For PrEP, 10 studies including around 900 subjects were identified and documented schedules from 1D to 3 visits, through 1 month resulting in SCR higher than 90%. PEP was documented in 24 studies including more than 2150 subjects. D14 SCR ranged from 70% (in HIV CD4 <200 mm3 patients) to 100%. All schedules including booster(s) at Y1 resulted in 100% SCR 7 and/or 14 days after it. Conclusion: ID administration of rabies vaccination is efficacious and future studies will help confirm this regarding PVRV PrEP ID delivery through abbreviated, updated WHO schedules.

Immunogenicity and safety of two-visit, intradermal pre-exposure rabies prophylaxis simultaneously administrated with chimeric live-attenuated Japanese encephalitis vaccine in children living in rabies and Japanese encephalitis endemic country

BackgroundReducing the number of doses required for pre-exposure prophylaxis (PrEP) would make it more feasible and cost-effective to implement in children at the highest risk of rabies exposure in Asia. We studied immune response of 2-site intradermal (ID) injection of rabies vaccine on days 0 and 28 for rabies PrEP simultaneously administrated with live-attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) for children living in endemic area. Research design and methodsSeronegative children (n = 49) aged 12–16 months were randomized 2:1 into two groups: Group A subjects were vaccinated with 0.1-mL ID injection of purified Vero cell rabies vaccine (PVRV), each at two sites on day (D) 0 and D28; Group B subjects were vaccinated with conventional 0.5-mL intramuscular PVRV on D0, D7 and D28. Both groups received one dose of JE-CV subcutaneously on D0 and D365. Rabies virus neutralizing antibody (RVNA) titers were measured on D0, D42 and D365 after vaccination; Japanese Encephalitis (JE) neutralizing antibody titers were determined on D0, D42, D365 and D379. ResultsAll children had RVNA ≥ 0.5 IU/mL on D42 (geometric mean titers [GMTs] of RVNA 14.35 IU/mL [Group A] and 14.83 IU/mL [Group B], p > 0.05]). On D365, RVNA GMTs of subjects in group A and B were 1.50 IU/mL and 2.00 IU/mL (p > 0.05), respectively. All children had seroprotection following booster dose of JE-CV. There were no vaccine-related SAEs observed. ConclusionThe 2-site ID PrEP with PVRV on days 0 and 28 co-administrated with JE-CV are safe and immunogenic.

Single-visit, 4-site intradermal (ID) rabies vaccination induces robust immune responses 5 years after 1-week, 4-site ID primary post-exposure prophylaxis in the Philippines

BackgroundIn a randomized controlled study (NCT01622062) a 1-week, 4-site intradermal (ID, 4-4-4-0-0) post-exposure prophylaxis (PEP) rabies vaccination regimen with purified Vero cell rabies vaccine (PVRV, Verorab®, Sanofi Pasteur), either without (Group 1) or with (Group 2) purified equine rabies immunoglobulin (ERIG), patients in the Philippines achieved seroconversion rates at Day 14 that were non-inferior to that of the updated Thai Red Cross (TRC) 28-day, 2-site (2-2-2-0-2) ID regimen with ERIG (Group 3). Presented here are the annual immunogenicity data up to five years after the last primary dose, and the immunogenicity and safety data following simulated PEP with single-visit, 4-site ID regimen. MethodsRabies virus neutralizing antibodies (RVNA) were determined by rapid fluorescent focus inhibition test (RFFIT). Participants (n = 397) received simulated PEP vaccination ID at Year 5 and RVNAs were assessed at Day 11 post-vaccination. ResultsSeroconversion rates (RVNA titres ≥ 0.5 IU/mL) during annual follow-up remained >95% in Group 1 and were relatively stable at 80–90% in Group 2, but decreased from 80% to 64% in Group 3. RVNA geometric mean titres (GMTs) in Group 1 were consistently higher than in the other two groups, and those in Group 3 were generally lower than in the other two groups. There was a clear anamnestic response to vaccination in all groups, with all participants achieving RVNA titres ≥ 0.5 IU/mL at Day 11 post-simulated PEP booster vaccination. There were no safety concerns raised during annual follow-up and with simulated post-exposure vaccination with PVRV. ConclusionThe shortened, 1-week, 4-site ID regimen with PVRV achieved persistently higher RVNA titres than the updated 2-site TRC regimen, and more participants remained seroprotected up to five years after the last dose of primary immunization. Simulated post-exposure with 4-site ID rapidly induced an anamnestic response indicative of robust protection.

Purified Vero Cell Rabies Vaccine (PVRV, Verorab®): A Systematic Review of Intradermal Use Between 1985 and 2019.

The purified Vero cell rabies vaccine (PVRV; Verorab®, Sanofi Pasteur) has been used in rabies prevention since 1985. Evolving rabies vaccination trends, including shorter intradermal (ID) regimens with reduced volume, along with WHO recommendation for ID administration has driven recent ID PVRV regimen assessments. Thus, a consolidated review comparing immunogenicity of PVRV ID regimens during pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) is timely and beneficial in identifying gaps in current research. A search of seven databases for studies published from 1985 to November 2019 identified 35 studies. PrEP was assessed in 10 studies (n = 926) with 1–3-site, 1–3-visit regimens of up to 3-months duration. Seroconversion (rabies virus neutralizing antibodies [RVNA] ≥ 0.5 IU/mL) rates of 90–100% were reported within weeks, irrespective of regimen, with robust booster responses at 1 year (100% seroconversion rates by day 14 post-booster). However, data are lacking for the current WHO-recommended, 2-site, 1-week ID PrEP regimen. PEP was assessed in 25 studies (n = 2136) across regimens of 1-week to 90-day duration. All ID PEP regimens assessed induced ≥ 99% seroconversion rates (except in HIV participants) by day 14–28. This review confirms ID PVRV suitability for rabies prophylaxis and highlights the heterogeneity of use in the field.

Antibody Response Following Pre-Exposure Immunization Against Rabies in High-Risk Professionals.

Vaccination against rabies and routine antibody testing of subjects participating in programs for the surveillance and control of rabies in animals is strongly recommended. The scope of this study is to describe the antibody level as measured by a commercial enzyme-linked immunosorbent assay (ELISA) after primary and booster intramuscular vaccination with a purified vero-cell rabies vaccine (PVRV) in high-risk professionals and to determine the influence of an array of factors on antibody level, that is, time elapsed since primary immunization series and booster dose, sex, age, pathologic conditions, high-risk occupation, and peak antibody level after initial scheme and booster dose. A primary series of three doses of PVRV was administered and a commercial ELISA was recommended 14 days postimmunization with continuous repetition at 6 months and yearly intervals for the laboratory personnel and the rest of the professionals, respectively. The protective antibody titer was defined as a minimum of 0.5 equivalent units/mL (EU/mL) (seroconvertion) and a booster dose was applied if the titer was determined nonprotective. The seroconversion rate (SCR) after primary vaccination was 100%, with a geometric mean titer (GMT) of 2.90 EU/mL (interquartile range [IQR]: 1.85-3.45). After booster vaccination due to nonprotective titer, the SCR was 100% and the GMT increased by 678% (95% confidence interval [CI]: 514-887) reaching 4.25 EU/mL (IQR: 4.00-4.60), 2.5 times higher than the GMT elicited by the primary vaccine scheme in the respective recipients. The titer dropped by 1.20% per month (95% CI: 0.52-1.89) regardless of booster administration or any other factor. Women had 51% higher titer compared with men (95% CI: 6-116). High-risk professionals should be verified for adequate antibody titers, but routine administration of a single booster dose of PVRV 1 year after the primary series could be considered; more evidence is needed to support the benefit in terms of immunity and logistics.

Study on Preparation of New Purified Vero Cell Rabies Vaccine

Rabies is a 100% vaccine-preventable disease. A cheap, rabies vaccine for humans that could be used in mass vaccination campaigns would be a valuable weapon against rabies. Despite the existence of safe and effective vaccines, rabies disease still causes an estimated more human deaths a year in the endemic areas in Asia and Africa. Rabies virus is single stranded negative sense RNA from genus lyssavirus and _ family rhabdoviridae.

A randomized open-label trial of 2-dose or 3-dose pre-exposure rabies prophylaxis among Thai children

BackgroundWorld Health Organization changed the recommendation for pre-exposure rabies prophylaxis from 3-dose to 2-dose regimen in 2018. Given limited data of 2-dose regimens in pediatric population, this study aimed to compare the immunogenicity between 2-dose and 3-dose pre-exposure rabies immunization. MethodsThis study was conducted among healthy children aged 2–12 years. They were randomized to 2-dose vaccination (2D) on days 0 and 28 or 3-dose vaccination (3D) on days 0, 7, and 28. Purified Vero cell rabies vaccine (PVRV-Verorab™) was administered intramuscularly. Rabies virus neutralizing antibody (RVNA) titers were measured at 3 time points: 14-day after complete vaccination, 1-year pre-booster vaccination, and 7-day post-booster dose to mimic scenario of rabies exposure. RVNA titers ≥0.5 IU/ml were considered adequate antibody. T cell specific response to rabies vaccine antigen was measured using the interferon-gamma enzyme linked immunospot assay. ResultsFrom September to October 2017, 107 participants (51% males), 78 in 2D group and 29 in 3D group were enrolled. Median age was 5.8 years (IQR 4.4–7.3). All participants had RVNA titers ≥0.5 IU/ml after primary vaccination [GMT 2D: 18.6 (95%CI 15.9–21.8) and 3D: 16.3 (95%CI 13.2–20.1 IU/ml), p = 0.35]. At 1-year prior to receiving the booster, only 80% of the children in 2D group maintained RVNA titers ≥0.5 IU/ml compared to 100% of the children in 3D group (p = 0.01). However, all participants in both groups had RVNA ≥0.5 IU/ml at 7-day post booster vaccination [GMT 2D: 20.9 (95%CI 17.4–25.3) and 3D: 22.2 (95%CI 15.8–31.4) IU/ml (P = 0.75)]. The median number of IFN-γ secreting cells at 7-day post-booster dose was 98 and 128 SFCs per 106 PBMCs in the 2D and 3D groups, respectively (P = 0.30). ConclusionsTwo-dose primary rabies immunization provided adequate antibody at post primary vaccination and post booster. The results support 2-dose regimen of pre-exposure rabies immunization in the pediatric population.

Intradermal post-exposure rabies vaccination with purified Vero cell rabies vaccine: Comparison of a one-week, 4-site regimen versus updated Thai Red Cross regimen in a randomized non-inferiority trial in the Philippines

BackgroundRabies post-exposure prophylaxis (PEP) via intradermal (ID) administration is standard practice in Asia. Accumulating evidence suggests that PEP shortened to 3 visits in one week does not adversely affect seroconversion rates or immune memory. ObjectiveTo determine whether the seroconversion rate at Day14 with a 1-week, 4-site (4-4-4-0-0) ID vaccination regimen with or without rabies immunoglobulin (RIG) was non-inferior to the updated Thai Red Cross (TRC) 28-day, 2-site (2-2-2-0-2) ID regimen with RIG during rabies PEP. We also assessed one-year antibody persistence. MethodsThis phase III, mono-center, open-label, randomized-controlled trial assigned participants aged ≤50 years (n = 600) exposed to suspected rabid animals and sustaining WHO Category II injuries (automatic allocation to G1) or Category III injuries (randomized to G2 or G3) to the following groups (1:1:1 ratio): G1 (n = 200), 1-week 4-site ID regimen with the purified Vero cell rabies vaccine (PVRV; Verorab®) without RIG; G2 (n = 201), 1-week 4-site ID regimen with PVRV, and purified equine rabies immunoglobulin (pERIG); G3 (n = 199), TRC 28-day, 2-site ID regimen with PVRV, and pERIG. Non-inferiority tests compared G1 vs. G3 and G2 vs. G3. Seroconversion rate was the proportion (%) of vaccinees with rabies virus neutralizing antibodies (RVNA) titers ≥0.5 IU/mL measured by rapid fluorescent focus inhibition test. ResultsOn Day14, after the third vaccine administration, seroconversion rates were non-inferior in both comparisons and were, respectively, 100%, 99.4%, 98.8% in G1, G2, G3 with a decrease to 97.6%, 89%, 79.8% at Year 1. At Day14, RVNA geometric mean titers were 11.3 IU/mL; 9.89 IU/mL; 6.15 IU/mL, respectively, decreasing to 2.96 IU/mL, 1.37 IU/mL, 0.97 IU/mL at Year1. Safety and tolerability were similar between the three groups. ConclusionThe seroconversion rate at Day 14 with the 1-week 4-site ID regimen, both with and without pERIG, was non-inferior to the reference TRC 28-day 2-site ID regimen with pERIG during rabies PEP with PVRV.ClinicalTrials.gov ID: NCT01622062.

Rabies Prophylaxis Strategy in Iran, a Need for an Alternative Strategy: Would the Essen Regimen be Replaced by Zagreb Protocol?

Rabies is a fatal zoonotic infectious disease, which can be prevented by prompt post-exposure prophylaxis that could be expensive in countries with a large population. The Essen protocol with injection of 5 single doses of human rabies vaccine on separate days is a well-known rabies prophylaxis schedule. Decreasing the number of vaccine doses and the number of clinical visits due to an effective alternative schedule is strongly needed. The 2-1-1 regimen, known as Zagreb, is one of the best candidates to succeed Essen. To evaluate the effectiveness of Zagreb regimen in the Iranian population by using the Purified Vero cell Rabies Vaccine (PVRV), anti-rabies antibody titer was measured in volunteers with second and third exposure through Rapid Fluorescent Focus Inhibition Test (RFFIT) and Enzyme Linked Immunosorbent Assay (ELISA) test and compared with patients, who were treated according to the Essen protocol. In all participants, anti-rabies antibody titer reached the protective level with no suppressive effect of rabies immunoglobulin in patients with third exposure in Zagreb regimen. Zagreb regimen could be considered a suitable alternative for the Essen protocol.

2279. A Randomized Open-Label Trial of 2-Dose or 3-Dose Primary Rabies Immunization Among Thai Children

BackgroundThe World Health Organization (WHO) recently recommended 2-dose primary rabies immunization instead of the 3-dose standard regimen. Given limited data of 2-dose regimens in pediatric population, this study was conducted. The objective was to compare the immunogenicity between 2-dose and 3-dose primary rabies immunization.MethodsThis study was an open-label clinical trial. Inclusion criteria were children aged 2–12 years with rabies virus neutralizing antibody (RVNA) titers < 0.5 IU/ml at baseline. The participants were divided into 2-dose vaccination (2D) on days 0 and 28 and 3-dose vaccination (3D) on days 0, 7, and 28 with a 2:1 ratio. A dose of 0.5 ml purified vero cell rabies vaccine (PVRV) was administered intramuscularly. RVNA titers were measured at 14-day post primary immunization. RVNA titers ≥ 0.5 IU/ml were considered seroprotective against rabies. Geometric mean titers (GMT) were calculated. T cell specific response to rabies vaccine antigen were measured from peripheral blood mononuclear cells (PBMCs) using the interferon-gamma enzyme-linked immunospot (IFN-gamma ELISpot) assay.ResultsFrom September to October 2017, 105 participants (52% male), 76 in 2D group and 29 in 3D group were enrolled. Median age and body weight was 70 months (IQR 53–88) and 19.2 kilograms (IQR 15.9–24.3), respectively. All participants had seroprotection at 14-day post primary immunization with GMT of 18.6 (95% CI 15.8-21.9) and 16.3 (95% CI 13.1–20.0) in 2D and 3D groups, respectively (P = 0.35). Median IFN-gamma level at 14-day post primary immunization was 60 spot forming cells (SFC) per 106PBMCs and 132 SFC per 106PBMCs in the 2D and 3D groups, respectively (P = 0.15).ConclusionThe immunogenicity of 2-dose primary rabies immunization at 14-day post primary vaccination is comparable to the 3-dose regimen. Participants are currently being followed for 1-year results.Disclosures All authors: No reported disclosures.

Analysis on the risks of severe adverse events in rabies post-exposure prophylaxis and appropriate decision-making procedure

ABSTRACT Severe adverse events (AEs) following post-exposure rabies vaccination had been occasionally described in previous studies. Once AEs occurred, immediate medical treatment and appropriate change of vaccine and vaccination schedule were of significance. It was also important and challengeable to determine the relationship among adverse reactions, vaccines residues and laboratory tests for patients, to choose a proper vaccine in resumed vaccination, to avoid the reoccurrence of AEs and to ensure adequate immune response. Here, we present steps about how to cope with AEs by giving an example with a two-year-old girl who was identified as category II exposure to rabies, suffered from anaphylaxis after first dose administration with human diploid rabies vaccine (HDCV) so vaccination was temporarily suspended. Dexamethasone was prescribed to her in anti-allergy therapy. Allergy tests indicated that the patient was not sensitive to allergens and heterologous proteins. Vaccine test report showed that residual kanamycin existed in that batch of vaccines. This reminded us to provide her antibiotic skin sensitivity test which found she was allergic to kanamycin. Thus, we could conclude it was the cause of AEs. Then, 0.5 mL lyophilized Purified Vero Cell Rabies Vaccine (PVRV) without any residues was enrolled in the resumed vaccination. To ensure successful immunization, immunogenicity test was also provided which showed adequate immune response (RVNA ≥ 0.5 IU/mL) starting from day14. Besides, no further AEs occurred afterward. This study emphasized the importance of in-depth survey, analysis and implied the necessity to scientifically and properly choose the optimal vaccine for patients and appropriately provide treatments if AEs occurred.

Single visit rabies pre-exposure priming induces a robust anamnestic antibody response after simulated post-exposure vaccination: results of a dose-finding study

The current standard 3-dose intramuscular rabies PrEP schedule suffers from a number of disadvantages that severely limit accessibility and availability. The cost of is often prohibitive, it requires 3 visits to the clinic, and there are regular vaccine shortages. Volunteers ( N = 30) were randomly assigned to 4 study arms: 1 standard dose intramuscular (IM) dose of PVRV (purified Vero cell rabies vaccine, Verorab), and 1/5th, 2/5th or 3/5th- fractional intradermal (ID) dose of PVRV in a single visit. All subjects received a simulated rabies post-exposure prophylaxis (D0, D3) 1 year later. Rabies virus neutralizing antibodies (RVNA) were determined by virus neutralization microtest (FAVN) on D0, D7, D28, Y1 and Y1 + D7. 28 out of 30 subjects (93%) seroconverted 1 month after primary vaccination; 1 subject in the 1-dose IM arm and 1 in the 1/5th-fractional dose ID arm did not. After 1 year, 22 out of 30 subjects (73%) no longer had RVNA above 0.5 IU/ml, with no discernible difference between study groups. After 1 year, all 30 subjects mounted a booster response within 7 days after simulated PEP, with the highest titers found in the single dose IM group ( P < 0.03). This dose finding study demonstrates that priming with a single dose of rabies vaccine was sufficient to induce an adequate anamnestic antibody response to rabies PEP in all subjects 1 year later, even in those in whom the RVNA threshold of 0.5 IU/ml was not reached after priming.

Development of a new purified vero cell rabies vaccine (Rabivax-S) at the serum institute of India Pvt Ltd

ABSTRACTIntroduction: Rabies is a 100% fatal disease with significant disease burden in Asia and Africa but preventable with vaccines and immunoglobulins. There are very few WHO prequalified cell culture derived rabies vaccines available globally for use in humans. We have developed a new purified vero cell rabies vaccine (Rabivax-S) to meet this demand.Areas covered: In this review, we have described the detailed manufacturing process of Rabivax-S and summary of preclinical and clinical development based on the data generated in-house.Expert commentary: Rabivax-S has been developed on Vero ATCC CCL81 cells using Pitman Moore (PM3218) strain. Following all the GMP requirements the vaccine was tested in GLP toxicology studies. Further it underwent clinical trials in preexposure and postexposure settings and was found safe and immunogenic.

Immunogenicity and safety of purified vero cell rabies vaccine (PVRV) produced by Liaoning Cheng Da Co. under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese adults aged 50 and above

ABSTRACTBackground: Two kinds of regimens (2-1-1 and 1-1-1-1-1) can be selected after Zagreb regimen(2-1-1)of PVRV was officially approved in Beijing in January 2015. Up to now, the subjects for most studies about the comparison between Zagreb and Essen regimen are under 50 y old, rarely at and above. Aging of the immune system may result in decreasing efficacy of vaccination, especially for adults aged above 65–70 y. This study compared the safety and immunogenicity of the Zagreb and Essen regimen in Chinese adults aged 50 and above with the goal to provide a supplemental data for this age group. Methods: A total of 114 cases were divided into 2 groups randomly, received PVRV under the Zagreb and Essen regimens respectively. Serum samples were collected at D0, D7, D14, D42, D180 and D365 to determine the rabies serum neutralizing antibody by rapid fluorescent focus inhibition test (RFFIT). Safety analyses were made by comparing the AEs in day-3, day-7, and day-(7 + 21) in Zagreb or day-(7 + 28) in Essen by gender and age cohorts. Results: 617 blood samples were obtained. Two groups showed similar immunogenicity, the neutralizing antibody titer of all subjects at D14 and D42 showed >0.5 IU/ml. Under the same regimen, Subjects ≥65 y had lower GMC than those who <65 years from D7 to D365 within 2 groups. This difference was significantly shown on D7, D14, D180 in Zagreb group, and on D180 in Essen group (t = 2.38, p = 0.02; t = 3.78, p < 0.001; t = 2.30, p = 0.03; t = 4.42, p < 0.001). Subjects<65 years had higher seroconversion rate compared to ≥65 y on D7, D180 and D365 in both 2 groups, this difference was also significantly shown on D180, D365 in Zagreb group and on D180 in Essen group (χ2 = 20.66, p < 0.001; χ2 = 6.56, p = 0.02; χ2 = 10.96, p = 0.002). Two regimens all showed favorable performances with mildly or common adverse events (AEs). The incidence of local AEs after 3 d in Essen group was higher than Zagreb group (χ2 = 9.69, p = 0.002). The most common local AE was pain, the incidences (8.8%) in Zagreb group was higher than Essen group (8.4%, χ2 = 5.12, p = 0.02). All AEs for Zagreb group and 52.3% of AEs for Essen group occurred during the first 72 hours. During the first 72 hours, subjects aged <65 in Zagreb group (16.26%) had higher incidences of AEs than Essen group (8.57%, χ2 = 4.54, p = 0.03), males in Zagreb group (16.05%) had higher incidence of AEs than Essen group (5.71%, χ2 = 5.34, p = 0.02). The incidences of AEs close in during the first 7 d. Conclusion: The Zagreb and Essen regimens demonstrated the similar safety and efficacy of PVRV in Chinese adults aged 50 and above. People ≥65 y showed reduced immune response to both regimens. More AEs for the Zagreb regimen were observed within the first 72 hours, especially for male and people < 65 y.