Rabies Immunoglobulin Research Articles

Unavailability of Dedicated Dosage Vials of Anti-rabies Vaccine and Immunoglobulin for Intradermal Route Despite its Proven Advantage over Intramuscular Route

Unavailability of Dedicated Dosage Vials of Anti-rabies Vaccine and Immunoglobulin for Intradermal Route Despite its Proven Advantage over Intramuscular Route

Allergic Manifestations to Equine Rabies Immunoglobulin: A Case Series

Allergic Manifestations to Equine Rabies Immunoglobulin: A Case Series

Rabies Exposure from Infected Horse Bite in an Urban Setting: A Case Study from Mongolia

Rabies is a highly fatal zoonotic disease that causes an estimated 60,000 human deaths each year, many of which occur in Africa and Asia where the disease is likely underreported. Uncontrolled transmission of rabies presents a major threat to public health in countries such as Mongolia, where 26% of the population lives a pastoralist lifestyle characterized by increased interaction with livestock animals. Here, we report a case of rabies exposure in a six-year-old male after being bitten by a horse in both the head region and the leg. At the suspicion of rabies, post-exposure prophylaxis (PEP) was initiated, with the patient receiving four doses of PEP vaccine as well as a single treatment of rabies immunoglobulin. The horse was later confirmed to be rabies-positive through rapid antigen testing and RT-PCR. Human rabies exposure from horses is unusual within Mongolia, given that historically over 70% of human rabies cases within the country are attributed to dogs, wolves, or foxes. This case further emphasizes the need for more routine vaccination of domestic animals within Mongolia. Additionally, animal bites, even from animals not frequently associated with rabies, should be treated as possible rabies exposure events.

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.

Postexposure prophylaxis after bite of abroad-winged bat with evidence of European bat lyssavirus1 (EBLV-1)

Germany has been considered free of terrestrial rabies since 2008 as aresult of intensive vaccination and surveillance efforts but reservoirs of the lyssaviruses EBLV‑1 and EBLV‑2 persist in bat colonies and thus pose apotential risk of infection. We report on apatient who suffered abat bite in an urban setting in which European bat lyssavirus1 (EBLV-1) was detected in the euthanized bat. We performed active and passive postexposure prophylaxis (PEP). This case study illustrates the ongoing risk of rabies infection due to close bat contacts in Germany and is intended to sensitize primary care physicians to take such exposure events seriously and to perform aregular PEP including administration of rabies immunoglobulin.

A Robust Phenotypic High-Throughput Antiviral Assay for the Discovery of Rabies Virus Inhibitors.

Rabies virus (RABV) causes severe neurological symptoms in mammals. The disease is almost inevitably lethal as soon as clinical symptoms appear. The use of rabies immunoglobulins (RIG) and vaccination in post-exposure prophylaxis (PEP) can provide efficient protection, but many people do not receive this treatment due to its high cost and/or limited availability. Highly potent small molecule antivirals are urgently needed to treat patients once symptoms develop. In this paper, we report on the development of a high-throughput phenotypic antiviral screening assay based on the infection of BHK-21 cells with a fluorescent reporter virus and high content imaging readout. The assay was used to screen a repurposing library of 3681 drugs (all had been studied in phase 1 clinical trials). From this series, salinomycin was found to selectively inhibit viral replication by blocking infection at the entry stage. This shows that a high-throughput assay enables the screening of large compound libraries for the purposes of identifying inhibitors of RABV replication. These can then be optimized through medicinal chemistry efforts and further developed into urgently needed drugs for the treatment of symptomatic rabies.

Evaluating the benefit of serology during potential Australian bat lyssavirus and rabies post-exposure prophylaxis

Post-exposure prophylaxis (PEP) for potential lyssavirus exposures consists of wound management, rabies vaccination and may include rabies immunoglobulin (RIG). Rabies serology is sometimes indicated if there is risk of PEP failure. ObjectivesEvaluate the benefit of serology by indication. MethodsChart review of potential lyssavirus exposures managed at a Public Health Unit (June 2015 – December 2022) where serology was requested was conducted. The proportion of non-therapeutic titres was compared by sex, age, Indigenous status, serology indication, and whether RIG was given. Results46 notifications with serology were included. Males (5/19) and people over 40 (3/16) were more likely to demonstrate a non-therapeutic response. 2/3 of cases where vaccine doses were not given in the deltoid were non-therapeutic. The rate of non-therapeutic titres was similar for RIG given into the ipsilateral arm (2/11) and given excess RIG for weight (1/4). Although this small sample was inconclusive in isolation, it was also noted that all cases who did not receive RIG had therapeutic serology, whereas 6/35 of those receiving RIG had non-therapeutic serology. ConclusionsThis study supports broader literature questioning the utility of systemic RIG administration as likely limited and potentially detrimental considering the increased risk of immune interference. Implications for public healthHighlights a need to review Australian national guidelines to align with World Health Organization advice recommending local RIG administration only.

Can a single visit rabies pre-exposure prophylaxis eliminate the need for rabies immunoglobulin in last minute travellers?

Highlight Current limited evidence indicate that one-visit intradermal/intramuscular rabies pre-exposure prophylaxis is effective in priming the immune system, followed by two-visit (on days 0 and 3) intramuscular post-exposure prophylaxis to rapidly boost antibodies to adequate levels in the event of potential rabies exposure.

Safety and immunogenicity of three dose levels of an investigational, highly purified Vero cell rabies vaccine: A randomized, controlled, observer-blinded, Phase II study with a simulated post-exposure regimen in healthy adults

ABSTRACT A serum-free, highly purified rabies vaccine produced in Vero cells is under development. The initial formulation, PVRV-NG, was evaluated in five Phase II studies and subsequently reformulated (PVRV-NG2). This multicenter, observer-blinded Phase II study investigated the safety and immune response of three different doses (antigen content) of PVRV-NG2 versus a licensed human diploid cell rabies vaccine (HDCV; Imovax rabies®). Healthy adults (N = 320) were randomized to receive PVRV-NG2 (low, medium, or high dose), PVRV-NG, or HDCV (2:2:2:1:1 ratio), according to a five-dose Essen simulated post-exposure regimen (Days [D] 0, 3, 7, 14, and 28). All participants received human rabies immunoglobulin intramuscularly on D0. Immunogenicity was assessed at D0, 14, 28, 42, and 6 months after the final injection using the rapid fluorescent focus inhibition test. Seroconversion rates were calculated as the percentage of participants achieving rabies virus neutralizing antibody titers ≥0.5 IU/mL. All analyses were descriptive. At each timepoint, geometric mean titers (GMTs) increased with antigen content (measured using an enzyme-linked immunosorbent assay). High-dose PVRV-NG2 GMTs were the highest at all timepoints, medium-dose PVRV-NG2 GMTs were similar to those with HDCV, and low-dose PVRV-NG2 GMTs were similar to PVRV-NG. The safety profile of PVRV-NG2 was comparable to PVRV-NG; however, fewer injection site reactions were reported with PVRV-NG2 or PVRV-NG (range 36.7–47.5%) than with HDCV (61.5%). This study demonstrated a dose–effect of antigen content at all timepoints. As post-exposure prophylaxis, the safety and immunogenicity profiles of the high-dose PVRV-NG2 group compared favorably with HDCV. Clinicaltrials.gov number: NCT03145766.

Human rabies encephalomyelitis in the background of rabies outbreak in animals in Gelephu, Bhutan, 2023: a case report

BackgroundRabies continues to pose significant public health challenges in many developing countries including Bhutan. A probable case of rabies was admitted to our hospital and its reporting led to the uncovering of an outbreak in domestic and wild animals. We discuss the challenges in the diagnosis and management of rabies in a resource-limited setting.Case presentationA 35-year-old male presented with intermittent fever, bilateral lower limb weakness that was rapidly progressive, urinary incontinence with episodes of palpitations and sweating. He had sustained a Category III bite on the right lower thigh with four bite marks, inflicted by a stray dog. He had received post-exposure prophylaxis with intra-dermal anti-rabies vaccine. On initial examination, the patient was in distress but cooperative for the interview. He had pulse rate ranging from 60 to 100/min with episodes of diaphoresis and palpitations, but with normal capillary blood glucose. In the lower limb, the muscle power was zero with absent tendon reflexes in the lower limb and impaired abdominal reflex below T10 level. He had hyperaesthesia below T8, hydrophobia, aerophobia and photophobia. He had multiple spontaneous fasciculations in both the thighs and right deltoid and these later involved the intercostal muscles, neck and face muscles. He had altered sensorium and desaturation for which he required mechanical ventilation. Polymerase chain reaction for rabies virus was negative in cerebrospinal fluid and saliva. Rabies virus neutralizing antibody was negative in cerebrospinal fluid but had high titres in the serum. He received Human Rabies Immunoglobulin after admission. He was managed in the intensive care unit and died 23 days later. After this case was notified, a rapid response team was deployed in the field, and uncovered rabies outbreak in animals in the locality.ConclusionsThis case called for a serious evaluation of the country’s efforts in achieving zero rabies deaths by 2030. The management of this case identified several critical areas of context-specific interventions in Bhutan. There is also an urgent need to improve diagnostic capabilities at the national reference laboratory and enhance the technical competencies of healthcare workers in the management of dog bite cases.Graphical

Boostability after single-visit pre-exposure prophylaxis with rabies vaccine: a randomised controlled non-inferiority trial

After rabies pre-exposure prophylaxis (PrEP) vaccination, scarcely available rabies immunoglobulins are not required for post-exposure prophylaxis (PEP). However, PrEP is not sufficiently accessible as it is cost-intensive and time-intensive. This study investigates whether rabies PrEP schedules can be shortened to one visit, removing some of these barriers. In a block-randomised (2:2:2:1) controlled, multicentre non-inferiority trial, healthy adult travellers (aged 18-50 years and >50 years) were randomly assigned to (A) single-visit intramuscular (1·0 mL); (B) single-visit intradermal (0·2 mL); (C) standard two-visit intramuscular (1·0 mL; day 0 and 7) PrEP; or (D) no rabies vaccination. 6 months later, participants received simulated intramuscular rabies PEP (1·0 mL; day 0 and 3). Rabies virus neutralising antibody (RVNA) concentrations were measured repeatedly. The primary outcome was the fold increase in geometric mean RVNA concentrations between day 0 and 7 after simulated PEP for all participants. The two main comparisons of this primary outcome are between the standard two-visit schedule and the one-visit intramuscular schedule, and between the standard two-visit schedule and the one-visit intradermal schedule. The non-inferiority margin was 0·67. This study is registered with EudraCT, 2017-000089-31. Between May 16, 2018, and March 26, 2020, 288 healthy adult travellers were randomly assigned and 214 participants were evaluated for the primary outcome. Single-visit intramuscular rabies PrEP induced an anamnestic antibody response non-inferior compared with the two-visit intramuscular schedule; single-visit intradermal PrEP did not. The fold increases in the single-visit intramuscular and the single-visit intradermal schedule were 2·32 (95% CI [1·43-3·77]) and 1·11 (0·66-1·87) times as high as the fold increase in the standard schedule, respectively. No vaccine-related serious adverse events were observed. Adverse events related to vaccination were mostly mild. Single intramuscular rabies vaccination can effectively prime travellers (aged 18-50 years), and potentially other populations, and could replace current standard two-visit rabies vaccination as PrEP. ZonMW. For the Dutch translation of the abstract see Supplementary Materials section.

Rabies elimination policy guidelines: Where do we stand?

Introduction: Rabies is one of the Neglected Tropical diseases. India accounts for 35% of rabies-related human deaths globally. Despite effective preventive and control strategies, India hasn't been able to eliminate rabies. Methodology: A narrative review was done by comparing various policies and programmes related to rabies control and elimination in India and other countries, and the gaps persisting in the Indian guidelines and its implementation were assessed. Results: There are multiple gaps in the Indian programme implementation ranging from multiple stockouts of vaccines, unavailability of rabies immunoglobulin, and lack of a robust surveillance system to lack of refreshing training of the health staff. Recommendations: For effective implementation, the population should have increased awareness, with increased production and an effective supply chain of vaccines and immunoglobulins. There should also be a robust surveillance system with periodic refresher training of the health staff.

Comparative Analysis of MEM, RPMI 1640 Media on Rabies Virus Propagation in Vero Cells and Virus Quantification by FAT

Rabies disease can be preventable through vaccination is the only way for effective control and the vaccine is administered as post exposure prophylaxis method (PEP) along with rabies immunoglobulin. For the preparation of the vaccine, the high titre rabies virus has to be propagated in suitable host system like Vero cells. In this study, the virus was propagated in tissue culture flask in two different tissue culture media namely MEM and RPMI-1640, keeping Vero cell line as the host system. This preliminary study is to find the media that yields a better viral titre as high, the influence of harvesting intervals on viral titre for the reason that the vaccine yield is directly proportional to the viral titre during the virus propagation stage and leads to cost effective vaccine. The Vero cell was revived from passage 154 and the part of cells were subjected for adaptation in RPMI-1640 media with gradual media replacement. The passaging of RPMI 1640 media cells were continued until it reaches the equal cell count of MEM (p-158). The confluent monolayer of Vero cells was maintained in the same passage level with appropriate media. The cell count of MEM media, RPMI-1640 were 10.28 x 106 and 10.35 x 106 respectively in 25cm2 tissue culture flasks. The Vero cells were sub-cultured in 175 cm2 tissue culture flasks infected with 0.2 MOI (Multiplicity of Infection) of virus and the viral titration was estimated through FAT test (Fluorescent Antibody Test). The highest viral titre obtained from RPMI-1640 media batch (10-6.125/ml) and MEM media batch (10-6.25 /ml). The two days interval viral harvests shows (Batch 1 &amp; 3) the viral titre log ranged between 10-4.375 to 10-5.875 and three days interval harvests (Batch 2 &amp; 4) the viral titre log ranged between 10-3.750 to 10-6.250 per mL.

Rabies post-exposure prophylaxis delivery to ensure treatment efficacy and increase compliance

ObjectivesSince rabies is lethal once symptoms appear, its prevention including community awareness, mass dog vaccination and post-exposure prophylaxis (PEP) is crucial. Although safe and potent rabies vaccines have long been available, the global rabies burden is still high and access to adequately-delivered PEP remains challenging. Here we offer healthcare providers up-to-date, simple, exhaustive, visual guidance on how to perform PEP steps correctly. ProtocolPEP consists of 1) washing the wound with water and soap for 15 min, 2) assessing the need for rabies biologicals based on specific criteria; 3) administering, if required, rabies immunoglobulin or monoclonal antibodies deep in and around all wounds; 4) starting, if necessary, the WHO-recommended intradermal 1-week vaccination regimen; 5) informing patients adequately throughout the PEP process to increase compliance and avoid dangerous misconceptions about animal bite treatment and rabies risk. DiscussionThe intradermal 1-week vaccination regimen recommended by WHO is as safe as other regimens but carries important cost-, dose- and time-sparing benefits. As fundamental as the correct administration of rabies biologicals is clear doctor-patient communication and sharing of up-to-date knowledge among healthcare professionals. ConclusionsThis resource will help ensuring that no life is lost to rabies, an incurable yet preventable disease.

Progress and prospect of clinical application of anti-rabies virus monoclonal antibody preparation

Rabies is a severe infectious disease caused by the rabies virus, which seriously damages the central nervous system. Once it occurs, the fatality rate is close to 100%. The World Health Organization's position paper on rabies vaccines recognizes that rabies immunoglobulin (RIG) should be used for post-exposure prophylaxis (PEP) in all category Ⅲ exposure for the first time, as well as in category Ⅱ exposure that suffer from severe immune deficiency, long-term massive use of immunosuppressants, and head and face exposure. The anti-rabies virus monoclonal antibody has high purity and specific activity, can be produced on a sustainable scale, and has no risk of blood source virus contamination. Preclinical pharmacodynamic studies and clinical trial results of the anti-rabies virus monoclonal antibody preparation have confirmed that the preparation has a broad-spectrum neutralization effect on the rabies virus. Additionally, its combined application with the vaccine has little impact on the active immunity of the vaccine. Therefore, the anti-rabies virus monoclonal antibody preparation shows great potential for clinical application in PEP.

Evaluation of Various Analytical Methods for Quantification of Rabies Antigen

Background: Rabies is a zoonotic viral disease caused by rabies virus. Rabies virus has special inclination towards central nervous system (CNS) where it causes life threatening acute encephalitis. Perhaps being extremely fatal, rabies can be 100% prevented by early, effective and complete post exposure prophylaxis (PEP). PEP for rabies include immediate toileting of bite wound, administration of rabies immunoglobulins (severe exposures), and a full course of anti-rabies vaccination (ARV). As ensuring the absence of any variations in the primary nucleotide sequence of the viral backbone after successive propagation in human cell lines is crucial to ensure that the expression vector does not produce variants of the antigen during production of vaccine, the present study was conducted with an aim to evaluate various analytical methods for quantification of rabies antigen. Method: Various analytical methods the Western Blot technique, the Sodium Dodecyl Sulphate Agarose Gel Electrophoresis(SDS-PAGE), ELLA method, the Enzyme-linked immunosorbent assay (ELISA) and extinction coefficient were used for quantification of rabies antigen. Results: When results of these tests were analyzed, it was observed that these analytical methods are easy, cost effective, accurate and most importantly rapid for quantification of rabies antigen. Conclusion: On the basis of observations noted in this study, Western Blot technique, the Sodium Dodecyl Sulphate Agarose Gel Electrophoresis(SDS-PAGE), ELLA method, the Enzyme-linked immunosorbent assay (ELISA) and extinction coefficient can be reliably recommended as analytical methods for quantification of rabies antigen..

A Case of a Serum Sickness-Like Reaction After Postexposure Rabies Prophylaxis

BackgroundSerum sickness secondary to rabies postexposure prophylaxis is not well documented in the medical literature. Our case describes serum sickness after exposure to human-derived rabies immunoglobulin (HRIG) and three human diploid rabies vaccines (HDCV) in a young adult male. Case ReportA 30-year-old previously healthy male patient presented to the Emergency Department with complaints of fever, rash, and jaundice, and had a hospital course complicated by biliary stenosis likely secondary to reactive periportal lymphadenopathy. His initial laboratory values demonstrated obstructive jaundice and slightly elevated complement component 4 levels. These symptoms likely are due to the course of HRIG and HDCV vaccines the patient completed after being exposed to a rabies-positive bat in his home. The patient was hospitalized for 8 days, during which he underwent an endoscopic retrograde cholangiopancreatography with sphincterotomy and biliary stenting. He had one repeat hospitalization for acute blood loss anemia attributed to sphincterotomy, which did not require transfusion or further intervention. Liver biopsy showed cholestatic hepatitis. Why Should an Emergency Physician Be Aware of This?Medical literature describing serum sickness or a serum sickness-like reaction occurring from exposure to HRIG or HDCV is sparse despite the commonality of postexposure rabies prophylaxis in health care. It is important to educate practitioners on this potential complication and highlight next potential consultations and treatments.

Antiviral mechanisms of two broad-spectrum monoclonal antibodies for rabies prophylaxis and therapy.

Rabies is an acute and lethal encephalomyelitis caused by lyssaviruses, among which rabies virus (RABV) is the most prevalent and important for public health. Although preventable through the post-exposure administration of rabies vaccine and immunoglobulins (RIGs), the disease is almost invariably fatal since the onset of clinical signs. Two human neutralizing monoclonal antibodies (mAbs), RVC20 and RVC58, have been shown to be effective in treating symptomatic rabies. To better understand how these mAbs work, we conducted structural modeling and in vitro assays to analyze their mechanisms of action, including their ability to mediate Fc-dependent effector functions. Our results indicate that both RVC20 and RVC58 recognize and lock the RABV-G protein in its pre-fusion conformation. RVC58 was shown to neutralize more potently the extra-cellular virus, while RVC20 mainly acts by reducing viral spreading from infected cells. Importantly, RVC20 was more effective in promoting effector functions compared to RVC58 and 17C7-RAB1 mAbs, the latter of which is approved for human rabies post-exposure treatment. These results provide valuable insights into the multiple mechanisms of action of RVC20 and RVC58 mAbs, offering relevant information for the development of these mAbs as treatment for human rabies.

Compliance to post-exposure prophylaxis among patients attending anti-rabies vaccination clinic in a tertiary health care centre in central India: a cross sectional study

Background: Rabies is a fatal but vaccine-preventable disease. Prevention of rabies in exposed individuals is possible by providing them with the proper post-exposure prophylaxis. This study aims to assess the compliance to post-exposure prophylaxis in animal bite cases and factors associated with it. Methods: A cross sectional study was conducted between September 2022 to November 2022 using a predesigned, pretested proforma to interview 300 patients attending anti-rabies vaccination clinic in a tertiary health care centre in central India. Results: Majority of the patients 268 (89.3%) suffered category 3 animal bite and 32 (10.7%) patients suffered category 2 animal bite. 125 (41.7%) patients washed the wound with water, soap and applied antiseptic. 234 (78%) patients completed their last dose of anti-rabies vaccine (ARV) while compliance to Rabies Immunoglobulin (RIG) was seen in 167 (63.3%) patients of all cases requiring it. Out of all the patients who took Equine RIG, 7 (4.5%) showed hypersensitivity reactions. Significant association was found between compliance to ARV with type of animal and status of animal after 10 days; and compliance to RIG with gender, socio-economic status, type of animal and type of wound. Conclusions: Compliance to ARV and RIG in our study was 78% and 63.3% respectively. Major reason for poor compliance to RIG was the price of immunoglobulin. Health education regarding significance of post-exposure prophylaxis is needed among the population.

Comparative Neutralization Activity of Commercial Rabies Immunoglobulin against Diverse Lyssaviruses.

Novel lyssaviruses, the causative agents of rabies, continue to be described mostly due to increased surveillance in bat hosts. Biologicals for the prevention of rabies in humans have, however, remained largely unchanged for decades. This study aimed to determine if commercial rabies immunoglobulin (RIG) could neutralize diverse lyssaviruses. Two commercial preparations, of human or equine origin, were evaluated against a panel consisting of 13 lyssavirus species. Reduced neutralization was observed for the majority of lyssaviruses compared to rabies virus and was more evident for lyssaviruses outside of phylogroup I. Neutralization of more diverse lyssaviruses only occurred at very high doses, except for Ikoma lyssavirus, which could not be neutralized by the RIG evaluated in this study. The use of RIG is a crucial component of rabies post-exposure prophylaxis and the data generated here indicate that RIG, in its current form, will not protect against all lyssaviruses. In addition, higher doses of RIG may be required for neutralization as the genetic distance from vaccine strains increases. Given the limitations of current RIG preparations, alternative passive immunization options should be investigated.