Rabies Immunoglobulin Research Articles

Dog bite of the orofacial region- Case series and update

Animal bites are a significant cause of morbidity and mortality across the globe and when involving the orofacial region, they commonly present to dental surgeons. Literature on their initial management provides a plethora of conflicting views and results and it is necessary to be up to date with the latest modalities of management of such facial injuries to give best functional and surgical outcomes to the patients. Antibiotics and anti-tetanus and anti-rabies vaccinations and immunoglobulins should be judiciously administered along with appropriate wound management.

Application of a caprylate/chromatography purification process for production of a high potency rabies immune globulin from pooled human plasma

BackgroundHuman rabies immunoglobulin (RIG) is an integral part of post-exposure prophylactic treatment of rabies (along with rabies vaccination). Infiltration of most, if not all, of the RIG dose at the wound site is recommended. RIG produced by a caprylate/chromatography manufacturing process (RIG-C; HyperRAB) increased the potency and purity of this product over the existing licensed RIG from a solvent/detergent process (RIG-S/D; HyperRAB-S/D). MethodsA series of studies were conducted to characterize the content and purity of RIG-C. A single-dose pharmacokinetic study in rabbits was performed to compare intramuscular (IM) immunoglobulin products manufactured by two different purification processes, solvent/detergent (IGIM-S/D) and caprylate/chromatography (IGIM-C). ResultsRIG-C was found to be a highly purified IgG formulation with high monomer content and formulated with twice the anti-rabies potency of RIG-S/D while maintaining the same overall protein concentration. RIG-C facilitates IM administration at the wound site by halving the injection volume. The new caprylate/chromatography process eliminated detectible levels of pro-coagulant impurities and IgA that were carried through in the prior S/D process. These impurities have been associated with thrombotic complications and allergic reactions in susceptible patients. After single dose administration, IGIM-C was pharmacokinetically equivalent to IGIM-S/D in rabbits. ConclusionRIG-C is a more potent RIG formulation with less impurities yielding a safer and more convenient product with similar pharmacokinetic profile.

Post-exposure Rabies Prophylaxis for Children in Southern Turkey.

To evaluate the prophylaxis practices used on children with animal exposures in a major southern city of Turkey, close to the Syrian border. Cross-sectional study. Emergency and Outpatient departments, Adana City Training and Research Hospital, Turkey between September 2017 and September 2018. The demographic data of the patients, who presented due to animal contact; the interval between animal contact and hospital presentation; species of exposed animals, type, and apparent condition of the animals; risk categories based on national assessment scale; the number of rabies vaccines and anti-rabies immunoglobulin (RIG) administrations; administration of tetanus prophylaxis; adherence of patients to the follow-up schedule; vaccine refusals; and development of rabies disease (if any), were recorded. Of the 2,068 presentations after animal exposure, 906 (43.8%) were children, mostly boys (62%), and the mean age was 97.15 ± 57.68 months. Risky contact was most frequently caused by cats (52.8%) and dogs (45.6%). Exposure to stray animals was the most common (58.5%). For serial prophylaxis vaccinations, 761 (83.99%) families were in full compliance and 145 (16%) families had discontinued vaccinations. The discontinuation rate of the immigrant population was significantly higher (p = 0.001). Risky contacts were mostly due to stray animals. Efforts to minimise the stray animal population should be increased. The rate of discontinuation of rabies prophylaxis follow-ups was 16%. Significantly higher prophylaxis discontinuation among the immigrant population was noted. Key Words: Rabies, Vaccines, Prophylaxis, Turkey.

Effect of an Endoplasmic Reticulum Retention Signal Tagged to Human Anti-Rabies mAb SO57 on Its Expression in Arabidopsis and Plant Growth.

Transgenic Arabidopsis thaliana expressing an anti-rabies monoclonal antibody (mAb), SO57, was obtained using Agrobacterium-mediated floral dip transformation. The endoplasmic reticulum (ER) retention signal Lys-Asp-Glu-Leu (KDEL) was tagged to the C-terminus of the anti-rabies mAb heavy chain to localize the mAb to the ER and enhance its accumulation. When the inaccurately folded proteins accumulated in the ER exceed its storage capacity, it results in stress that can affect plant development and growth. We generated T1 transformants and obtained homozygous T3 seeds from transgenic Arabidopsis to investigate the effect of KDEL on plant growth. The germination rate did not significantly differ between plants expressing mAb SO57 without KDEL (SO plant) and mAb SO57 with KDEL (SOK plant). The primary roots of SOK agar media grown plants were slightly shorter than those of SO plants. Transcriptomic analysis showed that expression of all 11 ER stress-related genes were not significantly changed in SOK plants relative to SO plants. SOK plants showed approximately three-fold higher mAb expression levels than those of SO plants. Consequently, the purified mAb amount per unit of SOK plant biomass was approximately three times higher than that of SO plants. A neutralization assay revealed that both plants exhibited efficient rapid fluorescent focus inhibition test values against the rabies virus relative to commercially available human rabies immunoglobulins. KDEL did not upregulate ER stress-related genes; therefore, the enhanced production of the mAb did not affect plant growth. Thus, KDEL fusion is recommended for enhancing mAb production in plant systems.

Small Volume of Rabies Immunoglobulin (RIG) is Effective for Local Wound Infiltration in Rabies Post-Exposure Prophylaxis whereas Intramuscular RIG is just a Wastage

Rabies is a zoonosis that is 100% fatal once symptoms of the disease appear. However, it is almost 100% preventable if the prophylactic measures with proper wound wash, vaccines and immunoglobulins are taken soon after exposure to the animal bite. A general tendency has been noticed among clinicians all over the world to inject Rabies Immunoglobulins (RIG) intramuscularly, mostly in the gluteal muscle, despite the guidelines that suggest infiltrating it into the wounds. This has resulted in failures of Post Exposure Prophylaxis in many countries leading to the death of patients due to rabies. Here we discuss how giving any amount or even large amount of RIG intramuscularly (IM) is not going to neutralise rabies virus at the wound site especially during the window period, exposing the patients to the risk of rabies, whereas a small volume of RIG injected into the wound(s) is a lifesaving intervention as it neutralises the virus there and then in the wound(s) especially during the initial window period when the exposed person is unprotected, as the response to concurrent vaccination may take 10-14 days after exposure/ bite.

Rabies virus neutralizing activity, pharmacokinetics, and safety of the monoclonal antibody mixture SYN023 in combination with rabies vaccination: Results of a phase 2, randomized, blinded, controlled trial

BackgroundSYN023-002 is a randomized, blinded, controlled study comparing rabies virus neutralizing activity (RVNA) and safety of SYN023, a monoclonal anti-rabies antibody mixture, to human-serum derived anti-rabies immunoglobulin (RIG) when administered with commercially available vaccines to healthy adult volunteers. MethodsParticipants were randomized among 4 treatment groups (SYN023 + Imovax, SYN023 + RabAvert, HyperRab + Imovax, HyperRab + RabAvert). On Day 0, subjects received 1 dose of RIG (0.3 mg/kg SYN023 or 20 IU/mL HyperRab) and their first of 5 vaccine doses. The primary objective was to compare cumulative RVNA between SYN023 and HyperRab recipients. Secondary objectives were to compare safety and to assess SYN023 pharmacokinetics and immunogenicity. ResultsAll 164 randomized subjects initiated treatment and were included in safety analyses. At least 34 subjects/treatment group received all treatment and had complete RVNA results, thus were included in the primary endpoint analysis. Mean RVNAs were approximately ten-fold higher in SYN023 recipients compared to HyperRab recipients until Day 14. From Day 14 onwards, mean RVNA was lower in SYN023 recipients, but remained above the RVNA level widely considered adequate (≥0.5 IU/mL) through Day 112 (study end). The point estimate of the cumulative RVNA (83.22% SYN023/HyperRab), but not the lower CI bound (90% CI: 66.06%, 104.83%), fell within the protocol-defined similarity margin. Each RIG + vaccine regimen appeared safe with mostly mild AEs and no serious or severe related events observed. Except injection site pain (22% HyperRab recipients vs. 6% SYN023 recipients), treatment-related AEs incidences were similar between RIGs. Anti-SYN023 antibodies were observed but had no apparent effects on PK or safety. ConclusionsSYN023 administered with commercially available vaccines provides adequate antibody coverage beginning earlier than other commercially available RIGs with an acceptable safety profile. Some suppression of vaccine response occurred, but RVNA levels ≥ 0.5 IU/mL were maintained throughout the relevant period. RegistrationClinicalTrials.gov #NCT02956746. FundingSynermore biologics.

Estimating the Volume of Equine Rabies Immunoglobulin (eRIG) Required for Local Infiltration in Soft Tissue Animal Bites in Children Using a Wound Size-Based Approach.

Post-exposure prophylaxis using rabies immunoglobulin (RIG) is universal recommendation for category III exposures. This study was conducted to determine quantity of RIG used to infiltrate animal bite wounds in relation to longest dimension and area of wound. Children aged 2-18 years reporting within 7 days of category III animal bite were included. eRIG (300 IU/ml) was used in all subjects. A predesigned proforma was filled for clinical and epidemiological details of subjects. Maximum length and width of wounds was measured by using non-stretchable measuring tape. RIG was infiltrated in wounds as per WHO recommendations and volume infiltrated was noted. A total of 100 subjects were enrolled. The mean (±SD) volume of RIG infiltrated in wounds per unit length was 0.75 (±0.21) ml/cm and per unit area was 3.18 (±1.75) ml/cm2. Regression equations were calculated. Proposed equations y = 0.6x + 0.3, where y is the volume of RIG (ml) and x is the length of the wound (cm) and y = 0.9x + 1.1, where y is the volume of RIG (ml) and x is the area of the wound (cm2) can prove to be a useful tool in RIG volume calculation for primary health care providers.

"As long as the patient tells you it was a dog that bit him, why do you need to know more?" A qualitative study of how healthcare workers apply clinical guidelines to treat dog bite injuries in selected hospitals in Uganda.

Dog-mediated rabies is on the increase in Uganda despite the availability of post-exposure prophylaxis (PEP). PEP procedures are expounded in the Uganda Clinical Guidelines (UCG) of 2016. We assessed adherence by health workers to UCG while managing dog bites in two PEP centers and obtained insights into motivations of their practices. Using qualitative methods, we observed the health worker-patient encounters, reviewed medical records, and interviewed 14 health workers that were involved in managing dog bite injuries. We used deductive thematic analysis to identify codes in themes developed from UCG. We found that much of the history of the bites was taken, but it was neither verified nor written down on the patient’s file. Classification of wounds was inaccurate and ancillary laboratory assessments like culture and sensitivity tests were not conducted in all cases. Although antibiotics were given for both treatment and prophylactic purposes, the prescription was based on availability and affordability, not UCG recommendations. Rabies immunoglobulin (RIG) was not administered to deserving patients due to unavailability and high costs to the patient. Anti-rabies vaccine (ARV) was prescribed indiscriminately and some health workers attributed this to pressure from patients. Health education regarding prevention of dog bites was not given to patients due to time constraints on the side of the providers as a result of high caseloads at the emergency departments. Challenges to adherence to guidelines were identified as frequent ARV stock outs; inadequate cooperation among health facilities; and insufficient knowledge and skills on how injuries and rabies should be managed. We conclude that clinical management of dog bites is not fully in line with UCG. We argue that adoption of an integrated bite case management and cost-saving strategies as well as continuing medical education programs on rabies control and management could improve the clinical management of dog bites.

Administration of rabies immunoglobulin: Improving evidence-based guidance for wound infiltration.

Rabies virus causes a fatal infection of the brain and spinal cord, accounting for approximately 59,000 deaths globally each year. Rabies postexposure prophylaxis (PEP), including both rabies immunoglobulin (RIG) and vaccination, is administered to 55,000 patients annually in the United States. With a nearly 100% case fatality rate, the optimal administration of rabies PEP cannot be understated. Updated rabies PEP guidelines issued by the World Health Organization (WHO) in 2018 recognized that local wound infiltration of RIG is the primary mechanism of protection, and the WHO now recommends only infiltration of wounds without distal intramuscular injection. We highlight potential points of failure involving wound infiltration of RIG, small-volume doses, and large-volume doses that may lead to suboptimal care and discuss implications of recent shifts toward evidence-based guidelines using wound type and RIG volumes.

A shorter post-exposure prophylaxis regimen for rabies, Pakistan.

ObjectiveTo assess the cost and effectiveness of the two-site, 1-week, intradermal rabies post-exposure prophylaxis regimen recommended by the World Health Organization (WHO) in 2018.MethodsWe compared the number of rabies vaccine and rabies immunoglobulin ampoules consumed at The Indus Hospital in Karachi, Pakistan and their cost before and after implementing WHO’s 2018 recommendations. In 2017, patients with suspected rabies-infected bites were treated using the two-site, 4-week, Thai Red Cross regimen, which involved administering four rabies vaccine doses intradermally over 4 weeks and infiltrating immunoglobulin into serious wounds, with the remainder injected into a distant muscle. In 2018, patients received three vaccine doses intradermally over 1 week, with a calculated amount of immunoglobulin infiltrated into wounds only. Remaining immunoglobulin was saved for other patients. The survival of patients bitten by apparently rabid dogs was used as a surrogate for effectiveness.FindingsDespite treating 8.5% more patients in 2018 (5370 patients) than 2017 (4948 patients), 140 fewer ampoules of rabies vaccine and 436 fewer ampoules of rabies immunoglobulin were used, at a cost saving of 4202 United States dollars. Of 56 patients bitten by apparently rabid dogs, 50 were alive at 6-month follow-up. The remaining six patients could not be contacted but did not present to any hospital with rabies.ConclusionThe new regimen was more economical than the two-site, 4-week regimen and was equally effective. This regimen is recommended for preventing rabies in countries where the disease is endemic and rabies vaccine and immunoglobulin are in short supply.

Incidence, Trend, and Mortality of Human Exposure to Rabies in Yemen, 2011-2017: Observational Study.

BackgroundRabies remains a neglected and poorly controlled disease throughout the developing world, particularly in Africa and Asia, where most human rabies deaths occur.ObjectiveThis study aimed to describe the epidemiology of rabies exposures, its trend, and its geographical distribution in Yemen.MethodsCumulative data from a rabies surveillance system for the period 2011-2017 were obtained from the National Rabies Control Program as paper-based annual reports. Data included the number of persons bitten by a suspected rabid animal, their gender and age, and the result of the animal’s laboratory test. Human cases were defined as those exposed to rabies virus bitten by a suspected rabid animal, exposed to a confirmed rabid animal and then received postexposure prophylaxis (PEP), and deaths occurred after exposure to a confirmed rabid animal after having rabies symptoms during 2011-2017.ResultsFrom 2011 to 2017, a total of 76,049 persons were bitten by a suspected rabid animal. Of these, 21,927 (28.83%) were exposed to positively confirmed rabid animals and then received PEP, and 295 (0.38%) rabies-related deaths occurred. Of all cases with rabies exposure, 50,882 (66.91%) were males. The most affected age group by animal bites (31,816/76,041, 41.84%), positive exposure (8945/21,927, 40.79%), and rabies deaths (143/295, 48.47%) was 5-14 years. Rabies vaccines and immunoglobulins quantities were least available in 2016 and 2017. The annual incidence rate of exposure to animal bites and rabies exposure was 50 and 14 per 100,000, respectively. The annual mortality rate was 2 per 1,000,000. The highest incidence rate of animal bites was in Dhamar (112 per 100,000) and Ibb (94 per 100,000), whereas the highest incidence of exposed cases was in Amanat Al Asimah (40 per 100,000) and Ibb (37 per 100,000). Mortality rate was the highest in Amanat Al Asimah (6 deaths per 1,000,000) followed by Ibb and Dhamar (4 deaths per 1,000,000 in both).ConclusionsRabies remains a worrying health problem in Yemen with higher percentage reported among children and males. Targeting school-age populations by education, communication, and information campaigns about preventive measures is strongly recommended. An electronic system should be introduced to improve reporting. It is important to have a sufficient supply of vaccines and immunoglobulins in control units, especially in the at-risk or impacted governorates. Future studies are suggested to determine incidences and risk factors of disease progression.

Rabies immunoglobulin as a component of post-exposure rabies prophylaxis.

Rabies immunoglobulin as a component of post-exposure rabies prophylaxis.

Burden of illness of dog-mediated rabies in India: A systematic review

IntroductionIndia accounts for 35% of global burden of rabies. This systematic review attempts to measure the burden of illness of dog bites and dog-mediated rabies in India. MethodsA systematic literature search was conducted on MEDLINE, EMBASE, Cochrane Central, PROQUEST, Sodhganga and Google Scholar. Two independent reviewers screened titles and abstracts and included full texts as per inclusion criteria. Critical appraisal of included studies was conducted using appropriate checklists. Data was extracted using standardized data extraction tools, analyzed and reported in narrative summary and tabular formats. Results35 studies were included for narrative synthesis after screening for inclusion criteria. The annual crude dog bite incidence was reported between 0.26% and 2.5% with stray dogs as main biting animal. The bites were mainly reported in males, between age group 10–40 years, individuals belonging to low socio-economic status and people working in fields. The annual economic and humanistic burden is estimated to be 2.85 million USD and 1.3 million DALYs respectively. Use of intradermal route of vaccination and equine rabies immunoglobulins has been reported to save cost and resources over use of intramuscular route of vaccination and human rabies immunoglobulins. ConclusionThe review highlighted the burden of disease at local, regional and national level. There has been dearth of studies reporting economic and humanistic burden at national level. Systematic review registrationPROSPERO ID: CRD42020213261.

Rabies Prophylactic and Treatment Options: An In Vitro Study of siRNA- and Aptamer-Based Therapeutics.

If the goal of eliminating dog-mediated human rabies by 2030 is to be achieved, effective mass dog vaccination needs to be complemented by effective prophylaxis for individuals exposed to rabies. Aptamers and short-interfering RNAs (siRNAs) have been successful in therapeutics, but few studies have investigated their potential as rabies therapeutics. In this study, siRNAs and aptamers—using a novel selection method—were developed and tested against rabies virus (RABV) in a post-infection (p.i.) scenario. Multiple means of delivery were tested for siRNAs, including the use of Lipofectamine and conjugation with the developed aptamers. One siRNA (N53) resulted in an 80.13% reduction in viral RNA, while aptamer UPRET 2.03 demonstrated a 61.3% reduction when used alone at 2 h p.i. At 24 h p.i., chimera UPRET 2.03-N8 (aptamer-siRNA) resulted in a 36.5% inhibition of viral replication. To our knowledge, this is the first study using siRNAs or aptamers that (1) demonstrated significant inhibition of RABV using an aptamer, (2) tested Lipofectamine RNAi-Max as a means for delivery, and (3) produced significant RABV inhibition at 24 h p.i. This study serves as a proof-of-concept to potentially use aptamers and siRNAs as rabies immunoglobulin (RIG) replacements or therapeutic options for RABV and provides strong evidence towards their further investigation.

A fatal rabies case and experiences of a mass post exposure prophylaxis among healthcare workers.

We aimed to monitor the adverse effects (AE) and efficacy of post exposure prophylaxis (PEP) in health care workers (HCWs) exposed to a rabies patient. In this study 109 HCWs and eight household contacts were PEP candidates. Contact persons without infection control precautions were in Group I (high risk-82 cases). HCWs indirectly exposed to environmental surfaces were classified in Group II (low risk-35 cases). PEP schedule was rabies vaccine (RBV) + equine rabies immunoglobulin (eRIG) in Group I and only RBV in Group II. Local and systemic AE were observed in all cases. Efficacy of post exposure prophylaxis (PEP) was determined by rabies development in a six month follow-up. 585 doses of RBV have been used in 117 cases and eRIG has been used in 82 cases. 32 Nurses (39%); 22 emergency medicine technicians (26.8%); 12 doctors (14%); six laboratory technicians (0.07%); six radiology technicians (0.07%); four cleaners (0.05%) were in Group I (82 cases), respectively. One doctor, laboratory technician, nurse and radiology technician (0.02%); two emergency medicine technicians (0.04%) and nine cleaners (25.7%) were in Group II (35 cases), respectively. Routes of transmission were blood in five (0.06%); saliva in 14 (17%); sweat in 50 (61%); CSF/serum in five (0.06%); sexual intercourse in one (0.01%); personal equipment in seven (0.09%) in Group I, respectively. Indirect contact was the only route in Group II. The most common local and systemic AE were seen in Group I; pain at injection side (19 cases) and fever (13 cases). Both of them showed statistically significant difference (P<0.05). Allergic rash has been seen at only one case. PEP failed in one case where the possible exposure way was sexual intercourse. PEP is the safest way to prevent rabies. Infection control precautions were still not enough applied. eRIGs are also safe and have rare AE.

&lt;i&gt;In vitro&lt;/i&gt; methods for rabies virus detection, and evaluation of their use in the production of rabies immunoglobulin

Current highly sensitive methods for rabies virus and rabies antibodies detection in biological material can be used not only for diagnosis and experimental research, but also for the production of antirabies medicines used for postexposure prophylaxis. The aim of the study was to analyse existing methods for rabies virus and rabies antibodies detection and to assess the potential for using these methods at the control stages during production of heterologous antirabies immunoglobulin obtained from equine serum. The search for cutting-edge highly sensitive in vitro control methods that could compete with the biological method, which is the main method used in antirabies immunoglobulin control, is an important prerequisite for improvement of the production technology and the quality of antirabies medicines. The study demonstrated that the following test methods can be used in the production of antirabies immunoglobulin: fluorescent antibody technique, enzyme-linked immunosorbent assay, cell culture methods, atomic force microscopy, and flow cytometry. These methods could be used alone or as an alternative to the biological method in white mice. These methods were chosen because of their high sensitivity, specificity, rapid and easy implementation, cost-effectiveness, and automatic recording of test results.

Anti-Rabies Vaccine Compliance and Knowledge of Community Health Worker Regarding Animal Bite Management in Rural Area of Eastern India.

BackgroundRabies is a public health problem in developing countries like India accounting for the second-highest number of rabies-related deaths worldwide. Anti-rabies vaccine (ARV) is the only proven and effective way of preventing death in this 100% fatal disease. However, compliance is a real concern. This study aims to assess the compliance of ARV and rabies immunoglobulin (RIG) among the ARV-clinic beneficiaries and also the knowledge of the health workers regarding animal bite management.MethodsA cross-sectional study was conducted in an ARV clinic of a community health centre in a rural Odisha (Eastern India) between February and April 2019. All the beneficiaries attending the ARV clinic were followed up for 28 days to assess their ARV and RIG compliance. Data were collected using a pre-designed semi-structured questionnaire and analysis was performed using SPSS v.22 (IBM Corp, Armonk, NY, USA). Proportion was calculated for categorical variables and mean for continuous variables. Chi-square test was applied to test for significance of categorical variables.ResultsA total of 468 beneficiaries were followed up. More than half (59.8%) of the animal bite victims had a category-II bite, followed by 33.4% having category-III, and 6.8% having a category-I bite. Around three-fourth were exposed to dog bite. Only 52.3% of the patients were compliant with ARV, and 49.4% were compliant with RIG. Knowledge of the health workers regarding wound management was found to be sub-optimal.ConclusionPoor ARV compliance was seen among the beneficiaries. Awareness activities need to be strengthened further to improve health-seeking behaviour. The significant gap in knowledge of the health workers indicates the need for professional training at regular intervals.

Process Yields Improvement of Filter Presses in Rabies Immunoglobulin Production

Process Yields Improvement of Filter Presses in Rabies Immunoglobulin Production

Isolation and Characterization of Cross-Reactive Human Monoclonal Antibodies That Potently Neutralize Australian Bat Lyssavirus Variants and Other Phylogroup 1 Lyssaviruses.

Australian bat lyssavirus (ABLV) is a rhabdovirus that circulates in four species of pteropid bats (ABLVp) and the yellow-bellied sheath-tailed bat (ABLVs) in mainland Australia. In the three confirmed human cases of ABLV, rabies illness preceded fatality. As with rabies virus (RABV), post-exposure prophylaxis (PEP) for potential ABLV infections consists of wound cleansing, administration of the rabies vaccine and injection of rabies immunoglobulin (RIG) proximal to the wound. Despite the efficacy of PEP, the inaccessibility of human RIG (HRIG) in the developing world and the high immunogenicity of equine RIG (ERIG) has led to consideration of human monoclonal antibodies (hmAbs) as a passive immunization option that offers enhanced safety and specificity. Using a recombinant vesicular stomatitis virus (rVSV) expressing the glycoprotein (G) protein of ABLVs and phage display, we identified two hmAbs, A6 and F11, which completely neutralize ABLVs/ABLVp, and RABV at concentrations ranging from 0.39 and 6.25 µg/mL and 0.19 and 0.39 µg/mL respectively. A6 and F11 recognize overlapping epitopes in the lyssavirus G protein, effectively neutralizing phylogroup 1 lyssaviruses, while having little effect on phylogroup 2 and non-grouped diverse lyssaviruses. These results suggest that A6 and F11 could be effective therapeutic and diagnostic tools for phylogroup 1 lyssavirus infections.

Safety and efficacy of rabies immunoglobulin in pediatric patients with suspected exposure

ABSTRACT Rabies is a deadly viral zoonosis with global disease burden. Following exposure to a rabid animal, post-exposure prophylaxis (PEP) is the standard of care for unvaccinated persons. Despite the large proportion of pediatric cases, limited safety and efficacy data exist for use in pediatric patients. We report the safety, efficacy, and immunogenicity of a phase 4, prospective, 2-center, open-label, single-arm clinical trial evaluating human rabies immunoglobulin (HRIG150; KEDRAB 150 IU/mL) as part of PEP in patients (aged <17) with suspected or confirmed rabies exposure, where PEP was indicated. Thirty participants received 20 IU/kg HRIG150 infiltrated into the detectable wound site(s), with any remainder injected intramuscularly, concomitantly with the first of a 4-dose series (days 0, 3, 7, and 14) of rabies vaccine. Rabies virus neutralizing antibody (RVNA) titers and tolerability were assessed on day 14 following administration. Participant safety was monitored for 84 days. No serious adverse events, rabies infections, or deaths were recorded. Twenty-one participants (70.0%) experienced a total of 57 treatment-emergent adverse events (TEAEs) within 14 days following administration. Twelve participants (40.0%) experienced a total of 13 adverse events deemed treatment related. All TEAEs were mild in severity. On day 14, 28 participants (93.3%) had RVNA levels of ≥0.5 IU/mL (mean±standard deviation: 18.89 ± 31.61). These results demonstrate that HRIG150 is well tolerated and effective in pediatric patients as a component of PEP. To the authors’ knowledge, this study is the first to establish pediatric safety and efficacy of HRIG in the US.