Immunogenicity and Safety of a Purified Vero Rabies Vaccine-Serum Free, Compared With 2 Licensed Vaccines, in a Simulated Rabies Post-Exposure Regimen in Healthy Adults in France: A Randomized, Controlled, Phase 3 Trial.

BACKGROUND: A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®). METHODS: This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection. RESULTS: Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines. CONCLUSIONS: In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines. CLINICAL TRIALS REGISTRATION: NCT03965962.

Ptosis Caused by Local Injection of Human Rabies Immunoglobulin.

Rabies is a fatal zoonotic disease. Patients with grade III injuries after exposure need timely injection of rabies vaccine and human rabies immunoglobulin treatment. This article introduces the diagnosis and therapy of ptosis caused by local injection of human rabies immunoglobulin in a patient bitten by a dog.

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

BACKGROUND: Serum 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 REPORT: A 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.

Serum Sickness like Reaction Postequine Rabies Immunoglobulins.

A 30-year-old, previously healthy adult male received equine rabies immunoglobulins (Ig) (ERIG) along with anti-rabies vaccinations as per protocol for postexposure prophylaxis after an unprovoked rabid dog bite of grade three wound over the shin of the left lower limb. On the 8th day, he developed urticarial rashes beginning from the site of the wound, which gradually became a widespread maculopapular rash. Development of the rash was followed by low-grade fever, nonspecific arthralgias and soreness in the throat. A diagnosis of serum sickness-like illness was made based on history, temporal correlation of administration of ERIG and development of symptoms. He responded well to antihistaminic and a short course of injectable steroids. The purpose of this article is to increase awareness regarding the clinical presentation and management of this rare yet potentially curable adverse event if identified timely.

Serologic Response of 2 Versus 3 Doses and Intradermal Versus Intramuscular Administration of a Licensed Rabies Vaccine for Preexposure Prophylaxis.

BACKGROUND: The World Health Organization recommends intradermal (ID) administration of rabies vaccine for preexposure prophylaxis. METHODS: In a randomized trial in adults assigned to 1 of 6 treatment groups (ID vs intramuscular [IM], 2 vs 3 doses, and controls), rabies neutralizing antibody titers were measured to 1 year postvaccination. RESULTS: ID vaccination produced acceptable antibody levels in all subjects (2- and 3-dose groups). At day 365, acceptable levels were 40% for IM and 50% for ID 2-dose schedule, and 70% for IM and 60% for ID 3-dose schedule. CONCLUSIONS: ID rabies vaccination induces acceptable antibody titers at a fraction of the dose. CLINICAL TRIALS REGISTRATION: NCT02374814.

Preexposure Intradermal Rabies Vaccination: A Noninferiority Trial in Healthy Adults on Shortening the Vaccination Schedule From 28 to 7 Days.

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

First case of Stevens-Johnson syndrome after rabies vaccination.

We describe the first case of Stevens-Johnson syndrome (SJS) occurring 8 days after the first dose of a three-dose rabies vaccination series. She had no history of vaccine-related rash or other adverse drug reactions, nor had she received any other drug therapy. The temporal relationship between the development of SJS and the vaccination suggests that the rabies vaccination probably was the causal agent. This case serves as a warning of a distinct cutaneous reaction of rabies vaccination.

Safety studies with the oral rabies virus vaccine strain SPBN GASGAS in the small Indian mongoose (Herpestes auropunctatus).

BACKGROUND: Oral vaccination of the small Indian mongoose against rabies has been suggested as a potential tool to eliminate mongoose-mediated rabies on several Caribbean islands. A recently developed oral rabies virus vaccine strain, SPBN GASGAS, has already been shown to be efficacious in this reservoir species. Since, all available oral rabies vaccines are based on replication-competent viruses and vaccine baits are distributed unsupervised in the environment, enhanced safety standards for such vaccine types are required. RESULTS: The results of safety studies, including overdose, repeated doses, dissemination and different routes of administration, in the target species are presented. It was shown that the construct was apathogenic, irrespective of dose and route of administration. Even when it was inoculated directly in the brain, it did not induce rabies infection. Furthermore, the vaccine strain did not spread within the target species after direct oral instillation beyond the site of entry. CONCLUSION: The vaccine strain SPBN GASGAS meets the safety requirements for live rabies virus vaccines in this target species, the small Indian mongoose.

Multiple evanescent white dot syndrome following rabies vaccination: a case report.

BACKGROUND: To report a case of multiple evanescent white dot syndrome (MEWDS) following simultaneous rabies vaccination. CASE PRESENTATION: Review of the clinical, laboratory, photographic, optical coherence tomographic (OCT), fundus autofluorescent, angiographic, electrophysiologic, and perimetric records of a patient suffering from MEWDS. RESULTS: A healthy 33-year-old Chinese female suffering from rapidly progressive visual loss of her left eye associated with photopsia and a para-central scotoma, seven days after receiving simultaneous rabies vaccination. Both anterior segments and fundus examination were unremarkable. The findings on OCT, electrophysiology, and perimetry were pathognomonic for MEWDS. CONCLUSIONS: The clinical presentation and the benign course were consistent with the diagnosis of MEWDS. No other events could be identified as a cause, other than the rabies vaccination. This case may suggest an autoimmune basis for MEWDS in predisposed patients.

Protective immune response of oral rabies vaccine in stray dogs, corsacs and steppe wolves after a single immunization.

In this study the safety and protective immunity of an oral rabies vaccine, based on the live, modified rabies virus strain VRC-RZ2, was examined in stray dogs (Canis Sp.), corsacs (Vulpes corsac) and steppe wolves (Canis lupus campestris). In the safety group (dogs, n=6; corsacs, n=3; wolves, n=3) which was vaccinated with a 10-times field dose/animal, no animals showed any signs of disease or changes in behavior or appetite during the period of clinical observation, similar to the animals in the negative control group. Saliva samples taken from animals prior and post (5th and 10th days) vaccination failed to demonstrate rabies virus antigen. Observations of immunogenicity in vaccinated carnivores (dogs, corsacs and wolves) during a 180 day period showed the titers of virus neutralizing antibodies (VNA) in the blood sera of vaccinated dogs to be within 0.59-1.37 IU/mL. On 14 days post vaccination (dpv), all the wild carnivores had detectable levels of neutralizing antibodies, with mean titers ranging from 0.50 ± 0.07 IU/mL (for wolves) to 0.59 ± 0.10 IU/mL (for corsacs). Weeks after vaccination, all the vaccinated wolves and corsacs had higher levels of neutralizing antibodies: 0.70 ± 0.10 - 0.71 ± 0.08 IU/mL at 30 dpv, 1.06 ± 0.08 - 1.28 ± 0.21 IU/mL at 60 dpv and 0.41 ± 0.09 - 047 ± 0.06 at 180 dpv. The highest level of VNA (˃1.0 IU/ml) was detected at 60 dpv, in all vaccinated animals. After challenge all vaccinated dogs remained healthy for 180 days. Control animals (unvaccinated dogs) developed symptoms of rabies on day 6 post administration of a virulent virus and died of rabies on days 11-13. Of note, the VNA titers in all the wild carnivores (corsacs and wolves) immunized with VRC-RZ2 were higher than 0.5 IU/ml (0.59 ± 0.11 IU/ml), even as early as 14 days post vaccination. These, presumably protective, titers of antibodies to rabies virus were present in the dogs and wild carnivores examined in this study for at least 180 days.

The Adverse Effect of the 2-1-1 Regimen for Rabies PEP in Preschool Children.

Post-exposure prophylaxis (PEP) has proved to be the most important measure for rabies prevention and control. There is little information regarding adverse reactions to the Essen and 2-1-1 regimens in preschool children (aged 0-6). We reexamined the outcomes of 1,109 preschool children who were vaccinated using SPEEDA under the Essen regimen between January 2011 and December 2012 and 1,267 preschool children under the 2-1-1 regimen between January 2013 and December 2014. We find that, in preschool children, the febrile reaction after the first 2-dose injection in the 2-1-1 regimen was significantly higher than that induced by the first 1-dose in the Essen procedure. Thus, we recommend that the Essen regimen should still be used for rabies PEP in preschool children.

Lichen planus secondary to rabies vaccination.

Lichen planus (LP) is a papulosquamous disease withdistinctive clinical manifestations. The etiology of LPremains unknown. Recently, numerous cases of LPdeveloping after hepatitis B, influenza, and combinedDTaP-IPV-MMR vaccine have been described. In thisreport, we present the second case of LP after rabiesvaccination.

[Rabbies vaccination]. / Impfung gegen Tollwut.

With very few exceptions, rabies is occurring around the globe. The clinical course of this mammal-transmitted infection is almost universally fatal. Thus, the disease is causing more human deaths than any other zoonosis. Due to the lack of effective therapeutic options, pre- or post-exposure vaccination remains the only effective means to avoid development of fatal disease. Save and highly effective cell culture vaccines which have been available for decades provide long-lasting protection. Various vaccination schedules have been tested and are being recommended.

A Case of Immune Thrombocytopenic Purpura After Rabies Vaccination.

We describe a case of immune thrombocytopenic purpura (ITP) occurring 15 days after the first dose of a 4-dose rabies vaccination series. ITP is thought to be an immune-mediated process triggered by an infection or toxin. There is little evidence in the literature beyond case reports of an association of ITP with vaccines other than with the measles, mumps, and rubella vaccine. This is the third reported case of ITP associated with rabies vaccination. Because of the rare occurrence of this adverse event relative to the severity of rabies infection, the benefits of rabies vaccination, when indicated, outweigh the low and possible risk of ITP.

Mood, behavior, testosterone, cortisol, and interleukin-6 in adults during immune activation: a pilot study to assess sickness behaviors in humans.

OBJECTIVES: Sickness behavior, a suite of behavioral changes subsequent to infection that includes depression, decreased social behaviors, and sleep disturbances, has been well described in model organisms. The phenomenon is relatively unexplored in humans due to methodological difficulties, and hormonal correlates of sickness behavior have not been studied. We therefore attempted to use a vaccine to elicit sickness behaviors outside of a clinical setting and uncover any correlations among testosterone, cortisol, and sickness behavior. METHODS: Eleven participants (five male, six female, mean age 22.8 years) naïve to the rabies vaccine were recruited from the School of Veterinary Medicine at Purdue University. Participants provided daily saliva and urine samples and completed questionnaires to assess mood and social behaviors for a period of 6 weeks. Saliva samples were assayed for cortisol and testosterone. Urine samples were assayed for interleukin-6 and creatinine. RESULTS: Analysis revealed an expected decrease in testosterone and an increase in cortisol. While mood did not differ, other behaviors, such as physical activity and hours slept, showed expected changes following vaccination. However, none of these results achieved statistical significance. CONCLUSION: Our results, while generally confirming previous research on sickness behavior and hormone changes during infection, are suggestive, but not statistically significant and so neither confirm nor contradict our hypotheses. We attribute this lack of significance to both the small sample size, as well as possible confounding factors, including the psychosocial stress of entering an intensive study program.

A Case Report of Post Rabipur (Purified Chick Embryo Rabies Vaccine) Acute Disseminated Encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease that typically occurs following a viral infection or vaccination. The incidence of ADEM following vaccination has become very low since introduction of non-neural rabies vaccine and only few cases had been reported due to pure chick embryo derived rabies vaccine (PCERV). Here we are reporting a rare case of delayed post vaccinal ADEM.