Claudius Malerczyk

Imported Human Rabies Cases in Europe, the United States, and Japan, 1990 to 2010

Rabies is an irreversible, fatal disease most frequently characterized by acute encephalitis that causes approximately 55,000 deaths annually in Africa and Asia. Disease occurs when rabies virus, a Lyssavirus , is transmitted to a human via the saliva of an infected mammalian carnivore or bat, usually a dog, if it comes in contact with mucous membranes or enters the body via a bite, scratch, or lick on broken skin. Animal reservoirs for rabies exist in all continental areas worldwide. Deaths are presumed to be underreported in areas with poor access to medical facilities. Children are considered to be at a higher risk than adults.1,2 Although the risk of contracting rabies in developed countries is generally low, those who travel to areas with high epizootic endemicity are at increased risk of exposure and death. Steffen and co‐workers evaluated the risk of rabies infection due to animal bites in travelers to developing countries and found an incidence rate per month between 0.1% and 1%.3 An epidemiological study of travelers presenting to GeoSentinel sites worldwide performed by the US Centers for Disease Control and Prevention (CDC) and the International Society of Travel Medicine (ISTM) found that 4.7% of this population required rabies post‐exposure prophylaxis.4 After acquisition of the virus, the incubation period is variable, usually between 20 and 90 d, although occasionally disease develops after only a few days, and, in rare cases, more than a year following exposure. Usually patients develop a furious form of the disease, with episodes of generalized hyperexcitability separated by lucid periods. Encephalitis results from viral replication in the brain. In 20% of cases, a paralytic form of the disease results in progressive immobility. Both forms of rabies, furious and paralytic, are always fatal. One documented case of recovery from symptomatic disease has been reported; … Corresponding Author: Claudius Malerczyk, MD, Novartis Vaccines and Diagnostics GmbH, Emil‐von‐Behring Strase 76, D‐35041 Marburg, Germany. E‐mail: claudius.malerczyk{at}novartis.com

A THREE-YEAR CLINICAL STUDY ON IMMUNOGENICITY, SAFETY, AND BOOSTER RESPONSE OF PURIFIED CHICK EMBRYO CELL RABIES VACCINE ADMINISTERED INTRAMUSCULARLY OR INTRADERMALLY TO 12-TO 18-MONTH-OLD THAI CHILDREN, CONCOMITANTLY WITH JAPANESE ENCEPHALITIS VACCINE

After concomitant administration of purified chick embryo cell rabies vaccine and Japanese encephalitis vaccine to toddlers, adequate rabies and Japanese encephalitis virus neutralizing antibodies concentrations were demonstrated by day 49, 7 days after a booster at 1 year, and in the majorly at 3 years postvaccination. The inclusion of rabies vaccine in the expanded program on immunization should be considered in rabies endemic countries.

Antibodies induced by vaccination with purified chick embryo cell culture vaccine (PCECV) cross-neutralize non-classical bat lyssavirus strains

Tissue-culture vaccines like purified chick embryo cell vaccine (PCECV) have been shown to provide protection against classical rabies virus (RABV) via pre-exposure or post-exposure prophylaxis. A cross-neutralization study was conducted using a panel of 100 human sera, to determine, to what extent after vaccination with PCECV protection exists against non-classical bat lyssavirus strains like European bat lyssavirus (EBLV) type 1 and 2 and Australian bat lyssavirus (ABLV). Virus neutralizing antibody (VNA) concentrations against the rabies virus variants CVS-11, ABLV, EBLV-1 and EBLV-2 were determined by using a modified rapid fluorescent focus inhibition test. For ABLV and EBLV-2, the comparison to CVS-11 revealed almost identical results (100% adequate VNA concentrations >or=0.5 IU/mL; correlation coefficient r(2)=0.69 and 0.77, respectively), while for EBLV-1 more scattering was observed (97% adequate VNA concentrations; r(2)=0.50). In conclusion, vaccination with PCECV produces adequate VNA concentrations against classical RABV as well as non-classical lyssavirus strains ABLV, EBLV-1, and EBLV-2.

30 Years of rabies vaccination with Rabipur: a summary of clinical data and global experience.

Rabies poses a threat to more than 3.3 billion people worldwide and is estimated to cause about 60,000 deaths a year. However, according to the WHO, it is still one of the most neglected diseases in developing countries. Human rabies vaccinations are critical components of pre-exposure and post-exposure prophylaxis. Rabipur®, the first purified chick embryo cell-culture vaccine, was licensed in Germany in 1984, and later in more than 60 countries worldwide. The immunogenicity, efficacy and safety of Rabipur have been assessed in numerous clinical trials in pre- and post-exposure regimens, using both intramuscular and intradermal routes of administration. The trial populations have involved adults and children, including healthy volunteers and individuals bitten by laboratory-proven rabid animals, malnourished children and immunocompromised individuals. Extensive, worldwide clinical experience with Rabipur over the past 30 years has shown the vaccine to be immunogenic, effective and generally well tolerated.

Rabies pre-exposure vaccination of children with purified chick embryo cell vaccine (PCECV)

Human rabies, mainly transmitted by dog bites, remains a major public health problem in developing countries. In Asian countries, such as India or the Philippines, where large free-ranging dog populations exist, the human death toll stays high. Children under the age of 15 y are at particular risk, representing up to half of the dog bite victims. While pre-exposure prophylaxis (PrEP) is commonly used in travelers from developed countries visiting areas of high endemicity, rabies vaccination is rarely used in highly endemic countries in contrast to post-exposure prophylaxis (PEP). Purified Chick Embryo Cell Vaccine (PCECV, Rabipur®/RabAvert®, Novartis Vaccines and Diagnostics) is approved for pre- and post-exposure prophylaxis, either by the intramuscular route, or—where registered—by the intradermal route of administration. In more than 25 y of use, PCECV has been widely used for PrEP in children. This review summarizes the pediatric pre-exposure clinical trials using PCECV. In total, PCECV has been administered to more than 1,200 children in clinical trials, from toddlers to those in elementary school, using intramuscular and intradermal schedules, demonstrating safety and immunogenicity. PrEP as part of routine pediatric vaccination programs may have a major role to play in human rabies prevention. Extensive clinical experience with PCECV supports intramuscular and intradermal PrEP in children as one pillar of human rabies prevention in developing countries.

Antibody response to an eight-site intradermal rabies vaccination in patients infected with Human Immunodeficiency Virus

OBJECTIVE To investigate the rabies virus neutralizing antibody response in HIV-1-infected patients with CD4+ cell count <or=200 cells/microL or >200 cells/microL after post-exposure prophylaxis using an eight-site intradermal rabies vaccination regimen. METHODS In a prospective cohort study, 27 HIV-1 infected patients were recruited, none of which had a history of rabies vaccination. All patients provided informed consent and were separated into two groups according to their CD4+ cell count (patients with CD4+ counts of <or=200 cells/microL and patients with CD4+ counts of >200 cells/microL). All patients received Purified Chick Embryo Cell rabies Vaccine (PCECV) using a modified eight-site regimen in which 0.1 mL of vaccine was injected intradermally on each of days 0, 3, 7, 14, and 30 (8-8-8-8-8). CD4+ cell counts, HIV-1 viral load and rabies virus neutralizing antibody (RVNAb) concentrations as determined by the Rapid Fluorescent Focus Inhibition Test (RFFIT) were evaluated on blood samples taken on days 0, 3, 7, 14, 30, 90, 180 and 365 after vaccination. RESULTS Of the 27 patients included in the study, 18 patients (67%) had CD4+ cell counts of >200 cells/microL and 9 patients (33%) had CD4+ counts of <or=200 cells/microL. No patients had detectable RVNAb concentrations on day 0. By day 14, all patients had adequate RVNAb concentrations (>or=0.5 IU/mL). There was no statistically significant difference in RVNAb concentrations between the two groups on days 3, 7, 14, 30, 90, 180 and 365 after vaccination. CONCLUSION PCECV is immunogenic in HIV-1-infected patients with CD4+ cell counts below 200 cells/microL when administered in a modified eight-site intradermal PEP regimen.

Cross-neutralization of antibodies induced by vaccination with Purified Chick Embryo Cell Vaccine (PCECV) against different Lyssavirus species

Background: Rabies is a neglected zoonotic disease caused by viruses belonging to the genus lyssavirus. In endemic countries of Asia and Africa, where the majority of the estimated 60,000 human rabies deaths occur, it is mainly caused by the classical rabies virus (RABV) transmitted by dogs. Over the last decade new species within the genus lyssavirus have been identified. Meanwhile 15 (proposed or classified) species exist, including Australian bat lyssavirus (ABLV), European bat lyssavirus (EBLV-1 and -2), Duvenhage virus (DUVV), as well as Lagos bat virus (LBV) and Mokola virus (MOKV) and recently identified novel species like Bokeloh bat lyssavirus (BBLV), Ikoma bat lyssavirus (IKOV) or Lleida bat lyssavirus (LLBV). The majority of these lyssavirus species are found in bat reservoirs and some have caused human infection and deaths. Previous work has demonstrated that Purified Chick Embryo Cell Rabies Vaccine (PCECV) not only induces immune responses against classical RABV, but also elicits cross-neutralizing antibodies against ABLV, EBLV-1 and EBLV-2. Material & Methods: Using the same serum samples as in our previous study, this study extension investigated cross-neutralizing activities of serum antibodies measured by rapid fluorescent focus inhibition test (RFFIT) against selected other non-classical lyssavirus species of interest, namely DUVV and BBLV, as well as MOKV and LBV. Results: Antibodies developed after vaccination with PCECV have neutralizing capability against BBLV and DUVV in the same range as against ABLV and EBLV-1 and -2. As expected, for the phylogenetically more distant species LBV no cross-neutralizing activity was found. Interestingly, 15 of 94 serum samples (16%) with a positive neutralizing antibody titer against RABV displayed specific cross-neutralizing activity (65-fold lower than against RABV) against one specific MOKV strain (Ethiopia isolate), which was not seen against a different strain (Nigeria isolate). Conclusion: Cross-neutralizing activities partly correlate with the phylogenetic distance of the virus species. Cross-neutralizing activities against the species BBLV and DUVV of phylogroup 1 were demonstrated, in line with previous results of cross-neutralizing activities against ABLV and EBLV-1 and -2. Potential partial cross-neutralizing activities against more distant lyssavirus species like selected MOKV strains need further research.

Immunogenicity of Simulated PCECV Postexposure Booster Doses 1, 3, and 5 Years after 2-Dose and 3-Dose Primary Rabies Vaccination in Schoolchildren

Objectives. To assess the immunogenicity of intradermal (ID) booster doses of Purified Chick Embryo Cell rabies vaccine (PCECV, Rabipur) administered to Thai schoolchildren one, three and five years after a primary ID pre-exposure (PrEP) vaccination series. Methods. In this follow-up study of a randomized, open-label, phase II clinical trial, two simulated post-exposure booster doses of PCECV were administered on days 0 and 3 intradermally to 703 healthy schoolchildren, one, three or five years after primary vaccination with either two or three ID doses of 0.1 mL PCECV. Blood was drawn immediately before and 7, 14 and 365 days after the first booster dose to determine rabies virus neutralizing antibody (RVNA) concentrations. Results. An anamnestic response of approximately 30-fold increase in RVNA concentrations was demonstrated within 14 days after booster. All children (100%) developed adequate RVNA concentrations above 0.5 IU/mL. No vaccine related serious adverse events were seen in any of the vaccinees. Conclusion. ID rabies PrEP with PCECV is safe and immunogenic in schoolchildren and the anamnestic response to a two booster dose vaccination series was found to be adequate one, three, and five years after a two- or three-dose primary PrEP vaccination series.

Rabies in South Africa and the FIFA Soccer World Cup : travelers awareness for an endemic but neglected disease

Rabies is endemic on every continent except Antarctica and is also considered to be a significant health problem in Africa, including South Africa. With the upcoming FIFA Soccer World Cup to be held in 2010 in cities throughout South Africa, this review depicts the rabies situation in South Africa and discusses what travelers visiting the games should know about rabies and rabies prophylaxis before or after an exposure to a potential rabid animal occurs.

Purified Chick-Embryo Cell Vaccine

Purified Chick Embryo Cell Vaccine (PCECV) production involves rabies virus (RABV), Flury low egg passage (LEP) strain, cultivation in propagated primary specific pathogen-free (SPF) chick embryo cells, inactivation with beta-propiolactone, and concentration and purification by zonal sucrose-density ultracentrifugation. The final vaccine is formulated with a gelatin stabilizer and lyophilized. This chapter provides details of vaccine production and release tests, including in-process controls, potency testing, and stability testing.