Evaluation of under-testing and under-diagnosis of tick-borne encephalitis in Germany.

BACKGROUND: Tick-borne encephalitis (TBE), a viral infectious disease affecting the central nervous system, potentially resulting in prolonged neurological symptoms and other long-term sequelae. Case identification can be challenging as TBE can be associated with non-specific symptoms, and even in cases consistent with typical TBE symptoms, the rate of laboratory testing to confirm cases is unknown. This study assessed real-world TBE laboratory testing rates across Germany. METHODS: In this retrospective cross-sectional study, physicians provided data on TBE decision-making, laboratory testing (serological), and diagnostics behavior via in-depth qualitative interviews (N = 12) or a web-based quantitative survey of their patient medical records (N = 166). Hospital-based physicians who specialized in infectious disease, intensive care unit, emergency room, neurology, or pediatrics with experience managing and ordering testing for patients with meningitis, encephalitis, or non-specific central nervous system symptoms in the past 12 months were included. Data were summarized via descriptive statistics. TBE testing and positivity rates were assessed for the aggregate sample of 1400 patient charts and reported by presenting symptoms, region, and tick bite exposure. RESULTS: TBE testing rates ranged from 54.0% (non-specific neurological symptoms only) to 65.6% (encephalitis symptoms only); the percentage of TBE positive results ranged from 5.3% (non-specific neurological symptoms only) to 36.9% (meningitis symptoms only). TBE testing rates were higher among those with a tick bite history and/or who presented with headache, high fever, or flu-like symptoms. CONCLUSIONS: The findings of this study suggest that patients with typical TBE symptoms are likely under-tested, thus likely leading to under-diagnosis in Germany. To ensure appropriate case identification, TBE testing should be consistently integrated into routine practice for all patients who present with relevant symptoms or exposure to common risk factors.

Ticks on the turf: investigating the presence of ixodid ticks on and around football fields in Germany.

Ixodes ricinus is the most abundant tick species and an important vector of pathogens in Germany and in large parts of Europe. A few other ixodid tick species, e.g., Dermacentor reticulatus, may also be of eco-epidemiological relevance. As ticks are not only found in natural but also in suburban areas (parks, gardens), the present study investigated whether ticks occur on and near football grounds thus posing a potential risk to players and visitors. Thirty-two football grounds from all 16 German federal states were selected, mainly situated adjacent to a green area (forest, park). Ticks were collected by the conventional flagging method in spring 2018, and nymphs and adults were counted and morphologically determined. Altogether 807 nymphal and adult ticks were collected from 29 football grounds: 714 I. ricinus, 64 Ixodes inopinatus, 2 Ixodes frontalis, 24 Ixodes sp. ticks, and 3 D. reticulatus. Ixodes inopinatus was found in 13 out of 16 German states. Three ticks were even found on the turf of two football fields. It can be concluded that ticks occur quite frequently and sometimes in high abundance near football grounds situated close or adjacent to a forest or a park.

Incidence of Lyme Borreliosis in Germany: Exploring Observed Trends Over Time Using Public Surveillance Data, 2016-2020.

Background: Public surveillance of Lyme borreliosis (LB) occurs in 9 out of 16 federal states of Germany and remains a critical facet of disease epidemiology and trends. We describe the incidence, time trends, seasonality, and geographic distribution of LB in Germany using publicly reported surveillance data. Methods: We obtained LB cases and incidence (2016-2020) from the online platform SurvStat@RKI 2.0, maintained by the Robert Koch Institute (RKI). Data included clinically diagnosed and laboratory-confirmed LB reported by nine out of 16 federal states of Germany where LB notification is mandatory. Results: During 2016-2020, the nine federal states reported 63,940 LB cases, of which 60,570 (94.7%) were clinically diagnosed, and 3370 (5.3%) also had laboratory confirmation, with an average of 12,789 cases annually. Incidence rates were mostly stable over time. The average annual LB incidence was 37.2/100,000 person-years and varied by spatial level, ranging from 22.9 to 64.6/100,000 person-years among nine states; from 16.8 to 85.6/100,000 person-years among 19 regions; and from 2.9 to 172.8/100,000 person-years among 158 counties. Incidence was lowest among persons 20-24 years old (16.1/100,000 person-years) and highest among those 65-69 years old (60.9/100,000 person-years). Most cases were reported between June and September, with a peak in July of every year. Conclusion: The risk of LB varied substantially at the smallest geographic unit and by age group. Our results underscore the importance of presenting LB data at the most spatially granular unit and by age to allow implementation of efficient preventive interventions and reduction strategies.

Vaccination rate and adherence of tick-borne encephalitis vaccination in Germany.

BACKGROUND: Tick-borne encephalitis (TBE) is an arboviral infection of the central nervous system. As there is no causal treatment of TBE, disease prevention by vaccination is especially important. Immunization consists of a three-dose primary vaccination schedule, followed by regular booster doses. In Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute recommends TBE vaccination for all those at high risk of contracting TBE. This includes individuals living in, traveling to and/or working in risk areas, and being exposed to ticks. To our knowledge, there are currently no reliable data on TBE vaccination rates in Germany available. METHODS: This retrospective cohort study based on anonymized German health claims data was conducted to determine vaccination rates of TBE primary immunization in 2012 to 2015 by federal state, compliance with the vaccination schedule, and TBE vaccination uptake for the 2011 birth cohort. Vaccination protection rates for each federal state were simulated based on a compartmental model. RESULTS: Vaccination rates of an initiated primary immunization ranged from about 3% in the southern federal states to <1% in the northern federal states. Across all federal states, compliance with the vaccination schedule decreased with each subsequent vaccination. Slightly higher TBE vaccination uptake was determined in the 2011 birth cohort, as compared to the German school entry health examination statistics in 2017. Simulated vaccination protection rates for each federal state ranged from 10% in Hamburg to 51% in Baden-Wuerttemberg. CONCLUSIONS: While there was an overall low vaccination uptake and a discrepancy between areas of high vs. low TBE risk, this study also indicates a concerning decline in vaccination compliance. Vaccinating physicians should address the importance of adherence upon initiation of TBE vaccination.

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.

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.

Protecting Indian schoolchildren against rabies: pre-exposure vaccination with purified chick embryo cell vaccine (PCECV) or purified verocell rabies vaccine (PVRV).

Although rabies can be effectively prevented by means of preexposure or post-exposure prophylaxis, in India, an estimated 17,000 to 20,000 human rabies deaths occur annually. Tragically, 50% of these victims are children under the age of 15. In addition to immediate post-exposure prophylaxis measures, including active and passive immunization, pre-exposure vaccination using tissue culture vaccines is a safe and effective but highly underutilized method of preventing rabies in humans living or working in areas at risk. This study assessed the safety and immunogenicity of Purified Chick Embryo Cell Vaccine (PCECV) and Purified Verocell Rabies Vaccine (PVRV), administered as a three-dose intramuscular pre-exposure regimen on days 0, 7 and 28 in 175 healthy schoolchildren. PCECV was administered after reconstitution using either 1.0 mL or 0.5 mL (half the diluent volume) and PVRV was given after reconstitution with 0.5 mL. Vaccine safety was assessed observer-blind, including pain assessment with a validated visual analogue scale for children. Rabies virus neutralizing antibody (RVNA) concentrations were measured on day 49 by RFFIT. All children developed adequate RVNA concentrations above 0.5 IU/mL. Solicited local and systemic reactions were within the range expected, pain after vaccination was reported in 2 to 12% of study subjects, fever was reported in 2 to 5%. There was no statistical difference by vaccination group or vaccination day. No unexpected or serious adverse event was reported during the study. In conclusion, PCECV and PVRV are safe and immunogenic when administered intramuscularly for pre-exposure prophylaxis of rabies in children. A 1.0 mL dilution volume for PCECV was as well tolerated as PVRV or PCECV reconstituted in half the volume.

Pre-exposure rabies vaccination using purified chick embryo cell rabies vaccine intradermally is immunogenic and safe.

OBJECTIVE: To demonstrate the safety and immunogenicity of intradermal rabies pre-exposure prophylaxis with purified chick embryo cell vaccine (PCECV) in schoolchildren age 5 to 8 years in Thailand. STUDY DESIGN: In a randomized, open-label, phase II clinical trial, 2 or 3 intradermal doses of 0.1 mL PCECV (Rabipur) were administered to 703 schoolchildren on days 0 and 28 or on days 0, 7, and 28. In 206 children, 2 simulated post-exposure booster doses were given 1 year after the primary vaccination series. Rabies virus- neutralizing antibody (RVNA) titers were determined by the rapid fluorescent focus inhibition test. RESULTS: In school-age children in Thailand, a pre-exposure immunization regimen of 3 intradermal doses of PCECV produced adequate immune responses. After primary vaccination, all subjects developed RVNA titers > or =0.5 IU/mL and demonstrated a rapid increase in RVNA titer after 2 simulated post-exposure booster immunizations 1 year after the primary vaccination series. No serious adverse drug reactions occurred. CONCLUSIONS: Rabies pre-exposure immunization with PCECV is safe and immunogenic, and its implementation could save the lives of many children in rabies-endemic areas.

Comparison of the immunogenicity and safety of the purified chick embryo cell rabies vaccine manufactured in India and Germany: A randomized, single blind, multicentre, phase IV clinical study.

This phase IV, single blind study assessed the immunogenicity and safety of India-manufactured purified chick embryo cell rabies vaccine (PCECV), compared with a German-manufactured batch obtained by the same production process. A total of 340 participants enrolled at 2 study sites in India were randomized (1:1:1:1) in 4 groups to receive a 5-dose Essen regimen with either 1 of the 3 Indian batches (PCECV-I) or the German batch (PCECV-G), administered on Days (D) 0, 3, 7, 14 and 30. The lot-to-lot consistency of PCECV-I batches in terms of induced immune response at D14 was demonstrated. The immune response elicited by PCECV-I was shown to be non-inferior to that induced by PCECV-G, as the lower limit of the 95% confidence interval for the ratio (PCECV-I/PCECV-G) of rabies virus neutralising antibody (RVNA) geometric mean concentrations was higher than 0.5 at D14. At least 96% of participants developed adequate RVNA concentrations (≥ 0.5 IU/mL) by D14 and all achieved RVNA concentrations ≥ 0.5 IU/mL by D90. RVNA levels were comparable across all groups throughout the entire study. Solicited local and general symptoms had a similar incidence in all groups. Unsolicited adverse events (AEs) were reported by 11% of participants. Only 1 serious AE (leg fracture) was reported and was not related to vaccination. No deaths and no rabies cases were recorded during the 90 days of observation. The study showed that the 3 PCECV-I and the PCECV-G batches induced a similar immune response and had a comparable safety profile when administered according to a 5-dose schedule.

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 [corrected], the first purified chick embryo cell-culture vaccine, was licensed in Germany in 1984, and later in more than 60 countries worldwide [corrected].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.

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.

A randomized open-labeled study to demonstrate the non-inferiority of purified chick-embryo cell rabies vaccine administered in the Zagreb regimen (2-1-1) compared with the Essen regimen in Chinese adults.

The Zagreb regimen has been used for 20 years in various countries. In China, until 2010, the Zagreb schedule was only approved for purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccines (PVRV). In this phase III clinical trial, we aimed to demonstrate the safety and immunogenic non-inferiority of the Zagreb regimen compared with the Essen regimen in healthy adult Chinese immunized with PCECV (Rabipur®). The study enrolled 825 subjects aged 18 to 50 years; serum samples were collected on Days 0, 7, 14, 42, and at 13 months to assess rabies virus neutralizing antibody (RVNA) concentrations. Solicited and unsolicited local and systemic reactions were recorded for 6 days following the day of vaccination, and collected throughout the entire study period (Day 1 until Month 13). The Zagreb regimen was non-inferior to the Essen regimen with regard to RVNA concentrations after 7, 14, and 42 days, and 13 months of immunization. The non-inferiority of seroconversion was established at Days 14 and 42. The incidence of local and systemic reactions was similar between groups, and mostly of mild or moderate severity. Vaccine-related adverse events occurred more frequently in the Essen group than in the Zagreb group. Vaccination with PCECV under a 2-1-1 regimen is as safe and immunogenic as under the traditional 5-dose Essen regimen for rabies post-exposure prophylaxis, and is a more cost-effective option, has a more practical vaccination schedule, and can potentially increase compliance.

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.

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.

Invasive meningococcal disease and travel.

The epidemiology of invasive meningococcal disease varies geographically and in time and the risk of acquiring the disease varies regionally, as well as with living conditions and behavior. An area, in which meningococcal disease outbreaks have frequently occurred, is the "African meningitis belt", where epidemics of meningococcal disease with a peak incidence as high as 100-800/100,000 population/year have been reported. Another risk factor is mass gatherings including the Islamic pilgrimage to Makkah (Mecca), where outbreaks of meningococcal disease have repeatedly occurred. The latest outbreaks occurred during the Hajj pilgrimages of 2000 and 2001, when a shift from serogroup A disease to serogroup W135 occurred. Vaccination against serogroups A, C, W-135 and Y with novel conjugate vaccines may help protect individuals and reduce the spread of bacterial carriage and disease. Individuals who should be vaccinated include travelers to epidemic or hyperendemic areas (as identified by international health authorities), travelers for Umra or Hajj (Hajj pilgrims), travelers to high risk countries or regions (African meningitis belt) during the dry season or countries in sub-Saharan Africa outside the meningitis belt (where outbreak of meningitis has been reported in the preceding 2-3 years), military recruits or deployed military personnel, immunocompromized travelers and high school and college students. This review presents the global epidemiology of meningococcal disease, and discusses prophylaxis options including meningococcal ACWY vaccines.

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.

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 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 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=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.