Berlin Center for Travel and Tropical Medicine

Berlin, Germany

Berlin Center for Travel and Tropical Medicine

Berlin, Germany
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Behrens R.H.,Hospital for Tropical Diseases | Behrens R.H.,London School of Hygiene and Tropical Medicine | Cramer J.P.,Bernhard Nocht Institute for Tropical Medicine | Jelinek T.,Berlin Center for Travel and Tropical Medicine | And 15 more authors.
The Lancet Infectious Diseases | Year: 2014

Background: Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the efficacy and safety of a skin-patch vaccine containing the pathogen's heat-labile toxin (LT) in a population of travellers to Mexico and Guatemala. Methods: In this phase 3, randomised, double-blind, placebo-controlled field trial, healthy adults (aged 18-64 years) travelling from Germany or the UK to Mexico or Guatemala were assigned in a 1:1 ratio by a dynamic electronic randomisation system to receive transcutaneous immunisation with a patch containing 37·5 μg of ETEC LT or a placebo patch. Participants, site staff, and the investigators who did the analyses were masked to group assignment. Participants were vaccinated before travel, with two patches given 14 days apart. In the destination country, participants tracked stool output in a diary and provided stool samples for pathogen identification if diarrhoea occurred. The primary endpoint was the proportion of participants with at least one episode of moderate-to-severe diarrhoea (defined as four or more unformed stools in a 24 h period) in which either or both ETEC enterotoxins (LT and heat-stable toxin [ST]) were detected. The study is registered at ClinicalTrials.gov, number NCT00993681. Findings: 2036 participants were recruited and randomly assigned between Oct 14, 2009, and Aug 13, 2010, with 1016 allocated to receive the LT patch and 1020 the placebo patch. 821 participants in the LT-patch group and 823 in the placebo group received both vaccinations and were analysed in the per-protocol population. 30 (3·7%, 95% CI 2·5-5·2) participants in the LT-patch group and 46 (5·6%, 4·1-7·4) in the placebo group had moderate or severe ETEC diarrhoea (vaccine efficacy 34·6%, -2·2 to 58·9; p=0·0621). 9333 local (ie, patch-site) adverse events (including erythema, rash, pruritus, hyperpigmentation, pain, hypopigmentation, and oedema) occurred in 943 (93%) of 1015 participants in the LT-patch group, compared with 1444 local adverse events in 574 (56%) of 1019 participants in the placebo group (p<0·0001). Serious adverse events occurred in 25 participants (14 in the LT-patch group and 11 in the placebo group), with all regarded as either unrelated or possibly related to treatment. Vaccine-induced hyperpigmentation persisted for at least 180 days after vaccination in 150 (18%) of the 849 participants who received both vaccinations and returned for final assessment in the LT-patch group, compared with none of the 842 participants in the placebo group. The vaccine was immunogenic, with a post-vaccination geometric mean titre of LT-specific serum immunoglobulin G of 3400·29, compared with 315·41 in the placebo group. Interpretation: Although the LT antigen was delivered effectively by the skin patch, the vaccine did not protect travellers against diarrhoea caused by ETEC or other organisms. Future vaccines against travellers' diarrhoea might need to include several antigens against various diarrhoeal pathogens, and might need to be able to generate mucosal and higher systemic immunity. Funding: Intercell USA. © 2014 Elsevier Ltd.


Schulz A.R.,Charité - Medical University of Berlin | Schulz A.R.,Center for Monitoring Research | Malzer J.N.,Charité - Medical University of Berlin | Domingo C.,Robert Koch Institute | And 7 more authors.
Journal of Immunology | Year: 2015

Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Applying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8+ T cell responses, and showed quantitatively and qualitatively altered YFspecific CD4+ T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4+ recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population. Copyright © 2015 by The American Association of Immunologists, Inc.


PubMed | Berlin Center for Travel and Tropical Medicine, Charité - Medical University of Berlin, Center for Monitoring Research and Robert Koch Institute
Type: Journal Article | Journal: Journal of immunology (Baltimore, Md. : 1950) | Year: 2015

Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Applying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8(+) T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4(+) T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4(+) recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population.


PubMed | Novartis, University of Zürich, University of Rostock, Ludwig Maximilians University of Munich and 4 more.
Type: Clinical Trial, Phase III | Journal: Journal of travel medicine | Year: 2016

Conventional rabies pre-exposure prophylaxis (PrEP) and Japanese encephalitis (JE) primary series vaccination regimens each require up to 4 weeks to complete and, thus, may not be feasible for individuals who need these immunizations on short notice. This Phase 3b, randomized, controlled, observer-blind study evaluated the immunogenicity and safety of concomitant administration of a purified chick embryo cell culture rabies vaccine and an inactivated, adsorbed JE vaccine according to an accelerated (1 week) regimen when compared with the conventional regimens (4 weeks). This report describes the kinetics of immune responses up to 1 year after vaccination.A total of 661 healthy adults (18 to 65 years) were randomized into the following accelerated or conventional vaccine regimens: Rabies+JE-Conventional, Rabies+JE-Accelerated, Rabies-Conventional and JE-Conventional. Immunogenicity was assessed by virus neutralization tests. Safety and tolerability were also evaluated.Irrespective of rabies vaccination regimen, 97% of subjects had adequate levels of rabies virus neutralizing antibody (RVNA) concentrations (0.5IU/ml) up to Day 57, with percentages of subjects with RVNA concentrations 0.5IU/ml at Day 366 ranging between 68% in the Rabies+JE-Accelerated group and 80% of subjects in the Rabies-Conventional group. The Rabies+JE-Accelerated group revealed high JE neutralizing antibody titers at all-time points. At Day 366, the percentage of subjects with antibody titers indicative of seroprotection (PRNT50 titers 1:10) remained high across JE vaccine groups (86-94%).The accelerated PrEP rabies and JE vaccination regimens, once licensed, could represent a valid alternative in the short-term to currently recommended conventional regimens. The concomitant administration of these two vaccines does not compromise immune responses to any of the vaccine antigens particularly when aiming for short-term protection. Further evidence will clarify the need for and timing to administration of rabies vaccine booster doses in subjects primed with an accelerated PrEP regimen. (NCT01662440).


Ringwald J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Grauer M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Eckstein R.,Friedrich - Alexander - University, Erlangen - Nuremberg | Jelinek T.,Berlin Center for Travel and Tropical Medicine
Travel Medicine and Infectious Disease | Year: 2014

New oral anticoagulants are increasingly used instead of vitamin K antagonists or low molecular weight heparins. Hence, more individuals treated with new oral anticoagulants will seek travel medicine advice. Travel medicine experts should therefore become familiar with new oral anticoagulants and with their impact and role in travel medicine. This review summarizes pharmacological characteristics and approved indications of dabigatran, rivaroxaban and apixaban, and highlights their relevance for travellers on permanent oral anticoagulation and for the prophylaxis of travellers' thrombosis. Compared to vitamin K antagonists, the new oral anticoagulants have many advantages: they do not have interactions with food, they have lower potential for drug-drug interactions and do not require regularly performed laboratory tests. The oral administration, obviating the need to carry needles and syringes during travel may give the new oral anticoagulants a further advantage over low molecular weight heparins. Clinical experience with the new oral anticoagulants, however, is still rather limited and there is concern regarding the clinical management of patients treated with new oral anticoagulants who suffer from severe bleeding or who need urgent invasive procedures. Overall, it remains an individual decision based on a risk/benefit analysis as to whether or not patients on long-term treatment with vitamin K antagonists should be switched to new oral anticoagulants for intended travel. Further caution is also indicated so that the availability of orally administered new anticoagulants should not lead to undifferentiated and unjustified prescription of anticoagulants for the prophylaxis of traveller's thrombosis. © 2013 Published by Elsevier Ltd.


Jelinek T.,Berlin Center for Travel and Tropical Medicine
Wiener Medizinische Wochenschrift | Year: 2012

Vaccines against tick-born encephalitis (TBE) are well established in Europe. Two highly immunogenic and safe products are available, FSME-IMMUN and Encepur. Extensive research has been published regarding all aspects of standard and rapid immunization schedules, covaccination, and vaccine interchangeability. Long-term effectiveness and resulting recommendations for booster intervals remain topics of discussion. Vaccination is recommended in Switzerland and in Germany for adults and children living in, or travelling to, endemic areas. Austria has recommended universal vaccination since 1981. It is noteworthy that Austria is the only country in Europe that has experienced a decrease in caseload during the last 20 years. This is almost certainly due to the very high vaccine coverage rate of 86 %. © Springer-Verlag Wien 2012.


Paulke-Korinek M.,Medical University of Vienna | Paulke-Korinek M.,Federal Ministry of Health | Kollaritsch H.,Medical University of Vienna | Kundi M.,Medical University of Vienna | And 3 more authors.
Vaccine | Year: 2015

BackgroundJapanese Encephalitis (JE) virus occurs in wide regions of Asia with over 3 billion people living in areas at risk for JE. An estimated 68,000 clinical cases of JE occur every year, and vaccination is the most effective prophylactic measure. One internationally licensed vaccine containing the inactivated JE virus strain SA14-14-2 is Ixiaro® (Valneva, Austria). According to recommendations, basic immunization consists of vaccinations on day 0, day 28, and a booster dose 12-24 months later. Protection in terms of neutralizing antibody titers has been assessed up to 12 months after the third dose of the vaccine. The current investigation was designed to evaluate antibody decline over time and to predict long-term duration of seroprotection after a booster dose. MethodIn a preceding trial, volunteers received basic immunization (day 0, day 28) and one booster dose against JE 15 months later. A follow up blood draw 6 years following their booster dose was carried out in 67 subjects. For antibody testing, a 50% plaque reduction neutralization test (PRNT50-test) was used. PRNT50 values of 10 and above are surrogate levels of protection according to WHO standards. ResultSeventy-six months following the booster dose, 96% of the tested subjects had PRNT50 titers of 10 or higher. Geometric mean titer (GMT) was 148 (95% CI confidence interval: 107-207). Antibody titers were lower in volunteers 50 years of age and older. Vaccination history against other flaviviruses (yellow fever or tick borne encephalitis) did not significantly influence PRNT50 titers. A two-step log-linear decline model predicted protection against JE of approximately 14 years after the booster dose. ConclusionSix years after a booster dose against JE, long-term protection could be demonstrated. According to our results, further booster doses should be scheduled 10 years following the first booster dose. © 2015 Elsevier Ltd.


Jelinek T.,Berlin Center for Travel and Tropical Medicine
Travel Medicine and Infectious Disease | Year: 2013

A steadily increasing number of Western travellers are exposed to malaria. Also, numbers of migrants from malarious areas are increasing. Fast and effective treatment options are needed to ensure effective malaria treatment in these groups in the future. Artemisinin combinations are well tolerated and have shown high efficacy in malaria endemic areas. Since 2001, 42 malaria endemic countries, 23 of them in Africa, have adopted artemisinin based combination therapies recommended by WHO. An additional 14 countries are in the process of changing their malaria treatment policy. Studies in non-immune travellers confirm a rapid parasite clearance time and very low rate of side effects. Outpatient clinics and hospitals in non-endemic countries should have standard operating procedures for diagnosing and managing patients with malaria. In this setting, artemisinin combinations should be available for treatment of uncomplicated malaria as they are clearly superior to any other oral antimalarial in their fast reduction of parasite biomass and in decreasing clinical symptoms. Also, they are the drugs of choice for travellers who are advised to carry stand-by emergency treatment during their journey.


Jelinek T.,Berlin Center for Travel and Tropical Medicine
Expert Review of Vaccines | Year: 2013

The mosquito-borne Japanese encephalitis virus causes an estimated 50,000 cases in Asia, accounting for at least 10,000 deaths and 15,000 cases of neuropsychiatric sequelae. IXIARO® (Intercell AG, Vienna, Austria), an inactivated, Vero cell-derived vaccine against Japanese encephalitis was introduced in 2009. The vaccine is highly immunogenic, showing significantly higher geometric mean antibody titers compared with previous, mouse brain-derived vaccines. Postmarketing studies have confirmed the excellent safety profile. Studies on children aged 2 months to 18 years have been published. Based on these data, positive opinion from the EMA for vaccination of children has recently been given. Since a safe and effective vaccine against Japanese encephalitis is now available, outdated guidelines and recommendations have to be revised: travelers to rural areas of Asia should generally be recommended vaccination. © 2013 Informa UK Ltd.


PubMed | Berlin Center for Travel and Tropical Medicine and Medical University of Vienna
Type: Clinical Study | Journal: Vaccine | Year: 2015

Japanese Encephalitis (JE) virus occurs in wide regions of Asia with over 3 billion people living in areas at risk for JE. An estimated 68,000 clinical cases of JE occur every year, and vaccination is the most effective prophylactic measure. One internationally licensed vaccine containing the inactivated JE virus strain SA14-14-2 is Ixiaro (Valneva, Austria). According to recommendations, basic immunization consists of vaccinations on day 0, day 28, and a booster dose 12-24 months later. Protection in terms of neutralizing antibody titers has been assessed up to 12 months after the third dose of the vaccine. The current investigation was designed to evaluate antibody decline over time and to predict long-term duration of seroprotection after a booster dose.In a preceding trial, volunteers received basic immunization (day 0, day 28) and one booster dose against JE 15 months later. A follow up blood draw 6 years following their booster dose was carried out in 67 subjects. For antibody testing, a 50% plaque reduction neutralization test (PRNT50-test) was used. PRNT50 values of 10 and above are surrogate levels of protection according to WHO standards.Seventy-six months following the booster dose, 96% of the tested subjects had PRNT50 titers of 10 or higher. Geometric mean titer (GMT) was 148 (95% CI confidence interval: 107-207). Antibody titers were lower in volunteers 50 years of age and older. Vaccination history against other flaviviruses (yellow fever or tick borne encephalitis) did not significantly influence PRNT50 titers. A two-step log-linear decline model predicted protection against JE of approximately 14 years after the booster dose.Six years after a booster dose against JE, long-term protection could be demonstrated. According to our results, further booster doses should be scheduled 10 years following the first booster dose.

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