Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial.

BACKGROUND: Vaccines based on mRNA coding for antigens have been shown to be safe and immunogenic in preclinical models. We aimed to report results of the first-in-human proof-of-concept clinical trial in healthy adults of a prophylactic mRNA-based vaccine encoding rabies virus glycoprotein (CV7201). METHODS: We did an open-label, uncontrolled, prospective, phase 1 clinical trial at one centre in Munich, Germany. Healthy male and female volunteers (aged 18-40 years) with no history of rabies vaccination were sequentially enrolled. They received three doses of CV7201 intradermally or intramuscularly by needle-syringe or one of three needle-free devices. Escalating doses were given to subsequent cohorts, and one cohort received a booster dose after 1 year. The primary endpoint was safety and tolerability. The secondary endpoint was to determine the lowest dose of CV7201 to elicit rabies virus neutralising titres equal to or greater than the WHO-specified protective antibody titre of 0·5 IU/mL. The study is continuing for long-term safety and immunogenicity follow-up. This trial is registered with ClinicalTrials.gov, number NCT02241135. FINDINGS: Between Oct 21, 2013, and Jan 11, 2016, we enrolled and vaccinated 101 participants with 306 doses of mRNA (80-640 µg) by needle-syringe (18 intradermally and 24 intramuscularly) or needle-free devices (46 intradermally and 13 intramuscularly). In the 7 days post vaccination, 60 (94%) of 64 intradermally vaccinated participants and 36 (97%) of 37 intramuscularly vaccinated participants reported solicited injection site reactions, and 50 (78%) of 64 intradermally vaccinated participants and 29 (78%) of 37 intramuscularly vaccinated participants reported solicited systemic adverse events, including ten grade 3 events. One unexpected, possibly related, serious adverse reaction that occurred 7 days after a 640 µg intramuscular dose resolved without sequelae. mRNA vaccination by needle-free intradermal or intramuscular device injection induced virus neutralising antibody titres of 0·5 IU/mL or more across dose levels and schedules in 32 (71%) of 45 participants given 80 µg or 160 µg CV7201 doses intradermally and six (46%) of 13 participants given 200 µg or 400 µg CV7201 doses intramuscularly. 1 year later, eight (57%) of 14 participants boosted with an 80 µg needle-free intradermal dose of CV7201 achieved titres of 0·5 IU/mL or more. Conversely, intradermal or intramuscular needle-syringe injection was ineffective, with only one participant (who received 320 µg intradermally) showing a detectable immune response. INTERPRETATION: This first-ever demonstration in human beings shows that a prophylactic mRNA-based candidate vaccine can induce boostable functional antibodies against a viral antigen when administered with a needle-free device, although not when injected by a needle-syringe. The vaccine was generally safe with a reasonable tolerability profile. FUNDING: CureVac AG.

Retrospective clinical case series study in 2017 identifies Plasmodium knowlesi as most frequent Plasmodium species in returning travellers from Thailand to Germany.

Febrile illnesses are common in travellers returning from south-east Asia. However, malaria is a rare diagnosis in this population. A series of Plasmodium knowlesi infections was noted in German travellers returning from Thailand since 2012. Infectious disease and tropical medicine facilities registered by the German Society for Tropical Medicine and International Health were contacted in March 2017, and asked to report previous P. knowlesi cases. In addition, surveillance data from the Robert Koch-Institute were analysed. The facilities reported a total of six P. knowlesi-positive cases, all were returning travellers from Thailand. The P. knowlesi-positive cases made up 6/9 of all diagnosed malaria cases imported from Thailand in the time period 2012 to 2017. In 4/5 of cases where a malaria rapid diagnostic test had been applied it revealed a negative result. P. knowlesi is an important differential diagnosis in travellers returning from south-east Asia with itineraries that include Thailand. This study highlights the importance of this Plasmodium species in this patient subgroup. Whenever malaria is suspected in a returning traveller from Thailand, P. knowlesi should be taken into consideration and a differential PCR be executed as currently the unequivocal diagnosis of P. knowlesi is based on nuclear amplification techniques.

Long-term kinetics of Zika virus RNA and antibodies in body fluids of a vasectomized traveller returning from Martinique: a case report.

BACKGROUND: The magnitude of the current Zika virus (ZIKV) epidemic has led to a declaration of a Public Health Emergency of International Concern by the WHO. Findings of viable viral particles in semen for several weeks are corroborating reports of sexual transmission of ZIKV. Serious consequences of a positive diagnostic result particularly in the pregnant patient are calling for precise diagnostic tools also at later time points after infection. Currently, recommendations suggest a diagnostic period of direct viral detection of 5 to 7 days after onset of symptoms in serum or plasma, and up to 3 weeks in urine samples. CASE PRESENTATION: A vasectomized 41-year-old German returning from Martinique presented at the outpatient clinic of the Department for Infectious Diseases and Tropical Medicine, Munich, with subfebrile temperature, rash, malaise, severe retro-orbital pain and occipital lymphadenopathy. The main complaints resolved after ten days without specific treatment. We are reporting on clinical course and results of direct and indirect detection methods of ZIKV in different sample types including whole blood, ejaculate, urine, serum, plasma and saliva samples up to 119 days post symptom onset. Ejaculate samples remained PCR positive for ZIKV until day 77, whole blood samples until day 101. CONCLUSIONS: The case presentation adds to the still limited knowledge of kinetics of detection of ZIKV by direct as well as indirect methods. Here, a complete data set including results from PCR, serology and cell culture is provided allowing an improved evaluation of optimum diagnostic periods for testing a variety of sample types. Moreover, a high viral load of ZIKV RNA was detected in ejaculate of the vasectomized patient. This finding sheds new light on the possible localizations of ZIKV replication in the human male reproductive tract.

A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients.

BACKGROUND: Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients. METHODS: We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 µg or 200 µg IC43 with adjuvant, or 100 µg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days. RESULTS: Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 µg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1-10.6%) was observed in the IC43 groups. CONCLUSION: This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 µg IC43 without adjuvant compared with 200 µg IC43 with adjuvant, the 100 µg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

Arboviral and other illnesses in travellers returning from Brazil, June 2013 to May 2016: implications for the 2016 Olympic and Paralympic Games.

We evaluated EuroTravNet (a GeoSentinel subnetwork) data from June 2013 to May 2016 on 508 ill travellers returning from Brazil, to inform a risk analysis for Europeans visiting the 2016 Olympic and Paralympic Games in Brazil. Few dengue fever cases (n = 3) and no cases of chikungunya were documented during the 2013-15 Brazilian winter months, August and September, the period when the Games will be held. The main diagnoses were dermatological (37%), gastrointestinal (30%), febrile systemic illness (29%) and respiratory (11%).

Local and International Implications of Schistosomiasis Acquired in Corsica, France.

We report 11 cases of schistosomiasis in international travelers who had bathed in rivers in Corsica, France, during 2012-2014. The infections were diagnosed in 2014 and reported to the GeoSentinel Surveillance Network and European Travel Medicine Network. Travelers can be sentinels for emerging infections; thus, this situation warrants a concerted human and veterinary epidemiologic response.

Illness in travelers returned from Brazil: the GeoSentinel experience and implications for the 2014 FIFA World Cup and the 2016 Summer Olympics.

BACKGROUND: Brazil will host the 2014 FIFA World Cup and the 2016 Olympic and Paralympic Games, events that are expected to attract hundreds of thousands of international travelers. Travelers to Brazil will encounter locally endemic infections as well as mass event-specific risks. METHODS: We describe 1586 ill returned travelers who had visited Brazil and were seen at a GeoSentinel Clinic from July 1997 through May 2013. RESULTS: The most common travel-related illnesses were dermatologic conditions (40%), diarrheal syndromes (25%), and febrile systemic illness (19%). The most common specific dermatologic diagnoses were cutaneous larva migrans, myiasis, and tungiasis. Dengue and malaria, predominantly Plasmodium vivax, were the most frequently identified specific causes of fever and the most common reasons for hospitalization after travel. Dengue fever diagnoses displayed marked seasonality, although cases were seen throughout the year. Among the 28 ill returned travelers with human immunodeficiency virus (HIV) infection, 11 had newly diagnosed asymptomatic infection and 9 had acute symptomatic HIV. CONCLUSIONS: Our analysis primarily identified infectious diseases among travelers to Brazil. Knowledge of illness in travelers returning from Brazil can assist clinicians to advise prospective travelers and guide pretravel preparation, including itinerary-tailored advice, vaccines, and chemoprophylaxis; it can also help to focus posttravel evaluation of ill returned travelers. Travelers planning to attend mass events will encounter other risks that are not captured in our surveillance network.

Acute muscular sarcocystosis: an international investigation among ill travelers returning from Tioman Island, Malaysia, 2011-2012.

BACKGROUND: Through 2 international traveler-focused surveillance networks (GeoSentinel and TropNet), we identified and investigated a large outbreak of acute muscular sarcocystosis (AMS), a rarely reported zoonosis caused by a protozoan parasite of the genus Sarcocystis, associated with travel to Tioman Island, Malaysia, during 2011-2012. METHODS: Clinicians reporting patients with suspected AMS to GeoSentinel submitted demographic, clinical, itinerary, and exposure data. We defined a probable case as travel to Tioman Island after 1 March 2011, eosinophilia (>5%), clinical or laboratory-supported myositis, and negative trichinellosis serology. Case confirmation required histologic observation of sarcocysts or isolation of Sarcocystis species DNA from muscle biopsy. RESULTS: Sixty-eight patients met the case definition (62 probable and 6 confirmed). All but 2 resided in Europe; all were tourists and traveled mostly during the summer months. The most frequent symptoms reported were myalgia (100%), fatigue (91%), fever (82%), headache (59%), and arthralgia (29%); onset clustered during 2 distinct periods: "early" during the second and "late" during the sixth week after departure from the island. Blood eosinophilia and elevated serum creatinine phosphokinase (CPK) levels were observed beginning during the fifth week after departure. Sarcocystis nesbitti DNA was recovered from 1 muscle biopsy. CONCLUSIONS: Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS, noting the apparent biphasic aspect of the disease, the later onset of elevated CPK and eosinophilia, and the possibility for relapses. The exact source of infection among travelers to Tioman Island remains unclear but needs to be determined to prevent future illnesses.

Regional variation in travel-related illness acquired in Africa, March 1997-May 2011.

To understand geographic variation in travel-related illness acquired in distinct African regions, we used the GeoSentinel Surveillance Network database to analyze records for 16,893 ill travelers returning from Africa over a 14-year period. Travelers to northern Africa most commonly reported gastrointestinal illnesses and dog bites. Febrile illnesses were more common in travelers returning from sub-Saharan countries. Eleven travelers died, 9 of malaria; these deaths occurred mainly among male business travelers to sub-Saharan Africa. The profile of illness varied substantially by region: malaria predominated in travelers returning from Central and Western Africa; schistosomiasis, strongyloidiasis, and dengue from Eastern and Western Africa; and loaisis from Central Africa. There were few reports of vaccine-preventable infections, HIV infection, and tuberculosis. Geographic profiling of illness acquired during travel to Africa guides targeted pretravel advice, expedites diagnosis in ill returning travelers, and may influence destination choices in tourism.

Evidence for significant influence of host immunity on changes in differential blood count during malaria.

BACKGROUND: Malaria has been shown to change blood counts. Recently, a few studies have investigated the alteration of the peripheral blood monocyte-to-lymphocyte count ratio (MLCR) and the neutrophil-to-lymphocyte count ratio (NLCR) during infection with Plasmodium falciparum. Based on these findings this study investigates the predictive values of blood count alterations during malaria across different sub-populations. METHODS: Cases and controls admitted to the Department of Infectious Diseases and Tropical Medicine from January 2000 through December 2010 were included in this comparative analysis. Blood count values and other variables at admission controlled for age, gender and immune status were statistically investigated. RESULTS: The study population comprised 210 malaria patients, infected with P. falciparum (68%), Plasmodium vivax (21%), Plasmodium ovale (7%) and Plasmodium malariae (4%), and 210 controls. A positive correlation of parasite density with NLCR and neutrophil counts, and a negative correlation of parasite density with thrombocyte, leucocyte and lymphocyte counts were found. An interaction with semi-immunity was observed; ratios were significantly different in semi-immune compared to non-immune patients (P <0.001).The MLCR discriminated best between malaria cases and controls (AUC = 0.691; AUC = 0.741 in non-immune travellers), whereas the NLCR better predicted severe malaria, especially in semi-immune patients (AUC = 0.788). CONCLUSION: Malaria causes typical but non-specific alterations of the differential blood count. The predictive value of the ratios was fair but limited. However, these changes were less pronounced in patients with semi-immunity. The ratios might constitute easily applicable surrogate biomarkers for immunity.

GeoSentinel surveillance of illness in returned travelers, 2007-2011.

BACKGROUND: International travel continues to increase, particularly to Asia and Africa. Clinicians are increasingly likely to be consulted for advice before travel or by ill returned travelers. OBJECTIVE: To describe typical diseases in returned travelers according to region, travel reason, and patient demographic characteristics; describe the pattern of low-frequency travel-associated diseases; and refine key messages for care before and after travel. DESIGN: Descriptive, using GeoSentinel records. SETTING: 53 tropical or travel disease units in 24 countries. PATIENTS: 42 173 ill returned travelers seen between 2007 and 2011. MEASUREMENTS: Frequencies of demographic characteristics, regions visited, and illnesses reported. RESULTS: Asia (32.6%) and sub-Saharan Africa (26.7%) were the most common regions where illnesses were acquired. Three quarters of travel-related illness was due to gastrointestinal (34.0%), febrile (23.3%), and dermatologic (19.5%) diseases. Only 40.5% of all ill travelers reported pretravel medical visits. The relative frequency of many diseases varied with both travel destination and reason for travel, with travelers visiting friends and relatives in their country of origin having both a disproportionately high burden of serious febrile illness and very low rates of advice before travel (18.3%). Life-threatening diseases, such as Plasmodium falciparum malaria, melioidosis, and African trypanosomiasis, were reported. LIMITATIONS: Sentinel surveillance data collected by specialist clinics do not reflect healthy returning travelers or those with mild or self-limited illness. Data cannot be used to infer quantitative risk for illness. CONCLUSION: Many illnesses may have been preventable with appropriate advice, chemoprophylaxis, or vaccination. Clinicians can use these 5-year GeoSentinel data to help tailor more efficient pretravel preparation strategies and evaluate possible differential diagnoses of ill returned travelers according to destination and reason for travel. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

Travel-associated illness trends and clusters, 2000-2010.

Longitudinal data examining travel-associated illness patterns are lacking. To address this need and determine trends and clusters in travel-related illness, we examined data for 2000-2010, prospectively collected for 42,223 ill travelers by 18 GeoSentinel sites. The most common destinations from which ill travelers returned were sub-Saharan Africa (26%), Southeast Asia (17%), south-central Asia (15%), and South America (10%). The proportion who traveled for tourism decreased significantly, and the proportion who traveled to visit friends and relatives increased. Among travelers returning from malaria-endemic regions, the proportionate morbidity (PM) for malaria decreased; in contrast, the PM trends for enteric fever and dengue (excluding a 2002 peak) increased. Case clustering was detected for malaria (Africa 2000, 2007), dengue (Thailand 2002, India 2003), and enteric fever (Nepal 2009). This multisite longitudinal analysis highlights the utility of sentinel surveillance of travelers for contributing information on disease activity trends and an evidence base for travel medicine recommendations.

Travel-associated diseases, Indian Ocean Islands, 1997-2010.

Data collected by the GeoSentinel Surveillance Network for 1,415 ill travelers returning from Indian Ocean islands during 1997-2010 were analyzed. Malaria (from Comoros and Madagascar), acute nonparasitic diarrhea, and parasitoses were the most frequently diagnosed infectious diseases. An increase in arboviral diseases reflected the 2005 outbreak of chikungunya fever.

Patterns of illness in travelers visiting Mexico and Central America: the GeoSentinel experience.

BACKGROUND: Mexico and Central America are important travel destinations for North American and European travelers. There is limited information on regional differences in travel related morbidity. METHODS: We describe the morbidity among 4779 ill travelers returned from Mexico and Central America who were evaluated at GeoSentinel network clinics during December 1996 to February 2010. RESULTS: The most frequent presenting syndromes included acute and chronic diarrhea, dermatologic diseases, febrile systemic illness, and respiratory disease. A higher proportion of ill travelers from the United States had acute diarrhea, compared with their Canadian and European counterparts (odds ratio, 1.9; P < .0001). During the 2009 H1N1 influenza outbreak from March 2009 through February 2010, the proportionate morbidity (PM) associated with respiratory illnesses in ill travelers increased among those returned from Mexico, compared with prior years (196.0 cases per 1000 ill returned travelers vs 53.7 cases per 1000 ill returned travelers; P < .0001); the PM remained constant in the rest of Central America (57.3 cases per 1000 ill returned travelers). We identified 50 travelers returned from Mexico and Central America who developed influenza, including infection due to 2009 H1N1 strains and influenza-like illness. The overall risk of malaria was low; only 4 cases of malaria were acquired in Mexico (PM, 2.2 cases per 1000 ill returned travelers) in 13 years, compared with 18 from Honduras (PM, 79.6 cases per 1000 ill returned travelers) and 14 from Guatemala (PM, 34.4 cases per 1000 ill returned travelers) during the same period. Plasmodium vivax malaria was the most frequent malaria diagnosis. CONCLUSIONS: Travel medicine practitioners advising and treating travelers visiting these regions should dedicate special attention to vaccine-preventable illnesses and should consider the uncommon occurrence of acute hepatitis A, leptospirosis, neurocysticercosis, acute Chagas disease, onchocerciasis, mucocutaneous leishmaniasis, neurocysticercosis, HIV, malaria, and brucellosis.

Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial.

INTRODUCTION: In a first-in-human study immune responses to rabies virus glycoprotein (RABV-G)-mRNA vaccine were dependent on the route of administration, necessitating specialized devices. Following successful preclinical studies with mRNA encapsulated in lipid nanoparticles (LNP), we tested an mRNA-LNP formulation (CV7202). METHODS: In this phase 1, multi-center, controlled study in Belgium and Germany we enrolled 55 healthy 18-40-year-olds to receive intramuscular injections of 5 µg (n = 10), 1 µg (n = 16), or 2 µg (n = 16) CV7202 on Day 1; subsets (n = 8) of 1 µg and 2 µg groups received second doses on Day 29. Controls (n = 10) received rabies vaccine, Rabipur, on Days 1, 8 and 29. Safety and reactogenicity were assessed up to 28 days post-vaccination using diary cards; immunogenicity was measured as RABV-G-specific neutralizing titers (VNT) by RFFIT and IgG by ELISA. RESULTS: As initially tested doses of 5 µg CV7202 elicited unacceptably high reactogenicity we subsequently tested 1 and 2 µg doses which were better tolerated. No vaccine-related serious adverse events or withdrawals occurred. Low, dose-dependent VNT responses were detectable from Day 15 and by Day 29%, 31% and 22% of 1, 2 and 5 µg groups, respectively, had VNTs ≥ 0·5 IU/mL, considered an adequate response by the WHO. After two 1 or 2 µg doses all recipients had titers ≥ 0.5 IU/mL by Day 43. Day 57 GMTs were not significantly lower than those with Rabipur, which elicited adequate responses in all vaccinees after two doses. CV7202-elicited VNT were significantly correlated with RABV-G-specific IgG antibodies (r2 = 0.8319, p < 0.0001). CONCLUSIONS: Two 1 µg or 2 µg doses of CV7202 were well tolerated and elicited rabies neutralizing antibody responses that met WHO criteria in all recipients, but 5 µg had unacceptable reactogenicity for a prophylactic vaccine. ClinicalTrials.gov Identifier: NCT03713086.

Sex and gender differences in travel-associated disease.

BACKGROUND: No systematic studies exist on sex and gender differences across a broad range of travel-associated diseases. METHODS: Travel and tropical medicine GeoSentinel clinics worldwide contributed prospective, standardized data on 58,908 patients with travel-associated illness to a central database from 1 March 1997 through 31 October 2007. We evaluated sex and gender differences in health outcomes and in demographic characteristics. Statistical significance for crude analysis of dichotomous variables was determined using chi2 tests with calculation of odds ratios (ORs) and 95% confidence intervals (CIs). The main outcome measure was proportionate morbidity of specific diagnoses in men and women. The analyses were adjusted for age, travel duration, pretravel encounter, reason for travel, and geographical region visited. RESULTS: We found statistically significant (P < .001) differences in morbidity by sex. Women are proportionately more likely than men to present with acute diarrhea (OR, 1.13; 95% CI, 1.09-1.38), chronic diarrhea (OR, 1.28; 95% CI, 1.19-1.37), irritable bowel syndrome (OR, 1.39; 95% CI, 1.24-1.57), upper respiratory tract infection (OR, 1.23; 95% CI, 1.14-1.33); urinary tract infection (OR, 4.01; 95% CI, 3.34-4.71), psychological stressors (OR, 1.3; 95% CI, 1.14-1.48), oral and dental conditions, or adverse reactions to medication. Women are proportionately less likely to have febrile illnesses (OR, 0.15; 95% CI, 0.10-0.21); vector-borne diseases, such as malaria (OR, 0.46; 95% CI, 0.41-0.51), leishmaniasis, or rickettsioses (OR, 0.57; 95% CI, 0.43-0.74); sexually transmitted infections (OR, 0.68; 95% CI 0.58-0.81); viral hepatitis (OR, 0.34; 95% CI, 0.21-0.54); or noninfectious problems, including cardiovascular disease, acute mountain sickness, and frostbite. Women are statistically significantly more likely to obtain pretravel advice (OR, 1.28; 95% CI, 1.23-1.32), and ill female travelers are less likely than ill male travelers to be hospitalized (OR, 0.45; 95% CI, 0.42-0.49). CONCLUSIONS: Men and women present with different profiles of travel-related morbidity. Preventive travel medicine and future travel medicine research need to address gender-specific intervention strategies and differential susceptibility to disease.

Travel and migration associated infectious diseases morbidity in Europe, 2008.

BACKGROUND: Europeans represent the majority of international travellers and clinicians encountering returned patients have an essential role in recognizing, and communicating travel-associated public health risks. METHODS: To investigate the morbidity of travel associated infectious diseases in European travellers, we analysed diagnoses with demographic, clinical and travel-related predictors of disease, in 6957 ill returned travellers who presented in 2008 to EuroTravNet centres with a presumed travel associated condition. RESULTS: Gastro-intestinal (GI) diseases accounted for 33% of illnesses, followed by febrile systemic illnesses (20%), dermatological conditions (12%) and respiratory illnesses (8%). There were 3 deaths recorded; a sepsis caused by Escherichia coli pyelonephritis, a dengue shock syndrome and a Plasmodium falciparum malaria.GI conditions included bacterial acute diarrhea (6.9%), as well as giardiasis and amebasis (2.3%). Among febrile systemic illnesses with identified pathogens, malaria (5.4%) accounted for most cases followed by dengue (1.9%) and others including chikungunya, rickettsial diseases, leptospirosis, brucellosis, Epstein Barr virus infections, tick-borne encephalitis (TBE) and viral hepatitis. Dermatological conditions were dominated by bacterial infections, arthropod bites, cutaneous larva migrans and animal bites requiring rabies post-exposure prophylaxis and also leishmaniasis, myasis, tungiasis and one case of leprosy. Respiratory illness included 112 cases of tuberculosis including cases of multi-drug resistant or extensively drug resistant tuberculosis, 104 cases of influenza like illness, and 5 cases of Legionnaires disease. Sexually transmitted infections (STI) accounted for 0.6% of total diagnoses and included HIV infection and syphilis. A total of 165 cases of potentially vaccine preventable diseases were reported. Purpose of travel and destination specific risk factors was identified for several diagnoses such as Chagas disease in immigrant travellers from South America and P. falciparum malaria in immigrants from sub-Saharan Africa. Travel within Europe was also associated with health risks with distinctive profiles for Eastern and Western Europe. CONCLUSIONS: In 2008, a broad spectrum of travel associated diseases were diagnosed at EuroTravNet core sites. Diagnoses varied according to regions visited by ill travellers. The spectrum of travel associated morbidity also shows that there is a need to dispel the misconception that travel, close to home, in Europe, is without significant health risk.

Dynamic changes in circulating T follicular helper cell composition predict neutralising antibody responses after yellow fever vaccination.

OBJECTIVES: T follicular helper (Tfh) cells are the principal T helper cell subset that provides help to B cells for potent antibody responses against various pathogens. In this study, we took advantage of the live-attenuated yellow fever virus (YFV) vaccine strain, YF-17D, as a model system for studying human antiviral immune responses in vivo following exposure to an acute primary virus challenge under safe and highly controlled conditions, to comprehensively analyse the dynamics of circulating Tfh (cTfh) cells. METHODS: We tracked and analysed the response of cTfh and other T and B cell subsets in peripheral blood of healthy volunteers by flow cytometry over the course of 4 weeks after YF-17D vaccination. RESULTS: Using surface staining of cell activation markers to track YFV-specific T cells, we found increasing cTfh cell frequencies starting at day 3 and peaking around 2 weeks after YF-17D vaccination. This kinetic was confirmed in a subgroup of donors using MHC multimer staining for four known MHC class II epitopes of YF-17D. The subset composition of cTfh cells changed dynamically during the course of the immune response and was dominated by the cTfh1-polarised subpopulation. Importantly, frequencies of cTfh1 cells correlated with the strength of the neutralising antibody response, whereas frequencies of cTfh17 cells were inversely correlated. CONCLUSION: In summary, we describe detailed cTfh kinetics during YF-17D vaccination. Our results suggest that cTfh expansion and polarisation can serve as a prognostic marker for vaccine success. These insights may be leveraged in the future to improve current vaccine design and strategies.