Pamela Rendi-Wagner

Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial

BACKGROUND Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis in southeast Asia. Although no treatment is currently available, vaccination effectively prevents the disease. In a non-inferiority study, we aimed to compare the safety and immunogenicity of a novel, second-generation, inactivated candidate vaccine for JEV with a licensed, mouse-brain-derived vaccine. METHODS We included 867 adults in a multicentre, multinational, observer-blinded, randomised controlled phase III trial. Study sites were located in the USA, Germany, and Austria. Volunteers received either the JEV test vaccine intramuscularly on a two-dose schedule (on days 0 and 28; n=430) or the licensed vaccine subcutaneously according to its recommended three-dose schedule (on days 0, 7, and 28; n=437). The primary endpoint was immunogenicity, with respect to neutralising JEV-specific antibodies assessed by a plaque-reduction neutralisation test, which was assessable in 725 patients in the per-protocol population. This trial is registered as a clinical trial, EudraCT number 2004-002474-36. FINDINGS The safety profile of the test vaccine was good, and its local tolerability profile was more favourable than that of the licensed vaccine. Frequency of adverse events was similar between treatment groups, and vaccine-related adverse events were generally mild. The seroconversion rate of the test vaccine was 98% compared with 95% for the licensed vaccine on day 56 (95% CI for the difference -1.33 to 3.43). Geometric mean titre for recipients of the test vaccine was 244 (range 5-19 783), compared with 102 (5-1864) for the licensed vaccine (ratio 2.3 [95% CI 1.967-2.75]). INTERPRETATION The test JEV vaccine has a promising immunogenicity and safety profile.

Universal mass vaccination against rotavirus gastroenteritis: impact on hospitalization rates in Austrian children.

Background: Since July 2007, rotavirus vaccinations have been subsidized in Austria for all children from the seventh week up to the sixth month of life. Vaccination coverage over the whole period was 72% with an increase to 87% in 2008. Methods: In a sentinel network including 11 pediatric hospital wards in Austria, data of children up to 15 years of age and hospitalized due to rotavirus gastroenteritis between January 2001 and December 2008 have been collected. Results: The hospitalization rates of children up to 12 months of age with rotavirus gastroenteritis were 2066 × 10−5 between 2001 and 2006 and decreased to 631 × 10−5 in 2008. For children between 12 and 24 months of age the hospitalization rate decreased from 1822 × 10−5 (2001–2006) to 1456 × 10−5 in 2008. In children aged 2 to less than 5 years, incidence rates were 436 ×10−5 (2001–2006) and 461 × 10−5 in 2008. In older children, the hospitalization rates remained unchanged. In the target population for the RV-vaccine, a decrease of hospitalization rates due to rotavirus gastroenteritis of 74% was observed compared to the era before the introduction of the vaccine. The field effectiveness of the vaccine was estimated between 61% and 98%, depending on assumptions about the vaccination status. Conclusions: Within 18 months, the universal mass vaccination program against rotavirus led to a substantial decrease in the hospitalization rates of the target cohort of the immunization program in Austria.

Herd immunity after two years of the universal mass vaccination program against rotavirus gastroenteritis in Austria

Austria was the first country in Europe implementing a universal mass vaccination program against rotavirus gastroenteritis (RV-GE) for all infants nationwide. Epidemiological data from a hospital based surveillance system show that incidence rates of children hospitalized with RV-GE decreased in 2009 compared to 2008 and compared to the prevaccination period 2001-2005. Decreasing hospitalization-rates from RV-GE were observed in children of all age groups, even in those not eligible for vaccination according to their age, suggesting herd immunity induced by universal mass vaccination against RV-GE. In 2009 the disease burden was highest in children below three months of age stressing the importance of the early start of the immunization course.

The seroepidemiology of Bordetella pertussis in Israel--Estimate of incidence of infection.

This study was undertaken to estimate the magnitude of Bordetella pertussis infections in a highly vaccinated population in Israel in order to evaluate the relationship between clinical notification data and serology-based evidence of infection. A cross-sectional survey was conducted on a total of 1982 serum samples from the National Serum Bank, collected from January 2000 through December 2001, in order to monitor high levels of pertussis toxin (PT) IgG antibody indicative of recent B. pertussis infection, by standardized methods. The estimation yielded an infection incidence rate of 2448 per 100,000 population (> or =3 years of age) for the year 2000 compared to an annual incidence of reported pertussis of 5.6 per 100,000 for the same period. The peaks of estimated incidence of infection were found in the groups of 15-19-year olds (5245 per 100,000) and older than 60 years (6469 per 100,000), whereas the majority of clinical pertussis cases were reported for the 10-14-year olds (20.5 per 100,000). The findings clearly show that despite a high vaccination coverage rate (>93%), there is still a considerable circulation of B. pertussis, particularly in adolescents and elderly. Population-based serosurveillance for pertussis offers the potential to assist interpretation of trends independent of notification and diagnostic bias.

Impact of a pertussis booster vaccination program in adolescents and adults on the epidemiology of pertussis in Austria

Background: A resurgence of pertussis has been observed in several countries; however, inconsistent data are available for Europe. In Austria, routine pertussis vaccination for babies is administered at 3, 4, and 5 months, and in the second year of life. Since 2002, regular boosters for all persons >6 years of age (including adults) are recommended. This study was undertaken to analyze epidemiologic trends of laboratory-reported pertussis to evaluate current vaccination strategy in Austria. Methods: Epidemiologic surveillance of laboratory-reported pertussis was conducted from January 1, 2000, to December 31, 2005. Infection was confirmed by positive serology, by positive culture of Bordetella pertussis, or by detection of sequences of the pertussis toxin gene by real-time polymerase chain reaction (RT-PCR). Data were assessed by age, hospitalization rate, seasonality, and incidence rate. Results: During the observation period 4395 reported cases of pertussis were eligible for analysis. The mean annual incidence increased from 6.4 per 100,000 population in 2000 to 11.1 cases per 100,000 population in 2005. Incidence rates were highest among children less than 1 year of age. Decreasing rates were observed for children and adolescents <16 years of age, whereas increasing rates were detected for persons 16 years of age and older. The mean age of reported pertussis cases increased from 30 years (±25.9 SD) in 2000 to approximately 44 years (±23.7 SD) in 2005. Hospitalization rates were highest in infants <6 months (86%) and lowest in those 10 to <50 years of age (17%), followed by an increase to 80% in persons 85 years of age and older. In general, no seasonal occurrence of disease was apparent. Conclusions: Pertussis incidence remains high among adults implying that coverage rates regarding booster vaccinations for adolescents and adults still are too low. Reinforced application of the current booster strategy is needed.

Effect of pre-existing anti-tick-borne encephalitis virus immunity on neutralising antibody response to the Vero cell-derived, inactivated Japanese encephalitis virus vaccine candidate IC51

Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis in Asia with a case fatality rate up to 35% and long-term sequelae up to 75%. This active-controlled, randomized, multi-centre, observer-blind, phase III trial investigated the neutralising antibody response to the new Japanese encephalitis (JE) vaccine IC51 in subjects with (N=81) and without (N=339) pre-existing tick-borne encephalitis (TBE) vaccine induced antibodies as determined by TBE enzyme-linked immunosorbent assay IgG (ELISA). Neutralising antibody response was statistically superior in TBE ELISA-positive subjects compared to TBE ELISA-negative subjects after the first (p<0.0001) but not after the second vaccination with IC51. Thus, pre-existing vaccine-induced TBE immunity enhances the neutralising JEV-specific antibody response after a single IC51 vaccination.

Booster vaccinations against tick-borne encephalitis: 6 Years follow-up indicates long-term protection

Five and 6 years post-booster, immunity to tick-borne encephalitis (TBE) virus was assessed in 225 and 195 vaccinees, respectively, out of 430 healthy volunteers with at least three TBE-immunizations prior to study inclusion and booster intervals exceeding recommended limits. Neutralizing antibody titers of > or = 1:10 (reliable level of protection) were present in 86-96% depending on age group, with lower percentages in participants >60 years. TBE antibody levels remained stable for many years in most vaccinees. However, in a few persons a shorter period of protection against TBE was indicated. Therefore, recommendations on booster intervals in TBE endemic areas should be adapted by weighting the risk of infection against the risk of short-lived immunity.

Active hospital-based surveillance of rotavirus diarrhea in Austrian children, period 1997 to 2003

ZusammenfassungHINTERGRUND: Rotaviren stellen die weltweit häufigste Ursache schwerer dehydrierender Diarrhoe im Säuglings- und Kleinkindesalter dar. Ziel dieser Studie war es, Daten über Rotavirus-assoziierte Hospitalisierungen von Kindern in Österreich zu erhalten als Basis für eine mögliche zukünftige Impfindikation. METHODEN: Die gegenständlichen Daten wurden mittels aktiver Rotavirus Sentinel Spitalssurveillance über den Zeitraum 1997 bis 2003 gewonnen. RESULTATE: Insgesamt waren während des siebenjährigen Beobachtungszeitraums 25,600 Kinder < 15 Jahren mit der Diagnose akuter Rotavirus Gastroenteritis hospitalisiert, wobei die Jahresverteilung Inzidenzgipfel in den Monaten Februar bis März zeigt. Fünf Prozent der Fälle zeigten erste Durchfallsymptome frühestens 48 Stunden nach Aufnahme, hinweisend auf einen nosokomialen Infektionsursprung. Die gemittelte jährliche Hospitalisierungsinzidenz für die Altersklasse < 5 Jahre und < 2 Jahre waren respektive 766 und 1742 pro 100,000 Kinder, das heißt 1 von 60 österreichischen Kindern < 2 Jahren bedurfte einer Hospitalisierung. Im Durchschnitt lag der Erkrankungsgipfel zwischen dem 8. und 14. Lebensmonat, 68 % der gemeldeten Fälle waren jünger oder gleich 2 Jahre. Die durchschnittliche Hospitalisierungsdauer pro Kind lag bei 4,7 Tage, entsprechend 17,200 Rotavirusassoziierte Spitalstagen pro Jahr. SCHLUSSFOLGERUNG: Die nationale Hospitalisierungsinzidenz liegt höher als in einigen anderen Industriestaaten. Die hier erhobenen Daten belegen eine beachtliche Anzahl Rotavirus-assoziierter Spitalstage pro Jahr, implizierend einen substantiellen direkten Kostenaufwand.SummaryBACKGROUND: Rotavirus is the most common pathogen causing severe dehydrating diarrhea in infants and young children worldwide. Any decision on implementation of rotavirus vaccination will be strongly influenced by the expected reduction in severe and therefore costly outcomes associated with rotavirus infection. The aim of this study was to provide data on hospitalization of young children with rotavirus infection in Austria. METHODS: The data were derived from active hospitalbased sentinel surveillance for rotavirus during the period 1997 to 2003. RESULTS: During this period 25,600 children < 15 years of age were hospitalized with acute laboratoryconfirmed rotavirus gastroenteritis, the infection showing seasonal peaks between February and March. In 5 % of the cases first symptoms of diarrhea occurred at a minimum of 48 hours after hospital admission, indicating healthcare-associated origin of infection. The mean annual incidence of hospitalization per 100,000 population for the age group < 5 years was 766 and for those < 2 years 1742, the latter meaning that 1 in 60 Austrian children up to 2 years of age required hospitalization. An average peak incidence was observed between 8 and 14 months of age, with an average of 68 % of the reported cases occurring in children aged ≤24 months. The mean length of hospital stay was 4.7 days, resulting in 17,200 rotavirus-associated hospital days per year. CONCLUSIONS: The observed incidence of hospitalization due to rotavirus in Austria is slightly higher than that reported in other industrialized countries. Our results reflect the considerable number of rotavirus-associated pediatric hospital in-patient days per year and the substantial annual direct costs of hospital care.

Advances in vaccination against tick-borne encephalitis

Tick-borne encephalitis (TBE) poses a growing health problem in many European countries and parts of Northern Asia. Thus, vaccination has been employed successfully for many years in endemic countries. Long-term experience gained from widespread use, however, prompted the development of improved vaccine formulations of the two licensed European TBE vaccines. Moreover, recent clinical trials also suggested the maintenance of high values of postvaccination neutralizing TBE antibodies for a longer period than expected; thus, also resulting in modifications with regards to immunization regimens. Recent advances in recombinant DNA technology have opened up future opportunities for developing novel live-attenuated vaccines against TBE virus and other flaviviruses. Animal experiments demonstrated safety and high immunogenicity profiles for these mutants; thus, making them promising vaccine candidates that will need to demonstrate a clear advantage if they are going to be alternatives to the traditional vaccines. Systematic TBE case monitoring by raising problem awareness, both inside and outside endemic regions, appears essential to provide evidence for a widely accepted TBE travel-vaccination recommendation in the future.

Correlation between humoral and cellular immune responses and the expression of the hepatitis A receptor HAVcr-1 on T cells after hepatitis A re-vaccination in high and low-responder vaccinees.

INTRODUCTION We recently published a study on the persistence of seroprotection 10 years after primary hepatitis A vaccination in an unselected study population of 1014 vaccinees. The majority of these vaccinees still exhibited sufficient protective antibody levels, while 2% displayed antibody concentrations below detection level. In order to investigate whether the low antibody levels were due to decline after primary vaccination or due to an intrinsic inability to sufficiently respond to hepatitis A antigen, we sought to recruit these low/no responder vaccinees to characterize their immune responses in more detail after booster vaccination in comparison to high responder vaccinees. MATERIALS AND METHODS Prior to and one week after booster vaccination with a hepatitis A vaccine, antibody levels, cytokine levels (IL-2, IFN-gamma and IL-10) and CD surface marker expression on peripheral blood mononuclear cells were determined in a study population comprised of 52 individuals. Additionally, the hepatitis A HAV cellular receptor 1 (HAVcr-1) TIM-1, being also expressed on CD4+ T cells and associated with immunomodulatory properties, was measured by RT-PCR before and after hepatitis A booster. RESULTS Our data indicate that there is indeed a small group of hepatitis A vaccinees that can be classified as low/no responders as their antibody levels remain below the seroprotection level of 20mIU/ml after booster vaccination. We further describe a good correlation between antibody concentrations and cellular responses, showing that low antibody production is associated with low antigen specific cytokine levels (IL-2, IFN-gamma, IL-10) and vice versa. While there was no significant difference in the expression of the most common surface markers on T and B cells before and after booster vaccination in low and high responder vaccinees, the expression of HAVcr-1 on CD4 T cells correlated significantly with the antibody responses and cytokine levels, suggesting this receptor as cellular prediction marker of immune responsiveness to hepatitis A. CONCLUSION Whether hepatitis A low/non-responders deserve particular attention as a risk group or might display certain resistance to hepatitis A infection due to a lack of the hepatitis A receptor needs further investigations. At this stage we suggest that persons at high exposure risk should be carefully observed.