Three-dose versus four-dose primary schedules for tick-borne encephalitis (TBE) vaccine FSME-immun for those aged 50 years or older: A single-centre, open-label, randomized controlled trial.

BACKGROUND: TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. METHODS: In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0-30-360) or one of two four-dose series (0-7-21-360; 0-30-90-360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neutralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. RESULTS: The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0-7-21-360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60, 120, 360). Using the other four-dose schedule (0-30-90-360), no such difference was observed on day 400 (63 versus 41, NS). CONCLUSION: Immune response to the TBE vaccine declined with age. A four-dose schedule (0-7-21-360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776.

The Vero cell-derived, inactivated, SA14-14-2 strain-based vaccine (Ixiaro) for prevention of Japanese encephalitis.

With an estimated 68,000 cases each year, Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia. Vaccination against the disease is recommended for endemic populations and also for travelers at risk. Recently, a Vero cell-derived, inactivated, SA14-14-2 strain-based JE vaccine (JE-VC) became available for travelers from non-endemic regions, replacing the traditional mouse brain-derived vaccines. First licensed in 2009, JE-VC is currently available in Europe, the USA, Canada, Australia and several other countries. In 2013, the vaccine was approved by the European Medicines Agency and the US Food and Drug Administration for use in children. This review summarizes current data on the immunogenicity, safety and clinical use of JE-VC.

Cross-protection elicited by primary and booster vaccinations against Japanese encephalitis: a two-year follow-up study.

BACKGROUND: The inactivated Vero cell-derived vaccine (JE-VC, IXIARO) has replaced the traditional mouse brain-derived preparations (JE-MB) in travelers' vaccinations against Japanese encephalitis. We showed recently that a single JE-VC dose efficiently boosts immunity in JE-MB-primed vaccinees, and that JE-VC elicits cross-protective immunity against non-vaccine genotypes, including the emerging genotype I. While these studies only provided short-term data, the present investigation evaluates the longevity of seroprotection in the same volunteers. METHODS: The study comprised 48 travelers who had received (1) JE-VC primary series, (2) JE-MB primary series followed by a single JE-VC booster dose, or (3) JE-MB primary series and a single JE-MB booster dose. Serum samples were collected two years after the last vaccine dose, and evaluated with the plaque-reduction neutralization test against seven Japanese encephalitis virus strains representing genotypes I-IV. PRNT50 titers ≥ 10 were considered protective. RESULTS: Two years after the primary series with JE-VC, 87-93% of the vaccinees proved to be cross-protected against test strains representing genotypes II-IV and 73% against those of genotype I. After a single homologous or heterologous booster dose to JE-MB-primed subjects, the two-year seroprotection rates against genotype I-IV strains were 89-100%. CONCLUSIONS: After JE-VC primary series, seroprotection appeared to wane first against genotype I. The first booster should not be delayed beyond two years. In JE-MB-primed subjects, a single JE-VC booster provided cross-protective immunity against genotype I-IV strains in almost all vaccinees, suggesting an interval of two years or even longer for the second booster. These data further support the use of a single JE-VC dose for boosting JE-MB immunity.

Dengue in travelers: kinetics of viremia and NS1 antigenemia and their associations with clinical parameters.

Despite the increasing numbers of travel-acquired dengue, few studies have assessed virologic markers of the disease in non-endemic populations. We examined the kinetics of diagnostic markers and their associations with clinical parameters in 93 patients with travel-acquired dengue fever. Kinetics analyses suggested a longer average duration for viremia (9 days, CI95%: 8-10) and non-structural protein 1 (NS1) antigenemia (15 days, CI95%: 12-20) than reported in endemic populations. While none of the tests sufficed alone, the best diagnostic coverage was achieved by combining antibody detection with RNA or NS1 testing. Studied by regression models, early relative levels of viremia and NS1 antigenemia proved to be significantly associated with several clinical parameters: high viremia predicted greater likelihood and increased length of hospitalization, the degree of NS1 antigenemia correlated positively with hematocrit and liver transaminases, and both viremia and NS1 antigenemia levels negatively with platelet counts in follow-up. Levels of viremia and NS1 antigenemia may serve as predictors of the clinical manifestations in travel-acquired dengue.

Cross-protective capacity of Japanese encephalitis (JE) vaccines against circulating heterologous JE virus genotypes.

Current Japanese encephalitis vaccines are derived from strains of genotype III, yet heterologous genotypes are emerging in endemic areas. Inactivated vaccines given to European travelers were found to elicit protective levels of neutralizing antibodies against heterologous strains of genotypes I-IV.

A single dose of vero cell-derived Japanese encephalitis (JE) vaccine (Ixiaro) effectively boosts immunity in travelers primed with mouse brain-derived JE vaccines.

BACKGROUND: A significant part of the world population lives in areas with endemic Japanese encephalitis (JE). For travelers from nonendemic countries, Vero cell-derived vaccine (JE-VC; Ixiaro) has replaced traditional mouse brain-derived vaccines (JE-MB) associated with safety concerns. The 2 vaccines are derived from different viral strains: JE-VC from the SA14-14-2 strain and JE-MB from the Nakayama strain. No data exist regarding whether JE-VC can be used to boost immunity after a primary series of JE-MB; therefore, a primary series of JE-VC has been recommended to all travelers regardless of previous vaccination history. METHODS: One hundred twenty travelers were divided into 4 groups: Volunteers with no prior JE vaccination received primary immunization with (group 1) JE-MB or (group 2) JE-VC, and those primed with JE-MB received a single booster dose of (group 3) JE-MB or (group 4) JE-VC. Immune responses were tested before and 4-8 weeks after vaccination using plaque reduction neutralization test (PRNT) against both vaccine strains. RESULTS: In vaccine-naive travelers, the vaccination response rate for test strains Nakayama and SA14-14-2 was 100% and 87% after primary vaccination with JE-MB and 87% and 94% after JE-VC, respectively. Antibody levels depended on the target virus, with higher titers against homologous than heterologous PRNT(50) target strain (P < .001). In travelers primed with JE-MB, vaccination response rates were 91% and 91%, and 98% and 95% after a booster dose of JE-MB or JE-VC, respectively. Subgroup analysis revealed that a higher proportion of primed (98%/95%) than nonprimed (39%/42%) volunteers responded to a single dose of JE-VC (P < .001). CONCLUSIONS: A single dose of JE-VC effectively boosted immunity in JE-MB-primed travelers. Current recommendations should be reevaluated. CLINICAL TRIALS REGISTRATION: NCT01386827.