Safety and Immunogenicity of the Quadrivalent Meningococcal Serogroups A, C, W and Y Tetanus Toxoid Conjugate Vaccine Coadministered With Routine Childhood Vaccines in European Infants: An Open, Randomized Trial.

BACKGROUND: This was the first study evaluating the immunogenicity and safety of the quadrivalent meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT) coadministered with routine childhood vaccines in young infants. METHODS: In this open, randomized, controlled, phase III study (NCT01144663), 2095 infants (ages 6-12 weeks) were randomized (1:1:1:1) into 4 groups to receive MenACWY-TT at 2, 3, 4 and 12 months of age, or MenACWY-TT, MenC-cross-reactive material (CRM197) or MenC-TT at 2, 4 and 12 months of age. All participants received PHiD-CV and DTPa-HBV-IPV/Hib at 2, 3, 4 and 12 months of age. Immune responses were measured by serum bactericidal activity assays using rabbit (rSBA) and human (hSBA) complement. Solicited and unsolicited symptoms were recorded during 8 and 31 days post-vaccination, respectively, and serious adverse events throughout the study. RESULTS: Noninferiority of immune responses to MenC induced by 2 or 3 doses of MenACWY-TT versus 2 doses of MenC-TT or MenC-CRM197 was demonstrated. Predefined criteria for the immunogenicity of MenACWY-TT to MenA, MenW and MenY were met. One month after 2 or 3 primary MenACWY-TT doses, ≥93.1% and ≥88.5% of infants had rSBA and hSBA titers ≥1:8 for all serogroups. The robust increases in rSBA and hSBA titers observed for all vaccine serogroups postbooster vaccination suggested that MenACWY-TT induced immune memory. MenACWY-TT coadministered with childhood vaccines had a clinically acceptable safety profile. CONCLUSIONS: This study supports the coadministration of MenACWY-TT with routine childhood vaccines as 2 or 3 primary doses during infancy followed by a booster dose in the second year of life.

Five year follow-up after primary vaccination against tick-borne encephalitis in children.

BACKGROUND: A first tick-borne encephalitis (TBE) vaccine booster in children is currently suggested 3 years after completing either a conventional (doses on Days 0, 28 and 300) or accelerated conventional (doses on Days 0, 14 and 300) TBE immunization schedule. This recommendation, however, may not be appropriate in cases where different TBE vaccines have been used interchangeably during the primary immunization series. METHODS: To provide robust data to better inform such recommendations, TBE antibody persistence was evaluated after 3-5 years in four groups of children (aged 5-15 years): two groups previously primed with three doses of Encepur(®) Children (conventional/accelerated conventional schedule); and two groups previously primed with two doses of FSME-IMMUN(®) followed by a third dose of Encepur(®) Children (conventional/accelerated conventional schedule). Immunogenicity was evaluated using neutralization (NT) assays based on both vaccine antigens as well as on the Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: In the two Encepur(®) Children groups (full series), protective NT titers of ≥10 were detected in 98-100% of children up to 5 years after their last primary vaccination, irrespective of schedule. In contrast, only 65-70% subjects in the FSME-IMMUN(®) Junior groups (mixed series) displayed NT titers ≥10 after 3 years. Thus, due to lower probability of achieving/maintaining long-term protective antibody levels (recently defined by the World Health Organization as an NT titer ≥10) after this time point, both FSME-IMMUN Junior groups were discontinued. CONCLUSION: A strong antibody response persists for at least 5 years after full primary vaccination with Encepur(®) Children. The study thus provides support for extending the time interval for a first booster dose after primary vaccination (conventional/accelerated conventional schedule) with Encepur(®) Children from 3 to 5 years.

Long-term immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in 10- to 14-year-old girls: open 6-year follow-up of an initial observer-blinded, randomized trial.

BACKGROUND: Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine were evaluated up to 6 years postvaccination (month 72) in preteen/adolescent girls. METHODS: Participants, who had received 3 HPV-16/18 AS04-adjuvanted vaccine doses at 10-14 years of age in an initial controlled, observer-blinded, randomized study (NCT00196924) and participated in the open 3-year follow-up (NCT00316706), were invited to continue the follow-up for up to 10 years postvaccination (NCT00877877). Anti-HPV-16 and -18 antibody titers were measured by enzyme-linked immunosorbent assays at yearly visits and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) and pregnancy information were recorded. RESULTS: In the according-to-protocol immunogenicity cohort, all participants (N = 505) with data available remained seropositive for anti-HPV-16 and -18 antibodies at month 72. In initially seronegative participants, anti-HPV-16 and -18 antibody geometric mean titers were 65.8- and 33.0-fold higher than those associated with natural infection (NCT00122681) and 5.0- and 2.5-fold higher than those measured at month 69-74 in a study demonstrating vaccine efficacy in women aged 15-25 years (NCT00120848). Exploratory antibody modeling, based on the 6-year data, predicted that vaccine-induced population anti-HPV-16 and -18 antibody geometric mean titers would remain above those associated with natural infection for at least 20 years postvaccination. The HPV-16/18 AS04-adjuvanted vaccine safety profile was clinically acceptable. CONCLUSIONS: In preteen/adolescent girls, the HPV-16/18 AS04-adjuvanted vaccine induced high anti-HPV-16 and -18 antibody levels up to 6 years postvaccination, which were predicted to remain above those induced by natural infection for at least 20 years.

Long-term persistence of tick-borne encephalitis antibodies in children 5 years after first booster vaccination with Encepur Children.

Tick-borne encephalitis (TBE) is a serious viral infection, which can lead to permanent neurological sequelae in children. The incidence of TBE disease is increasing in many European countries and is particularly pronounced in some regional populations. Vaccination is the most effective method for preventing TBE disease and is recommended for all those living and working in TBE-endemic areas. Encepur Children is licensed for TBE vaccination in children 1-11 years of age. Following primary vaccination, booster vaccinations are recommended; however, the optimal timing for booster vaccination of children is not known. The aim of this study was to assess the persistence of TBE antibodies in children at 3 and 5 years after their first booster vaccination with Encepur Children and to re-evaluate booster vaccination recommendations. Children 1-11 years of age (n=335) who received primary TBE vaccination according to the rapid schedule (Days 0, 7, and 21) in a previous study received a booster vaccination 12-18 months later, and were invited for follow-up at 3 and 5 years post-booster. TBE antibodies were measured using a virus neutralization test (NT; in-house, Novartis Vaccines) and also using anti-TBE IgG ELISA (Enzygnost, Siemens, Germany). In this analysis, 275 of 278 (99%) subjects and all 190 (100%) subjects who completed the follow-up at 3 and 5 years, respectively, had NT titres > or = 10. Likewise, all 275 of 278 (99%) and 188 of 190 (99%) subjects tested positive by ELISA at 3 and 5 years after the booster vaccination, respectively. Based on serological data, the interval for subsequent booster vaccinations with Encepur Children can be extended from 3 to 5 years after receiving primary vaccination and a first booster vaccination 12-18 months later.

Antibody response following administration of two paediatric tick-borne encephalitis vaccines using two different vaccination schedules.

Two paediatric tick-borne encephalitis vaccines, Encepur Children and FSME-IMMUN Junior, are used widely in Europe. This study compared the immunogenicity and safety of both vaccines, administered using the conventional (Days 0, 28, and 300) or accelerated (Days 0, 14, and 300) schedule and evaluated whether a third dose of Encepur Children can complete a primary vaccination course initiated with FSME-IMMUN Junior. A total of 334 children 1 to < 11 years of age were enrolled in this Phase IV randomized, controlled, single-blind, multi-centre trial. All subjects, irrespective of study arm, received Encepur Children as the third dose on Day 300. The percentage of subjects with antibody titres > or = 10, as determined by neutralization test (NT), was assessed and local and systemic reactions were monitored and solicited. Within both the conventional and accelerated schedules, the proportion of subjects achieving an NT > or = 10 was higher in the group that received Encepur Children, compared with the group that received FSME-IMMUN Junior, at Days 42 and 300 (conventional schedule Day 300, P < 0.001 Encepur Children versus FSME-IMMUN Junior; accelerated schedule Days 42 and 300, P<0.001 Encepur Children versus FSME-IMMUN Junior). The third dose of Encepur Children led to a substantial increase in the proportion of subjects in the FSME-IMMUN Junior groups achieving NT > or = 10. Overall, >95% of all children achieved NT > or = 10, on completion of the primary vaccination course. Encepur Children provides an immune response, measured by neutralizing TBE antibodies, that is superior to FSME-IMMUN Junior and can successfully be used to complete a primary vaccination course initiated with FSME-IMMUN Junior. Both vaccines were well tolerated, with comparable safety profiles; no vaccine-related serious adverse events were reported.