Fong Seng Lim

Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: Randomised, double-blind, controlled study

This study evaluates the safety and efficacy against severe rotavirus gastroenteritis of the oral live attenuated human rotavirus vaccine RIX4414 (Rotarix) during the first 2 years of life in Asian infants from high-income countries. Healthy infants were enrolled to receive 2 doses of RIX4414 (N=5,359) or placebo (N=5,349). From 2 weeks post-dose 2 to 2 years of age, vaccine efficacy was 96.1% (95%CI:85.1%; 99.5%) against severe rotavirus gastroenteritis, 100% (95%CI:80.8%; 100%) against wild-type G1P[8] and 93.6% (95%CI:74.7%; 99.3%) against circulating non-G1 rotavirus types. No intussusception cases were reported within 31 days post-vaccination. RIX4414 shows a good safety profile and offers high protection during the first 2 years of life with potentially significant public health impact in this population.

Immunogenicity and tolerability of an AS03A-adjuvanted prepandemic influenza vaccine: A phase III study in a large population of Asian adults

The immunogenicity and lot-to-lot consistency of an AS03-adjuvanted H5N1 vaccine were evaluated in 1206 Asian adults, randomised to receive two doses of adjuvanted (3.75 microg haemagglutinin) or diluent-mixed vaccines, 21 days apart. Post-Dose 2, 96.0% of vaccinees in the H5N1-AS03 group demonstrated a four-fold increase in neutralising antibody titres against the vaccine strain A/Vietnam/1194/2004 and 91.4% against strain A/Indonesia/05/2005. Haemagglutination-inhibiting antibodies (titre > or = 1:40) against A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains were observed in 94.3% and 50.2% of subjects, respectively. Lot-to-lot consistency of the AS03-adjuvanted vaccine combinations was demonstrated. The AS03-adjuvanted vaccine was well tolerated, induced a high frequency of immune responses to the vaccine strain, allowed antigen sparing and promoted cross-clade immunity. These characteristics make it suitable for presumptive use if an H5N1 pandemic were considered to be imminent.

Safety and immunogenicity of early vaccination with two doses of tetravalent measles-mumps-rubella-varicella (MMRV) vaccine in healthy children from 9 months of age.

Background:This open, randomized, controlled study [208136/018] assessed the safety and immunogenicity of early vaccination with an experimental tetravalent measlesmumps-rubella-varicella (MMRV) vaccine (GlaxoSmithKline Biologicals) compared to concomitant administration of separate licensed MMR (Priorix™) and varicella (Varilrix™) vaccines (MMR+V).Methods:Vaccines were administered as a two-dose course in healthy children at 9 and 12 months of age (N = 153 in the MMRV group and N = 146 in the MMR+V group).Results:The incidence of fever of any intensity (axillary temperature ≥ 37.5 °C) during the 15 days of follow-up post-dose 1 was higher in the MMRV group than in the MMR+V group (48.3% vs 25.7%, respectively) but was low in both groups post-dose 2 (20.3% and 22.1%, respectively). The incidence of fever > 39.0 °C and the incidence of solicited local symptoms (pain, redness, swelling) were low ( ≤ 5.3% and ≤ 13.7%, respectively) in the two groups after each vaccine dose. Seroconversion rates were similar in the two groups for all vaccine antigens after each vaccine dose and were ≥ 99.2% for each antigen post-dose 2. Anti-measles GMT was higher in the MMRV group than in the MMR+V group after the first vaccine dose. After the second dose, slight to moderate increases in measles, mumps and rubella antibody titers and a substantial increase in varicella antibody titer were seen in both groups, leading to higher GMTs in the MMRV group compared with the MMR+V group for measles, mumps and varicella. Anti-rubella antibody GMTs were similar in the two groups post-dose 2.Conclusion:Early vaccination with two doses of this experimental MMRV vaccine at 9 and 12 months of age was well-tolerated and at least as immunogenic as two doses of separate licensed MMR and varicella vaccines.

Rotavirus vaccine RIX4414 efficacy sustained during the third year of life: a randomized clinical trial in an Asian population.

RIX4414 (Rotarix™), has shown high efficacy during the first 2-years of life. A 2-year randomized, double-blind, placebo-controlled trial in Singapore, Hong Kong, and Taiwan was extended for another year. Infants (6-17 weeks) received 2-doses (1-2 months apart) of RIX4414 (n=5359) or placebo (n=5349). During the third-year follow-up, 4359 (RIX4414) and 4328 (placebo) infants were monitored. 64 (1.2%) and 2 (0.04%) infants in the placebo and RIX4414 groups, respectively, reported severe rotavirus-gastroenteritis (RVGE), resulting in a vaccine efficacy of 96.9% (95% CI [88.3-99.6]). Efficacy was 100% (67.5-100) in the third-year. RIX4414 was efficacious against G1 (100.0% [84.8-100]) and pooled non-G1 RV types (94.9% [80.2-99.4]). This study shows that the vaccine is highly efficacious, regardless of circulating RV-types, up to the first 3 years of life in affluent Asian urban populations.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9–14 years: Results to month 12 from a randomized trial

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9–14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49–1.91] for anti-HPV-16 and 4.52 [3.97–5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54–1.93] for anti-HPV-16 and 3.22 [2.82–3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9–14 years).

Incidence of rotavirus gastroenteritis by age in African, Asian and European children: Relevance for timing of rotavirus vaccination

ABSTRACT Variability in rotavirus gastroenteritis (RVGE) epidemiology can influence the optimal vaccination schedule. We evaluated regional trends in the age of RVGE episodes in low- to middle- versus high-income countries in three continents. We undertook a post-hoc analysis based on efficacy trials of a human rotavirus vaccine (HRV; Rotarix™, GSK Vaccines), in which 1348, 1641, and 5250 healthy infants received a placebo in Europe (NCT00140686), Africa (NCT00241644), and Asia (NCT00197210, NCT00329745). Incidence of any/severe RVGE by age at onset was evaluated by active surveillance over the first two years of life. Severity of RVGE episodes was assessed using the Vesikari-scale. The incidence of any RVGE in Africa was higher than in Europe during the first year of life (≤2.78% vs. ≤2.03% per month), but much lower during the second one (≤0.86% versus ≤2.00% per month). The incidence of severe RVGE in Africa was slightly lower than in Europe during the first year of life. Nevertheless, temporal profiles for the incidence of severe RVGE in Africa and Europe during the first (≤1.00% and ≤1.23% per month) and second (≤0.53% and ≤1.13% per month) years of life were similar to those of any RVGE. Any/severe RVGE incidences peaked at younger ages in Africa vs. Europe. In high-income Asian regions, severe RVGE incidence (≤0.31% per month) remained low during the study. The burden of any RVGE was higher earlier in life in children from low- to middle- compared with high-income countries. Differing rotavirus vaccine schedules are likely warranted to maximize protection in different settings.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and 4vHPV vaccine administered according to two- or three-dose schedules in girls aged 9–14 years: Results to month 36 from a randomized trial

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of two doses (2D) of the HPV-16/18 AS04-adjuvanted vaccine (2D of AS04-HPV-16/18) vs. two or three doses of the 4vHPV vaccine [2D or 3D of 4vHPV] in 1075 healthy girls aged 9-14 years. Girls were randomized (1:1:1) to receive 2D of AS04-HPV-16/18 at months (M) 0, 6 (N = 359), 2D of 4vHPV at M0, 6 (N = 358) or 3D of 4vHPV at M0, 2, 6 (N = 358). 351, 339 and 346 girls, respectively, returned for the concluding visit at M36. Superiority was demonstrated at M7 and M12; comparison of the immune response to both vaccine antigens was made between 2D of AS04-HPV-16/18 and 2D or 3D of 4vHPV at subsequent time points in the according-to-protocol immunogenicity cohort (ATP-I; N = 958 at M36) and the total vaccinated cohort (TVC: N = 1036 at M36). HPV-16/18-specific T-cell- and B-cell-mediated immune responses and safety were also investigated. At M36, anti-HPV-16/18 ELISA responses in the 2D AS04-HPV-16/18 group remained superior to those of the 2D and 3D 4vHPV groups. In the M36 TVC, geometric mean titers were 2.78-fold (HPV-16) and 6.84-fold (HPV-18) higher for 2D of AS04-HPV-16/18 vs. 2D of 4vHPV and 2.3-fold (HPV-16) and 4.14-fold (HPV-18) higher vs. 3D of 4vHPV. Results were confirmed by vaccine pseudovirion-based neutralisation assay. Numbers of circulating CD4+ T cells and B cells appeared similar across groups. Safety was in line with the known safety profiles of both vaccines. In conclusion, superior HPV-16/18 antibody responses were elicited by 2D of the AS04-HPV-16/18 compared with 2D or 3D of the 4vHPV vaccine in girls aged 9-14 years. CLINICAL TRIAL REGISTRATION NCT0146235.