Htay-Htay Han

Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study

BACKGROUND We aimed to assess the efficacy of the oral live attenuated human rotavirus vaccine Rotarix (RIX4414) for prevention of rotavirus gastroenteritis in European infants during their first 2 years of life. METHODS 3994 study participants were enrolled from six countries and were randomly assigned two oral doses of either RIX4414 (n=2646) or placebo (n=1348), which were coadministered with the first two doses of specific childhood vaccinations. Follow-up for gastroenteritis episodes was undertaken from 2 weeks post-dose two through the two consecutive rotavirus seasons following vaccinations (combined efficacy follow-up period; mean duration 17 months [SD 1.6]). Our primary endpoint was vaccine efficacy against rotavirus gastroenteritis of any severity during the first efficacy follow-up period (2 weeks post-dose two to the end of the first rotavirus season). Stool specimens obtained during gastroenteritis episodes were tested for rotavirus by ELISA and typed by RT-PCR. Episodes scoring 11 or greater on the 20-point Vesikari scale were classified as severe. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140686 (eTrack102247). FINDINGS 120 infants were excluded from the according-to-protocol analysis. During the first efficacy follow-up period (mean duration 5.7 months [SD 1.2]), 24 of 2572 infants allocated RIX4414 versus 94 of 1302 given placebo had rotavirus gastroenteritis episodes of any severity, resulting in a vaccine efficacy of 87.1% (95% CI 79.6-92.1; p<0.0001). For the combined efficacy follow-up period, vaccine efficacy against severe rotavirus gastroenteritis was 90.4% (85.1-94.1; p<0.0001), for admission owing to rotavirus gastroenteritis 96.0% (83.8-99.5; p<0.0001), and for rotavirus-related medical attention 83.8% (76.8-88.9; p<0.0001), and significant protection against severe rotavirus gastroenteritis by circulating G1, G2, G3, G4, and G9 rotavirus types was shown. INTERPRETATION In a European setting, two doses of RIX4414 coadministered with childhood vaccines provided high protection against any and severe rotavirus gastroenteritis, with an overall reduction of admissions for gastroenteritis over two consecutive rotavirus epidemic seasons.

Immunogenicity and safety of the human rotavirus vaccine Rotarix™ co-administered with routine infant vaccines following the vaccination schedules in Europe

This study assessed the immunogenicity and safety of a human rotavirus vaccine RIX4414; the effect of co-administration of childhood vaccines on the immune responses was also assessed. Healthy infants aged 6-14 weeks received two doses of RIX4414/placebo concomitantly with the primary childhood vaccination (Infanrix hexa, Infanrix quinta,Meningitec and/or Prevnar), respecting the vaccination schedule of each country. Anti-rotavirus IgA seroconversion rate (ELISA cut-off 20 U/ml) was measured pre-vaccination and 1-2 months post-Dose 2. Immune response against diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, inactivated polio virus, pneumococcal polysaccharide conjugate (France and Germany) and meningococcal group C conjugate vaccines (Spain) were measured approximately 1-month post-Dose 3. An overall anti-rotavirus IgA seroconversion rate of 86.5%(95% CI: 83.9-88.8) was observed in the RIX4414 group 1-month post-Dose 2. The seroconversion rate in Finland and Italy (3 and 5-month schedule) was 94.6%(95% CI: 90.0-97.5) and 92.3%(95% CI: 64.0-99.8), respectively. Immune response to the childhood vaccines was unaffected following co-administration with RIX4414. Reactogenicity profile was similar for RIX4414 and placebo groups. RIX4414 was immunogenic and well tolerated in European infants and the co-administration of routine childhood vaccines with RIX4414 did not negatively impact the immune responses to these vaccines.

Reactogenicity and immunogenicity profiles of a novel pentavalent diphtheria-tetanus-whole cell pertussis-hepatitis B and haemophilus influenzae type B vaccine : A randomized dose-ranging trial of the hib tetanus-conjugate content

Background: Combined vaccines containing diphtheria-tetanus-pertussis whole-cell (DTPw), Haemophilus influenzae type b (Hib), and hepatitis-B vaccines are essential for the continuing success of vaccination programs in developing nations. This randomized, dose-ranging study assessed the immunogenicity and reactogenicity of primary and booster vaccination with pentavalent DTPw-HBV/Hib vaccines containing 10, 5 or 2.5μg of polyribosylribitol phosphate (PRP) conjugated to tetanus toxoid (trials Hib-052/064). Methods: Six hundred eighty infants were randomized to receive one of 5 vaccine combinations at 6, 10, and 14 weeks of age. Of these, 351 received the same vaccine at 15–24 months of age. The immune response was evaluated on blood samples collected 1 month after the 3-dose primary course and before and 6 weeks after the booster dose. Reactogenicity was assessed during a 4-day period after each vaccine dose using diary cards. Results: After primary vaccination, all subjects had seroprotective anti-PRP antibody concentrations (≥0.15 μg/mL) and >95% had concentrations ≥1.0 μg/mL, irrespective of the PRP dose administered. Anti-PRP antibody avidity after primary vaccination and antibody persistence until the second year of life were similar among groups. The booster dose induced marked increases in anti-PRP antibody GMCs and antibody avidity, indicative of effective priming and the presence of immune memory. All vaccination regimens elicited good immune responses and comparable antibody persistence to the other vaccine antigens, with significant increases in all antibody concentrations observed after boosting. All vaccination regimens were safe, with similar overall reactogenicity profiles. Conclusion: Hib conjugate vaccines containing reduced amounts of PRP can be effectively combined with the licensed DTPw-HBV vaccine to provide protection against 5 major childhood pathogens in a single injection.

Immunogenicity of a live-attenuated human rotavirus RIX4414 vaccine with or without buffering agent

Aim: The lyophilized form of the human rotavirus RIX4414 vaccine (Rotarix™) is usually reconstituted with a liquid calcium carbonate (CaCO3) buffer and administered orally. However, errors in the reconstitution could occur (e.g. reconstituted with water instead of CaCO3 buffer) or the buffer might be temporarily unavailable in few instances. This study was conducted to evaluate the immunogenicity of the RIX4414 vaccine if the vaccine was reconstituted with other agents (e.g. water) instead of CaCO3 buffer. Methods: Healthy infants aged 6–12 weeks, received two oral doses of the RIX4414 vaccine/placebo, reconstituted either with injectable water or CaCO3 buffer according to a 0, 2 month schedule. Seroconversion rates in terms of anti-rotavirus Immunoglobulin A (anti-RV IgA) antibody levels (cut off: ≥ 20U/ml by ELISA) and vaccine take were calculated 2 months post-Dose 2. Solicited and unsolicited symptoms reported during the 15- and 31-day follow-up period after each dose and serious adverse events (SAEs) reported during the entire study period were recorded. Results: There was no statistical difference detected between RIX4414 vaccine reconstituted with buffer or water in vaccine take or in seroconversion rate. The anti-RV IgA seroconversion rate 2 months post-Dose 2 was 84.7% (95% CI: 78.1–90.0) for the group with buffer and 78.6% (95% CI: 71.2–84.8) for the group with water. Solicited and unsolicited symptoms reported were similar across groups. No vaccine related SAEs were reported. Conclusion: Administration of RIX4414 vaccine in the absence of CaCO3 buffer was shown to be well tolerated and immunogenic in Thai infants.

Immunogenicity and safety of 3-dose primary vaccination with combined DTPa-HBV-IPV/Hib vaccine in Canadian Aboriginal and non-Aboriginal infants.

This study compared immune responses of healthy Aboriginal and non-Aboriginal infants to Haemophilus influenzae type b (Hib) and hepatitis B virus (HBV) components of a DTaP-HBV-IPV/Hib combination vaccine, 1 month after completing dosing at 2, 4 and 6 months of age. Of 112 infants enrolled in each group, 94 Aboriginal and 107 non-Aboriginal infants qualified for the immunogenicity analysis. Anti-PRP concentrations exceeded the protective minimum (≥0.15 μg/ml) in ≥97% of infants in both groups but geometric mean concentrations (GMCs) were higher in Aboriginal infants (6.12 μg/ml versus 3.51 μg/ml). All subjects were seroprotected (anti-HBs ≥10 mIU/mL) against HBV, with groups having similar GMCs (1797.9 versus 1544.4 mIU/mL, Aboriginal versus non-Aboriginal, respectively). No safety concerns were identified. We conclude that 3-dose primary vaccination with DTaP-HBV-IPV/Hib combination vaccine elicited immune responses to Hib and HBV components that were at least as high in Aboriginal as in non-Aboriginal Canadian infants. Clinical Trial Registration NCT00753649.

Immunogenicity of a human rotavirus vaccine (RIX4414) after storage at 37 °C for seven days.

Aim: The lyophilized formulation of the human rotavirus vaccine, RIX4414 (RotarixTM), is recommended to be stored at 2°C–8°C for optimal immunogenicity. In some settings with inadequate infrastructure for vaccine storage, unforeseen circumstances may cause cold chain breakage, resulting in the vaccine to be left at ambient temperatures. This study evaluated the heat stability of lyophilized RIX4414 vaccine in terms of immunogenicity when stored at tropical room temperature (37°C) for 7 days before reconstitution. Results: There was no statistically significant difference detected between RIX4414 vaccine stored at 2°C–8°C (Group RIX4414_control, n = 171) and that stored at 37°C for 7 days (Group RIX4414_37°C, n = 47) in terms of seroconversion rate and vaccine take. The anti-rotavirus IgA seroconversion rate 2 months post-Dose 2 was 84.7% (95% CI: 78.1%–90%) and 87.8% (95% CI: 73.8%–95.9%) in Groups RIX4414_control and RIX4414_37°C, respectively. None of the 25 infants in placebo group seroconverted. The vaccine take in the respective vaccine groups were 88% (95% CI: 82.1%–92.5%) and 93.5% (95% CI: 82.1%–98.6%) and Geometric Mean Concentrations (GMCs) were 134.4 U/mL (95% CI: 104.5–172.9) and 163.7 U/mL (95% CI: 98.9–271.1). Methods: Healthy infants aged 6–12 weeks, received two oral doses of either the RIX4414 vaccine stored at 2°C–8°C, RIX4414 vaccine stored at 37°C for 7 days or placebo, according to a 0, 2 month schedule. Seroconversion rates in terms of anti-rotavirus IgA antibody levels (cut off: ≥20 U/mL by ELISA), anti-rotavirus IgA antibody GMCs and vaccine take were calculated 2 months post-Dose 2. Conclusion: Lyophilized RIX4414 vaccine stored at 37°C for 7 days before reconstitution has similar immunogenicity as the vaccine stored at 2°C–8°C. These results supported the use of RIX4414 in settings where the vaccine might be exposed to higher than the recommended storage temperatures.

Immunogenicity, reactogenicity, and safety of a human rotavirus vaccine, Rotarix, in Taiwanese infants who received a dose of hepatitis B immunoglobulin after birth

UNLABELLED This Phase-IV study evaluated the human rotavirus (RV) vaccine Rotarix (RIX4414) to provide additional local clinical data to the Taiwan Food and Drug Association (NCT01198769). Healthy infants aged 6-12 weeks who were given a hepatitis B immunoglobulin (HBIg) dose after birth, received two doses of RIX4414 (0, 2-month schedule). Anti-RV IgA antibody concentrations were measured using ELISA. A total of 15 infants were enrolled, and included in the according-to-protocol cohort. The anti-RV IgA antibody seroconversion rate 2 months post-Dose 2 was 100% (95% confidence interval = 78.2-100) and the geometric mean concentration was 254.7 U/ml (95% confidence interval = 145.0-447.7). Two episodes of gastroenteritis were reported, and one stool sample was tested for RV, which was negative. No fatal serious adverse events were reported during the study period between November 2010 and April 2011. The two-dose regimen of RIX4414 was highly immunogenic and safe when administered to healthy Taiwanese infants who received a HBIg dose after birth. TRIAL REGISTRATION NUMBER NCT01198769.