Prymula Roman, Szenborn Leszek, Silfverdal Sven-Arne, Wysocki Jacek, Albrecht Piotr, Traskine Magali, Gardev Asparuh, Song Yue, Borys Dorota
Department of Social Medicine, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
Department and Clinic of Pediatric Infectious Diseases, Wroclaw Medical University, 2-2A, Chalubinskiego, 50-368 Wroclaw, Poland.
Vaccine. 2017 Aug 16;35(35 Pt B):4603-4611. doi: 10.1016/j.vaccine.2017.07.008. Epub 2017 Jul 17.
Vaccination with formulations containing pneumococcal protein antigens such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) may extend serotype-related protection of pneumococcal conjugate vaccines (PCVs) against Streptococcus pneumoniae.
This phase II, multi-center, observer-blind trial conducted in Europe (NCT01204658) assessed 2 investigational vaccines containing 10 serotype-specific polysaccharide conjugates of PHiD-CV and either 10 or 30µg of dPly and PhtD each. Infants randomized 1:1:1:1 received 4 doses of PHiD-CV/dPly/PhtD-10, PHiD-CV/dPly/PhtD-30, PHiD-CV, or 13-valent PCV (PCV13), co-administered with DTPa-HBV-IPV/Hib, at ages ∼2, 3, 4 and 12-15months. Occurrences of fever >40.0°C following primary vaccination with PHiD-CV/dPly/PhtD vaccines compared to PHiD-CV (non-inferiority objective), dose superiority, safety and immunogenicity were assessed.
575 children received primary vaccination, and 564 booster vaccination. The non-inferiority objective was met; no fever >40.0°C causally related to vaccination was reported during primary vaccination. Incidence of adverse events appeared similar between the 3 PHiD-CV groups. Serious adverse events were reported in 13, 9, 21 (1 related to vaccination), and 17 children in the PHiD-CV/dPly/PhtD-10, PHiD-CV/dPly/PhtD-30, PHiD-CV, and PCV13 groups, respectively. PHiD-CV/dPly/PhtD-30 was superior to PHiD-CV/dPly/PhtD-10 in terms of post-dose 3 anti-Ply and Anti-PhtD antibody levels. Anti-Ply and anti-PhtD antibody levels were higher in both PHiD-CV/dPly/PhtD groups than in controls and increased from post-primary to post-booster timepoint. Post-primary and booster vaccination, for each PHiD-CV serotype, ≥98.5% of participants in PHiD-CV/dPly/PhtD groups had antibody concentrations ≥ 0.2μg/mL, except for 6B (≥72.3%) and 23F (≥82.7%) post-primary vaccination. Similar results were observed in the PHiD-CV group. Immune responses to protein D and DTPa-HBV-IPV/Hib were within similar ranges for the 3 PHiD-CV groups.
Both PHiD-CV/dPly/PhtD formulations co-administered with DTPa-HBV-IPV/Hib in infants were well-tolerated and immunogenic for dPly and PhtD antigens, while immune responses to serotype-specific, protein D and co-administered antigens did not appear altered in comparison to PHiD-CV group.
接种含有肺炎球菌蛋白抗原（如肺炎溶血素类毒素（dPly）和组氨酸三联体蛋白D（PhtD））的疫苗制剂，可能会扩大肺炎球菌结合疫苗（PCV）对肺炎链球菌的血清型相关保护作用。
在欧洲开展的这项II期、多中心、观察者盲法试验（NCT01204658）评估了2种研究用疫苗，它们含有10种血清型特异性的肺炎球菌结合疫苗（PHiD-CV）多糖结合物，以及每种10或30μg的dPly和PhtD。按1:1:1:1随机分组的婴儿在约2、3、4和12 - 15月龄时接受4剂PHiD-CV/dPly/PhtD-10、PHiD-CV/dPly/PhtD-30、PHiD-CV或13价肺炎球菌结合疫苗（PCV13），并与白百破-乙肝-脊髓灰质炎灭活疫苗/ Hib联合接种。评估了与PHiD-CV相比，PHiD-CV/dPly/PhtD疫苗初次接种后体温>40.0°C的发生率（非劣效性目标）、剂量优势、安全性和免疫原性。
575名儿童接受了初次接种，564名儿童接受了加强接种。达到了非劣效性目标；初次接种期间未报告与疫苗有因果关系的体温>40.0°C情况。3个PHiD-CV组的不良事件发生率似乎相似。PHiD-CV/dPly/PhtD-10、PHiD-CV/dPly/PhtD-30、PHiD-CV和PCV13组分别有13、9、21名（1例与疫苗相关）和17名儿童报告了严重不良事件。在第3剂接种后，PHiD-CV/dPly/PhtD-30在抗Ply和抗PhtD抗体水平方面优于PHiD-CV/dPly/PhtD-10。两个PHiD-CV/dPly/PhtD组的抗Ply和抗PhtD抗体水平均高于对照组，且从初次接种后到加强接种后时间点有所增加。在初次接种和加强接种后，对于每种PHiD-CV血清型，PHiD-CV/dPly/PhtD组中≥98.5%的参与者抗体浓度≥0.2μg/mL，但初次接种后6B型（≥72.3%）和23F型（≥82.7%）除外。在PHiD-CV组中观察到类似结果。3个PHiD-CV组对蛋白D和白百破-乙肝-脊髓灰质炎灭活疫苗/ Hib的免疫反应在相似范围内。
在婴儿中与白百破-乙肝-脊髓灰质炎灭活疫苗/ Hib联合接种的两种PHiD-CV/dPly/PhtD制剂对dPly和PhtD抗原耐受性良好且具有免疫原性，而与PHiD-CV组相比，对血清型特异性、蛋白D和联合接种抗原的免疫反应似乎未改变。
