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首页> 外文期刊>Vaccine >Assessment of nine candidate DTP-vaccines with reduced amount of antigen and/or without adjuvant as a fourth (booster-) dose in the second year of life
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Assessment of nine candidate DTP-vaccines with reduced amount of antigen and/or without adjuvant as a fourth (booster-) dose in the second year of life

机译：在生命的第二年评估九种候选DTP疫苗，它们的抗原量减少和/或没有佐剂，作为第四剂（加强剂）

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BACKGROUND: The incidence of local reactions to diphtheria-, tetanus and acellular pertussis (DTaP-) vaccines in infants and toddlers increases with each subsequent dose, and entire thigh swellings (ETS) have been reported. Lowering the amount of antigen or of adjuvant may decrease the reactogenicity of DTaP while maintaining a protective immune response. OBJECTIVES: Following priming with three doses of a DTaP vaccine during infancy, the safety, reactogenicity and immunogenicity of nine different candidate DTaP-vaccines with reduced amounts of antigen and/or adjuvant given as fourth (booster) dose were evaluated. METHODS: Study participants were healthy infants aged 15-27 months at the time of booster vaccination. Each participant had received three doses of a DTaP vaccine (Infanrixtrade mark, GlaxoSmithKline, Rixensart, Belgium; "reference DTaP") at age 3, 4, and 5 months as part of a previous clinical trial. More than 20,000 children were eligible for participation in the current study protocol at the time. In a first phase at a University hospital-based vaccination study center, nine sequential cohorts of 63-119 study subjects received one of nine different candidate vaccines. Patients and study personal were blinded with regard to which vaccine was currently in use. Reactogenicity was solicited from parents using diary cards. Blood was drawn prior to and 4 weeks after vaccination and immediately centrifuged. The serum was stored at -20 degrees C until serology was performed by ELISA tests. As soon as the first candidate vaccine with adequate reactogenicity and immunogenicity profile was identified in the first study phase, a second study phase was initiated in parallel, to evaluate the safety and reactogenicity of the respective candidate vaccine in private practices in large cohorts (1613-2095 study subjects per group). RESULTS: In the first study phase, DTaP with no aluminum induced the highest frequency of ETS and fever. All other candidate vaccines caused lower rates of local and general reactions than the reference DTaP. As a general rule, vaccines with less antigen induced fewer reactions, although there was no strict dose-response effect and the difference, e.g. between a one-tenth and a one-fifth DTaP dose (DTaP 1/5; DTaP 1/10) was not clinically relevant. Separate injections of Td and aP caused fewer general reactions than the respective TdaP combination and local reactions were higher at the aP than at the Td injection site. Again, as a general rule, reduced amounts of antigen induced lower antibody concentrations, although all vaccines induced "protective" anti-tetanus and anti-diphtheria antibody responses. A total of 92-100% of children showed seroresponses to pertussis antigens even when vaccinated with reduced amounts of the respective pertussis antigen. Elimination of aluminum from DTaP vaccine induced higher anti-tetanus-antibody concentrations and so did a reduction of the amount of diphtheria antigen. Additional examples for antigen interaction were increased antibody concentrations, observed with injection of Td and aP into different limbs. In the second study phase, all three vaccines evaluated (one with a reduced amount of diphtheria antigen, TdaP; one with reduced amounts of all antigens, tdap; and one with a fifth dose of the reference vaccine (DTaP 1/5)) were safe and had an acceptable reactogenicity profile in a total of 4871 study subjects. CONCLUSIONS: Local reactions due to DTaP booster doses in the second year of life can be reduced by reducing the amount of antigen in the respective vaccine while an adequate immunogenicity is maintained. Aluminum-free vaccines induced ETS and fever most commonly. Any changes in vaccine composition should lead to a full evaluation of the new product.
机译：背景：婴幼儿对白喉，破伤风和无细胞百日咳（DTaP-）疫苗的局部反应的发生率随其后每次剂量的增加而增加，并且已报道了整个大腿肿胀（ETS）。降低抗原或佐剂的量可以降低DTaP的反应原性，同时保持保护性免疫应答。目的：在婴儿期初次接种三剂DTaP疫苗后，对九种不同的DTaP候选疫苗的安全性，反应原性和免疫原性进行了评估，这些疫苗的抗原和/或佐剂量减少，作为第四剂（加强剂）。方法：研究参与者是加强免疫时年龄在15-27个月的健康婴儿。作为先前临床试验的一部分，每个参与者在3、4和5个月大时分别接受了三剂DTaP疫苗（Infanrixtrade商标，GlaxoSmithKline，比利时Rixensart;“参考DTaP”）。当时有20,000多名儿童有资格参加当前的研究方案。在大学医院疫苗接种研究中心的第一阶段中，九个连续队列的63-119个研究对象接受了九种不同候选疫苗中的一种。患者和研究人员对目前正在使用哪种疫苗视而不见。使用日记卡向父母征求反应原性。在接种之前和之后4周抽血，并立即离心。将血清储存在-20℃下直至通过ELISA测试进行血清学检测。一旦在第一个研究阶段中确定了具有足够的反应原性和免疫原性特征的第一种候选疫苗，就平行启动了第二个研究阶段，以评估大型人群在私人实践中各自候选疫苗的安全性和反应性（1613-每组2095个研究主题）。结果：在第一个研究阶段，不含铝的DTaP引起ETS和发烧的频率最高。所有其他候选疫苗引起的局部和一般反应率均低于参考DTaP。一般而言，抗原含量较少的疫苗诱导的反应较少，尽管没有严格的剂量反应作用，并且差异很大。在DTaP剂量的十分之一和五分之一之间（DTaP 1/5; DTaP 1/10）与临床无关。分别注射Td和aP引起的一般反应少于相应的TdaP组合，并且aP处的局部反应要比Td注射部位高。再次，作为一般规则，尽管所有疫苗都诱导了“保护性”抗破伤风和抗白喉抗体反应，但减少的抗原量导致了较低的抗体浓度。总计92-100％的儿童对百日咳抗原显示出血清反应，即使接种了减少量的百日咳抗原也是如此。从DTaP疫苗中消除铝可诱导更高的抗破伤风抗体浓度，因此白喉抗原的量也会减少。抗原相互作用的其他例子是抗体浓度的增加，这是通过将Td和aP注射到不同肢体中观察到的。在第二个研究阶段，评估的所有三种疫苗（一种减少了白喉抗原TdaP的量;一种减少了所有抗原tdap的量;另一种减少了第五剂的参考疫苗（DTaP 1/5））共有4871个研究对象，具有安全性并具有可接受的反应原性。结论：通过减少相应疫苗中抗原的量，同时保持足够的免疫原性，可以减少由于出生后第二年DTaP加强剂量引起的局部反应。无铝疫苗最容易诱发ETS和发烧。疫苗成分的任何变化都应导致对新产品的全面评估。

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