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新的脑膜炎疫苗可以让婴儿有比较好的免疫力

来源:医源世界 作者:佚名 2008-3-26
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摘要: Snape和同事指出,美国所有的青少年都需接种脑膜炎双球菌四价糖共轭疫苗(血清型 ACWY),不过,目前核准的疫苗对婴儿的免疫力差,而婴儿的发病率却是最高,因此发展出这种新的四价脑膜炎双球菌糖共轭疫苗(MenACWY)。有别于目前的疫苗,MenACWY使用CRM-197这种白喉毒素(diphtheria toxin)的自然突变物质作为载体蛋白,另......


  根据1月版的美国医疗协会期刊中的随机控制多中心试验结果,一种新的脑膜炎疫苗可以比目前使用的脑膜炎双球菌四价糖共轭(meningococcal tetravalent glycoconjugate)疫苗让婴儿有更好的免疫力。
  
  英国牛津大学牛津疫苗小组的Matthew D. Snape和同事指出,美国所有的青少年都需接种脑膜炎双球菌四价糖共轭疫苗(血清型 ACWY),不过,目前核准的疫苗对婴儿的免疫力差,而婴儿的发病率却是最高,因此发展出这种新的四价脑膜炎双球菌糖共轭疫苗(MenACWY)。
  
  有别于目前的疫苗,MenACWY使用CRM-197这种白喉毒素(diphtheria toxin)的自然突变物质作为载体蛋白,另外使用铝磷佐剂,选择糖链的品质与长。
  
  从2004年8月到2006年9月,这项开放标签研究纳入了225位英国和196位加拿大的2个月大婴儿,英国的婴儿随机指派接受一般时程的MenACWY (于2、3、4个月或者于2和4个月)或者Neisseria meningitidis血清型C单价脑膜炎双球菌糖共轭疫苗 (MenC;于2和4个月);全部的婴儿都在12个月时接种MenACWY。
  
  加拿大的婴儿在2、4、6个月或者于2和4个月时接受MenACWY,12 个月时,他们接种MenACWY、无添加四价多糖疫苗(plain tetravalent polysaccharide vaccine)或者不接受疫苗;初级终点是,在MenACWY一般时程与12个月的追加之后,达到人类完全血清杀菌力(hSBA)效价1:4或以上的婴儿比率,次级终点是MenACWY的安全性与不良反应状况。
  
  预定之按方案分析显示,一般接种时程之后,2、3、4个月接受MenACWY 者,hSBA 效价1:4或以上的比率在血清型A为93% (95% 信心区间 [CI], 84% – 98%)、血清型C为96% (95% CI, 89% – 99%)、血清型W-135为97% (95% CI, 90% – 100%),血清型Y 为94% (95% CI, 86% –98%)。
  
  在事后治疗意向分析以估算值处理疏漏资料时,血清型C和Y的上述百分比没有改变,血清型A变成92% (95% CI, 84% – 97%),血清型 W-135则是97% (95% CI, 91% – 99%)。
  
  至于在2、4、6个月接受MenACWY者的按方案分析,血清型A的反应率是81% (95% CI, 71% – 89%)、血清型C 是98% (95% CI, 92% – 100%)、血清型W-135是99% (95% CI, 93% – 100%)、血清型Y是 98% (95% CI, 92% – 100%);使用估算值分析后改变为,血清型A 是83% (95% CI, 74% – 89%)、血清型C是98% (95% CI, 93% – 99%)、血清型W-135是99% (95% CI, 94% – 100%)、血清型Y是98% (95% CI, 92% – 99%)。
  
  一般免疫之后,根据按方案与估算分析,2和4个月接受MenACWY者有至少84%达到血清型C、W-135和 Y的 hSBA效价1:4或以上,血清型A则至少有 60%;13个月时,按方案与估算分析显示,至少有95%的一般与追加MenACWY接受者达到血清型C、W-135和 Y的 hSBA效价1:4或以上,血清型A 则至少有 84%。
  
  一般接种时程中观察到的副作用,脚移动时出现接种后疼痛在英国MenACWY 2和4个月组有2%,MenC 2和4个月组有4%,至于发烧到38°C以上,在两组分别是4%和 2%;这些副作用都会自我缓解。
  
  作者指出,MenACWY对婴儿耐受良好且有免疫效果,不过,在2和4个月给予两剂的一般时程获得的血清型A反应率低,若于12个月时给予追加MenACWY,将可获得至少95%达到血清型C、W-135和 Y之反应, 血清型A则至少有 84%。
  
  这项研究的研究限制,包括样本数太少,而无法做出有关疫苗安全性的确定结论,而且未直接比较并用或不并用肺炎双球菌糖共轭疫苗的MenACWY免疫力。
  
  Novartis Vaccines药厂赞助此研究与雇用3位作者,其他作者有一些报告与Wyeth Vaccines、Novartis Vaccines、GlaxoSmithKline、Wyeth等主要疫苗制造厂、Sanofi-Aventis和/或 Sanofi-Pasteur MSD有各种不同的财金安排。
  
  一篇伴随而来的评论中,匹兹堡大学的Lee H. Harrison医师形容这些发现是“预防脑膜炎双球菌疾病上的明显进步”。
  
  Harrison医师表示,综观所有进行中的研究,对于此病的预防作为在全球无人能出其右,如果这疫苗最后获得核准,在取得认可之后也可能提出其他问题,免疫力的维持期间将是一个重要议题,牵涉到是否需要在孩童期与青少年时期追加疫苗。
  
  Harrison医师报告与疾病控制与预防中心、国家过敏与感染症研究中心、Sanofi Pasteur、 GlaxoSmithKline和Novartis Vaccines有各种财金安排。

New Meningitis Vaccine May Offer Better Immunity in Infants

 

By Laurie Barclay, MD
Medscape Medical News


A new meningitis vaccine may be better able to produce immunity in infants than the current meningococcal tetravalent glycoconjugate vaccine, according to the results of a randomized controlled multicenter trial reported in the January 9/16 issue of the Journal of the American Medical Association.

"Immunization with a meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine is recommended for all US adolescents," write Matthew D. Snape, FRACP, from the Oxford Vaccine Group, University of Oxford, England, and colleagues. "However, the currently licensed vaccine is poorly immunogenic in infancy, when the highest rates of disease are observed.... A novel tetravalent meningococcal glycoconjugate vaccine (MenACWY) has therefore been developed."

Unlike the currently licensed vaccine, MenACWY uses CRM-197, a natural mutant of the diphtheria toxin, as the carrier protein, and it also differs in the use of an aluminum phosphate adjuvant and the quantity and lengths of the saccharide chains selected.

From August 2004 to September 2006, this open-label study enrolled 225 UK and 196 Canadian infants 2 months of age. The UK infants were randomly assigned to receive a primary course of MenACWY (at 2, 3, and 4 months or at 2 and 4 months) or Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine (MenC; at 2 and 4 months). All infants received MenACWY at 12 months.

The Canadian infants received MenACWY at 2, 4, and 6 months or at 2 and 4 months. At 12 months, they received MenACWY, a plain tetravalent polysaccharide vaccine, or no vaccine. The primary endpoint was the proportion of infants who had a human complement serum bactericidal activity (hSBA) titer of 1:4 or more after a primary course of MenACWY and after a 12-month booster. Secondary outcomes were safety and reactogenicity of MenACWY.

The prespecified per-protocol analysis revealed that the percentages of MenACWY 2-, 3-, and 4-month recipients with hSBA titers of 1:4 or more after primary immunization were 93% for serogroup A (95% confidence interval [CI], 84% – 98%), 96% for serogroup C (95% CI, 89% – 99%), 97% for serogroup W-135 (95% CI, 90% – 100%), and 94% for serogroup Y (95% CI, 86% – 98%).

Using imputed values for missing data in a post hoc intention-to-treat analysis, the above percentages were unchanged for serogroups C and Y. For serogroup A, values were 92% (95% CI, 84% – 97%), and for W-135, they were 97% (95% CI, 91% – 99%).

For the per-protocol analysis of MenACWY 2-, 4-, and 6-month recipients, the percentages of responders were 81% for A (95% CI, 71% – 89%), 98% for C (95% CI, 92% – 100%), 99% for W-135 (95% CI, 93% – 100%), and 98% for Y (95% CI, 92% – 100%). Using imputed value analysis shifted these values to 83% for A (95% CI, 74% – 89%), 98% for C (95% CI, 93% – 99%), 99% for W-135 (95% CI, 94% – 100%), and 98% for Y (95% CI, 92% – 99%).

After primary immunization, at least 84% of MenACWY 2- and 4-month recipients had hSBA titers of 1:4 or more for serogroups C, W-135, and Y, as did at least 60% for serogroup A, based on per-protocol and imputation analysis. At 13 months, per-protocol and imputation analysis revealed that at least 95% of primary and booster MenACWY recipients had hSBA titers of 1:4 or more for serogroups C, W-135, and Y, as did at least 84% for serogroup A.

Adverse events observed during the primary immunization course included postimmunization pain on leg movement in 2% of UK MenACWY 2- and 4-month recipients and in 4% of MenC 2- and 4-month recipients, as well as a temperature of 38°C or greater in 4% and 2% of recipients, respectively. These adverse effects resolved spontaneously.

"MenACWY is well tolerated and immunogenic in infancy," the authors write. "Although the 2-dose primary series given at 2 and 4 months of age resulted in lower seroprotection rates for serogroup A, administration of a booster dose of MenACWY at 12 months of age to participants receiving a 2-dose priming regimen resulted in at least 95% of participants achieving seroprotection against each of the serogroups C, W-135, and Y and at least 84% for serogroup A."

Limitations of this study include sample size too small to draw firm conclusions regarding vaccine safety and study not designed to directly compare the immunogenicity of MenACWY with or without concomitant pneumococcal glycoconjugate vaccine.

Novartis Vaccines funded this study and employs 3 authors. Some of the other authors report various financial arrangements with Wyeth Vaccines, Novartis Vaccines, GlaxoSmithKline, Wyeth, all major vaccine manufacturers, Sanofi-Aventis, and/or Sanofi-Pasteur MSD.

In an accompanying editorial, Lee H. Harrison, MD, from the University of Pittsburgh in Pennsylvania, calls these findings "a substantial advance in the vaccine prevention of meningococcal disease."

"Taken together with other ongoing progress, the outlook for comprehensive global prevention of this devastating disease has never been better," Dr. Harrison writes. ""Assuming that the vaccine eventually becomes licensed, additional questions will likely be addressed postlicensure. The duration of immunity is an important issue to determine whether additional doses will need to be given between a childhood series and adolescence."

Dr. Harrison reports various financial arrangements with the Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, Sanofi Pasteur, GlaxoSmithKline, and Novartis Vaccines.

JAMA. 2008;299(2):173–184; 217–219.


 


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