Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIAID/NIH), Rockville, Maryland, USA.
Malar J. 2011 Jan 19;10:13. doi: 10.1186/1475-2875-10-13.
A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Donéguébougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons.
To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis.
A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect.
While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations.
在马里的 Donéguébougou 和 Bancoumana，对血液阶段疟疾疫苗 AMA1-C1/Alhydrogel 进行了一项 1-2b 期研究，共有 336 名儿童参与。在研究的 2 期部分（n=300），未观察到寄生虫密度或临床疟疾的影响；然而，与接受比较疫苗（Hiberix）的儿童相比，接受研究疫苗的儿童贫血（定义为血红蛋白<8.5 g/dL）的频率更高。这种影响是众多测试之一，在调整多重比较后并不显著。
为了进一步研究疫苗接种对贫血的可能影响，进行了其他分析，包括来自 1 期研究的患者，并控制基线血红蛋白、血红蛋白类型 S 或 C、α-地中海贫血、G6PD 缺乏症和年龄。使用乘法强度模型，该模型将 Cox 回归推广到允许多个事件。每个受试者的脆弱性效应用于解释同一受试者中多个贫血事件的相关性。强度率是根据日历时间计算的，而不是根据随机化后的时间，以考虑疟疾发病率的分批注册和季节性影响。使用类似的分析进一步探讨了贫血与抗 AMA1 抗体的关系。
即使在调整了基线血红蛋白、血红蛋白病和年龄，并使用更复杂的统计模型后，疫苗对贫血发生率的影响仍然很强（风险比[AMA1-C1 与比较疫苗（Hiberix）] = 2.01，95%置信区间 [1.26,3.20]）。抗 AMA1 抗体水平与这种影响无关。
虽然这些额外的分析显示了疫苗接种对贫血的明显影响，但这是对次要结果的深入探索，因此应谨慎解释。讨论了 AMA1-C1/Alhydrogel 疫苗接种对血红蛋白产生明显不良反应的可能机制及其对血液阶段疫苗开发的影响。在疟疾暴露人群中进行 AMA1 和其他血液阶段疫苗的临床试验时，应密切评估其对疟疾相关贫血的潜在影响。
