Oxford Vaccine Group and the NIHR Oxford Biomedical Research Centre, University of Oxford, Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK.
Vaccine. 2012 Jun 13;30(28):4153-9. doi: 10.1016/j.vaccine.2012.04.063. Epub 2012 May 1.
Negative correlations between baseline antibody concentrations and increases in antibody concentrations (after booster doses of vaccines) have been reported previously. Such correlation coefficients are widely reported by statisticians to be subject to mathematical coupling. Negative correlations may be attributable partly or wholly to the combination of mathematical coupling and measurement error (or other short term fluctuations in measurements) and therefore not clinically interpretable. In this study we re-analysed the serum antibody responses from five clinical trials of serogroup C meningococcal conjugate vaccine (MenCV) given to infants for priming followed by boosting with MenCV or a meningococcal A/C polysaccharide vaccine (MenA/C) at 12 months of age. Using Pearson's correlation method to assess the effect of pre-booster MenC-IgG concentration on the relative increase in MenC-IgG concentration post-booster, a significant negative correlation was observed for all the groups, indicating that high pre-booster antibody was associated with a smaller rise in antibody post-booster. We tested two additional statistical methods that account for mathematical coupling. Using Blomqvist method of adjustment to assess the plausible extent of bias, correlation coefficients were still negative providing error variance was low. The other method, a multilevel modelling specification of Oldham's method appeared not to be appropriate. In contrast, using Pearson's correlation method a consistent negative correlation between carrier protein-specific baseline antibody concentration and the increase in MenC-specific antibody concentration was only observed following booster immunisation with the protein-polysaccharide conjugate vaccine but not following the MenA/C plain polysaccharide vaccine. These findings suggest that analysis of the inhibitory effect of baseline antibody on the response to booster immunisation is challenging and should account for the possibility of mathematical coupling and measurement error. That an inhibitory effect of baseline antibody cannot be assumed a priori is supported by observations in animal models, which show that baseline antibody can both suppress or enhance the antibody response to a specific antigen.
先前已有报道称，基线抗体浓度与抗体浓度增加（疫苗加强针后）之间呈负相关。此类相关系数常被统计学家报告为存在数学耦合。负相关可能部分或完全归因于数学耦合和测量误差（或测量的其他短期波动）的组合，因此在临床上无法解释。在这项研究中，我们重新分析了五项脑膜炎球菌 C 群结合疫苗（MenCV）临床试验的血清抗体反应，这些试验将 MenCV 疫苗接种于婴儿作为初免，然后在 12 个月时再用 MenCV 或脑膜炎球菌 A/C 多糖疫苗（MenA/C）加强免疫。使用 Pearson 相关方法评估预加强 MenC-IgG 浓度对加强后 MenC-IgG 浓度相对增加的影响，所有组均观察到显著的负相关，表明高预加强抗体与加强后抗体升高幅度较小相关。我们测试了另外两种考虑数学耦合的统计方法。使用 Blomqvist 调整方法评估偏倚的可能程度，相关系数仍然为负，只要误差方差较低。另一种方法，即 Oldham 方法的多层次建模规范似乎并不适用。相比之下，使用 Pearson 相关方法，仅在使用蛋白-多糖结合疫苗进行加强免疫后，观察到载体蛋白特异性基线抗体浓度与 MenC 特异性抗体浓度增加之间存在一致的负相关，而在使用 MenA/C 单纯多糖疫苗时则没有。这些发现表明，分析基线抗体对加强免疫反应的抑制作用具有挑战性，并且应该考虑到数学耦合和测量误差的可能性。在动物模型中的观察结果支持了这样的观点，即不能先验地假设基线抗体的抑制作用，因为这些观察结果表明，基线抗体既可以抑制也可以增强对特定抗原的抗体反应。
