Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity.

中文翻译：

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电子传输链容量扩大了黄热病疫苗的免疫原性。


疫苗接种已成功控制了几种传染病，但仍需要更好的疫苗。宿主对疫苗接种研究的反应已经确定了疫苗免疫原性的相关性，这可能有助于指导未来疫苗的开发和选择。然而，目前尚不清楚这些发现是否仅代表统计相关性或反映与疫苗免疫原性的功能关联。功能关联，而不是统计相关性，将为疫苗诱导的适应性免疫提供机制见解。通过一项人体实验研究来测试抗糖尿病药物二甲双胍的免疫调节特性，我们偶然发现了中和抗体的功能决定因素。尽管已知疫苗病毒血症与抗体反应相关，但我们发现，在未检测到黄热病 17D 病毒血症或黄热病 17D 病毒血症水平较低的健康志愿者中，接受二甲双胍治疗的志愿者比接受安慰剂治疗的志愿者产生了更高的中和抗体滴度。转录和代谢组学分析共同表明，在 YF17D 疫苗接种前 3 天开始并在疫苗接种后 3 天停止的短暂二甲双胍疗程，增强了氧化磷酸化和蛋白质翻译能力。这些增加的能力与 YF17D 中和抗体滴度直接相关，与安慰剂治疗的志愿者相比，活性氧反应降低。因此，我们的研究结果证明了细胞呼吸与疫苗诱导的体液免疫之间的功能关联，并提出了增强疫苗免疫原性的潜在方法。