Collins Craig P, Herzog Christian, Vick Logan V, Nielsen Ryan, Harville Yanping Izak, Longo Dan L, Arthur John M, Murphy William J
School of Medicine, University of California, Davis, CA 95817, USA.
Department of Internal Medicine Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Vaccines (Basel). 2025 Feb 24;13(3):224. doi: 10.3390/vaccines13030224.
BACKGROUND/OBJECTIVES: Novel mRNA vaccines have been successfully utilized to curtail the SARS-CoV-2 pandemic. However, the immunology underlying CoV2 vaccinations, particularly with repeated boosting, has not been properly characterized due to limitations in the preclinical modeling of SARS-CoV-2 infection/vaccinations as well as constantly changing vaccine formulations. The immunoregulatory aspects involved in such vaccine approaches remain unclear. Antibodies, due to inherent immunogenicity by VDJ gene rearrangement, have the potential to induce antibodies directed towards them called anti-idiotype antibodies, which can play a downregulatory role in responses. The paratope of some of these anti-idiotype antibodies can also act as a mirror to the original antigen, which, in the case of SARS-CoV-2 vaccines, would be to the spike protein and, therefore, also be capable of binding its target, ACE2, potentially causing adverse effects.
To investigate if sequential SARS-CoV-2 mRNA vaccination can induce anti-idiotype antibody responses, K18 hACE2 transgenic mice were serially vaccinated with a SARS-CoV-2 mRNA construct to determine the kinetics of anti-spike and anti-ACE2 responses via custom-made ELISAs.
While sequential vaccination produced robust anti-spike responses, anti-ACE2 levels were also detected and gradually amplified with each boost. These anti-ACE2 antibodies persisted for 3 months after the final vaccination and showed evidence of hACE2 binding, as levels were lower in K18 mice in comparison to the wild type.
These data would suggest that sequential SARS-CoV-2 mRNA vaccination has the potential to induce anti-ACE2 antibodies in mice, with each boost amplifying the amount of antibody.
背景/目的：新型mRNA疫苗已成功用于遏制SARS-CoV-2大流行。然而，由于SARS-CoV-2感染/疫苗接种临床前模型的局限性以及疫苗配方不断变化，CoV2疫苗接种的免疫学原理，尤其是重复加强接种的情况，尚未得到充分表征。此类疫苗方法所涉及的免疫调节方面仍不清楚。抗体由于VDJ基因重排具有内在免疫原性，有可能诱导针对它们的抗体，即抗独特型抗体，其可在反应中发挥下调作用。其中一些抗独特型抗体的互补决定区也可作为原始抗原的镜像，就SARS-CoV-2疫苗而言，即针对刺突蛋白，因此也能够结合其靶标ACE2，可能导致不良反应。
为研究序贯SARS-CoV-2 mRNA疫苗接种是否能诱导抗独特型抗体反应，用SARS-CoV-2 mRNA构建体对K18 hACE2转基因小鼠进行连续接种，通过定制酶联免疫吸附测定法确定抗刺突和抗ACE2反应的动力学。
虽然序贯接种产生了强烈的抗刺突反应，但也检测到了抗ACE2水平，且每次加强接种后逐渐升高。这些抗ACE2抗体在最后一次接种后持续3个月，并显示出与hACE2结合的证据，因为与野生型相比，K18小鼠中的水平较低。
这些数据表明，序贯SARS-CoV-2 mRNA疫苗接种有可能在小鼠中诱导抗ACE2抗体，每次加强接种都会增加抗体量。
