Baseline immunotypes and immune entropy are indicators of multiple vaccine responsiveness

Immune aging is associated with decreased vaccine responses, but biomarkers for vaccine responsiveness remain unidentified. We analyzed immunotypes describing baseline immune cell profiles and their associations with triple vaccine responsiveness to influenza, pneumococcal, and SARS-CoV-2 vaccines in adults aged 25-78 years. Additionally, we developed an innovative measure, immune entropy, to quantify cumulative perturbations in the immune cell subset network. Specific immunotypes associated with either weak or robust triple vaccine responsiveness. In addition, immune entropy was inversely related to vaccine responsiveness regardless of age. In a validation cohort of older adults, higher immune entropy was also associated with a lower antibody response to the BNT162b2 vaccine. A separate cohort of kidney transplant recipients, typically exhibiting diminished vaccine responses, demonstrated significantly increased immune entropy compared to healthy counterparts. Our findings suggest immunotypes and immune entropy as potential indicators to identify individuals at risk for suboptimal vaccine responses, potentially guiding personalized vaccination strategies. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NL69701.041.19, EudraCT 2019-000836-24 ### Funding Statement The VITAL project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 806776 and the Dutch Ministry of Health, Welfare and Sport. The JU receives support from the European Union's Horizon 2020 research and innovation program and EFPIA‐members. The VITAL-Corona study was funded by the Dutch Ministry of Health, Welfare and Sport. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained through the Medical Research Ethics Committee Utrecht (NL69701.041.19, EudraCT: 2019-000836-24). All participants provided written informed consent and all procedures were performed with Good Clinical Practice and in accordance with the principles of the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets generated during the current studies are not made available in a public database since the study is ongoing. We will share pseudonymized data upon reasonable request as long as data transfer is in agreement with the clinical protocol and EU legislation on the General Data Protection Regulation, which should be regulated in a data sharing agreement.