Early Pro-Inflammatory Signal and T-Cell Activation Associate With Vaccine-Induced Anti-Vaccinia Protective Neutralizing Antibodies

• Published in: Frontiers in immunology Vol. 12; p. 737487
• Main Authors: Hou, Jue, Wang, Shuhui, Li, Dan, Carpp, Lindsay N, Zhang, Tong, Liu, Ying, Jia, Manxue, Peng, Hong, Liu, Chang, Wu, Hao, Huang, Yunda, Shao, Yiming
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11.10.2021
• Subjects: Adult; AIDS Vaccines - administration & dosage; AIDS Vaccines - adverse effects; AIDS Vaccines - genetics; AIDS Vaccines - immunology; Antibodies, Neutralizing - blood; Cytokines - genetics; Cytokines - metabolism; Female; Genetic Vectors; HIV Infections - immunology; HIV Infections - prevention & control; HIV Infections - virology; HIV-1 - immunology; HIV-1 - pathogenicity; Host-Pathogen Interactions; Humans; Immunogenicity, Vaccine; Immunology; inflammation; Inflammation Mediators - metabolism; Lymphocyte Activation - drug effects; Male; Middle Aged; neutralizing antibodies; systems immunology; T-cell activation; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Time Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome; Treatment Outcome; Vaccination; Vaccines, DNA - administration & dosage; Vaccines, DNA - adverse effects; Vaccines, DNA - genetics; Vaccines, DNA - immunology; vaccinia vaccination; Vaccinia virus - genetics; Vaccinia virus - immunology; neutralizing antibodies; inflammation; systems immunology; vaccinia vaccination; T-cell activation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.737487

Both vaccine "take" and neutralizing antibody (nAb) titer are historical correlates for vaccine-induced protection from smallpox. We analyzed a subset of samples from a phase 2a trial of three DNA/HIV-1 primes and a recombinant Tiantan vaccinia virus-vectored (rTV)/HIV-1 booster and found that a proportion of participants showed no anti-vaccinia nAb response to the rTV/HIV-1 booster, despite successful vaccine "take." Using a rich transcriptomic and vaccinia-specific immunological dataset with fine kinetic sampling, we investigated the molecular mechanisms underlying nAb response. Blood transcription module analysis revealed the downregulation of the activator protein 1 (AP-1) pathway in responders, but not in non-responders, and the upregulation of T-cell activation in responders. Furthermore, transcriptional factor network reconstruction revealed the upregulation of AP-1 core genes at hour 4 and day 1 post-rTV/HIV-1 vaccination, followed by a downregulation from day 3 until day 28 in responders. In contrast, AP-1 core and pro-inflammatory genes were upregulated on day 7 in non-responders. We speculate that persistent pro-inflammatory signaling early post-rTV/HIV-1 vaccination inhibits the nAb response.