Molecular determinants of vaccine-induced antibody durability - This research proposal aims to define the molecular determinants of durable versus non-durable antibody responses in vaccinated individuals. Given the critical role of antibodies in combating infectious diseases, it is essential to understand why some antibody responses are long-lasting while others are transient. This distinction is pivotal for improving vaccine development and enhancing protection against pathogens such as HIV-1, Influenza, and SARS-CoV-2, where current vaccines either fail to induce long-term immunity or require frequent re-administration. The primary objective is to investigate the cellular and molecular mechanisms underpinning the longevity of antibody responses post-vaccination. The study will focus on the dynamics of antibody-secreting cells (ASCs) including plasmablasts, short-lived, and long-lived plasma cells, which are believed to be central to maintaining long-term antibody levels. We propose a benchmark prospective human study to characterize ASC populations and their antibody production over time in response to vaccines that induce varying durations of antibody responses. This involves a clinical trial with vaccine-naïve volunteers using the licensed HPV vaccine, GARDASIL 9, for long-term responses, and an investigational HIV vaccine, IHV01, for short-lived responses. The study will span all zones of antibody dynamics post-vaccination, with comprehensive sampling from peripheral blood, lymph nodes, and bone marrow. Aim 1- A clinical trial will be carried out by vaccinating healthy volunteers intramuscularly with the HPV vaccine on the right thigh and IHV01 on the left thigh, three times at 0, 1, and 6 months with scheduled collections of peripheral blood, lymph node fine needle aspirations (FNA), and bone marrow for 42 months to generate specimens spanning all phases of circulating antibody dynamics. Aim 2- The goal of Aim 2 is to quantify and characterize B cell responses the HPV capsid protein and gp120 epitopes in IHV01 over the course of the clinical trial described above in the following specimens: 1) circulating antibodies; 2) circulating and LN memory B cells; 3) follicular and germinal center B cells; 4) circulating and LN plasmablasts; and 5) bone marrow plasma cell subsets. The specimens/populations will be queried with state-of-the-art methods including cellular phenotyping, transcriptomics, VH/VL lineage analyses, antigen-binding cell frequencies. Aim 3- The goal of Aim 3 is to develop mathematical models relating the molecular and cellular signatures from Aim 2 to the dynamics of the durable and non-durable antibody responses generated to the HPV capsid and the HIV-1 gp120 protein, respectively. The anticipated outcomes include a predictive model of antibody response durability, which will inform future vaccine design and the development of dose-predictive strategies. Successful completion of this study will also provide a valuable resource to the scientific community by archiving and sharing the biological specimens collected, facilitating further research into vaccine-induced immunity.
