2025 Theses Doctoral

Human Immune Memory to COVID-19 mRNA Vaccines

Davis-Porada, Julia

The human immune system is made up of cells and molecules distributed across the body, which provide protection from acute viral infection and can be maintained in diverse tissue sites as memory to protect against repeat viral exposure. Vaccine technology has leveraged our understanding of human immunity to induce immune memory in humans without infection. However, we continue to encounter novel infections, as evidenced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which necessitates the development of new vaccines and formulations, including the mRNA vaccine platform. Vaccine development began with serendipitous discoveries and, even today, often relies on empirical approaches that prioritize clinical outcomes over immunologic ones. For the recently developed coronavirus disease of 2019 (COVID-19) mRNA vaccines, we know that they confer clinical protection that wanes over time but have a more limited understanding of the immune memory they induce. Specifically, we do not know the tissue distribution of vaccine memory, these vaccines’ capacity to induce tissue-resident memory or various functional programs, and the relative role of B and T cells in protection.

Through a unique collaboration with the New York City area organ procurement organization, LiveOnNY, we collected blood, bone marrow, spleen, lung, and various lymph nodes (LN) from human organ donors who had received COVID-19 mRNA vaccines. Using these tissues, we employed multimodal, high-dimensional analysis tools to investigate the localization, phenotype, maintenance, and functions of COVID-19 vaccine-induced memory in the context of host factors such as age, time post-vaccination, and prior SARS-CoV-2 infection. In samples from 63 organ donors aged 23-86, we found that COVID-19 vaccine memory was distributed across tissues, especially in LN, and was more durable across time post-vaccination and age in tissues than in circulation. Vaccine-specific B cells were mostly class-switched resident memory, while vaccine-specific T cells were variably tissue-resident depending on infection history. Vaccine-specific T cell effector functions were diverse and site-specific with an enhanced regulatory profile in tissues compared to circulating populations.

To investigate the interaction between T and B cells in immune memory generation and their relative roles in protection, we also compared the quantity and quality of circulating COVID-19 vaccine induced memory from patients with multiple sclerosis taking B cell depleting (BCD) therapies to those taking other immunomodulatory therapies (non-BCD). In 281 samples from 216 subjects aged 24-78 we found that COVID-19 vaccine induced humoral immunity was completely diminished in the context of B cell depletion, but that cellular immunity, especially CD8+T cells, were enhanced in this context and maintained over time. Further, BCD subjects experienced equivalent numbers of infections following vaccination as non-BCD subjects. Together, these findings demonstrate that T cell responses can develop independently from, and may even be limited by, B cell responses, and that T cells but not B cells are critical for vaccine-induced protection. Ultimately, these findings provide critical insights for future vaccine development; studies must assess LN responses and aim to generate a robust cellular response that includes both regulatory and effector functional profiles within tissues.