# Immune memory to SARS2 in a changing landscape

> **NIH NIH U19** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2024 · $757,011

## Abstract

PROJECT SUMMARY – Project 2
 SARS-CoV-2 (SARS2) remains a fundamental threat to global health and a leading cause of death. Here,
we will address a number of important outstanding questions in the field of T cell memory to SARS2. Accordingly,
we’ve established novel donor cohorts, including the Multiple Vaccinations and Infections (MVI) Cohort, with
over 450 donors enrolled in an ongoing longitudinal study (total of 8 years). These samples reflect the real-life
evolution of memory responses, from donors with up to 5 distinct immunizations and up to 4 different infections.
The Breakthrough Infection (BTI) Cohort includes donors who provided large blood donations (leukapheresis)
during the Delta and Omicron waves, and on-going recruitment as new variant waves arise. The Discordant
Pairs (DP) cohort enrolled people sharing living arrangements where one individual experienced BTI infection,
while the other tested negative.
 First, we will determine the evolution of memory T cell responses over repeated exposures and vaccinations
in a real-life study spanning several years, using a multifaceted approach. We hypothesize that a history of
immunization plus infection is associated with broad responses against antigens beyond S (spike), indicating a
qualitative advantage in T cell responses. We will also consider the alternative, that previous immunizations
imprint T cell responses and a pre-existing S response inhibits development of T cell responses against other
SARS2 antigens. We will also study long term evolution of T cell memory responses as a function of type and
number of exposures. We hypothesize that we will observe progressive functional maturation of memory T cells.
Alternatively, we might observe progressive exhaustion and loss of functionality. We will also measure T cell
memory longevity as a function of type and number of exposures. Finally, we will assess the impact of age on
real-life evolution of SARS2-specific memory T cells in the context of repeated vaccinations and reinfections, by
comparing responses between donors aged 20-39, 40-59, and 60 and over.
 We will further determine memory T cell responses in the BTI cohort utilizing apheresis samples collected in
a shorter pre/post-infection time frame, leveraging knowing the exposure window and variant wave of exposure.
We will probe if broad responses are detected against antigens beyond S, or if a pre-existing S response inhibits
development of responses to other antigens. Further, is the epitope repertoire modulated with new, variant-
specific epitopes being recognized? We will also determine SARS2-specific T cell responses from donors in the
DP cohort. To explain why SARS2 exposed donors do not develop overt infection, we hypothesize that they
might be higher vaccine responders; might be associated with previous asymptomatic infections and/or high
levels of pre-existing immunity; and/or might have experienced an abortive infection. Finally, we will test the
hypothesis that BTIs ar...

## Key facts

- **NIH application ID:** 10825345
- **Project number:** 2U19AI142742-06
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Alessandro Sette
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $757,011
- **Award type:** 2
- **Project period:** 2019-03-11 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825345

## Citation

> US National Institutes of Health, RePORTER application 10825345, Immune memory to SARS2 in a changing landscape (2U19AI142742-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10825345. Licensed CC0.

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