# Project 2: The Impact of Immunotherapy on Human Vaccination

> **NIH NIH U19** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $359,130

## Abstract

Project Summary
Infectious diseases contribute three of the top ten causes of death worldwide. Moreover, billions of people remain
infected with persisting pathogens such as hepatitis B virus, malaria and HIV, and ~half a million people die
annually from influenza (Flu) and other respiratory infections. Much of our knowledge of how the human immune
system responds to pathogens or vaccination remains observational rather than direct perturbation of specific
molecules. Here, we will exploit the revolution in immunotherapy of cancer to directly interrogate how key immune
regulatory pathways impact T cell, B cell and antibody (Ab) responses to human vaccination toward developing
a foundation of empirical evidence that informs how to use checkpoint blockade and targeting of other specific
immune pathways to treat or prevent infectious disease.
T cell and B cell activation and differentiation are regulated in part by the PD-1:PD-L1/2 inhibitory receptor
pathway, which also influences T cell exhaustion. These functions are targeted by a new class of biologic
drugs that block PD-1 signals to treat cancer. Yet, the role of the PD-1 pathway in human immune responses
to vaccination remains unclear. In particular, cells in germinal centers (GC), including follicular helper T cells
(TFH), follicular regulatory T cells (TFR), and GC and memory B cells (mBc), have high expression of PD-1 and/or
its ligands, but the contribution of the PD-1 pathway to GC responses and humoral, TFH and B cell memory is
poorly understood. Further, despite widespread use of anti-PD-1 (αPD-1) therapy in recent years, there is
essentially no information on how this treatment impacts TFH, TFR, B cell or Ab responses or whether patients on
checkpoint blockade should or should not be vaccinated. Thus, the overarching hypothesis of this Project is
that blocking PD-1 in humans will impact the magnitude and/or quality of the TFH, TFR, B cell and humoral
response to Flu vaccination through an underlying effect on GC biology. We will:
AIM 1: DETERMINE HOW αPD-1 IMPACTS THE FUNCTIONAL DIVERSITY, MAGNITUDE, TCR REPERTOIRE, DURABILITY
AND TRANSCRIPTIONAL PROGRAM OF VACCINE-INDUCED CD4 T CELL RESPONSES.
AIM 2: DETERMINE HOW αPD-1 IMPACTS THE MAGNITUDE, BCR REPERTOIRE, DURABILITY AND TRANSCRIPTIONAL
PROGRAM OF VACCINE-INDUCED B CELL RESPONSES AND QUANTITY/QUALITY OF VACCINE-INDUCED AND OTHER
ANTIVIRAL ANTIBODY RESPONSES.
This work will inform how to better vaccinate vulnerable populations (e.g. cancer patients; the elderly), and will
identify mechanisms by which the PD-1 pathway controls human immunity, providing a platform for future studies
of immune perturbation in humans. By its nature Project 2 is highly interactive with Project 1 and all Cores.
Core B will generate samples and this Project will use Core C and D services. Projects 1 and 2 will
synergize and interact extensively to understand PD-1-based immune perturbation in humans.

## Key facts

- **NIH application ID:** 10180876
- **Project number:** 5U19AI082630-13
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** E. John Wherry
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $359,130
- **Award type:** 5
- **Project period:** 2009-06-08 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180876

## Citation

> US National Institutes of Health, RePORTER application 10180876, Project 2: The Impact of Immunotherapy on Human Vaccination (5U19AI082630-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10180876. Licensed CC0.

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