# Project 2: Epigenetic ontogeny of vaccine response, susceptibility to respiratory infectious disease and asthma

> **NIH NIH U19** · BOSTON CHILDREN'S HOSPITAL · 2022 · $155,757

## Abstract

SUMMARY – Project 2 (PR2)
 Early life microbial exposures can shape an individual’s basal immune state influencing acute responses
to infections, vaccines and responses to environmental allergens. Perinatal microbial exposures are known to
influence immune ontogeny and are linked to rising rates of allergy and asthma, yet mechanisms remain poorly
defined. Colonisation of the mucosae by microbiota, vaccinations and systemic infections all modify immune
ontogeny, but a mechanistic understanding of the combinatorial interactions of these events in the early life
course, and their resulting programming effects on immune development in early life (IDEAL) are lacking. Project
2 (PR2) will investigate epigenetic mechanisms as a basis for understanding microbially-mediated programming
of IDEAL. A growing body of work highlights an important role for epigenetic regulation of the genome in both
central and peripheral immune cells following vaccination and infection. Dynamic changes in epigenetic
modifications at gene enhancers and promoters in innate cells are mechanistically linked to pathogen recognition
receptor (PRR) signalling. These mechanisms therefore bridge the microbial environment, host genome and
immune ontogeny. Early life microbial exposures are a complex construct considering the broad scope of
interactions and factors to consider. Yet our collaborators in the Clinical Core (CC; Lead Pichichero) have
demonstrated reproducibly that some children display a phenotype of low production of protective antibody (Ab)
levels to routine vaccinations with concomitant low cellular immune memory (low vaccine responders, LVR),
whilst others exhibit robust protective immunity (high vaccine responders, HVR). In addition to this, some children
are prone to recurrent respiratory infections (infection prone, IP) whilst others with similar pathogen burden are
resilient (non-infection prone, NIP). These phenotypic subgroups will be capitalized upon as latent variables that
reflect the construct of microbially-mediated immune programming through a latent class analysis. The overall
effort will define trajectories of mucosal and systemic (e.g., immune ontogeny and microbiome across our IDEAL
Meta Cohort (IMC) comprised of four diverse longitudinal childhood cohorts in relation to VR, IP and asthma.
Epigenome-wide association analysis will identify methylation-sensitive genes that characterize trajectories of
IDEAL. We posit that these phenotypes and sub-phenotypes of IDEAL contribute to the development of
childhood illness and will therefore identify methylation-sensitive genes associated with IDEAL trajectories that
predict endotypes and sub-phenotypes of VR, IP and asthma. We consider endotypes are likely to have distinct
pathophysiology mechanisms and that epigenetic biomarkers of microbially-mediated immune programming can
provide early detection as well as novel targets for precision interventions. Outcomes from PR2 will include
enhanced mechanistic understan...

## Key facts

- **NIH application ID:** 10435042
- **Project number:** 1U19AI168643-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Tobias R. Kollmann
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $155,757
- **Award type:** 1
- **Project period:** 2022-03-10 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435042

## Citation

> US National Institutes of Health, RePORTER application 10435042, Project 2: Epigenetic ontogeny of vaccine response, susceptibility to respiratory infectious disease and asthma (1U19AI168643-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10435042. Licensed CC0.

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