# Mechanisms of differential responses to whole cell and acellular pertussis vaccination

> **NIH NIH U19** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2021 · $731,513

## Abstract

PROJECT SUMMARY
Project 2
In the mid-1990s, vaccine-related side effects prompted the replacement of the whole Pertussis (wP) vaccine by
a new acellular Pertussis vaccine (aP). Unexpectedly, whooping cough cases have recently increased,
particularly in teenagers. In the preliminary data, we compared individuals born before 1995 and vaccinated in
infancy with wP, with individuals born in 1996 or later and vaccinated with aP in infancy. Activation Induced
Marker (AIM) assays allowed examination of responses directly ex vivo, highlighting a Th2 vs Th1/Th17
polarization of pertussis (PT)-specific CD4+ T cells. Remarkably, we detected differences in response to a
contemporary aP booster, even though the first aP or wP priming occurred more than 18 years previously. aP
priming was associated with 1) increased IL-9 and TGF-β and decreased IL-17 production in response to PT
epitopes ex vivo, and 2) defective ex vivo capacity to expand memory cells one to two months following a booster
aP immunization and in vitro proliferation in response to PT epitopes. However, the biological significance of
these observations is limited by the fact that only responses in blood are measured and whether the same
phenotypic differences are observed in situ, in the lymphatic tissues where memory T cell reside and immune
responses are orchestrated. Accordingly, we propose to define the molecular mechanisms underlying the
differential IL-9/IL-17 polarization of donors originally primed with aP vs wP (Aim 1). We will define the cellular
characteristics of IL-9+ PT-specific CD4+ T cells after aP vaccination and molecular mechanisms underlying their
development. We will study the IL-17 signature seen in wP vaccine-primed individuals, by targeted flow
cytometry and AIM studies, and perform single-cell RNA-seq with the PT-specific CD4+ T cells.
 In Aim 2, the mechanisms involved in differential proliferation will be addressed by blocking in vitro TGF-b
related pathways, and downregulating the ANAPC2 and WDR1 genes, which were identified in the preliminary
data. The cellular basis of the differential proliferation of donors originally primed with aP vs wP will be
investigated by cell depletion experiments.
 Aim 3 will use Lymph Node (LN) Fine Needle Aspirates (FNA) to interrogate PT responses in individuals
originally primed with either wP or aP to assess differential germinal center (GC) Tfh cell and GC B cell responses
in LNs of vaccine recipients, define whether differential antibody isotype responses of wP- vs aP-primed
individuals is due to biases in GC Tfh helper functions to B cells and determine if circulating CD4+ T cells correlate
with the vaccine immune response in the draining LN, the primary immune response site. In conclusion, we
believe that results from this study will illuminate molecular reasons for lesser aP efficacy and illustrate human
CD4+ T cell biological principles generally applicable to vaccinology and immunology.

## Key facts

- **NIH application ID:** 10107757
- **Project number:** 5U19AI142742-03
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Alessandro Sette
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $731,513
- **Award type:** 5
- **Project period:** 2019-03-11 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107757

## Citation

> US National Institutes of Health, RePORTER application 10107757, Mechanisms of differential responses to whole cell and acellular pertussis vaccination (5U19AI142742-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107757. Licensed CC0.

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