---
title: "Vaccine delivery route and its impact on immune imprinting in influenza vaccination"
id: "pubmed-42705168"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42705168"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42705168/"
doi: "10.1016/j.vaccine.2026.129109"
published_at: "2026-10-24T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Vaccine delivery route and its impact on immune imprinting in influenza vaccination
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42705168
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42705168/)
- **DOI:** [10.1016/j.vaccine.2026.129109](https://doi.org/10.1016%2Fj.vaccine.2026.129109)
- **Published At:** 2026-10-24T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The review examines how the **vaccine delivery route** may interact with **immune imprinting** to shape influenza vaccine responses, drawing on mechanistic and translational literature. - Early-life influenza exposures create durable immune biases toward priming-strain epitopes; authors reported this limits recruitment of naïve B cells against drifted or shifted viruses. - The paper states there is essentially no direct evidence that changing delivery route can reprogram established imprinting to alter epitope hierarchy or recruit new B cell clones in primed hosts. - Available data instead show route-dependent differences in antibody compartment, isotype distribution, and anatomical localization of responses. - The authors describe how distinct antigen-presenting cell networks, lymphoid structures, and mucosal versus systemic compartments engaged by different routes likely influence clonal selection and immunodominance. - The review frames antigen design, adjuvants, and delivery route as an integrated design space for potentially modulating imprinting and broadening protection. - Key translational gaps noted: limited incorporation of immune history into experiments, insufficient use of epitope-resolved assays and mucosal readouts, and a paucity of clinical trials addressing imprinting-specific endpoints. - The authors outline experimental models and recommend targeted studies combining conserved antigens, adjuvants, and alternative routes to test whether imprinting expression can be rebalanced for universal vaccine strategies.
## Clinical Analysis & Structured Key Points
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Epub 2026 Sep 7. # Influence of vaccine delivery route on immune imprinting in influenza vaccination [Vidhi Thakkar](https://pubmed.ncbi.nlm.nih.gov/?term=Thakkar+V&cauthor_id=42705168)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#full-view-affiliation-1 "Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA."), [Yashvi Aryan](https://pubmed.ncbi.nlm.nih.gov/?term=Aryan+Y&cauthor_id=42705168)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#full-view-affiliation-1 "Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA."), [Surabhi Gautam](https://pubmed.ncbi.nlm.nih.gov/?term=Gautam+S&cauthor_id=42705168)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#full-view-affiliation-2 "Department of Anatomy, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India."), [Rutwik Joshi](https://pubmed.ncbi.nlm.nih.gov/?term=Joshi+R&cauthor_id=42705168)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#full-view-affiliation-3 "Department of Chemical Engineering, Texas Tech University, Lubbock, TX, USA."), [Sanjeev Kumar](https://pubmed.ncbi.nlm.nih.gov/?term=Kumar+S&cauthor_id=42705168)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#full-view-affiliation-4 "Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India. Electronic address: sanjeevkumar@aiims.edu."), [Devyani Joshi](https://pubmed.ncbi.nlm.nih.gov/?term=Joshi+D&cauthor_id=42705168)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#full-view-affiliation-5 "Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. Electronic address: devyani.joshi@mcphs.edu.") Affiliations Expand ### Affiliations * 1 Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. * 2 Department of Anatomy, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India. * 3 Department of Chemical Engineering, Texas Tech University, Lubbock, TX, USA. * 4 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India. Electronic address: sanjeevkumar@aiims.edu. * 5 Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. Electronic address: devyani.joshi@mcphs.edu. * PMID: **42705168** * DOI: [ 10.1016/j.vaccine.2026.129109 ](https://doi.org/10.1016/j.vaccine.2026.129109) Free article Item in Clipboard Review # Influence of vaccine delivery route on immune imprinting in influenza vaccination Vidhi Thakkar et al. Vaccine. 2026. Free article Show details Display options Display options Format Abstract PubMed PMID Vaccine Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Vaccine%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Vaccine%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42705168/) . 2026 Oct 24:92:129109. doi: 10.1016/j.vaccine.2026.129109. Epub 2026 Sep 7. ### Authors [Vidhi Thakkar](https://pubmed.ncbi.nlm.nih.gov/?term=Thakkar+V&cauthor_id=42705168)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#short-view-affiliation-1 "Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA."), [Yashvi Aryan](https://pubmed.ncbi.nlm.nih.gov/?term=Aryan+Y&cauthor_id=42705168)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#short-view-affiliation-1 "Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA."), [Surabhi Gautam](https://pubmed.ncbi.nlm.nih.gov/?term=Gautam+S&cauthor_id=42705168)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#short-view-affiliation-2 "Department of Anatomy, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India."), [Rutwik Joshi](https://pubmed.ncbi.nlm.nih.gov/?term=Joshi+R&cauthor_id=42705168)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#short-view-affiliation-3 "Department of Chemical Engineering, Texas Tech University, Lubbock, TX, USA."), [Sanjeev Kumar](https://pubmed.ncbi.nlm.nih.gov/?term=Kumar+S&cauthor_id=42705168)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#short-view-affiliation-4 "Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India. Electronic address: sanjeevkumar@aiims.edu."), [Devyani Joshi](https://pubmed.ncbi.nlm.nih.gov/?term=Joshi+D&cauthor_id=42705168)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42705168/#short-view-affiliation-5 "Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. Electronic address: devyani.joshi@mcphs.edu.") ### Affiliations * 1 Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. * 2 Department of Anatomy, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India. * 3 Department of Chemical Engineering, Texas Tech University, Lubbock, TX, USA. * 4 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India. Electronic address: sanjeevkumar@aiims.edu. * 5 Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA. Electronic address: devyani.joshi@mcphs.edu. * PMID: **42705168** * DOI: [ 10.1016/j.vaccine.2026.129109 ](https://doi.org/10.1016/j.vaccine.2026.129109) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Influenza vaccines are predominantly administered intramuscularly. Yet, their effectiveness remains variable across seasons, age groups, and exposure histories, due to immune imprinting or original antigenic sin. Immune imprinting arises when early-life exposures to influenza durably bias subsequent immune responses toward epitopes from the priming strains. This limits the recruitment of naïve B cells and the breadth of responses to drifted or shifted viruses. As next-generation universal vaccines increasingly focus on conserved antigens and novel platforms, understanding how the vaccination route interacts with imprinting has become a critical but underexplored question. This review summarizes the mechanistic basis of influenza immune imprinting and how the vaccine delivery route might modulate imprinted responses. Importantly, direct evidence that the vaccination route can reprogram established imprinting by changing epitope hierarchy or recruiting naïve B cell clones in primed hosts is essentially lacking; most available data instead demonstrate route-dependent shifts in antibody compartment, isotype, and anatomical localization. We describe the cellular and molecular features of imprinting, and compare intramuscular vaccination with alternative strategies. We emphasize that each route engages distinct antigen-presenting cell networks, lymphoid structures, and systemic versus mucosal compartments, which are likely to influence clonal selection and epitope hierarchy. Further, we discuss the interplay between delivery route, antigen design, and adjuvants as an integrated design space for potentially modulating influenza immunity and the expression of imprinting. We highlight experimental models to analyze route-dependent imprinting and identify key translational gaps, including limited incorporation of immune history, inadequate use of epitope-resolved and mucosal readouts, and lack of clinical trials focused on investigating imprinting-related endpoints. Finally, we outline future directions, arguing that rational combinations of conserved antigens, adjuvants, and routes offer a tractable path to broaden and rebalance imprinted responses. This has direct implications for universal vaccine development and for age- or history-tailored vaccination strategies. **Keywords:** Adjuvants; Conserved antigens; Immune imprinting; Influenza; Universal vaccine; Vaccine delivery route. Copyright © 2026 The Author(s). Published by Elsevier Ltd.. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ The impact of egg adaptation and immune imprinting on influenza vaccine effectiveness. ](https://pubmed.ncbi.nlm.nih.gov/40812022/) Ashraf M, Stein AN, Youhanna J, Rockman S, McMahon M, McGovern I, Rajaram S, Miller MS.Ashraf M, et al.Vaccine. 2025 Aug 30;62:127393. doi: 10.1016/j.vaccine.2025.127393. Epub 2025 Aug 13.Vaccine. 2025.PMID: 40812022Review. * [ Repeated vaccination with homologous influenza hemagglutinin broadens human antibody responses to unmatched flu viruses. ](https://pubmed.ncbi.nlm.nih.gov/41231113/) Deng Y, Tang M, Ross TM, Schmidt AG, Chakraborty AK, Lingwood D.Deng Y, et al.Elife. 2025 Nov 13;14:e107042. doi: 10.7554/eLife.107042.Elife. 2025.PMID: 41231113Free PMC article. * [ Personality Theories. ](https://pubmed.ncbi.nlm.nih.gov/42475469/) Gallios JM, Iyer V, Kaylor LE.Gallios JM, et al.2026 Jun 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–.2026 Jun 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–.PMID: 42475469Free Books & Documents. * [ Epitope-spanning antigenic variation reprograms immunodominance and broadens immunity in sequential influenza vaccination. ](https://pubmed.ncbi.nlm.nih.gov/41771913/) Wan XF, Guan M, Balamalaliyage P, Chen H, Prasai K, Alcala A, Driver J, Olivier AK, Gu W, Frymire C, Madrid DMC, Gao C, Wang C, Li T, Tunterak W, Yang Q, Ramesh A, Ali M, Smith D, Li L, Sant AJ, Hang J, Xie H, Zhou M, Tao YJ.Wan XF, et al.Nat Commun. 2026 Mar 2;17(1):3340. doi: 10.1038/s41467-026-70202-y.Nat Commun. 2026.PMID: 41771913Free PMC article. * [ Beyond strain-specific immunity: Conserved antigenic targets, emerging platforms, and translational challenges in universal influenza and pan-coronavirus vaccine development. ](https://pubmed.ncbi.nlm.nih.gov/42324038/) Ikrar T, Muchsin W, Sophian A.Ikrar T, et al.J Virol Methods. 2026 Sep;345:115432. doi: 10.1016/j.jviromet.2026.115432. Epub 2026 Jun 21.J Virol Methods. 2026.PMID: 42324038Review. 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