Intranasal boosting promotes greater variant-specific response at both the serum and cellular levels than i.m.n. boosting, and ongoing B cell repertoire and mAb analyses will provide mechanistic insight into how vaccination route reshapes clonal selection and maturation, informing rational vaccination design.
Abstract
Immune imprinting is a phenomenon in which prior antigen exposure limits variant-specific de novo immune responses to subsequent related antigens. The serum response to Omicron boosters in mice and human are strongly imprinted by prior vaccines encoding SARS-CoV-2 Wuhan-1 spike (e.g., mRNA-1273). Strategies including changes of dosage and interval have had limited success in enhancing variant-specific immunity. Intranasal (i.n.) vaccination is a promising approach that elicits mucosal and systemic immunity. Here we analysed the response of variant boosters delivered i.m. or i.n. after mRNA-1273 priming at the serum, cellular, and B cell repertoire levels to understand how boosting routes modulate the imprinting effect.
C57BL/6 mice were primed i.m. with mRNA-1273 and heterologously boosted i.m. or i.n. with a chimpanzee adenoviral-vectored vaccine (ChAd-SARS-CoV-2-S) against XBB.1.5 spike. Serum and bronchoalveolar lavage fluid (BALF) were analysed for cross-reactive and strain-specific spike-binding IgG/IgA. Neutralizing activity was assessed using pseudovirus neutralization assays. Cross-reactive and strain-specific spike-binding memory B cells (MBCs) in draining lymph nodes (dLNs) were quantified. Ongoing studies are using single-cell BCR sequencing to analyse plasmablast clonotypes, with selected ones expressed as mAbs for functional and epitope analyses.
Intranasal boosting with ChAd-SARS-CoV-2-S against XBB.1.5 spike induced higher fractions of XBB.1.5-specific serum IgG and BALF IgA with greater neutralizing activity. Intranasal vaccination increased XBB.1.5-specific MBCs in dLNs, indicating a route-dependent shift in B cell specificity.
Intranasal boosting promotes greater variant-specific response at both the serum and cellular levels than i.m. boosting. Ongoing B cell repertoire and mAb analyses will provide mechanistic insight into how vaccination route reshapes clonal selection and maturation, informing rational vaccination design.
Moderna and NIH R01AI157155
Vaccines and Immunotherapy (VAC)
It is shown that a Wuhan-lineage-based multi-antigen VLP vaccine can provide cross-protection against an antigenically divergent SARS-CoV-2 variant that is not fully explained by detectable serum neutralizing activity alone, suggesting the importance of integrated immune responses involving humoral, cellular, and local immune mechanisms.
Seung-Ji Kim, Howon Kim, Seung-Eun Son et al.· Vaccine· 0 citations
Objective(s): Intranasal vaccination mimics natural infection and induces mucosal immunity against respiratory viruses. This study compared the immunogenicity and protective efficacy of a nucleoside-modified messenger RNA (mRNA) encoding the SARS-CoV-2 spike protein, encapsulated in lipid nanoparticles (LNPs), administered via intranasal (I.N) versus intramuscular (I.M) routes. Materials and Methods: BALB/c mice received mRNA-LNP vaccines at 1, 5, or 10 µg doses intramuscularly. Antibody responses (Immunoglobulin G/IgA [IgG/IgA]), neutralization titers (conventional virus neutralization test [cVNT]), and interferon-gamma (IFN-γ) responses were assessed to select the optimal dose. The selected 5 µg dose was then administered to mice and Syrian hamsters via I.N or I.M routes. Post-challenge, lung viral loads (50% Tissue Culture Infectious Dose [TCID50]/ml) and weight changes were evaluated. Results: The 5 µg dose induced robust humoral and cellular immunity (cVNT >5 log₂). Intranasal delivery elicited strong spike-specific IgA in nasal washes. Although I.M vaccination produced higher serum neutralizing titers (51.2 vs. 22.0), I.N vaccination conferred superior protection with a 4-log reduction in lung viral load (~10¹ TCID50/ml) versus I.M and controls (~10² TCID50/ml). I.N-vaccinated hamsters were completely protected from weight loss, whereas I.M-vaccinated animals showed mild weight reduction (~1%). Conclusion: Intranasal mRNA-LNP administration elicits potent mucosal and systemic immunity and provides superior protection against SARS-CoV-2 challenge compared to I.M vaccination, underscoring its promise as a transformative strategy for respiratory virus vaccines.
Mohsen Abdoli, H. Soleimanjahi, S. Soudi et al.· Iranian Journal of Basic Med...· 0 citations
Results demonstrate that AZD6563, at reduced doses, matches the cellular immunogenicity of BNT162b2 while enhancing B cell cross-reactivity and TCR diversity in older adults, supporting its potential as a next-generation COVID-19 vaccine candidate.
Michael D. Powell, Nicholas G. Battaglia, Lee-Jah Chang et al.· Journal of Immunology· 0 citations
A chimpanzee adenovirus (AdC68)-vectored vaccine expressing the Delta-XBB receptor-binding domain (RBD)-dimer is constructed and comprehensively compared the immune responses induced by intramuscular injection, intranasal administration, or aerosol inhalation, revealing that aerosol inhalation provided significantly better protection, without detectable replicating virus in the nasal tissue.
Xue-Yuan Liu, Yaling An, Huixin Duan et al.· mBio· 0 citations
Introduction Vaccines against SARS-CoV-2 and influenza require reformulation due to viral evolution. It remains unclear how vaccination against evolving antigens influences T-cell responses and the impact of reformulation on T-cell responses to new variants in immunocompromised hosts. Solid organ transplant recipients (SOTRs) had significantly lower antibody levels following vaccination and required repeated boosting during the COVID-19 pandemic. Methods With the introduction of the Omicron spike (S) to the bivalent mRNA vaccines in 2022, the relative contribution of T-cell responses cross-reactive for Omicron mutated S sequences was assessed via intracellular cytokine staining using peptide pools containing conserved or mutated S sequences. Results S-specific CD4 T cells recognize both conserved and Omicron mutated S sequences pre- and post-bivalent vaccination, even in the absence of evidence of prior infection as detected by T-cell responses to a novel peptide pool. CD4 T-cell responses to both conserved and Omicron mutated sequences correlated with antibody pseudo-neutralization of BA.5 S. Importantly, pre-bivalent conserved S CD4 T-cell responses significantly correlated with antibody pseudo-neutralization of BA.5 S post-bivalent. Discussion These results emphasize the importance of conserved and cross-reactive responses in vaccine immunogenicity, providing a mechanism through which repeated boosting enhances vaccine immunogenicity in SOTRs and other immunocompromised populations.
Georgia Stavrakis, Katerina Roznik, Laila Stoddart et al.· Frontiers in Immunology· 0 citations
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.
Vidhi D Thakkar, Yashvi Aryan, Surabhi Gautam et al.· Vaccine· 0 citations
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