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Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

ABSTRACT: A universal influenza vaccine that elicits a strong and lasting stalk-specific antibody response is advantageous. We utilize nucleoside-modified mRNA in lipid nanoparticles (mRNA-LNP) and unmodified self-amplifying mRNA in modified dendritic nanoparticles (sam-MDNP), expressing chimeric hemagglutinin (cHA) antigens to induce stalk-specific humoral immunity in non-human primates (NHPs) with preexisting influenza virus immunity. mRNA-LNP immunization induces strong stalk-specific binding antibodies, protecting mice from lethal heterologous influenza virus challenges, along with bone marrow plasma cells (BMPC) that persist for up to 8 months. sam-MDNP vaccine induces lower humoral immunity, despite showing strong innate activation. Transcriptomic and cytokine analyses reveal a more persistent induction of interferon responses, IL-1β signaling, and IL-6 production in the mRNA-LNP group, correlating with the induction of serum antibody responses and BMPC. We identify a transcriptional signature associated with induction of BMPC following mRNA vaccination and highlight the utility of cHA-based mRNA-LNP vaccines in inducing persistent stalk-directed protective antibody responses.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE304256 | GEO | 2025/12/04

REPOSITORIES: GEO

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AS03-adjuvanted chimeric HA-based influenza vaccine induces long-lived stalk-specific plasma cells in bone marrow and lymph nodes of non-human primates

Project description:Current influenza vaccines face challenges due to antigenic evolution of the circulating virus and waning immunity in humans. Here, we investigated the durability of humoral immunity induced by an AS03-adjuvanted chimeric hemagglutinin (cHA) based influenza vaccine in non-human primates (NHPs). Two groups of NHPs (n=7 or 8) received two doses of a seasonal quadrivalent influenza vaccine (QIV) on weeks 0 and 4, followed by sequential immunization with split virus cHA vaccines cH8/1N1 (week 21), and cH5/1N1 (weeks 33 and 94). One group received cHA immunizations with AS03 adjuvant. We monitored serum antibodies and long-lived plasma cells in bone marrow for nearly 2 years after the final vaccination. The seasonal QIV vaccine induced poor HA stalk-specific antibodies and failed to give rise to detectable long-lived plasma cells in bone marrow. In contrast, cHA vaccines significantly induced stalk-specific antibody responses. Importantly, the addition of AS03 enhanced both the magnitude and durability of humoral immunity by establishing the persistence of long-lived plasma cells in the bone marrow and lymph nodes for nearly 2 years. Passive transfer of NHP serum provided protection against challenge with heterologous influenza A virus strains in mice. This study highlights the potential of the AS03-adjuvanted chimeric HA vaccine strategy to provide durable and broadly protective humoral immunity.

2025-09-04 | GSE294334 | GEO

Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 high-pathogenicity avian influenza virus with reduced adverse reactions (using whole lymph node)

Project description:Messenger RNA vaccines based on lipid nanoparticles (mRNA-LNPs) are promising vaccine modalities. However, mRNA-LNP vaccines frequently cause adverse reactions such as swelling and fever in humans, partly due to the inflammatory nature of LNP. Modification of the ionizable lipids used in LNP is one approach to avoid these adverse reactions. Herein, we report the development of mRNA-LNP vaccines with better protective immunity and reduced adverse reactions using LNP, including SS-cleavable and pH-activated lipid-like materials with oleic acid (ssPalmO) as an ionizable lipid (LNPssPalmO). We used mRNA expressing H5N1 subtype high-pathogenicity avian influenza virus-derived hemagglutinin or neuraminidase to generate mRNA-LNP vaccines against H5N1 influenza. Compared with conventional LNP, mRNA-LNPssPalmO induced comparable antigen-specific antibodies and better IFN--producing Th1 responses in mice. Both mRNA-LNPssPalmO and conventional mRNA-LNP conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNPssPalmO showed better cross-protection against heterologous H5N1 virus challenge compared to conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNPssPalmO induced less inflammatory responses (e.g., inflammatory cytokine production and vascular hyperpermeability) and fewer adverse reactions (e.g., weight loss and fever) compared with conventional mRNA-LNP. These results suggest that mRNA-LNPssPalmO would be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy.

2025-03-05 | GSE279743 | GEO

Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 high-pathogenicity avian influenza virus with reduced adverse reactions (using dendritic cell of lymph node)

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Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins II

Project description:In a phase I clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single cell RNA-sequencing and B cell receptor repertoire sequencing. We have shown that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At one-year post-immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.

2025-03-04 | GSE260941 | GEO

Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

2025-03-04 | GSE260836 | GEO

Transcriptome signatures preceding the induction of anti-stalk antibodies elicited by a chimeric hemagglutinin-based universal influenza virus vaccine

Project description:A phase 1 clinical trial to test the immunogenicity of a chimeric group 1 HA (cHA) universal influenza virus vaccine targeting the conserved stalk domain of the hemagglutinin of influenza viruses was carried out. Vaccination with adjuvanted-inactivated vaccines induced high anti-stalk antibody titers. We sought to identify gene expression signatures that correlate with such induction. Messenger-RNA sequencing in whole blood was performed on peripheral blood of 53 vaccinees, at early and late time points after priming and boosting. We generated longitudinal data on peripheral blood of 53 volunteers, at early (days 3 and 7) and late (28 days) time points after priming and boosting with cHAs. Differentially expressed gene analysis showed no differences between placebo and live-attenuated vaccine groups. However, an upregulation of genes involved in innate immune responses and type I interferon signaling was found at day 3 after vaccination with inactivated adjuvanted formulations. Cell type deconvolution analysis revealed a significant enrichment for monocyte markers and different subsets of dendritic cells as mediators for optimal B cell responses and significant increase of anti-stalk antibodies in sera. A significant upregulation of immunoglobulin related genes was only observed after administration of adjuvanted vaccines (either as primer or booster) with specific induction of anti-stalk IGVH1-69. This approach informed of specific immune signatures that correlate with robust anti-stalk antibody responses, while also helping to understand regulation of gene expression induced by cHA proteins under different vaccine regimens.

2022-12-13 | GSE217770 | GEO

Recruitment of plasma cells from follicular and extrafollicular immune reactions to the bone marrow I

Project description:Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observed in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.

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Recruitment of plasma cells from follicular and extrafollicular immune reactions to the bone marrow II

2024-04-16 | GSE253857 | GEO

B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

Project description:In a phase I clinical trial, the chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain. However, the landscape of the B cell specificities and subsets induced by this vaccine remain undetermined. Here, we paired single cell RNA-sequencing and B cell receptor repertoire sequencing to analyze the relationship between transcriptome and B cell specificity following cHA immunization. We show that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell phenotype against two broadly neutralizing epitopes of the stalk domain. The overall specificities of the acute plasmablast and memory B cell responses were distinct, with the plasmablast compartment largely targeting non-neutralizing epitopes of the HA stalk. Altogether, these data indicate the B cell landscape following cHA vaccination includes diverse B cell subsets that are differentially induced by distinct vaccine formulations, including memory and de novo B cell responses against diverse broadly conserved epitopes.

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Immune response genes at the mRNA vaccine delivery sites and draining lymph nodes of rhesus macaques

Project description:mRNA vaccines are emerging as a powerful vaccine platform as they are well-tolerated and scalable. Modified non-replicating mRNA encoding Influenza hemagglutinin and encapsulated in lipid nanoparticles (LNP) induced robust antibody and CD4 T cell responses after intramuscular or intradermal delivery in rhesus macaques. We investigated the local innate immune responses modulating such vaccine-induced immunity at the sites of immunization (skeletal muscle and skin) and their draining lymph nodes (LNs). Rapid mobilization of antigen presenting cells was found at the LNP/mRNA-injection sites and LNs. Dendritic cells efficiently internalized the LNPs, translated the mRNA cargo and upregulated co-stimulatory molecules. In addition, several type I interferon-inducible genes were expressed at the immunization sites and draining LNs. The innate immune activation was transient and resulted in priming of antigen-specific CD4+ T cells exclusively in the vaccine-draining LNs. Collectively, mRNA-based vaccines induce type I interferon-polarized innate immunity and antigen production by antigen presenting cells, which resulted potent vaccine-specific responses.

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