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.
Abstract
mRNA-encoded virus-like particles (VLPs) are an emerging advancement in vaccine technology, enabling the self-assembly of viral antigens into structures that closely resemble native viruses. This innovative approach to conventional mRNA vaccination may boost vaccine-induced adaptive immune responses and allow for reduced dosing. To evaluate this technology, we developed AZD6563, an mRNA VLP vaccine targeting the COVID-19 XBB1.5 spike variant.
The phase 1 clinical study ARTEMIS-C was conducted to assess cellular immunogenicity in adults aged 18—64 years and ≥65 years following administration of AZD6563 (5 µg or 10 µg) or the licensed BNT162b2 XBB.1.5 mRNA vaccine (30 µg).
AZD6563 drove spike-specific CD4+ and CD8+ T cell responses comparable to those elicited by higher dose of BNT162b2. Functional analysis of these cells revealed similar cytokine production profiles across groups; however, the 10µg dose of AZD6563 led to higher TCR diversity within the ≥65-year cohort. Notably, expansion of spike-specific B cells was most pronounced in the AZD6563 10µg group, with marked increases in cross-reactive XBB.1.5 spike-specific B cells that also recognized Omicron BA.4/5 and ancestral SARS-CoV-2 variants.
Collectively, these 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.
n/a
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
Although mRNA-based COVID-19 vaccines have demonstrated high efficacy, their widespread global use remains constrained by high production costs and cold-chain requirements. Modified vaccinia virus Ankara (MVA) is a highly attenuated and thermostable viral vector with low production costs, potent immunogenicity, and strong potential for global distribution. Here, we compared head-to-head the long-term immunogenicity and efficacy of an MVA-based vaccine candidate with an approved mRNA vaccine in K18-hACE2 mice, both expressing the SARS-CoV-2 Omicron XBB.1.5 spike (S) protein. Mice received by intramuscular route homologous (mRNA/mRNA and MVA/MVA), heterologous (mRNA/MVA), or single-dose MVA regimens. SARS-CoV-2-specific humoral and cellular responses were evaluated at 10 days and 9 months after the last vaccination, as well as antibody levels at intermediate time points, and protection was assessed following intranasal SARS-CoV-2 XBB.1.5 challenge at 9 months post-vaccination. Binding IgG antibodies against the XBB.1.5 S protein remained high throughout the 9-month period in all vaccinated groups, whereas neutralizing antibody titers peaked early after the last vaccination and progressively declined, converging across regimens over time. S-specific CD8+ T-cell responses were strongest in mRNA-containing regimens at day 10 after the last vaccination and, although they contracted over time, they remained detectable at 9 months after the last vaccination in all two-dose groups, with a trend toward enhanced persistence in the heterologous mRNA/MVA regimen. In contrast, S-specific CD4+ T-cell responses remained low across all groups. All two-dose regimens markedly reduced viral RNA levels and infectious viral titers in both the upper and lower respiratory tract following SARS-CoV-2 XBB.1.5 challenge. Transcriptomic analysis of lung tissue after virus challenge revealed reduced expression of genes associated with inflammatory myeloid responses, interferon signalling and cellular stress in vaccinated mice compared with infected controls. Distinct post-challenge lung transcriptional profiles were observed across vaccination regimens, with differential modulation of genes associated with humoral, innate, and cellular immune responses. Overall, our findings demonstrate that MVA-based vaccination induces durable immunity in mice and achieves long-term control of SARS-CoV-2 XBB.1.5 replication comparable to that of mRNA vaccination, supporting its use as an alternative and complementary vaccine platform against SARS-CoV-2 and other emerging respiratory viruses.
Patricia Pérez, G. Esteso, Isabel García-García et al.· Frontiers in Immunology· 0 citations
Self-amplifying mRNA (samRNA) vaccines can induce potent immune responses at lower doses than conventional non-replicating mRNA vaccines; however, large RNA size and manufacturing considerations associated with 5' capping remain important challenges. Here, we developed a capless samRNA (CLsamRNA) vaccine platform derived from a Coxsackievirus B5 replicon that uses IRES-mediated cap-independent translation. Systematic optimization of key genetic elements enhanced antigen expression from the CLsamRNA backbone. Using reporter RNAs, LNP-formulated CLsamRNA showed rapid early expression and RNA amplification, with expression kinetics distinct from VEEV-based saRNA and nucleoside-modified mRNA comparators. When encoding the hemagglutinin antigen of highly pathogenic avian influenza clade 2.3.4.4 H5 viruses, CLsamRNA induced potent immune responses after LNP formulation. In mouse models, CLsamRNA induced potent neutralizing antibody responses, cross-reactive activity against clade 2.3.4.4b H5N1 virus, Th1-skewed humoral immunity, and strong antigen-specific cellular immune responses. CLsamRNA also elicited platform-specific early inflammatory and lymph-node immune gene signatures associated with antigen presentation, costimulation, and cellular immune priming. Notably, a minimal 0.01 μg dose of CLsamRNA conferred complete protection against lethal H5N8 influenza virus challenge in BALB/c mice. These findings support CLsamRNA as a distinct cap-independent RNA vaccine platform with dose-sparing protective efficacy against HPAI H5 viruses.
Beom Kyu Kim, Ji-Hyun Park, Won-Suk Choi et al.· Molecular Therapy· 0 citations
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.
Xinyi Liu, Chieh-Yu Liang, Michael S. Diamond· Journal of Immunology· 0 citations
The results illustrate an IgG4-dominated immunological signature in both adults and children and highlight that immune priming by prior infection may shape subsequent mRNA vaccine-induced antibody responses.
T. Pongrácz, U. Marking, O. Bladh et al.· Scientific Reports· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
