Background incidence rates and observed-to-expected ratios of adverse events of special interest after covid-19 mRNA vaccination during pregnancy in France: a nationwide population-based study.

mRNA COVID-19 vaccination induces minimal IgA in saliva in the absence of prior clinical or subclinical infection.

SARS-CoV-2 spike-directed T cells and anti-receptor-binding-domain antibodies in hematological patients receiving three mRNA COVID-19 vaccine doses

A Self-amplifying mRNA vaccine for infectious laryngotracheitis virus (ILTV) induces efficient protective immunity.

Effect of time-of-day vaccination on the antibody response to mRNA and protein COVID-19 vaccine in adults.

Recent advances in engineering approaches for delivery of mRNA-based therapeutics.

Targeted cytosolic delivery of mRNA immunotherapeutics: From vaccine delivery to protein replacement.

Several systematic reviews and meta-analyses have been published with conflicting results on the risk of herpes zoster after coronavirus disease 2019 (COVID-19) vaccination. We aimed to study the risk of herpes zoster after COVID-19 vaccination using electronic health record data of general practices, from a large cohort in the Netherlands. Persons aged ≥ 12 years who received at least one COVID-19 vaccination and were registered in the general practice databases of PHARMO and Nivel Primary Care Database were included. This study used a self-controlled design comparing the risk of herpes zoster in the risk period (28 days after COVID-19 vaccination) with the control period. Poisson regression was used to calculate incidence rate ratios, adjusting for severe acute respiratory syndrome coronavirus 2 infection. There were 2,098,683 COVID-19 vaccinated persons aged ≥ 12 years included, of whom 1,058,646 (50.4%) were female. An increased risk for herpes zoster was found after all the doses grouped together and the third dose of all COVID-19 vaccination (adjusted incidence rate ratio: all doses 1.07, 95% confidence interval [CI] 1.02-1.13 and third dose 1.21, 95% CI 1.05-1.38). After stratification on vaccine type, all doses and the third dose of messenger RNA vaccination (adjusted incidence rate ratio: all doses 1.06, 95% CI 1.00-1.12 and third dose 1.21, 95% CI 1.05-1.40) showed an increased risk. Our study showed a slight increased risk of herpes zoster when taking into account all doses and all types of vaccines. After stratification on vaccine type, no increased risk of herpes zoster after the primary vaccination series and a slightly elevated risk after the third/booster vaccination with a messenger RNA vaccine were found.

mRNA vaccines for viral diseases: mechanism, advances, and future perspective.

ABSTRACT Individuals with inborn errors of immunity often mount suboptimal responses to vaccination, yet the molecular determinants underlying their variable responses to mRNA vaccines remain poorly defined. The present study aimed to identify baseline immune transcriptional signatures predictive of humoral responses to the BNT162b2 (Comirnaty) mRNA vaccine in individuals with inborn errors of immunity. Twenty-one SARS-CoV-2-naïve participants with diverse inborn errors of immunity were stratified as high or low responders to the BNT162b2 vaccine based on anti-SARS-CoV-2 spike IgG titers at day 28 post-vaccination. Although vaccine-induced T cell responses were broadly comparable, low responders had significantly lower frequencies of switched memory B cells (p = .014). Transcriptional profiling revealed 41 differentially expressed genes between groups at baseline. Activated memory B cells and peripheral T follicular helper cells from high responders exhibited greater induction of activation and memory-related genes, including NFKB1, CD69, TIGIT, CD40L, and BATF, indicating greater intrinsic readiness to support coordinated antibody production. These findings demonstrate that distinct pre-vaccination gene expression patterns within specific immune subsets are associated with differential humoral responses to mRNA vaccination in individuals with inborn errors of immunity. More broadly, the study highlights that baseline molecular immune features substantially influence vaccine efficacy and suggests that pre-vaccination transcriptional profiling may enable more personalized vaccination strategies for individuals with impaired immunity.

The Crimean-Congo Hemorrhagic Fever Virus (Orthonairovirus haemorrhagiae) causes a hemorrhagic fever with mortality rates reaching up to 40%. For years, this virus has maintained its position among the top priority pathogens identified by the World Health Organization (WHO). This is due to its endemic presence across a vast region-from Africa and Spain to the Balkans, the Middle East, and throughout Asia-its potential for human-to-human transmission, and the lack of an effective and approved vaccine or treatment. Therefore, the development of an effective vaccine against CCHFV is of critical importance. Building on the success of mRNA-based vaccines during the Coronavirus Disease 2019 (COVID-19) pandemic, this study reports the development of a messenger ribonucleic acid (mRNA) vaccine candidate expressing the nucleocapsid protein (NP) of CCHFV. The CCHFV NP in vitro transcript (IVT) was designed with pseudouridine (Ψ) nucleoside modification. As part of the preclinical characterization of the IVT vaccine candidate, the biochemical and immunological properties of NP were confirmed in Huh-7 cells transfected with IVT NP-ΨmRNA. Afterwards, the efficacy of IVT NP-ΨmRNA immunization was evaluated in immunocompetent BALB/c and transiently immunosuppressed (IS) C57BL/6 mice. In CCHFV challenge studies, IS C57BL/6 mice were used. IS C57BL/6 mice were immunized intramuscularly with 2 doses of IVT NP- ΨmRNA, either naked or encapsulated in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, administered 14 days apart. High levels of CCHFV NP-specific humoral (IgM and IgG) and cellular (cytokine and lymphoproliferative) responses were demonstrated in BALB/c mice immunized with IVT NP- ΨmRNA. In challenge experiments, 100% survival was observed with both the naked and PLGA-encapsulated IVT NP-ΨmRNA immunizations. These findings demonstrate 100% survival following lethal CCHFV challenge under the experimental conditions tested in this mouse model and support the potential of NP-encoding pseudouridine-modified mRNA vaccines. Additionally, 100% survival was observed in mice immunized with inactivated CCHFV, whereas only 20% survival was detected in the unmodified IVT NP-mRNA vaccinated animals. In the protected mice, viral clearance was observed in the spleen, liver tissues, and blood on day 14 post-challenge. This study demonstrates that NP, the most abundant protein of the virus, is capable of providing significant survival benefits in the tested mouse model. Furthermore, our report represents a significant step in identifying a potential vaccine candidate and provides a solid foundation for further preclinical studies necessary to support future clinical development.

Advanced age is one of the greatest risk factors for a severe outcome of COVID-19. Although mRNA vaccines were highly successful in protecting the elderly, the strongest increase in morbidity and mortality upon infection with emerging SARS-CoV-2 variants was among the elderly. To better understand SARS-CoV-2 pathogenicity and to thoroughly evaluate novel vaccination strategies, better models reliably reproducing human SARS-CoV-2 pathogenicity are needed. Here, we generated mice expressing a human-mouse chimera of ACE2 (chACE2) by CRISPR/Cas9-mediated gene editing in C57BL/6 mouse zygotes. ChACE2 mice express the chimeric viral receptor at physiological levels, enabling efficient SARS-CoV-2 infection without the heightened mortality seen in K18-hACE2 mice due to neuroinvasion. We used the chACE2 model to analyze SARS-CoV-2 infection as well as antiviral immune responses in vitro and in vivo. Similar to SARS-CoV-2 in elderly humans, aged chACE2 mice suffered from a highly aggravated disease. In addition, we found that a live attenuated vaccine candidate, LAVNsp16, induces robust mucosal and systemic immune responses in these mice despite being highly attenuated. The immunization with LAVNsp16 protected aged chACE2 mice from otherwise severe pathogenicity of SARS-CoV-2 by blocking viral replication of homologous and heterologous SARS-CoV-2 variants. The newly developed chACE2 model allows for longer observation periods of SARS-CoV-2 infection in mice, which is essential for assessing the immunogenicity of novel vaccine designs or monitoring viral pathogenicity over time. Immunization with LAVNsp16 induced robust and protective immune responses in young and aged mice, making viruses lacking 2'-O-methyltrasferse activity promising candidates for future live attenuated vaccine development.

Inflammatory changes play a central role in both diseases and therapeutic interventions. Wearables are a promising novel method for inflammation detection and tracking through identifying subtle, individualized physiologic changes. We evaluated a wearable-derived individualized digital biomarker, inflammatory multivariate change index (iMCI) against serum biomarkers and reactogenicity following vaccination. Sixty-one volunteers received one of four mRNA vaccines (80 total doses) and wore a torso sensor patch for 14 days starting seven days before vaccination. Changes in serum inflammatory biomarkers symptoms were tracked post-vaccine. iMCI showed moderate to strong correlation against C-reactive protein (CRP; Spearman ρ = 0.59, p < 0.01) and interferon-γ (IFN-γ; ρ = 0.56, p < 0.01), comparable to the CRP-IFN-γ correlation (ρ = 0.60, p < 0.01). Associations with systemic reactogenicity were moderate for all three measures (iMCI ρ = 0.48, p < 0.01; IFN-γ ρ = 0.34, p = 0.01; CRP ρ = 0.36, p < 0.01). These results indicate that a personalized digital biomarker offers a scalable alternative to serial blood testing for real-time inflammation tracking.

Background: Hematological patients have a high risk of developing severe COVID-19 (37%). Most mRNA vaccine trials in hematological patients showed a low immunogenicity after two doses, while long-term data are scarce. Methods: In this monocentric retrospective observational study, we evaluated humoral and T cell-mediated immune responses in 230 hematological patients after three doses of the Pfizer-BioNTech mRNA COVID-19 vaccine. Patients were stratified by age, disease type/state, prior COVID-19 infection, and treatment status and regimens (anti-CD20 monoclonal antibodies, BTK and BCL-2 inhibitors, and treatment line). Antibody titer to SARS-CoV-2 was assessed by electrochemiluminescence immunoassay and T cell response by QuantiFERON interferon-γ release assay (IGRA). Data were analyzed using univariate (Fisher’s exact test) and Firth’s bias-reduced penalized-likelihood logistic regression. Results: A robust humoral response was observed with 91.55% of patients developing anti-spike antibodies (GMT 988.83 U/mL). Anti-CD20-bendamustine treatment was associated with a significantly lower antibody positivity compared to untreated subjects. Prior COVID-19 infection significantly boosted both antibody positivity (95.9% vs. 85.2%) and GMT (847.02 U/mL vs. 258.79 U/mL). Conversely, T cell response was suboptimal (36.1% positive), particularly in anti-CD20-bendamustine-treated and multi-treated patients (27.1%), but highest in those treated with BTK inhibitors (50%). Multivariable logistic regression analysis linked multiple treatments to lower T cell response. Following vaccination, 29.1% of patients contracted SARS-CoV-2, but only 0.89% developed severe COVID-19. Conclusions: Three doses of mRNA vaccine elicit a strong humoral but a low T cell response, as detected by IGRA, in hematological patients. These findings underscore the importance of completing vaccination before initiating immunosuppressive therapies.

Bird flu: mRNA vaccine trial begins in UK.

Messenger RNA (mRNA) vaccines have transformed cancer immunotherapy, yet delayed immune activation, multi-dose requirements, and poor efficacy in immunosuppressive tumor microenvironments (TMEs) hinder current platforms. Here, a structurally stabilized lipopolymer nanoparticle (LPNP) platform is proposed for in situ mRNA vaccination targeting antigen-presenting cells (APCs). Central to this system is a rationally engineered double-branched lipopolymer, P6CIT, whose unique molecular architecture enhances hydrophobic microviscosity and intermolecular packing, increasing particle rigidity and preventing premature disassembly in biological fluids. This stabilization enhances circulation stability and promotes favorable biodistribution to tumor sites and lymphoid organs, resulting in a 6.9-fold increase in the spleen and a 13.6-fold increase in lymph nodes, key sites for adaptive immune activation. Upon intratumoral administration, the LPNP co-delivers mRNAs encoding tumor antigens and IL-12, synergistically reprogramming the TMEs and amplifying APC-mediated T cell priming. In situ vaccination achieves a 42% complete response in a B16-OVA melanoma model and outperforms ALC-0315 LNPs in wild-type B16F10 tumors. This work highlights chemical-level structural optimization enabling potent, simplified mRNA immunotherapy.

Tumor microenvironment activatable immunomodulator for cancer immunotherapy.

COVID-19 remains a substantial public health challenge in the Netherlands. Next-generation COVID-19 vaccine, mRNA-1283, is approved in the European Union, with potential for higher relative vaccine efficacy compared with originally licensed COVID-19 vaccines. The potential public health and economic impact of mRNA-1283 in adults ≥ 60 years and high-risk adults aged 18-59 years was modeled versus no vaccination and originally licensed mRNA-1273 and BNT162b2, adapting a published static Markov model with a 1-year time horizon. COVID-19 burden reflected two full post-pandemic seasons. Vaccine efficacy versus mRNA-1273 was based on pivotal phase 3 NextCOVE trial data; efficacy versus BNT162b2 was derived from an indirect treatment comparison. The economically justifiable price (EJP) of mRNA-1283 versus no vaccination and price premiums over existing vaccines were determined at a willingness-to-pay threshold of €50,000/quality-adjusted life-year (QALY) gained. Without COVID-19 vaccination, an estimated 460,000 infections, 23,800 hospitalizations, and 5300 deaths would occur. With current coverage, mRNA-1283 was estimated to prevent 68,000 infections, 5400 hospitalizations, and 1200 deaths, saving 9667 QALYs and over €66.5 million in treatment costs. The EJP was €238 versus no vaccination. Compared with mRNA-1273 and BNT162b2, mRNA-1283 was estimated to prevent additional burden (e.g., 1309 and 1679 hospitalizations, respectively) and was cost-effective at an incremental EJP of €62 versus mRNA-1273 and €80 versus BNT162b2. The results support continued COVID-19 vaccination to mitigate the ongoing health and societal burden of SARS-CoV-2 in the Netherlands. The comparative analyses indicate that mRNA-1283 may be associated with substantial health benefits over originally licensed mRNA vaccines; consequently, its use may further improve health outcomes and economic efficiency within COVID-19 vaccination programs.

People living with HIV infection (PLWH) often have attenuated responses to infections and vaccination. This study aimed to better understand how HIV-associated inflammation and chronic T-cell activation influenced the immune responses to mRNA vaccination or neutralization assay analyses. PLWH on ART or healthy donor controls were analyzed using systems serology and viral T-cell phenotyping to Spike or HIV-1 Gag peptide stimulation after primary mRNA COVID-19 vaccination. Neutralization assays using a lentiviral pseudovirus construct were compromised by the presence of integrase strand transfer inhibitor (INSTI) drugs in plasma from HIV + subjects taking certain ART. This combination of lentiviral pseudovirus reporter assays and INSTIs led to false positive neutralization results. Spike-specific IgG1, IgG3, IgA1, IgA2, and antibody-dependent cellular phagocytosis (ADCP) were altered post-vaccination in PLWH compared to controls. Network and multivariate analyses revealed post-vaccination outcomes were strongly correlated to CD4 immunodeficiency and Gag-specific T-cells, including effector CD8 T-cells and Th1 CD4 T-cells. Given the growing use of pseudovirus neutralization assays for serological evaluation and mRNA technology in novel vaccines that could be recommended for PLWH Pseudovirus neutralization assays need to be carefully selected to prevent ART drugs in patient samples from impacting results. Spike-specific antibody and CD4 T-cell phenotypes are influenced by both CD4 immunodeficiency and Gag-specific T-cell effector populations. This work has clinical relevance beyond COVID, with future considerations of pseudovirus assay evaluations and mRNA vaccine design for chronically infected hosts.

Current mRNA-LNP systems face challenges in efficient co-delivery of nucleic acid adjuvants, limiting their capacity to elicit robust cellular immunity. To overcome the dissociation limitations of physically admixed CpG in conventional lipid nanoparticles, we developed a covalent conjugation platform that integrates TLR9 agonists with phospholipids via amide bonding. We synthesized a DSPE-CpG conjugate, which exhibited high loading efficiency (97.1%) onto mRNA-LNPs. The immune activation efficacy was evaluated in models encoding SARS-CoV-2 spike protein and HBV antigens. The DSPE-CpG-mRNA LNP system demonstrated enhanced cellular uptake via clathrin-mediated endocytosis, superior lymph node targeting of the adjuvant, and improved antigen expression in vivo. In the SARS-CoV-2 model, it induced high levels of IFN-γ⁺CD8⁺ T cells and elicited higher titers of specific IgG and neutralizing antibodies. In the HBV model, it significantly enhanced antigen-specific CD107a+ and FasL+ CTLs. Acute toxicity tests revealed no significant adverse effects. This covalent conjugation strategy, by ensuring co-localized delivery of antigen and adjuvant, provides an innovative and translatable platform for enhancing mRNA vaccine efficacy.