The strong relationship between myocardial infarction (MI) and inflammation has been supported by numerous observations; targeting inflammatory signalling pathways represents a crucial approach to rescue cardiac function after MI. Our team has designed and developed therapeutic vaccines, ILRQβ-007 and ILRQβ-008, which target interleukin-1 receptor, type I (IL-1R1). The aim of this study is to investigate the effect of the vaccines on short-term and long-term MI animal models. The ILRQβ-007 and ILRQβ-008 vaccines were prepared and then used to immunize C57BL/6J (C57) mice with MI and observed their effects at 7 and 28 days, respectively. Cardiac ultrasound and histological staining were used to assess cardiac function and remodelling after MI in C57 mice. Flow cytometry and molecular biology tests were used to evaluate the systemic inflammatory infiltrate. While transesophageal catheter pacing was used to assess susceptibility to atrial fibrillation in mice. The vaccines produced high titres of antibodies and reduced IL-1R1 expression levels in the heart after MI. They significantly reduced myocardial infarct size and systemic inflammation following short-term MI, as well as protecting cardiac function and reducing cardiac fibrosis following long-term MI. Moreover, the susceptibility to atrial fibrillation was reduced in both the short and long-term models. Further, the vaccines improved mitochondrial dynamics and thus maintained mitochondrial homeostasis protecting the heart. This study demonstrates that vaccines targeting IL-1R1 can be applied to the prevention and treatment of MI, providing a new direction for MI research.
Over the past several decades, immunotherapy has emerged as a transformative paradigm in oncology. Within this domain, vaccines targeting tumor-specific neoantigens represent one of the most advanced approaches, engineered to activate the host immune system and elicit potent, antigen-specific T-cell responses. By stimulating both CD8+ cytotoxic and CD4+ helper T cells, these vaccines enable highly selective tumor cell elimination while establishing durable immunological memory. Despite their promise, the rational development and clinical translation of neoantigen-based vaccines remain constrained by substantial challenges that limit their broad therapeutic impact. This review provides a comprehensive synthesis of the field, tracing the entire pipeline from the molecular origin and computational prediction of neoantigens to the design principles guiding vaccine formulation. It examines mechanisms of action across diverse platforms-including mRNA, peptide, and dendritic cell vaccines-and explores synergistic strategies that combine adjuvants or immune checkpoint blockade to enhance efficacy. In addition, we critically evaluate key barriers to success, such as immunosuppressive tumor microenvironments, T-cell dysfunction, and antigenic escape. Finally, we highlight recent clinical advances aimed at overcoming these barriers, thereby outlining a framework for optimizing neoantigen vaccine design to maximize their therapeutic potential in cancer treatment. Notably, encouraging progress has been reported in malignancies such as non-small cell lung cancer and melanoma, underscoring the translational promise of this strategy.
Bexsero (4CMenB) and Trumenba (MenB-fHbp) were designed and licensed to protect against meningococcal serogroup B disease, however, the antigens in these vaccines are shared among other meningococcal serogroups. This study assessed the immunogenicity of the two licensed serogroup B vaccines against a hyperinvasive serogroup X strain. Sera from adults immunised with either 4CMenB (before and after 1, 2 or 3 doses of vaccine) or MenB-fHbp (before and after 2 doses) were assayed in the Serum Bactericidal Antibody (SBA) assay against serogroup X BF 2/97. A four-fold increase in SBA titres were seen in 70.0% (95% CI: 45.7-88.1) and 51.5 % (95% CI: 41.3-61.6) of subjects following 2 doses of 4CMenB and MenB-fHbp, respectively. A significant increase in SBA GMT and percentage of subjects with SBA titres ≥4 from baseline to post two doses of both serogroup group B vaccines was observed. These data provide evidence that the licensed serogroup B vaccines can induce bactericidal antibodies against serogroup X, but it is noted the optimal control for serogroup X would be use of a conjugate vaccine that reduces acquisition of carriage as well as giving direct protection.
Cancer immunotherapies are a promising method for treating cancers and directly enhance the antitumor capabilities of a patient's immune system. In particular, therapeutic mRNA cancer vaccines are an attractive strategy as they offer a specificity and safety level that other immunotherapies are unable to achieve. Incorporation of tumor-specific or tumor-associated antigens in mRNA vaccines aims to enhance tumor antigen-specific T cells. mRNA vaccine adjuvants often encode immune stimulating proteins such as proinflammatory cytokines, costimulatory molecules, and pattern recognition receptors or their corresponding agonists. This review summarizes prominent clinical and preclinical therapies utilizing mRNA tumor-associated or tumor-specific antigens and mRNA encoding immunostimulants delivered either as vaccine adjuvants or as monotherapies for the treatment of cancer. The limitations, challenges, and future directions of therapeutic mRNA vaccines are also discussed.
Ferritins are vital macromolecules that have been widely used in a number of biotechnological fields. Ferritin-based hybrid nanoparticles, composed of different types of subunits and conjugates, represent a next generation of tools, which can significantly enhance their efficiency and expand the range of existing applications. This review outlines the application landscape of these hybrids in developing recombinant vaccines, drug delivery and imaging systems. We highlight the increasing trend towards the development of ferritin-based mosaic vaccines and some of them are already in the first or second phases of clinical studies. In comparison, drug delivery research, which is mostly focused on cancer theranostics, to our knowledge, has not progressed beyond the preclinical stage. Herein, we describe the key limitations and challenges of ferritin-based drug delivery systems development, suggest strategies that address these limitations and discuss promising future research directions. We conclude that engineered ferritin hybrids hold significant potential as useful tools for immunology, theranostics and other biomedical applications.
Protein-based mosaic-8 nanoparticles displaying eight SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) elicited broadly cross-reactive antibodies that could protect from zoonotic spillovers. Here, we extend the mosaic-8 concept to mRNA by encoding membrane-bound RBD quartets (four linked RBDs) as dual quartet RBD-mRNA and dual quartet RBD-EABR-mRNA, the latter leveraging ESCRT- and ALIX-binding region (EABR) technology for display on cell surfaces and secreted virus-like particles. Compared with protein-based mosaic-8, mRNA-encoded mosaic-8 induced equivalent or enhanced antibody breadth, neutralization potencies, and conserved epitope targeting, while eliciting enhanced T cell responses and more balanced IgG subclass profiles consistent with potentially superior Fc effector functions. Finally, systems serology-polyclonal epitope mapping (SySPEM) revealed distinct IgG-subclass-specific epitope signatures across mRNA, EABR-mRNA, and protein vaccines, demonstrating that the mode of antigen display can shape epitope recognition. Successful conversion of a multivalent protein vaccine to mRNA platforms informs the design of broadly protective vaccines and advances mosaic-8 toward clinical development.
Tuberculosis (TB) remains a major global health threat, underscoring the need for vaccines that surpass BCG efficacy. We developed QTAP-R, a novel mRNA-lipid nanoparticle (LNP) vaccine encoding Ag85B, Hsp70, and ESAT-6, to enhance immunity against Mycobacterium tuberculosis. QTAP efficiently encapsulated and delivered mRNA with high transfection efficiency and low cytotoxicity. In C57BL/6 mice, QTAP-R induced strong antigen-specific IgG and T-cell responses, including elevated CD4⁺ and CD8⁺ activation and increased polyfunctional cytokines (IFN-γ, TNF-α, IL-2, IL-17A). When combined with BCG (BCG + QTAP-R), the vaccine elicited enhanced immune memory, reduced bacterial burden in lungs and spleen, and minimized lung pathology following M. tuberculosis challenge. Subcutaneous QTAP-R (QTAP-SQ) provided partial protection under high-dose challenge, outperforming intranasal delivery. Transcriptomic profiling revealed upregulation of inflammatory cytokines (IL-1, IL-6, IL-12) and chemokines (CCL3, CCL4, CXCL9, CXCL10), indicating enhanced immune recruitment and activation. CD4⁺ T-cell depletion abolished protection, confirming their critical role in QTAP-R-mediated immunity. Overall, QTAP-R demonstrates potent immunogenicity and synergistic efficacy with BCG, positioning it as a promising mRNA-based TB vaccine candidate.
Vaccine preventable infections (VPIs) contribute substantially to morbidity and mortality in solid organ transplant (SOT) recipients. Recent outbreaks and declining herd immunity have brought attention to optimizing vaccination pre and posttransplant, as many patients remain incompletely immunized at the time of transplant. This review summarizes modern evidence and evolving recommendations regarding live vaccination in SOT candidates and recipients. Vaccination coverage at the time of transplant remains suboptimal, although targeted interventions have shown improvements in uptake. Accumulating data, largely from pediatric liver and kidney SOT cohorts, support the safety and immunogenicity of posttransplant measles, mumps, rubella (MMR) and varicella (VAR) vaccination under defined clinical and immunologic criteria. These findings have informed updated guidance and clinical practice for select pediatric SOT recipients, and multicenter experience with posttransplant live vaccination continues to expand. Growing evidence suggests that live vaccine administration may be feasible in carefully selected pediatric SOT recipients and may reduce susceptibility to VPIs. Important knowledge gaps remain, particularly for adult SOT recipients, nonliver transplant populations, and other live vaccines. Further research and prospective studies are needed to better define safety, immunogenicity, and optimal vaccination timing in these populations.
The substantial antigenic diversity of Influenza A virus (IAV) presents significant challenges to the development of broadly protective vaccines for swine. Moreover, pigs vaccinated with whole-inactivated virus or hemagglutinin (HA) subunit vaccines may experience more severe lung consolidation than non-vaccinated pigs when exposed to antigenically mismatched IAV strains, a phenomenon known as vaccine-associated enhanced respiratory disease (VAERD). We recently developed a lipid nanoparticle-encapsulated DNA (LNP-DNA) vaccine encoding the HA of IAV, which elicited robust immune responses following a single immunization and protected pigs against homologous IAV challenges. In this study, we compared the immunogenicity and protective efficacy between the HA protein-based vaccine and the HA DNA-based vaccine against an antigenically mismatched IAV strain in pigs. Neither vaccine induced cross-reactive hemagglutination inhibition (HI) antibodies nor prevented viral shedding in nasal secretions following heterologous challenge. However, while the HA protein-based vaccine exacerbated lung lesions compared to non-vaccinated controls, the HA DNA-based vaccine prevented the development of gross lung pathology. Transcriptomic analyses revealed distinct gene expression profiles between the two vaccine groups. These findings suggest that the LNP-DNA vaccine platform may offer a safer and more effective strategy for developing vaccines against IAV in swine.
Respiratory syncytial virus (RSV) remains a major cause of severe acute respiratory infections across the life course, particularly in infants, older adults, and immunocompromised individuals. For decades, clinical management relied almost exclusively on supportive care, while ribavirin, the only licensed antiviral, offered limited therapeutic benefit. The recent introduction of prefusion F (pre-F)-based vaccines and long-acting monoclonal antibodies has reshaped RSV prevention and represents the most significant advance since the discovery of the virus. Nevertheless, effective pharmacological treatment of established infection continues to be an unmet need, and the burden of RSV-associated hospitalizations and mortality persists worldwide. This review critically synthesizes current and emerging RSV therapeutic strategies from a pharmacological and translational perspective, integrating approved interventions with emerging antiviral pipelines. Licensed vaccines and monoclonal antibodies have demonstrated high efficacy in preventing lower respiratory tract disease; however, their impact is constrained by limited access and uptake, as well as the absence of complementary direct-acting antivirals (DAAs). Investigational agents targeting the fusion protein and the N/L replication complex have shown potent antiviral activity, but clinical trials have highlighted challenges related to the timing of administration, host immunity, and resistance selection. Advances in structural biology, air-liquid interface models, high-throughput screening, and artificial intelligence are accelerating the identification of new molecular targets and host-directed strategies. Overall, RSV control will require an integrated therapeutic framework in which vaccines and monoclonal antibodies prevent severe disease, while early-administered DAAs and resistance-aware combination strategies treat established infection and reduce breakthrough disease in high-risk populations.
Conventional adjuvants such as aluminum salts rarely drive robust Th1 immunity, which limits cancer vaccine efficacy. A double-stranded DNA-loaded manganese phosphate nanoadjuvant was generated by dsDNA-templated biomimetic mineralization. The resulting DNA@MnP exhibited favorable physiological stability and pH-responsive release properties: at pH 5.5, the cumulative release rates of Mn2+ and DNA reached 72% and 78%, respectively, within 12 h. Following cytosolic delivery, released Mn2+ from DNA@MnP could augment the cGAS recognition of dsDNA. The cooperative action of Mn2+ and dsDNA produced cascade amplification that potently activated the cGAS-STING pathway in dendritic cells. In vitro experiments demonstrated that DNA@MnP significantly promoted the maturation of BMDCs (with a maturation rate 2.10-fold elevation compared with the control group) and induced RAW264.7 macrophages to polarize toward the M1 phenotype (with an M1/M2 ratio 8.31-fold elevation compared with the control group). Animal experiments demonstrated that DNA@MnP not only significantly enhanced antigen-specific humoral immunity, achieving a 16-fold increase in IgG titers, and elicited a balanced Th1/Th2 response but also effectively activated both innate and adaptive antitumor immunity. Furthermore, this platform was extended to develop a personalized tumor vaccine by encapsulating tumor lysates (TLs) into TLs-loaded manganese phosphate nanovaccines (TLs@MnP). When coadministered with an anti-TIGIT antibody, it potently suppressed tumor growth, recurrence, and metastasis: in the postoperative recurrence model, 42.9% of mice in the TLs@MnP multidose combined with aTIGIT group achieved long-term tumor-free survival. Therefore, this study presented a manganese phosphate-based biomineralization strategy for the concise preparation of autologous tumor vaccines, opening a promising avenue for personalized immunotherapy and clinical translation.
Bovine brucellosis and bovine tuberculosis are chronic diseases that cause economic and animal health concerns in the global beef and dairy industries due to production losses. The etiologic agents of these diseases, Brucella abortus and Mycobacterium bovis, are intracellular, zoonotic bacterial pathogens that pose a risk to human health. Brucella abortus strain RB51 (RB51) and Bacillus Calmette-Guérin (BCG) are live attenuated vaccines for bovine brucellosis and tuberculosis, respectively, and are known to reduce incidence of these diseases in cattle. However, recent work has suggested that the genetic background of cattle may influence immune responses to these two vaccines. Control of brucellosis and tuberculosis depends on T helper 1 (Th1) mediated immune responses; however, both RB51 and BCG are intracellular bacteria that predominantly localize in monocytes and macrophages which are responsible for initiating immune responses to disease. This study investigates the difference in responses of Hereford and Holstein monocyte-enriched peripheral blood mononuclear cells infected in vitro with RB51, BCG, and combined RB51 + BCG. Transcriptomic data was collected to conduct a targeted evaluation of differentially expressed genes between cell conditions from Holsteins and Herefords related to innate immune responses against intracellular bacteria and the downstream generation of adaptive immune responses. Additionally, breed-specific differences in the production of pro-inflammatory, anti-inflammatory, and Th1-related cytokines by infected monocyte-enriched cells were evaluated. After 16 h of infection with RB51, BCG, or RB51 + BCG, monocyte-enriched cells from Holsteins displayed a transcriptomic profile consistent with enhanced pro-inflammatory and Th1-polarizing responses compared to infected cells from Herefords. Further, Holstein cells also produced significantly higher amounts of Th1-polarizing cytokine than Hereford cells after 72 h of intracellular infection. The breed-specific differences in cellular responses presented here following in vitro infection with RB51, BCG, and RB51 + BCG provide evidence that Hereford and Holstein cattle may develop variable immune responses in vivo to these two vaccines. Results of this study suggest that vaccine efficacy may be influenced by cattle host genetic background within the same species and thus warrants consideration when optimizing vaccination strategies.
Streptococcus suis (S. suis, SS), a significant zoonotic pathogen, causes large-scale swine epidemics and substantial economic losses. Based on capsule antigen differences, at least 29 serotypes have been identified. Given that existing commercial vaccines target only serotypes 2 or a few others, and lack immunoprotection against serotype 9, this study designed and developed a bivalent inactivated candidate vaccine to cover serotypes 2 and 9, evaluation of the protective efficacy of weaning piglets. The vaccinated piglets were in normal condition without adverse reactions and deaths, indicating that the vaccine was very safe. Experimental vaccine induced significantly higher levels of specific antibodies than the commercial vaccine. Further pathogenicity tests confirmed that the vaccine exhibited 100% immunoprotection efficacy against both Streptococcus suis serotype 2 and serotype 9 strains, and significantly reduced mortality and clinical severity of disease following infection with these two bacterial strains. According to a search of the public literature, this study provides evidence that the bivalent vaccine demonstrates no less than the efficacy of existing commercial vaccines, while exhibiting high safety and superior immunoprotection efficacy, offering a reliable technical solution for the prevention and control of co-infection with Streptococcus suis type 2 and type 9.
Licensed influenza vaccines primarily target the variable hemagglutinin protein and provide inadequate cross-protection against mismatched or drifted viral strains. One promising approach to enhance the breadth of protection is to target the viral neuraminidase by incorporating a stable, recombinant neuraminidase protein with an effective adjuvant. We evaluated an intramuscular recombinant neuraminidase vaccine (N1-MPP) adjuvanted with a lipidated toll-like receptor (TLR)7/8 agonist (INI-4001), a synthetic TLR4 agonist (INI-2002), or both (TRAC-478) delivered as aqueous, liposomal, or squalene oil-in-water emulsions in mice. TLR agonists offset the Th2 bias of squalene emulsions and boosted antibody responses. Combining ligands synergistically amplified CD4⁺ immunity-increasing polyfunctional cytokine-producing T cells in lungs and spleen-while promoting Th1 cytokine production and antibody class switching. Aqueous and emulsion TRAC-478 N1-MPP induced high titers of cross-reactive, functional antibodies that exhibited strong ADCC activity and conferred protection in passive-transfer experiments. TRAC-478 N1-MPP vaccination protected against both H5N1 clade 1 and clade 2.3.4.4b viruses and recent H1N1 isolates, supporting the further development of N1-MPP adjuvanted with TRAC-478 emulsion as a stand-alone vaccine or potentially as a supplement for current vaccination regimens to improve protection against both seasonal influenza virus and strains with pandemic potential.
No published study to date has reported on the association between preferred language and COVID-19 vaccine uptake during pregnancy, and even less is known about COVID-19 vaccine disparities during lactation. To assess COVID-19 vaccine uptake during pregnancy and lactation by language, English proficiency, and race/ethnicity. We conducted a retrospective cohort study using electronic health records (EHR) from four US healthcare systems. The study included patients receiving prenatal care who had a live birth between December 2020 September 2022 and no COVID-19 vaccinations before pregnancy (pregnancy analysis) or delivery (lactation analysis). Self-identified (i) preferred language, (ii) limited English proficiency, based on patient request for an interpreter, and (iii) race and ethnicity were identified from EHR. The primary outcome was receipt of the first dose of the COVID-19 vaccine during pregnancy for the pregnancy analysis, and between delivery and human milk feeding discontinuation, up to 180 days after delivery, for the lactation analysis. Adjusted rate ratios (aRR) and 95% confidence intervals (CI) for receipt of first COVID-19 vaccine dose during pregnancy or lactation were estimated separately. Among 10,332 individuals eligible for initial COVID-19 vaccine during pregnancy, groups with lower uptake during pregnancy included Ethiopian languages (aRR 0.60, 95% CI 0.43-0.83) and Somali (aRR 0.39, 95% CI 0.28-0.54) versus English language, limited versus no limited English proficiency (aRR 0.66, 95% CI 0.58-0.76), and non-Hispanic Black versus White (aRR 0.56, 95% CI 0.51-0.62). Among 9271 individuals, groups with lower uptake during lactation included Ethiopian languages (aRR 0.48, 95% CI 0.30-0.77) and Somali (aRR 0.60, 95% CI 0.46-0.80) versus English language, and non-Hispanic Black versus White (aRR 0.77, 95% CI 0.70-0.86). Temporal trends showed lower vaccine uptake for non-English preferred language and non-Hispanic Black groups during pregnancy and lactation, especially during the earlier months of vaccine roll-out. There were language and racial/ethnic disparities in initial perinatal COVID-19 vaccination. The findings highlight the need to address language-related and other barriers during the rollout of new vaccines.
Current treatment for atherosclerotic cardiovascular diseases (ASCVD) mainly focuses on the modification of systemic risk factors, such as hyperglycemia and hyperlipidemia. Despite significant efforts and expanse, achieving early and proper diagnosis of ASCVD to improve clinical outcomes remains challenging, and vascular-targeted therapies or genetic editing, while ideal, are still limited. The development of nanomedicine-based mRNA vaccines for SARS-CoV-2 has demonstrated the potential of nanotechnology to target previously inaccessible molecules. Precision therapies by nanomedicine targeting specific tissues/molecules hold potential for new treatment paradigms by precisely modulating disease-causing molecular pathways within diseased tissues, including dysfunctional vasculature. By leveraging insights into the pathogenic contributors of atherogenesis, researchers have optimized nanoplatforms' composition, synthesis strategies, and surface design to enhance therapeutic efficacy and enable early diagnosis. Herein, we present an updated overview of therapeutic and diagnostic strategies using nanomedicine for ASCVD, and explore future research directions and innovative approaches for nanomedicine-driven theranostics in cardiovascular care.
Human norovirus (HuNoV) is a leading global cause of acute viral gastroenteritis, placing a particularly high burden on pediatric and elderly populations. Despite significant progress in HuNoV vaccine development, including advanced clinical trials of virus-like particle (VLP)-based candidates, no vaccine has received regulatory approval to date. In this study, we developed a recombinant baculovirus-based vaccine, AcHERV-HuNoV, designed to express the human norovirus (HuNoV) VP1 protein. This vaccine utilizes the AcHERV platform, which consists of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) with the human endogenous retrovirus (HERV) envelope protein to enhance delivery efficiency. The AcHERV-HuNoV vaccine incorporates HERV-W-derived Syncytin-1 on the baculovirus envelope and the VP1 gene from either the GII.4 or GII.17 genotype to represent prevalent strains in Korea. This system enhances gene delivery to mammalian cells while preventing in vivo replication. Norovirus VLPs were produced and purified from insect cells to serve as control vaccines and comparative antigens. Immunogenicity was evaluated in BALB/c mice following intramuscular and intranasal administration of AcHERV-HuNoV. The vaccine induced robust immune responses, with serum IgG geometric mean titers (GMTs) reaching 14,132 (95% CI: 9080-21,979) and IgA levels of 262 (95% CI: 70-982) specific for GII.4 after final immunization, as well as potent surrogate neutralizing activity determined by the porcine gastric mucin (PGM)-blocking assay. Furthermore, it induced robust cellular immunity characterized by increased production of Th1, Th2, and Th17 cytokines. These results demonstrate the promising potential of AcHERV-HuNoV as a genetic vaccine candidate capable of inducing both humoral and cellular immune responses against HuNoV infection.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by dementia, confusion, irritability, a lack of cognition, and mood swings. Since its discovery in 1906, many small molecules have been designed to block disease progression by targeting the primary targets β-amyloid and tau proteins. Subsequent research focused on small-molecule inhibitors targeting secondary targets, such as β-secretases and γ-secretases. However, the clinically approved conventional therapies include acetylcholinesterase inhibitors and N-methyl-D-aspartate inhibitors that relieve only disease symptoms, and their efficacy remains limited. Recently, approved novel approaches, such as monoclonal antibodies and vaccines, aim to slow disease progression by targeting the molecular mechanisms underlying amyloid and tau proteins. In addition, these drugs have controversial side effects, which call into question their therapeutic efficacy. A newer strategy involving small peptides is gaining traction because of their lower toxicity, improved permeability, and target specificity. Various homogenous and heterogeneous peptidomimetic inhibitors have been designed to target traditional protein targets. Although various peptidomimetic inhibitors have demonstrated therapeutic efficacy, none have entered clinical trials. Upon conducting an extensive literature survey, we identified several regions, targets, and technologies that could be leveraged to ameliorate Alzheimer's disease progression. In this review, we address the progression of AD, its historical context, and the development of therapeutic approaches that target this disease. We focus on the evolution of subsequent therapies aimed at alleviating the disease and highlight recent developments in drug delivery and formulation techniques that enhance therapeutic efficacy and address the shortcomings of traditional treatments.
There is need for international tools to measure and monitor childhood immunisation programme uptake, validated specifically for local country context. Childhood vaccine coverage has declined in Aotearoa New Zealand (ANZ) since 2016, especially for Māori and Pacific Peoples. To adapt the Australian Vaccine Barriers Assessment Tool (VBAT) for ANZ context, to support improvement of vaccination coverage, particularly for Māori and Pacific Peoples children. The NZ VBAT was developed and validated in three stages: (1) Literature review and cognitive theory, refined through cognitive testing in ANZ. (2) Surveys assessing reliability of potential items and selection of items via expert consensus. (3) Surveys assessing predictive validity of future immunisation, with responses linked to vaccination records. Confirmatory Composite Analysis (CCA) assessed fit of the final preferred models. Stage 1 identified 80 items, refined to 45 through cognitive testing. In stage 2, 467 surveys assessed item reliability. In stage 3, 314 out of 492 (64%) carers/parents (82% Māori and Pacific Peoples) completed the final 35 item survey, with 176 responses linked to immunisation records. Logistic regression showed strong associations between access and acceptance barriers and vaccine uptake. The final 6-item short survey had five domains encompassing safety, access, effectiveness, intention and influence; whilst the 14 -item long survey incorporated two additional domains: social responsibility and relationship with provider. Both surveys outperformed the US Parent Attitudes Childhood Vaccines (PACV) Survey, explaining 13% and 14% of uptake variation compared to PACV's 10%. The NZ Vaccine Barriers Assessment tools (NZ VBAT) is a culturally appropriate tool to identify the social and behavioural drivers of suboptimal vaccination in children <5 years in NZ. It will support development of targeted interventions to achieve optimal immunisation coverage and reduce equity gaps.