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.
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.
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.
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.
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.
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.
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.
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.
The world's most prevalent malignancy, skin cancer, is a major public health problem due to its high mortality, morbidity, and rising incidence. There are still limitations, such as off-target toxicity, risk of recurrence, and resistance to therapy, particularly in advanced disease, even with the progress in early detection and conventional therapies such as surgery, radiation, and chemotherapy. Employing the immune system of the body to generate targeted anti-tumor responses, immunotherapy is a game-changing strategy. Its broader success is, however, limited by clinical challenges, including immune evasion, low response rates, and adverse immune-related side effects. The application of nanotechnology to immunotherapy and theranostics is discussed in this chapter and presents a synergistic approach to refining the precision, efficacy, and individualization of skin cancer therapy. Real-time image-guided therapy, better local concentration, reduced systemic toxicity, and enhanced immunotherapeutic delivery are all facilitated through nanomaterials, ranging from liposomes and polymeric nanoparticles to metallic and carbon-based platforms. Molecular pathophysiology of the two most common types of skin cancer, melanoma and non-melanoma and most current immunotherapeutic strategies, clinical outcomes, and associated toxicities are discussed in this chapter. The applications of nanotechnology in theranostics for concurrent therapy and diagnosis, targeted delivery of checkpoint inhibitors, cancer vaccines, and adoptive cell therapy are highlighted with specific emphasis. Combinatorial nanoplatforms and bionanomaterials that can be programmed have the possibility to bypass tumor resistance and offer truly personalized treatment. The chapter concludes with consideration of the present clinical applications, challenges, and possible future directions of theranostics and nanotechnology-enabled immunotherapy for skin cancer.
Tuberculosis continues to kill over a million people every year, with an additional 10 million people falling ill. The ongoing efforts to eradicate the disease are hampered by an incomplete understanding of the mechanisms involved in the defense against tuberculosis. It has become clear that next to the well-known T-cell responses other components of the immune system also play important roles, both protective and detrimental, in the host defense against tuberculosis. In particular, the role of antibodies and complement are increasingly appreciated. However, the contribution of the complement system during Mycobacterium tuberculosis infection and disease remains poorly understood. The complement system is an intricate network of plasma proteins, which upon activation can achieve a powerful cytotoxic effect. Additionally, a range of antimicrobial and immune-modulating effector molecules, such as opsonins and chemoattractants, are generated. As a consequence, the role of the complement system in host defense extends beyond its cytotoxic effect, influencing both the innate and adaptive immune response. In this review, we discuss the many-faceted role of the complement system in tuberculosis, reviewing its involvement in infection, disease progression, and response to therapy, and provide a perspective on how the complement system can be harnessed to improve tuberculosis diagnostics, vaccines and therapeutics.
HLA molecules play a crucial role in immune reactivity, influencing autoimmune diseases, transplantation immunology, susceptibility to infectious diseases, drug hypersensitivity, and personalized medicine. Here, we highlight the transformative impact of HLA research on transplantation immunology, personalized medicine, and immunotherapeutic development by summarizing fundemental concepts, challenges in HLA-based interventions, and recent technological innovations and future directions. HLA research has significant theoretical and practical implications to characterize the immune response and transplant compatibility. Although the HLA system is seen as a barrier to transplantation, in the era of precision medicine, HLA has become the master key to unlocking personalized immunotherapy, predicting drug toxicities, and engineering the next generation of cancer vaccines.
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.
Tetanus, diphtheria, and acellular pertussis (Tdap) vaccination in pregnancy is recommended to provide passive immunity to newborns. Few studies have assessed how pregnancy modifies vaccinated individuals' immune response to Tdap vaccination, with most focused on short-term responses (i.e., within 1 month). Here, we assessed anti-pertussis toxin (PT) immunoglobulin G (IgG) levels 9-15 months following Tdap vaccination in pregnant and non-pregnant active duty service members (ADSMs). This observational cohort study included 240 ADSMs pregnant at Tdap vaccination, 1:1 matched with 240 non-pregnant ADSMs on age, time between vaccine and serum collection, and receipt of other same-day vaccines (2011-2016). Serum samples (0-6 weeks before and 9-15 months after vaccination) were obtained from the Department of Defense Serum Repository. Anti-PT IgG levels were assessed using geometric mean concentrations (GMCs), and associations between pregnancy status at vaccination and anti-PT IgG levels were estimated through multivariable linear regression models. Pregnant vs. non-pregnant ADSMs had higher anti-PT IgG GMCs in both pre- (9.01 vs. 5.81, P < .01) and post-vaccine (27.71 vs. 22.33, P = .02) serums. Post-vaccine multivariable models adjusting for pre-vaccine levels were not significantly different between pregnant vs. non-pregnant ADSMs (b = -0.05, P = .42). Associations were modified by time since prior Tdap booster, and statistically different for pregnant individuals who received a booster <2 years prior (b = -0.22, P = .02). Tdap vaccination in pregnancy yielded a similar long-term anti-PT IgG response to vaccination outside of pregnancy; findings substantiate the current recommended vaccine schedule.