Vaccines最新文献

Toll-like receptor 2 (TLR2) signaling is a pivotal component of immune system activation, and it is closely linked to the lipidation of bacterial proteins. This lipidation is guided by bacterial signal peptides (SPs), which ensure the precise targeting and membrane anchoring of these proteins. The lipidation process is essential for TLR2 recognition and the activation of robust immune responses, positioning lipidated bacterial proteins as potent immunomodulators and adjuvants for vaccines against bacterial-, viral-, and cancer-related antigens. The structural diversity and cleavage pathways of bacterial SPs are critical in determining lipidation efficiency and protein localization, influencing their immunogenic potential. Recent advances in bioinformatics have significantly improved the prediction of SP structures and cleavage sites, facilitating the rational design of recombinant lipoproteins optimized for immune activation. Moreover, the use of SP-containing lipobox motifs, as adjuvants to lipidate heterologous proteins, has expanded the potential of vaccines targeting a broad range of pathogens. However, challenges persist in expressing lipidated proteins, particularly within heterologous systems. These challenges can be addressed by optimizing expression systems, such as engineering E. coli strains for enhanced lipidation. Thus, lipoprotein signal peptides (SPs) demonstrate remarkable versatility as adjuvants in vaccine development, diagnostics, and immune therapeutics, highlighting their essential role in advancing immune-based strategies to combat diverse pathogens.

Background/Objectives: The respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in children and adults. With nearly everyone infected by the age of five, there is an opportunity to develop booster vaccines that enhance B-cell immunity, promoting potent and broadly neutralizing antibodies. One potential approach involves using anti-idiotypic antibodies (anti-IDs) to mimic specific antigenic sites and enhance preexisting immunity in an epitope-specific manner. RB1, a monoclonal antibody (mAb) that binds to site IV of the RSV fusion (RSV F) protein, is a potent and broadly neutralizing against RSV A and B viruses. It is the precursor for MK1654 (clesrovimab), which successfully completed a Phase III clinical trial. Methods: In this study, we isolated two anti-IDs, 1A6 and 1D4, targeting RB1 CDR regions, demonstrating that 1A6 competes fully with RSV F in binding to RB1. Results: We resolved the RB1-1A6 and RB1-1D4 Fab-Fab complex structures and proved that 1A6 mimics the RSV F site IV better than 1D4. In an immunogenicity study, mice primed with RSV F and boosted with 1A6 Fab showed a site IV-specific antibody response with a concurrent increase in RSV virus neutralization. Conclusions: These results suggest that anti-IDs could be potentially used as booster vaccines for specific epitopes.

Adjuvants are a diverse group of substances that can be added to vaccines to enhance antigen-specific immune responses and improve vaccine efficacy. The first adjuvants, discovered almost a century ago, were soluble crystals of aluminium salts. Over the following decades, oil emulsions, vesicles, oligodeoxynucleotides, viral capsids, and other complex organic structures have been shown to have adjuvant potential. However, the detailed mechanisms of how adjuvants enhance immune responses remain poorly understood and may be a barrier that reduces the rational selection of vaccine components. Previous studies on mechanisms of action of adjuvants have focused on how they activate innate immune responses, including the regulation of cell recruitment and activation, cytokine/chemokine production, and the regulation of some "immune" genes. This approach provides a narrow perspective on the complex events involved in how adjuvants modulate antigen-specific immune responses. A comprehensive and efficient way to investigate the molecular mechanism of action for adjuvants is to utilize systems biology approaches such as transcriptomics in so-called "systems vaccinology" analysis. While other molecular biology methods can verify if one or few genes are differentially regulated in response to vaccination, systems vaccinology provides a more comprehensive picture by simultaneously identifying the hundreds or thousands of genes that interact with complex networks in response to a vaccine. Transcriptomics tools such as RNA sequencing (RNA-Seq) allow us to simultaneously quantify the expression of practically all expressed genes, making it possible to make inferences that are only possible when considering the system as a whole. Here, we review some of the challenges in adjuvant studies, such as predicting adjuvant activity and toxicity when administered alone or in combination with antigens, or classifying adjuvants in groups with similar properties, while underscoring the significance of transcriptomics in systems vaccinology approaches to propel vaccine development forward.

Background: Noroviruses, which cause epidemic acute gastroenteritis, and Plasmodium parasites, which lead to malaria, are two infectious pathogens that pose threats to public health. The protruding (P) domain of norovirus VP1 and the αTSR domain of the circumsporozoite protein (CSP) of Plasmodium sporozoite are the glycan receptor-binding domains of the two pathogens for host cell attachment, making them excellent targets for vaccine development. Modified norovirus P domains self-assemble into a 24-meric octahedral P nanoparticle (P₂₄ NP).

Methods: We generated a unique P₂₄-αTSR NP by inserting the αTSR domain into a surface loop of the P domain. The P-αTSR fusion proteins were produced in the Escherichia coli expression system and the fusion protein self-assembled into the P₂₄-αTSR NP.

Results: The formation of the P₂₄-αTSR NP was demonstrated through gel filtration, electron microscopy, and dynamic light scattering. A 3D structural model of the P₂₄-αTSR NP was constructed, using the known cryo-EM structure of the previously developed P₂₄ NP and P₂₄-VP8* NP as templates. Each P₂₄-αTSR NP consists of a P₂₄ NP core, with 24 surface-exposed αTSR domains that have retained their general conformations and binding function to heparan sulfate proteoglycans. The P₂₄-αTSR NP is immunogenic, eliciting strong antibody responses in mice toward both the norovirus P domain and the αTSR domain of Plasmodium CSP. Notably, sera from mice immunized with the P₂₄-αTSR NP bound strongly to Plasmodium sporozoites and blocked norovirus VLP attachment to their glycan receptors.

Conclusion: These data suggest that the P₂₄-αTSR NP may serve as a combination vaccine against both norovirus and Plasmodium parasites.

In the following Special Issue of Vaccines, entitled "Acceptance and Hesitancy in Vaccine Uptake," seventeen diverse papers examine the critical role of vaccination in health promotion and disease prevention [...].

Background: Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis in adults. The schedule for HEV 239, the only approved anti-HEV vaccine, consists of three doses at 0, 1, and 6 months, which is unsuitable for use in emergency and outbreak situations where quick protection is desired. We, therefore, undertook a systematic review of data on immunogenicity, efficacy, and effectiveness of alternative accelerated schedules. Methods: Data sources on immunogenicity, efficacy, and effectiveness of the HEV 239 vaccine following accelerated schedules published between 22 January 2005 and February 2024 were identified from five electronic databases, and the relevant data were extracted. Results: The search identified seven relevant reports, including one phase II pre-licensure trial, three reports from the phase III licensure trial, and three post-licensure reports. In these studies, following administration of the HEV 239 vaccine in two doses at 0 and 1 month or a three-dose rapid (0, 7, and 21 days) schedule, anti-HEV antibody seroconversion rates were similar to and geometric mean concentrations of anti-HEV antibody were only slightly lower than those following the standard three-dose schedule. In individuals who were seropositive for anti-HEV antibodies at baseline, the antibody response persisted for several years irrespective of the number of vaccine doses, and in those who were seronegative at baseline, administration of two vaccine doses induced antibodies whose level remained substantially high till at least 13 months of follow-up. Administration of two doses was also associated with a high protective efficacy against HEV infection and associated disease. Conclusions: The available data indicate that two doses of HEV 239 administered one month apart confer sufficiently high antibody titers and protection for at least 13 months, a duration which should be adequate for its use as an outbreak control measure.

The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is in its sixth year and is being maintained by the inability of current spike-alone-based COVID-19 vaccines to prevent transmission leading to the continuous emergence of variants and sub-variants of concern (VOCs). This underscores the critical need for next-generation broad-spectrum pan-Coronavirus vaccines (pan-CoV vaccine) to break this cycle and end the pandemic. The development of a pan-CoV vaccine offering protection against a wide array of VOCs requires two key elements: (1) identifying protective antigens that are highly conserved between passed, current, and future VOCs; and (2) developing a safe and efficient antigen delivery system for induction of broad-based and long-lasting B- and T-cell immunity. This review will (1) present the current state of antigen delivery platforms involving a multifaceted approach, including bioinformatics, molecular and structural biology, immunology, and advanced computational methods; (2) discuss the challenges facing the development of safe and effective antigen delivery platforms; and (3) highlight the potential of nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP) as the platform that is well suited to the needs of a next-generation pan-CoV vaccine, such as the ability to induce broad-based immunity and amenable to large-scale manufacturing to safely provide durable protective immunity against current and future Coronavirus threats.

Background: Respiratory syncytial virus (RSV) infections usually cause mild, cold-like symptoms in most people, but are a leading infectious disease causing infant death and hospitalization and can result in increased morbidity and mortality in older adults and at-risk individuals. Pfizer has developed Abrysvo^®, an unadjuvanted bivalent recombinant protein subunit vaccine containing prefusion-stabilized fusion (F) proteins representing RSV A and RSV B subgroups (RSVpreF). It is the only RSV vaccine approved for both maternal immunization to protect infants and active immunization of older adults (≥60 years) and 18-59-year-old individuals with high-risk conditions for prevention of RSV disease. Methods: Nonclinical safety studies, including a repeat-dose toxicity (RDT) study in rats and a combined developmental and reproductive toxicity (DART) study in rabbits, were conducted to support early clinical development. Study designs and parameters evaluated in these studies were consistent with principles and practices as outlined in relevant regulatory guidelines. RSVpreF bivalent vaccine, with or without Al(OH)₃, was administered intramuscularly (IM) at 2× the human dose to animals in both studies. Results: Locally tolerated, reversible, inflammatory responses at the injection sites and the draining lymph nodes were observed as typical findings following vaccination. No effect of RSVpreF, with or without Al(OH)₃, was observed on female fertility or on embryo-fetal or postnatal survival, growth, or development in the DART study. In both studies, robust immune responses to both RSV A and B antigens were observed, especially with the Al(OH)₃ formulation. Conclusions: RSVpreF was well-tolerated both locally and systemically without any adverse effects on reproductive and developmental endpoints.

Background: Available assays to measure pox virus neutralizing antibody titers are laborious and take up to 5 days. In addition, assays to measure T cell responses require the use of specific antigens, which may not be the same for all pox viruses. This study reports the development of robust assays for the measurement of mpox-specific neutralizing antibodies and IFN-γ-producing T-cell responses.

Methods: Fourteen samples from 7 volunteers who received Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) were used. The focused reduction neutralization test (FRNT) was performed using the mpox-specific A29 monoclonal antibody. Optimization and further development of FRNT were conducted using the plaque reduction neutralization test (PRNT) as the gold standard. The mpox-specific IFN-γ ELISPOT assay was optimized using different mpox antigen preparations. Results with pre-vaccination samples were compared with post-vaccination samples using the Wilcoxon matched-pairs test.

Results: Pre-vaccination and post-vaccination sera (n = 7) had FRNT50 (i.e., titers that inhibited at least 50% of the virus) of 109.1 ± 161.8 and 303.7 ± 402.8 (mean ± SD), respectively. Regression analysis of fold changes in FRNT50 and PRNT50 showed that the two assays closely agree (n = 25 tests on paired samples, R² of 0.787). Using UV-inactivated mpox as an antigen, the number of IFN-γ spot-forming T cells (SFC) in pre-vaccination samples (16.13 ± 15.86, mean ± SD) was significantly lower than SFC in post-vaccination samples (172.9 ± 313.3, mean ± SD) with p = 0.0078.

Conclusions: Our newly developed microneutralization test has a good correlation with PRNT. UV-inactivated mpox is an appropriate antigen for the ELISPOT assay that measures mpox cross-reactive T cells. These assays will be useful in future mpox vaccine studies.

Background: The recent resurgence of mpox in central Africa has been declared a new public health emergency of international concern (PHEIC) requiring coordinated international responses. Vaccination is a priority to expand protection and enhance control strategies, but the vaccine's need exceeds the currently available doses. Intradermal (ID) administration of one-fifth of the standard modified vaccinia Ankara (MVA-BN) dose was temporarily authorized during the 2022 PHEIC. Studies conducted before 2022 provided evidence about the humoral response against the vaccinia virus (VACV) after vaccination but not against the mpox virus (MPXV). Moreover, no data are available on the T-cell response elicited by MVA-BN administered subcutaneously or intradermally.

Methods: We compare the two vaccine administration routes according to reactogenicity (n = 943) and immunogenicity (n = 225) of vaccine recipients attending INMI Spallanzani hospital during the 2022 vaccination campaign in Rome, Italy.

Results: We found that the ID route elicited higher titers of MPXV-specific IgG (mean difference of 0.26 log₂, p = 0.05) and nAbs (0.24 log₂, p = 0.08) than the subcutaneous (SC) route one month after the complete vaccination cycle. At the same time, no evidence for a difference in cellular response was found.

Conclusions: MVA-BN was globally well tolerated despite higher reactogenicity for the ID than the SC route, especially for the reactions at the local injection site. The ID dose-sparing strategy was proven safe and immunogenic and would make vaccination available to more people. Our data support the current WHO recommendation of using the ID route in low-medium-income countries (LMIC), although response data in people infected with the new 1b clade are urgently needed.