Vaccine Research Articles

The immune response to Covid-19 mRNA vaccination among Lymphoma patients receiving anti-CD20 treatment.

The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine "take" in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients.

A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8+ T cell and antiviral responses.

In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires new and highly functional CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that enhances, broadens, and prolongs CD8+ T cell responses. We developed a therapeutic HBV vaccine based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, that targets conserved and highly immunogenic regions of the viral polymerase (pol) and core antigens fused into HSV gD. The vaccine was tested with, and without gD, in mice for immunogenicity and in an adeno-associated virus (AAV)8-1.3HBV vector model for antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular (i.m.) injection of AdC6-gDHBV2 achieved significant and sustained declines of circulating HBV DNA copies (cps) and HBV surface antigen (HBsAg); both inversely correlated with HBV specific CD8+ T cell frequencies in spleens and livers. AdC6-gDHBV2 is the first therapeutic vaccine to show significant reductions in levels of HBV genome copies and HBsAg when used alone, even when vaccination was delayed for months from infection.

Mitochondrial rewiring with small-molecule drug-free nanoassemblies unleashes anticancer immunity

The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.

The descriptive epidemiology of adverse events following two doses of mRNA COVID-19 vaccination in Curaçao, the Caribbean

Background BNT162b2 and mRNA-1273 COVID-19 vaccines have been used for mass vaccinations in Curaçao, the Caribbean but information on adverse events (AEs)in this population is unavailable. This study describes the characteristics of vaccinees that incurred AEs, explores the associations between AEs by vaccine and doses, and estimates the rate of AEs. Methods Vaccination and AEs data for all persons of age 5 years (range 5–105 years) and older who received two doses of COVID-19 vaccine at 71 centres in Curaçao between February 24, 2021, and April 5, 2023, were included in this retrospective observational study. Results The vaccines differed significantly in the frequency distribution of vaccinees by age, age groups, sex, AEs, and prior COVID-19 infection. Occurrence of AEs was strongly associated with mRNA vaccine brand, sex, number of doses, but not with age, age group, and prior COVID-19 infection. Of 209,720 doses, 84 persons (0.04%) incurred AEs following two doses of mRNA vaccines (overall rate of 40.1 per 100,000 persons (95% CI 32.4–49.6). AEs were also significantly higher in females compared to males.AE rates associated with BNT162b2, and mRNA-1273 vaccines were low, but BNT162b2 vaccinees incurred substantially significantly higher AE rates (58.3 per 100,000 persons, 95% CI 45.4–74.9) than mRNA-1273 vaccinees (21.9 per 100,000 persons, 95% CI 14.6–32.8). mRNA-1273 vaccine was associated with a significantly lower risk of AEs. Conclusions AE reporting varied by age, sex, and vaccine used as well as the number of doses. Future studies with follow-up and longer-term reporting of AEs should be conducted.

Influenza B Virus Vaccine Innovation through Computational Design.

As respiratory pathogens, influenza B viruses (IBVs) cause a significant socioeconomic burden each year. Vaccine and antiviral development for influenza viruses has historically viewed IBVs as a secondary concern to influenza A viruses (IAVs) due to their lack of animal reservoirs compared to IAVs. However, prior to the global spread of SARS-CoV-2, the seasonal epidemics caused by IBVs were becoming less predictable and inducing more severe disease, especially in high-risk populations. Globally, researchers have begun to recognize the need for improved prevention strategies for IBVs as a primary concern. This review discusses what is known about IBV evolutionary patterns and the effect of the spread of SARS-CoV-2 on these patterns. We also analyze recent advancements in the development of novel vaccines tested against IBVs, highlighting the promise of computational vaccine design strategies when used to target both IBVs and IAVs and explain why these novel strategies can be employed to improve the effectiveness of IBV vaccines.

Therapeutic Vaccination Strategies for Breast Cancer

AbstractEven though the impact of the immune system on the clinical course of cancer has been known for decades, its role in the treatment of various tumor entities has often been given little consideration. In recent years, the treatment landscape for breast cancer has undergone significant changes. Routine treatment has been revolutionized, in particular, by the use of T cell-based immunotherapies in the form of immune checkpoint inhibitors (ICIs). While this underscores the importance of the immune system in the treatment of breast cancer, other T cell-based immunotherapies, such as therapeutic vaccines, do still not play a significant role in clinical practice. In recent years, numerous studies on various vaccine candidates have been conducted, some of which have demonstrated a successful induction of an immune response. The selection of antigens and routes of administration/adjuvants capable of inducing long-lasting and clinically effective T cell responses remains a key challenge. The combination of ICIs with therapeutic vaccines could also hold promise for the future, by enhancing the specificity of the T cell response and thus augmenting the anti-tumor effect.

A Review On Human Brucellosis: An Important Occupational Hazard

Human brucellosis is a re-emerging and neglected zoonotic disease caused by Brucella spp., with Brucella melitensis being the principal cause worldwide. Despite the disease's prevalence, serological surveillance is not routinely practiced, even in countries where Brucella is endemic. Although eradication efforts have been successful in many developed and developing countries, brucellosis continues to pose a significant health risk to both animals and humans. Transmission to humans occurs by direct or indirect contact with infected animals or their products. Veterinary professionals, especially those conducting per-vaginal examinations without proper protective gear, and animal handlers are particularly vulnerable to infection. The pathogenesis of brucellosis is complex, involving bacterial invasion of host cells, immune evasion, and the potential for chronic infection. In humans, brucellosis often becomes chronic, but in acute cases, it presents as undulant fever with nonspecific symptoms. To reduce morbidity and mortality, early diagnosis and timely antibiotic treatment are most important. For diagnosis of Brucella spp. reliable, rapid, sensitive, specific, easy-to-perform, and automated detection systems are urgently required. Currently, there is no safe and effective vaccine available for humans. Prevention relies on controlling the disease in domestic livestock, primarily through mass vaccination, effective heat treatment of dairy products, and hygienic precautions to minimize occupational exposure. Treatment requires prolonged antibiotic therapy with a combination of drugs. To control human brucellosis, awareness programs, safe livestock practices, and timely diagnosis are essential

A multi-epitope self-amplifying mRNA SARS-CoV-2 vaccine design using a reverse vaccinology approach

Background and purpose: Massive vaccine distribution is a crucial step to prevent the spread of SARS-CoV2 as the causative agent of COVID-19. This research aimed to design the multi-epitope self-amplifying mRNA (saRNA) vaccine from the spike and nucleocapsid proteins of SARS-CoV2. Experimental approach: Commonly distributed constructions class I and II alleles of the Indonesian population were used to determine peptide sequences that trigger this population’s high specificity T-cell response. The best vaccine candidate was selected through the analysis of tertiary structure validation and molecular docking of each candidate with TLR-4, TLR-8, HLA-A*24:02, and HLA-DRB1*04:05. The selected multi-epitope vaccine combined with the gene encoding the replication machinery that allows the RNA amplification in the host cell. Findings/Results: Seven B-cell and four T-cell epitopes from the protein target were highly antigenic and conserved, non-allergen, non-toxic, and hydrophilic. Tertiary structure validation then determined the best multi-epitope construction with 269 AA in length containing hBD-2 adjuvant and PADRE. Most residues are predicted to be accessible by solvent and show high population coverage (99,26%). Molecular docking analysis demonstrated a stable and strong binding affinity with immune receptors. A recombinant plasmid as the template for mRNA production was constructed by inserting the multi-epitope DNA and non-structural polyprotein 1-4 gene of VEEV, which encodes the RNA replication complex to the cloning site of pcDNA3.1(+). Conclusion and implication: In silico, design of self-amplifying mRNA could be a potential COVID-19 vaccine candidate since its ability to be amplified in the host cell can efficiently reduce the intake doses.

A Novel Natural Graph for Efficient Clustering of Virus Genome Sequences

Background: This study addresses the need for analyzing viral genome sequences and understanding their genetic relationships. The focus is on introducing a novel natural graph approach as a solution. Objective: The objective of this study is to demonstrate the effectiveness and advantages of the proposed natural graph approach in clustering viral genome sequences into distinct clades, subtypes, or districts. Additionally, the aim is to explore its interpretability, potential applications, and implications for pandemic control and public health interventions. Methods: The study utilizes the proposed natural graph algorithm to cluster viral genome sequences. The results are compared with existing methods and multidimensional scaling to evaluate the performance and effectiveness of the approach. Results: The natural graph approach successfully clusters viral genome sequences, providing valuable insights into viral evolution and transmission dynamics. The ability to generate directed connections between nodes enhances the interpretability of the results, facilitating the investigation of transmission pathways and viral fitness. Conclusion: The findings highlight the potential applications of the natural graph algorithm in pandemic control, transmission tracing, and vaccine design. Future research directions may involve scaling up the analysis to larger datasets and incorporating additional genetic features for improved resolution. : The natural graph approach presents a promising tool for viral genomics research with implications for public health interventions.

Glycan-specific IgM is critical for human immunity to Staphylococcus aureus

Staphylococcus aureus is a major human pathogen, yet the immune factors that protect against infection remain elusive. High titers of opsonic IgG antibodies, achieved in preclinical animal immunization studies, have consistently failed to provide protection in humans. Here, we investigate antibody responses to the conserved S.aureus surface glycan wall teichoic acid (WTA) and detect the presence of WTA-specific IgM and IgG antibodies in the plasma of healthy individuals. Functionally, WTA-specific IgM outperforms IgG in opsonophagocytic killing of S.aureus and protects against disseminated S.aureus bacteremia through passive immunization. In a clinical setting, patients with S.aureus bacteremia have significantly lower WTA-specific IgM but similar IgG levels compared to healthy controls. Importantly, low WTA-IgM levels correlate with disease mortality and impaired bacterial opsonization. Our findings may guide risk stratification of hospitalized patients and inform future design of antibody-based therapies and vaccines against serious S.aureus infection.

The rational design of mRNA vaccine: From empirical method to artificial intelligence-based design

The rational design of mRNA vaccine: From empirical method to artificial intelligence-based design

In silico design of Mycobacterium tuberculosis multi-epitope adhesin protein vaccines

Mycobacterium tuberculosis (Mtb) adhesin proteins are promising candidates for subunit vaccine design. Multi-epitope Mtb vaccine and diagnostic candidates were designed using immunoinformatic tools. The antigenic potential of 26 adhesin proteins were determined using VaxiJen 2.0. The truncated heat shock protein 70 (tnHSP70), 19 kDa antigen lipoprotein (lpqH), Mtb curli pili (MTP), and Phosphate transport protein S1 (PstS1) were selected based on the number of known epitopes on the Immune Epitope Database (IEDB). B- and T-cell epitopes were identified using BepiPred2.0, ABCpred, SVMTriP, and IEDB, respectively. Population coverage was analysed using prominent South African specific alleles on the IEDB. The allergenicity, physicochemical characteristics and tertiary structure of the tri-fusion proteins were determined. The in silico immune simulation was performed using C-ImmSim. Three truncated sequences, with predicted B and T cell epitopes, and without allergenicity or signal peptides were linked by three glycine-serine residues, resulting in the stable, hydrophilic molecules, tnlpqH-tnPstS1-tnHSP70 (64,86 kDa) and tnMTP-tnPstS1-tnHSP70 (63,96 kDa). Restriction endonuclease recognition sequences incorporated at the N- and C-terminal ends of each construct, facilitated virtual cloning using Snapgene, into pGEX6P-1, resulting in novel, highly immunogenic vaccine candidates (0,912–0,985). Future studies will involve the cloning, recombinant protein expression and purification of these constructs for downstream applications.

Dendritic Cell-Hitchhiking In Vivo for Vaccine Delivery to Lymph Nodes.

Therapeutic cancer vaccines are among the first FDA-approved cancer immunotherapies. Among them, it remains a major challenge to achieve robust lymph-node (LN) accumulation. However, delivering cargo into LN is difficult owing to the unique structure of the lymphatics, and clinical responses have been largely disappointing. Herein, inspired by the Migrated-DCs homing from the periphery to the LNs, an injectable hydrogel-based polypeptide vaccine system is described for enhancing immunostimulatory efficacy, which could form a local niche of vaccine "hitchhiking" on DCs. The OVA peptide modified by lipophilic DSPE domains in the hydrogel is spontaneously inserted into the cell membrane to achieve "antigen anchoring" on DCs in vivo. Overall, OVA peptide achieves active access LNs through recruiting and "hitchhiking" subcutaneous Migrated-DCs. Remarkably, it is demonstrated that the composite hydrogel enhances LNs targeting efficacy by approximately six-fold compared to free OVA peptide. Then, OVA peptide can be removed from the cell surface under a typical acidic microenvironment within the LNs, further share them with LN-resident APCs via the "One-to-Many" strategy (One Migrated-DC corresponding to Many LN-resident APCs), thereby activating powerful immune stimulation. Moreover, the hydrogel vaccine exhibits significant tumor growth inhibition in melanoma and inhibits pulmonary metastatic nodule formation.

999MO HARE-40: A phase I/II trial of therapeutic HPV vaccine (BNT113) in patients with HPV16 driven carcinoma

999MO HARE-40: A phase I/II trial of therapeutic HPV vaccine (BNT113) in patients with HPV16 driven carcinoma

1397TiP Phase III trial of the therapeutic cancer vaccine OSE2101 versus docetaxel in patients with metastatic non-small cell lung cancer and secondary resistance to immunotherapy

1397TiP Phase III trial of the therapeutic cancer vaccine OSE2101 versus docetaxel in patients with metastatic non-small cell lung cancer and secondary resistance to immunotherapy

22P Pre-clinical development of CVGBM: A therapeutic mRNA-based multiepitope vaccine for glioblastoma

22P Pre-clinical development of CVGBM: A therapeutic mRNA-based multiepitope vaccine for glioblastoma

879P VERSATILE-002: Survival with first-line treatment with PDS0101 therapeutic vaccine and pembrolizumab in HPV16-positive recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)

879P VERSATILE-002: Survival with first-line treatment with PDS0101 therapeutic vaccine and pembrolizumab in HPV16-positive recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)

The impact of coronavirus pandemic shutdowns on immunization completion in Hadeetha, Anbar, Iraq: A case-study of vaccine completion in a recovering healthcare system

The SARS-COV2 pandemic caused significant disruptions in immunization delivery. Baseline deficit gaps in immunization completion exacerbated ongoing disparities in immunization coverage in low- and middle-income. Emerging reports focused on global strategies for return to routine immunization schedules. Currently, there are no studies that examined the dual challenge of returning to normal immunization in a conflict-recovery setting, such as the ISIS (Islamic State of Iraq and Syria) occupation of Iraq post-COVID-19 pandemic.The objective of this study was to estimate the number of children in Hadeetha, Iraq from 12 to 24 months of age who continued to be lost to the routine immunization schedule due to the COVID-19 pandemic shutdowns. Random sampling occurred from a compiled district health facility registrar of all children in the target birth cohort who had a 12-month immunization scheduled during the 2020 lockdown and were lost to the immunization schedule. A total of 171 households from the sampling frame were included in the final sample. In this cross-sectional study, survey data was collected on the head of the household, the caregiver and the child. Additional questions assessed vaccine hesitancy, vaccine information trusted sources and COVID-19 impact on healthcare access. A risk factor analysis was applied to assess using Chi-square (Χ2) for predictors of lack of DTP3 (Diphtheria, Tetanus and Polio) third dose completion. Of children in the study, 67.3 % did not complete the 6-antigen series at 12-months of age and 46.2 % were missing DTP3 for vaccines to be completed during the pandemic shutdown. Specific risk factors for lack of immunization for the DTP3 vaccine included area of residence, age and caregiver knowledge of vaccines. Respondents indicated a dependence on mass vaccination campaigns but also indicated a willingness to receive phone reminders and television campaigns about vaccination schedules.

Proteomic characterization of Tenacibaculum dicentrarchi under iron limitation reveals an upregulation of proteins related to iron oxidation and reduction metabolism, iron uptake systems and gliding motility.

A strategy for vaccine design involves identifying proteins that could be involved in pathogen-host interactions. The aim of this proteomic study was to determine how iron limitation affects the protein expression of Tenacibaculum dicentrarchi, with a primary focus on virulence factors and proteins associated with iron uptake. The proteomic analysis was carried out using two strains of T. dicentrarchi grown under normal (control) and iron-limited conditions, mimicking the host environment. Our findings revealed differences in the proteins expressed by the type strain CECT 7612T and the Chilean strain TdCh05 of T. dicentrarchi. Nonetheless, both share a common response to iron deprivation, with an increased expression of proteins associated with iron oxidation and reduction metabolism (e.g., SufA, YpmQ, SufD), siderophore transport (e.g., ExbD, TonB-dependent receptor, HbpA), heme compound biosynthesis, and iron transporters under iron limitation. Proteins involved in gliding motility, such as GldL and SprE, were also upregulated in both strains. A negative differential regulation of metabolic proteins, particularly those associated with amino acid biosynthesis, was observed under iron limitation, reflecting the impact of iron availability on bacterial metabolism. Additionally, the TdCh05 strain exhibited unique proteins associated with gliding motility machinery and phage infection control compared to the type strain. These groups of proteins have been identified as virulence factors within the Flavobacteriaceae family, including the genus Tenacibaculum. These results build upon our previous report on iron acquisition mechanisms and could lay the groundwork for future studies aimed at elucidating the role of some of the described proteins in the infectious process of tenacibaculosis, as well as in the development of potential vaccines.

MRNA Vaccination: An Outlook on Innate Sensing and Adaptive Immune Responses.

Vaccination has led to significant dismantling of infectious diseases worldwide. Since the dawn of the SARS-CoV-2 pandemic, there has been increased popularity in the usage and study of the mRNA vaccine platform. Here, we highlight fundamental knowledge on mRNA vaccine pharmacology, followed by the immunity conferred by innate sensing and adaptive responses resulting from exposure to the mRNA vaccine construct and encapsulation materials. A better understanding of these immune mechanisms will shed light on further improvements in mRNA vaccine design, aiming to improve efficiency and optimize immune responses upon inoculation.