SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: NPJ vaccines

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The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill-defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these modifications were associated with profound changes in lipid composition, alteration of endoplasmic reticulum (ER) morphology and activation of the unfolded protein response pathway. In vivo, treatment with a chemical chaperone or deletion of the ER stress sensor kinase IRE1α in myeloid cells decreased AS03-induced cytokine production and its capacity to elicit high affinity antigen-specific antibodies. In summary, our results indicate that IRE1α is a sensor for the metabolic changes induced by AS03 in monocytic cells and may constitute a canonical pathway that could be exploited for the design of novel vaccine adjuvants.

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With increasing age, as the incidence of Alzheimer’s disease is increasing, finding a therapeutic intervention is becoming critically important to either prevent or slow down the progression of the disease. Passive immunotherapy has been demonstrated as a successful way of reducing large aggregates and improving cognition in animal models of both tauopathies and Alzheimer’s disease. However, with all the continuous attempts and significant success of immunotherapy in preclinical studies, finding a successful clinical therapy has been a great challenge, possibly indicating a lack of accuracy in targeting the toxic species. Both active and passive immunotherapy approaches in transgenic animals have been demonstrated to have pros and cons. Passive immunotherapy has been favored and many mechanisms have been shown to clear toxic amyloid and tau aggregates and improve memory. These mechanisms may differ depending on the antibodie’s' target and administration route. In this regard, deciding on affinity vs. specificity of the antibodies plays a significant role in terms of avoiding the clearance of the physiological forms of the targeted proteins and reducing adverse side effects. In addition, knowing that a single protein can exist in different conformational states, termed as strains, with varying degrees of neurotoxicity and seeding properties, presents an additional level of complexity. Therefore, immunotherapy targeting specifically the toxic strains will aid in developing potential strategies for intervention. Moreover, an approach of combinatorial immunotherapies against different amyloidogenic proteins, at distinct levels of the disease progression, might offer an effective therapy in many neurodegenerative diseases.

Concepts: Alzheimer's disease, Protein, Peptide, Neurology, Neurodegeneration, Neurodegenerative disorders, Beta amyloid, Tau protein

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Vaccination is the mainstay of preventative medicine for many infectious diseases. Pregnant women, unborn fetuses, and neonates represent three at-risk populations that can be simultaneously protected by strategic vaccination protocols. Because the pathogenesis of different infectious microbes varies based on tissue tropism, timing of infection, and host susceptibility, the goals of immunization are not uniform across all vaccines. Mechanistic understanding of infectious disease pathogenesis and immune responses is therefore essential to inform vaccine design and the implementation of appropriate immunization protocols that optimize protection of pregnant women, fetuses, and neonates.

Concepts: Immune system, Medicine, Disease, Infectious disease, Fetus, Vaccination, Infection, Smallpox

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The parasite Theileria parva is the causative agent of East Coast fever (ECF), one of the most serious cattle diseases in sub-Saharan Africa, and directly impacts smallholder farmers' livelihoods. There is an efficient live-parasite vaccine, but issues with transmission of vaccine strains, need of a cold chain, and antibiotics limit its utilization. This has fostered research towards subunit vaccination. Cytotoxic T lymphocytes (CTL) are crucial in combating the infection by lysing T. parva-infected cells. Tp1 is an immunodominant CTL antigen, which induces Tp1-specific responses in 70-80% of cattle of the A18 or A18v haplotype during vaccination with the live vaccine. In this study, human adenovirus serotype 5 (HAd5) and modified vaccinia Ankara (MVA) were assessed for their ability to induce Tp1-specific immunity. Both viral vectors expressing the Tp1 antigen were inoculated in cattle by a heterologous prime-boost vaccination regimen. All 15 animals responded to Tp1 as determined by ELISpot. Of these, 14 reacted to the known Tp1 epitope, assayed by ELISpot and tetramer analyses, with CTL peaking 1-week post-MVA boost. Eleven animals developed CTL with specific cytotoxic activity towards peripheral blood mononuclear cells (PBMC) pulsed with the Tp1 epitope. Moreover, 36% of the animals with a Tp1 epitope-specific response survived a lethal challenge with T. parva 5 weeks post-MVA boost. Reduction of the parasitemia correlated with increased percentages of central memory lymphocytes in the Tp1 epitope-specific CD8+ populations. These results indicate that Tp1 is a promising antigen to include in a subunit vaccine and central memory cells are crucial for clearing the parasite.

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Unlike drug dose optimisation, mathematical modelling has not been applied to vaccine dose finding. We applied a novel Immunostimulation/Immunodynamic mathematical modelling framework to translate multi-dose TB vaccine immune responses from mice, to predict most immunogenic dose in humans. Data were previously collected on IFN-γ secreting CD4+ T cells over time for novel TB vaccines H56 and H1 adjuvanted with IC31 in mice (1 dose groups (0.1-1.5 and 15 μg H56 + IC31), 45 mice) and humans (1 dose (50 μg H56/H1 + IC31), 18 humans). A two-compartment mathematical model, describing the dynamics of the post-vaccination IFN-γ T cell response, was fitted to mouse and human data, separately, using nonlinear mixed effects methods. We used these fitted models and a vaccine dose allometric scaling assumption, to predict the most immunogenic human dose. Based on the changes in model parameters by mouse H56 + IC31 dose and by varying the H56 dose allometric scaling factor between mouse and humans, we established that, at a late time point (224 days) doses of 0.8-8 μg H56 + IC31 in humans may be the most immunogenic. A 0.8-8 μg of H-series TB vaccines in humans, may be as, or more, immunogenic, as larger doses. The Immunostimulation/Immunodynamic mathematical modelling framework is a novel, and potentially revolutionary tool, to predict most immunogenic vaccine doses, and accelerate vaccine development.

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Tuberculosis (TB) is the leading cause of infectious death worldwide. Development of improved TB vaccines that boost or replace BCG is a major global health goal. ID93 + GLA-SE is a fusion protein TB vaccine candidate combined with the Toll-like Receptor 4 agonist adjuvant, GLA-SE. We conducted a phase 1, randomized, double-blind, dose-escalation clinical trial to evaluate two dose levels of the ID93 antigen, administered intramuscularly alone or in combination with two dose levels of the GLA-SE adjuvant, in 60 BCG-naive, QuantiFERON-negative, healthy adults in the US (ClinicalTrials.gov identifier: NCT01599897). When administered as 3 injections, 28 days apart, all dose levels of ID93 alone and ID93 + GLA-SE demonstrated an acceptable safety profile. All regimens elicited vaccine-specific humoral and cellular responses. Compared with ID93 alone, vaccination with ID93 + GLA-SE elicited higher titers of ID93-specific antibodies, a preferential increase in IgG1 and IgG3 subclasses, and a multifaceted Fc-mediated effector function response. The addition of GLA-SE also enhanced the magnitude and polyfunctional cytokine profile of CD4+ T cells. The data demonstrate an acceptable safety profile and indicate that the GLA-SE adjuvant drives a functional humoral and T-helper 1 type cellular response.

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There is a need for a broad and efficient testing strategy for the detection of both known and novel viral adventitious agents in vaccines and biologicals. High-throughput sequencing (HTS) is an approach for such testing; however, an optimized testing method is one with a sample-processing pipeline that can help detect any viral adventitious agent that may be present. In this study, 11 commercial methods were assessed for efficient extraction of nucleic acids from a panel of viruses. An extraction strategy with two parallel arms, consisting of both the Invitrogen PureLink™ Virus RNA/DNA kit for total nucleic acid extraction and the Wako DNA Extractor® kit with an RNase A digestion for enrichment of double-stranded nucleic acid, was selected as the strategy for the extraction of all viral nucleic acid types (ssRNA, dsRNA, and dsDNA). Downstream processes, such as double-strand DNA synthesis and whole-genome amplification (WGA), were also assessed for the retrieval of viral sequences. Double-stranded DNA synthesis yielded larger numbers of viral reads, whereas WGA exhibited a strong bias toward amplification of double-stranded DNA, including host cellular DNA. The final sample-processing strategy consisted of the dual extraction approach followed by double-stranded DNA synthesis, which yielded a viral population with increased detection of some viruses by 8600-fold. Here we describe an efficient extraction procedure to support viral adventitious agent detection in cell substrates used for biological products using HTS.

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Koala retrovirus (KoRV) infects the majority of Australia’s koalas (Phascolarctos cinereus) and has been linked to several life-threatening diseases such as lymphoma and leukemia, as well as Chlamydia and thus poses a threat to the continued survival of this species. While quarantine and antiretroviral drug treatment are possible control measures, they are impractical, leaving vaccination as the only realistic option. In this study, we examined the effect of a recombinant envelope protein-based anti-KoRV vaccine in two groups of South Australian koalas: KoRV infected or KoRV free. We report a successful vaccination response in the koalas with no vaccine-associated side effects. The vaccine induced a significant humoral immune response as well as the production of neutralizing antibodies in both groups of koalas. We also identified B-cell epitopes that were differentially recognized in KoRV-infected versus KoRV-free koalas following vaccination. Importantly, we also showed that vaccination had a therapeutic effect on koalas infected exogenously with KoRV by reducing their circulating viral load. Together, this study highlights the possibility of successfully developing a vaccine against KoRV infection in koalas.

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Transmission-blocking vaccines are based on eliciting antibody responses in the vertebrate host that disrupt parasite development in the mosquito vector and prevent malaria transmission. The surface protein Pfs47 is present in Plasmodium falciparum gametocytes and female gametes. The potential of Pfs47 as a vaccine target was evaluated. Soluble full-length recombinant protein, consisting of three domains, was expressed in E. coli as a thioredoxin fusion (T-Pfs47). The protein was immunogenic, and polyclonal and monoclonal antibodies (mAb) were obtained, but they did not confer transmission blocking activity (TBA). All fourteen mAb targeted either domains 1 or 3, but not domain 2 (D2), and immune reactivity to D2 was also very low in polyclonal mouse IgG after T-Pfs47 immunization. Disruption of the predicted disulfide bond in D2, by replacing cysteines for alanines (C230A and C260A), allowed expression of recombinant D2 protein in E. coli. A combination of mAbs targeting D2, and deletion proteins from this domain, allowed us to map a central 52 amino acid (aa) region where antibody binding confers strong TBA (78-99%). This 52 aa antigen is immunogenic and well conserved, with only seven haplotypes world-wide that share 96-98% identity. Neither human complement nor the mosquito complement-like system are required for the observed TBA. A dramatic reduction in ookinete numbers and ookinete-specific transcripts was observed, suggesting that the antibodies are interacting with female gametocytes and preventing fertilization.