Comparison of the effects of different potent adjuvants on enhancing the immunogenicity and cross-protection by influenza virus vaccination in young and aged mice.

Vaccination against influenza viruses suffers from low efficacy in conferring homologous and cross-protection, particularly in older adults. Here, we compared the effects of three different adjuvant types (QS-21+MPL, CpG+MPL and bacterial cell wall CWS) on enhancing the immunogenicity and homologous and heterosubtypic protection of influenza vaccination in young adult and aged mouse models. A combination of saponin QS-21 and monophosphoryl lipid A (QS-21+MPL) was most effective in inducing T helper type 1 (Th1) T cell and cross-reactive IgG as well as hemagglutination inhibiting antibody responses to influenza vaccination. Both combination adjuvants (QS-21+MPL and CpG+MPL) exhibited high potency by preventing weight loss and reducing viral loads and enhanced homologous and cross-protection by influenza vaccination in adult and aged mouse models. Bacillus Calmette-Guerin cell-wall skeleton (CWS) displayed substantial adjuvant effects on immune responses to influenza vaccination but lower adjuvant efficacy in inducing Th1 IgG responses, cross-protection in adult mice, and in conferring homologous protection in aged mice. This study has significance in comparing the effects of potent adjuvants on enhancing humoral and cellular immune responses to influenza virus vaccination, inducing homologous and cross-protection in adult and aged populations.

Polyethylenimine-coated PLGA nanoparticles-encapsulated Angelica sinensis polysaccharide as an adjuvant for H9N2 vaccine to improve immune responses in chickens compared to Alum and oil-based adjuvants.

Inactivated H9N2 influenza vaccines required adjuvants to induce strong immune responses to protect poultry from the infections of H9N2 influenza viruses. Recently, positively charged nanoparticles-based adjuvant delivery systems have been extensively investigated as the novel vaccine adjuvant due to the protection antigens and drugs from degradation, promoting antigens and drugs uptake by antigen presenting cells (APCs), and inducing strong humoral and cellular immune responses. In this study, the immunostimulant Angelica sinensis polysaccharide (ASP) was encapsulated into Poly (lactic-co-glycolic acid) PLGA nanoparticles, and the Polyethylenimine (PEI) was coated on the nanoparticles to develop a novel adjuvant (ASP-PLGA-PEI). To further investigate the adjuvant activities of ASP-PLGA-PEI nanoparticles for H9N2 vaccines in chickens and compare the adjuvant activities of nanoparticles adjuvant and conventional adjuvants (Alum and oil-based adjuvant), the H9N2 antigen was incubated with three different adjuvants and then immunized with chickens to evaluate the ability of inducing humoral and cellular immune responses. The results revealed that compared to Alum adjuvant, ASP-PLGA-PEI nanoparticles adjuvant stimulated higher antibody responses, promoted the activation of CD4+ T cells and CD8+ T cells, increased the expression of Th1 cytokines IFN-γ. Compared to oil-based adjuvant (ISA-206), ASP-PLGA-PEI nanoparticles adjuvant induced comparable antibody immune responses at later period after immunization, improved the activation of CD4+ T cells and CD8+ T cells. Therefore, compared to Alum and oil-based adjuvant, the ASP-PLGA-PEI nanoparticles serve as an efficient adjuvant for H9N2 vaccine and have the potential to induce vigorous humoral and cellular immune responses in chickens.

Sunflower seed oil containing ginseng stem-leaf saponins (E515-D) is a safe adjuvant for Newcastle disease vaccine.

Vaccination is an effective method to prevent Newcastle disease (ND) in chickens. Marcol 52 and #10 white oil are mineral-based adjuvants and can be found in commercial inactivated ND virus vaccines. The present study demonstrated that a vegetable origin oil E515-D had lower polycyclic aromatic hydrocarbons and higher flash point than the commercial products Marcol 52 and #10 white oil. E515-D could be mixed with an aqueous phase containing ND virus antigen to form a stable water-in-oil vaccine emulsion and exhibited more potent adjuvant effects on the immune response than Marcol 52 and #10 white oil. Moreover, the absorption of E515-D-adjuvanted vaccine was faster than absorption of Marcol 52- and #10 white oil-adjuvanted vaccines when ND virus vaccines were injected in broilers. Therefore, E515-D was safe and could be a suitable adjuvant used in vaccines for food animals. In addition，E515-D is not easy to be flammable during shipping and storage owing to its higher flash point.

Quality control and immunological activity of lentinan samples produced in China.

Lentinan is widely used as a therapeutic agent for treatment of malignant tumors in clinical practice. The chemical structure of lentinan is highly associated with its biological activity. In this study, the correlation between the structure of lentinan and its immune activity was investigated to assess the function of key parameters that can influence quality control of lentinan. The results showed that the batch-to-batch consistency of two lentinan samples was satisfactory, indicating the stability of production process of lentinan. However, although the chemical composition and triple-helical conformation (THC) of the tested samples were relatively similar, their Mw, polydispersity index (PDI), and Rgz remarkably varied due to different production processes. In vitro immunomodulatory assay reflects that lentinan could stimulate the macrophages phagocytic capacity. Meanwhile, lentinan samples could improve the spleen and thymus indices, promote the proliferation of lymphocytes and adjust for the percentages of CD4+ and CD8+ T cells in vivo. Furthermore, the immunomodulatory effect of lentinan sample B (Mw: 650,700 g/mol) was superior than that of the sample A (Mw: 4,818,700 g/mol). It was noted that the Mw should be detected as a necessary index for quality control of lentinan to ensure stability and effectiveness of the production process.

Novel Technologies to Improve Vaccines for Older Adults.

Vaccine development has traditionally been driven by the need to prevent high numbers of childhood deaths due to infectious disease. With few exceptions, vaccines for adults are the same as vaccines for infants, although it has long been apparent that they become less effective as age increases. It is only in the last few years that concerted efforts have commenced to develop life-long vaccination strategies through into older age. Impressive progress has been made in the field of vaccine technologies which, when they will be applied to vaccination of older adults, could change the landscape for disease prevention in this age group. The recently licensed adjuvanted herpes zoster vaccine shows that immunosenescence need not be a barrier to highly effective vaccination, and that highly effective vaccines for older adults can be achieved with good vaccine design. One of the greatest public health challenges of the 21st century is ensuring the health and well-being of the aged. New or improved vaccines targeting pathogens with a high disease burden in older adults have the potential to major contributions to the longevity and productivity of the older aged population.

Toward precision adjuvants: optimizing science and safety.

PURPOSE OF REVIEW: The gradual replacement of inactivated whole cell and live attenuated vaccines with subunit vaccines has generally reduced reactogenicity but in many cases also immunogenicity. Although only used when necessary, adjuvants can be key to vaccine dose/antigen-sparing, broadening immune responses to variable antigens, and enhancing immunogenicity in vulnerable populations with distinct immunity. Licensed vaccines contain an increasing variety of adjuvants, with a growing pipeline of adjuvanted vaccines under development. RECENT FINDINGS: Most adjuvants, including Alum, Toll-like receptor agonists and oil-in-water emulsions, activate innate immunity thereby altering the quantity and quality of an adaptive immune response. Adjuvants activate leukocytes, and induce mediators (e.g., cytokines, chemokines, and prostaglandin-E2) some of which are biomarkers for reactogenicity, that is, induction of local/systemic side effects. Although there have been safety concerns regarding a hypothetical risk of adjuvants inducing auto-immunity, such associations have not been established. As immune responses vary by population (e.g., age and sex), adjuvant research now incorporates principles of precision medicine. Innovations in adjuvant research include use of human in vitro models, immuno-engineering, novel delivery systems, and systems biology to identify biomarkers of safety and adjuvanticity. SUMMARY: Adjuvants enhance vaccine immunogenicity and can be associated with reactogenicity. Novel multidisciplinary approaches hold promise to accelerate and de-risk targeted adjuvant discovery and development. VIDEO ABSTRACT: http://links.lww.com/MOP/A53.

Comparative effectiveness of H7N9 vaccines in healthy individuals.

BACKGROUND: Avian H7N9 influenza viruses possess a potential pandemic threat to public health worldwide, and have caused severe infection and high mortality in humans. A series of clinical trials of H7N9 vaccines have been completed. Meta-analyses need to be performed to assess the immunogenicity and safety of H7N9 vaccines. METHODS: Database research with defined selection criteria was conducted in PubMed, Cochrane Central Register of Controlled Trials, the World Health Organization's International Clinical Trials Registry Platform, ClinicalTrials.gov, etc. Data from randomized clinical trials regarding the immunogenicity and safety of H7N9 vaccines were collected and meta-analyzed. RESULTS: For non-adjuvanted H7N9 vaccines, high dose formulations induced limited immunogenicity and increased the risk of local and systemic adverse events, simultaneously. For adjuvanted H7N9 vaccines, on the one hand, ISCOMATRIX, MF59, AS03 and aluminium adjuvants applied in H7N9 vaccines could improve immune responses effectively, and non-aluminium adjuvants had superior performance in saving vaccine dose; on the other hand, aluminium adjuvant had the advantages of safety amongst these adjuvants applied in H7N9 vaccines. CONCLUSION: H7N9 influenza vaccines with adjuvant might represent the optimal available option in an influenza pandemic, at present.

Effect of adjuvant hormone therapy in patients with prostate cancer: A meta-analysis of randomized controlled trials.

OBJECTIVES: To summarize the evidence regarding the treatment effect of adjuvant hormone therapy (AHT) in patients with prostate cancer (PCa). AHT following radiotherapy, chemotherapy, or surgery is widely used in patients with PCa. However, the treatment effect is inconsistent in individual trials. METHODS: The electronic databases including PubMed, EmBase, and Cochrane Library were searched to identify randomized controlled trials (RCTs) in September 2016. RCTs that evaluated the effects of AHT in patients with PCa were included. Hazard ratio (HR) and relative risks (RR) were used to measure the treatment effects of AHT using a random effects model. The analyses were further stratified by factors that could affect the treatment efficacy. RESULTS: A total of 14,594 potential studies were identified, and 27 RCTs were included. Compared with the control group, patients who received AHT were associated with a significant improvement in overall survival (OS) (HR: 0.78; 95% confidence interval [CI]: 0.71-0.85; P <.001), disease-free survival (DFS) (HR: 0.50; 95% CI: 0.39-0.65; P <.001), total mortality (RR: 0.90; 95% CI: 0.85-0.96; P = .001), recurrence (RR: 0.70; 95% CI: 0.60-0.81; P <.001), and disease-specific mortality (RR: 0.70; 95% CI: 0.56-0.87; P <.001). However, no significant difference was observed between AHT and control for response rate (RR: 1.75; 95% CI: 0.91-3.37; P = .095). CONCLUSIONS: The findings of this meta-analysis confirmed that patients who received AHT had a significant improvement in OS, DFS, total mortality, recurrence, and disease-specific mortality. Further, large-scale RCTs are required to evaluate the treatment effect in specific subpopulations.

Background and Update for S1602 "A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming with Intradermal BCG Before Intravesical Therapy for BCG-naïve High-grade Non-muscle-invasive Bladder Cancer.

The S1602 Intergroup trial is a randomized phase III clinical trial that aims to test two important hypotheses: (1) priming with intradermal bacillus Calmette-Guérin (BCG) vaccine prior to standard intravesical BCG improves response to BCG in terms of recurrence-free survival and (2) Tokyo-172 BCG strain is non-inferior to TICE BCG in terms of time to high-grade recurrence. The study was approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and activated in spring 2017. Here, we provide a synopsis of the study background, design, and update of the clinical trial.

Propranolol efficacy as a novel adjuvant for immunization against Toxoplasma gondii tachyzoites.

Severe or lethal damages, caused by Toxoplasma gondii infection in congenital cases and immunocompromised patients implies the necessity for development of a vaccine and an appropriate adjuvant would be needed to elicit a protective Th1 biased-immune response. The adjuvant activity of propranolol was surveyed and compared with alum by immunization of BALB/c mice with protein components of T. gondii tachyzoites. Five groups of BALB/c mice were immunized with phosphate buffered saline (negative control), Toxoplasma lysate antigen (TLA), alum plus TLA, Propranolol plus TLA, and alum, propranolol and TLA. Immunization efficacy was evaluated by lymphocyte proliferation and DTH tests, challenge with live tachyzoites, IFN-γ production by spleen cells, serum TNF-α concentration and anti- Toxoplasma total IgG, IgG1 and IgG2a measurements. Mice of the PRP-TLA group induced significantly more IFN-γ and TNF-α production and lymphocyte proliferation than other groups. This group of mice also showed more anti-T. gondii IgG2a and DTH responses and showed a significantly increased survival time after challenge. These findings indicate that propranolol as an adjuvant in combination with TLA, may enhance cellular immunity against T. gondii.

Influenza infection in human host: challenges in making a better influenza vaccine.

Influenza is a ubiquitous infection with a spectrum ranging from mild to severe. The mystery regarding such variability in the clinical spectrum has not been fully unravelled, although a role for the complex interplay among virus characteristics, host immune response and environmental factors has been suggested. Antivirals and current vaccines have a limited role in prophylaxis and treatment because they primarily target surface glycoproteins which undergo antigenic/genetic changes under host immune pressure. Targeting conserved internal proteins could lead the way to a universal vaccine which can be used against various types/subtypes. However, this is on the distant horizon, so in the meantime, developing improved vaccines should be given high priority. In this review, we discuss where the current influenza research stands in terms of vaccines, adjuvants, and how we can better predict the vaccine strains for upcoming influenza seasons by understanding complex phenomena which drive the continuous antigenic evolution.

Co-administration of interleukins 7 and 15 with DNA vaccine improves protective immunity against Toxoplasma gondii.

Toxoplasma gondii is an obligatory intracellular parasite, which can infect all warm-blooded animals including humans. Cytokines, including IL-15 and IL-7, play a critical role in the regulation of the homeostasis of naive and memory T cells. Co-administration the DNA vaccine with cytokines may improve its efficacy. IL-7 and IL-15 from splenic tissues of Kunming mice were cloned, and eukaryotic plasmid pVAX-IL-7-IL-15 was constructed. Kunming mice were administrated with DNA vaccine expressing T. gondii calcium-dependent protein kinase 1 (TgCDPK1), pVAX-CDPK1, in the presence or absence of IL-7 and IL-15 plasmids (pVAX-IL-7-IL-15), immune responses were analyzed including lymphoproliferative assay, cytokine and serum antibody measurements, flow cytometric surface markers on lymphocytes, and thus protective immunity against acute and chronic T. gondii infection was estimated. Mice injected with pVAX-CDPK1 supplemented with pVAX-IL-7-IL-15 showed higher Toxoplasma-specific IgG2a titers, Th1 responses associated with the production of IFN-γ, IL-2 as well as cell-mediated cytotoxic activity where stronger frequencies of IFN-γ secreting CD8+ and CD4+ T cells (CD8+/CD4+ IFN-γ+ T cells) compared to controls. Co-administration of pVAX-IL-7-IL-15 and pVAX-CDPK1 significantly (P < 0.05) increased survival time (18.07 ± 5.43 days) compared with pVAX-CDPK1 (14.13 ± 3.85 days) or pVAX-IL-7-IL-15 (11.73 ± 1.83 days) alone, and pVAX-IL-7-IL-15 + pVAX-CDPK1 significantly reduced the number of brain cysts (73.5%) in contrast to pVAX-CDPK1 (46.0%) or pVAX-IL-7-IL-15 alone (45.0%). Our results indicate that supplementation of DNA vaccine with IL-7 and IL-15 would facilitate specific humoral and cellular immune responses elicited by DNA vaccine against acute and chronic T. gondii infection in mice.

[Intra-articular injection of cortisone]. / Intraartikuläre Injektion mit Kortison.

Intra-articular injections with glucocorticoids are standard procedures according to therapy guidelines in many rheumatic conditions. There is increasing evidence from clinical trials on the treatment of rheumatoid arthritis that more patients will attain the target of remission using a combination of systemic medication and intra-articular injections with glucocorticoids compared to systemic medication alone. Intra-articular injections with glucocorticoids play an important role in the therapeutic management of pediatric rheumatic diseases. In many countries competency in performing intra-articular injections is among the important skills necessary for certification as a specialist in rheumatology.

[Injection treatment with hyaluronic acid]. / Injektionsbehandlung mit Hyaluronsäure.

This article presents the spectrum of indications for the use of hyaluronic acid (HA) based on the recommendations of the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), the Osteoarthritis Research Society International (OARSI), the International Institute for Health and Clinical Excellence (NICE) and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) taking the reality of patient care in Europe into account.

Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs.

Use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on aluminium salts, monophosphoryl lipid A and oil emulsions are currently approved for human use. Recent strategic initiatives to support adjuvant development by the National Institutes of Health should translate into greater adjuvant choices in the future. Mechanistic studies have been valuable for better understanding of adjuvant action, but mechanisms of adjuvant toxicity are less well understood. The inflammatory or danger-signal model of adjuvant action implies that increased vaccine reactogenicity is the inevitable price for improved immunogenicity. Hence, adjuvant reactogenicity may be avoidable only if it is possible to separate inflammation from adjuvant action. The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer's disease. While existing adjuvants based on aluminium salts have a strong safety record, there are ongoing needs for new adjuvants and more intensive research into adjuvants and their effects.

Optimizing manufacturing and composition of a TLR4 nanosuspension: physicochemical stability and vaccine adjuvant activity.

BACKGROUND: Nanosuspensions are an important class of delivery system for vaccine adjuvants and drugs. Previously, we developed a nanosuspension consisting of the synthetic TLR4 ligand glucopyranosyl lipid adjuvant (GLA) and dipalmitoyl phosphatidylcholine (DPPC). This nanosuspension is a clinical vaccine adjuvant known as GLA-AF. We examined the effects of DPPC supplier, buffer composition, and manufacturing process on GLA-AF physicochemical and biological activity characteristics. RESULTS: DPPC from different suppliers had minimal influence on physicochemical and biological effects. In general, buffered compositions resulted in less particle size stability compared to unbuffered GLA-AF. Microfluidization resulted in rapid particle size reduction after only a few passes, and 20,000 or 30,000 psi processing pressures were more effective at reducing particle size and recovering the active component than 10,000 psi. Sonicated and microfluidized batches maintained good particle size and chemical stability over 6 months, without significantly altering in vitro or in vivo bioactivity of GLA-AF when combined with a recombinant malaria vaccine antigen. CONCLUSIONS: Microfluidization, compared to water bath sonication, may be an effective manufacturing process to improve the scalability and reproducibility of GLA-AF as it advances further in the clinical development pathway. Various sources of DPPC are suitable to manufacture GLA-AF, but buffered compositions of GLA-AF do not appear to offer stability advantages over the unbuffered composition.

Technology transfer of an oil-in-water vaccine-adjuvant for strengthening pandemic influenza preparedness in Indonesia.

With the current enzootic circulation of highly pathogenic avian influenza viruses, the ability to increase global pandemic influenza vaccine production capacity is of paramount importance. This has been highlighted by, and is one of the main pillars of, the WHO Global Action Plan for Influenza Vaccines (GAP). Such capacity expansion is especially relevant in developing countries. The Vaccine Formulation Laboratory at University of Lausanne is engaged in the technology transfer of an antigen-sparing oil-in-water adjuvant in order to empower developing countries vaccine manufacturers to increase pandemic influenza vaccine capacity. In a one-year project funded by United States Department of Health and Human Services, the Vaccine Formulation Laboratory transferred the process know-how and associated equipment for the pilot-scale manufacturing of an oil-in-water adjuvant to Bio Farma, Indonesia's state-owned vaccine manufacturer, for subsequent formulation with H5N1 pandemic influenza vaccines. This paper describes the experience acquired and lessons learnt from this technology transfer project.

Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania.

Many developing countries lack or have inadequate pandemic influenza vaccine manufacturing capacity. In the 2009 H1N1 pandemic, this led to delayed and inadequate vaccine coverage in the developing world. Thus, bolstering developing country influenza vaccine manufacturing capacity is urgently needed. The Cantacuzino Institute in Bucharest, Romania has been producing seasonal influenza vaccine since the 1970s, and has the capacity to produce ∼5 million doses of monovalent vaccine in the event of an influenza pandemic. Inclusion of an adjuvant in the vaccine could enable antigen dose sparing, expanding vaccine coverage and potentially allowing universal vaccination of the Romanian population and possibly neighboring countries. However, adjuvant formulation and manufacturing know-how are difficult to access. This manuscript describes the successful transfer of oil-in-water emulsion adjuvant manufacturing and quality control technologies from the Infectious Disease Research Institute in Seattle, USA to the Cantacuzino Institute. By describing the challenges and accomplishments of the project, it is hoped that the knowledge and experience gained will benefit other institutes involved in similar technology transfer projects designed to facilitate increased vaccine manufacturing capacity in developing countries.

Innovations in vaccine development: can regulatory authorities keep up?

Vaccine Production Summit San Francisco, CA, USA, 4-6 June 2012 IBC's 3rd Vaccine Production Summit featured 28 presentations discussing regulatory challenges in vaccine development, including the use of adjuvants, vaccine manufacturing and technology transfer, process development for vaccines and the role of quality by design, how to address vaccine stability, and how vaccine development timelines can be improved. The conference was run in parallel with the single-use applications for Biopharmaceutical Manufacturing conference. Approximately 250 attendees from large pharmaceutical companies, large and small biotech companies, vendors and a more limited number from academia were allowed to access sessions of either conference, including one shared session. This article summarizes the recurring themes across various presentations.

Initial characterization of an autoclaved Toxoplasma vaccine in mice.

Toxoplasmosis is a zoonotic protozoal disease that has a major significance from the perspectives of public health and veterinary medicine. Therefore, an obvious long-term goal of many scientists would be the development of an effective vaccine. In this study, autoclaved vaccine was evaluated for its ability to protect mice against Toxoplasma gondii RH challenge as an acute infection model. Results showed that autoclaved Toxoplasma vaccine (ATV) when combined with BCG as an adjuvant was effective in triggering cell mediated immunity as shown by a significant increase in the percentage of splenic CD8+ T-lymphocytes. Following challenge, death of mice vaccinated with ATV was delayed for nine days. There was a significant decrease in parasite density in different organs, and a marked reduction of pathological changes in the liver suggesting that significant immune responses were mounted following vaccination. Future studies are warranted to test the vaccine against challenge with brain cysts as a chronic infection model and to evaluate it with other recent immunization strategies that can further enhance its immunogenicity.