Child maltreatment and protection in the Arab Gulf Cooperation Council countries: A scoping review.

BACKGROUND: Research on child maltreatment and protection in the Arab Gulf Cooperation Council countries-Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates (UAE)-is limited but growing, as is child protection as a sector. OBJECTIVES: We aimed to identify themes and gaps in existing research on child maltreatment and protection, identify opportunities for building capacity in research and practice. PARTICIPANTS AND SETTING: N/A. METHODS: We conducted a scoping review of empirical studies published in peer-reviewed journals in English and Arabic and reported methods and findings according to the PRISMA-ScR reporting protocol. Articles were coded by country, topic of research, and type of abuse studied, if any. RESULTS: Our database search returned 6109 articles and 160 articles were included in our review. Themes included (1) prevalence, incidence, and characteristics of maltreatment, (2) outcomes associated with maltreatment, (3) attitudes, awareness, and reporting, (4) accidental injury and death potentially associated with neglect, (5) policy and practice. Eighty-seven articles studied Saudi Arabia, while 28 studied the UAE, 21 Kuwait, 13 Qatar, 12 Oman, and 11 Bahrain. Physical abuse was studied in 77 articles, followed by sexual abuse in 54 articles and emotional abuse in 54. CONCLUSION: Although the medical community produces an encouraging volume of child maltreatment research, gaps remain. Intervention research is lacking, and further inquiry into family dynamics, culture, and spirituality could inform the development of effective interventions. Cross-sectoral collaboration among education, social work, law enforcement, and healthcare is also needed to safeguard children's rights in the GCC.

US Health Care Expenditures, GDP and Health Policy Reforms: Evidence from End-of-Sample Structural Break Tests.

This research investigates the over-time stability of the aggregate US healthcare expenditure (HCE)-GDP relationship, focusing on periods of healthcare reforms. The most consequential reforms-Medicaid/Medicare and the Affordable Care Act (ACA)-are challenging to study because they occur near the ends of the available data. Using annual national- and state-level data and a battery of structural break tests, we find the HCE-GDP relationship to be overwhelmingly stable. An ancillary analysis around the 2006 Massachusetts healthcare reform, which avoids the confounding effects of the Great Recession and the staggered rollout of the ACA, likewise finds no change.

State-wide Genomic Epidemiology Investigations of COVID-19 Infections in Healthcare Workers: Insights for Future Pandemic Preparedness

BackgroundCOVID-19 has resulted in many infections in healthcare workers (HCWs) globally. We performed state-wide SARS-CoV-2 genomic epidemiological investigations to identify HCW transmission dynamics and provide recommendations to optimise healthcare system preparedness for future outbreaks. MethodsGenome sequencing was attempted on all COVID-19 cases in Victoria, Australia. We combined genomic and epidemiologic data to investigate the source of HCW infections across multiple healthcare facilities (HCFs) in the state. Phylogenetic analysis and fine-scale hierarchical clustering were performed for the entire Victorian dataset including community and healthcare cases. Facilities provided standardised epidemiological data and putative transmission links. FindingsBetween March and October 2020, approximately 1,240 HCW COVID-19 infection cases were identified; 765 are included here. Genomic sequencing was successful for 612 (80%) cases. Thirty-six investigations were undertaken across 12 HCFs. Genomic analysis revealed that multiple introductions of COVID-19 into facilities (31/36) were more common than single introductions (5/36). Major contributors to HCW acquisitions included mobility of staff and patients between wards and facilities, and characteristics and behaviours of individual patients including super-spreading events. Key limitations at the HCF level were identified. InterpretationGenomic epidemiological analyses enhanced understanding of HCW infections, revealing unsuspected clusters and transmission networks. Combined analysis of all HCWs and patients in a HCF should be conducted, supported by high rates of sequencing coverage for all cases in the population. Established systems for integrated genomic epidemiological investigations in healthcare settings will improve HCW safety in future pandemics. FundingThe Victorian Government, the National Health and Medical Research Council Australia, and the Medical Research Future Fund.

Prevalence of Mycobacterium tuberculosis infection as measured by the QuantiFERON-TB Gold assay and ESAT-6 free IGRA among adolescents in Mwanza, Tanzania.

BACKGROUND: The prevalence of latent tuberculosis infection (LTBI) is vastly higher than that of tuberculosis (TB) disease and this enormous reservoir of individuals with LTBI impacts the global TB control strategy. Adolescents are at greatest risk of TB infection and are thus an ideal target population for a potential effective TB vaccine to be added to the current BCG programme as it could reduce the number of latent infections and consequently the number of adults with TB disease. However, LTBI rates are often unknown for this population. This study aims to estimate the magnitude of LTBI and to determine if Tanzanian adolescents would be a good population for a prevention of TB infection trial. METHODS: This was a descriptive cross-sectional study that recruited 193 adolescents aged 12 and 16 years from government schools and directly from the community in Mwanza Region, Tanzania. Socio-demographic characteristics were collected for all enrolled participants. Blood was drawn and tested using QuantiFERON-TB Gold In-Tube (QFT-GIT), and Early Secretory Antigenic Target-6-Free Interferon-gamma Release Assay (ESAT-6 free IGRA). Concordance between QFT-GIT and ESAT-6 free IGRA was evaluated using the McNemar's test. RESULTS: Overall estimates of LTBI prevalence were 19.2% [95%CI, 14.1; 25.2] and 18.6% [95%CI, 13.6; 24.6] as measured by QFT-GIT IGRA and ESAT-6 free IGRA, respectively. The 16-year-old cohort had a higher LTBI prevalence (23.7% [95%CI, 16.1; 32.9]) as compared to 12-year-old cohort (14.6% [95%CI, 8.6; 22.7]) as measured by QFT-GIT IGRA. When measured by ESAT-6 Free IGRA, LTBI prevalence was 24.7% (95%CI, 16.9; 34.0) for the 16-year-old cohort and 12.5% (95%CI, 7.0; 20.3) among the 12-year-old cohort. According to both tests the prevalence of TB infection and the corresponding annual risk of tuberculosis infection (ARTI) and force of infection were high and increased with age. Of all enrolled participants, 97.4% had concordant results for QFT-GIT IGRA and ESAT-6 free IGRA (p = 0.65). CONCLUSIONS: The prevalence of LTBI and the associated ARTI and force of infection among adolescents is high and increases with age in Mwanza Region. There was a high concordance between the QFT-GIT and the novel ESAT-6 free IGRA assays. These findings suggest Mwanza is a promising area to conduct novel TB vaccine research prevention of infection (POI) studies targeting adolescents.

The effect of tobacco policies on youth physical activity.

Our research examines the effects of tobacco policies on teenagers' physical activity. Smoking and physical activity are both strategies for weight management, and exercise may be a way to reduce some of the ill effects of smoking. These different links suggest that cigarette taxes could either increase or decrease physical activity. We explore this relationship using repeated cross-sectional 1991-2017 data from the national and state Youth Risk Behavior Surveillance System (YRBSS), combined with state-level policies and controls. Our smoking participation results confirm past work; cigarette taxes have a negative effect on smoking that has waned in recent years. The estimated effects of cigarette taxes on physical activity echo those of smoking; cigarette taxes decrease physical activity and, like smoking, these effects have waned recently. However, one likely avenue - sports participation - is unaffected. These results suggest that increased cigarette taxes lead to modest declines in teen physical activity, a finding consistent with youth using exercise to compensate for the health effects of smoking.

Comparison of two different PEGylation strategies for the liposomal adjuvant CAF09: Towards induction of CTL responses upon subcutaneous vaccine administration.

Using subunit vaccines, e.g., based on peptide or protein antigens, to teach the immune system to kill abnormal host cells via induction of cytotoxic T lymphocytes (CTL) is a promising strategy against intracellular infections and cancer. However, customized adjuvants are required to potentiate antigen-specific cellular immunity. One strong CTL-inducing adjuvant is the liposomal cationic adjuvant formulation (CAF)09, which is composed of dimethyldioctadecylammonium (DDA) bromide, monomycoloyl glycerol (MMG) analogue 1 and polyinosinic:polycytidylic acid [poly(I:C)]. However, this strong CTL induction requires intraperitoneal administration because the vaccine forms a depot at the site of injection (SOI) after subcutaneous (s.c.) or intramuscular (i.m.) injection, and depot formation impedes the crucial vaccine targeting to the cross-presenting dendritic cells (DCs) residing in the lymph nodes (LNs). The purpose of the present study was to investigate the effect of polyethylene glycol (PEG) grafting of CAF09 on the ability of the vaccine to induce antigen-specific CTL responses after s.c. administration. We hypothesized that steric stabilization and charge shielding of CAF09 by PEGylation may reduce depot formation at the SOI and enhance passive drainage to the LNs, eventually improving CTL induction. Hence, the vaccine (antigen/CAF09) was post-grafted with a novel type of anionic PEGylated peptides based on GDGDY repeats, which were end-conjugated with one or two PEG1000 moieties, resulting in mono- and bis-PEG-peptides of different lengths (10, 15 and 20 amino acid residues). For comparison, CAF09 was also grafted by inclusion of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(PEG)-2000 (DSPE-PEG2000) in the bilayer structure during preparation. Grafting of CAF09 with either type of PEG resulted in charge shielding, evident from a reduced surface charge. Upon s.c. immunization of mice with the model antigen ovalbumin (OVA) adjuvanted with PEGylated CAF09, stronger CTL responses were induced as compared to immunization of mice with unadjuvanted OVA. Biodistribution studies confirmed that grafting of CAF09 with DSPE-PEG2000 improved the passive drainage of the vaccine to LNs, because a higher dose fraction was recovered in DCs present in the draining LNs, as compared to the dose fraction detected for non-PEGylated CAF09. In conclusion, PEGylation of CAF09 may be a useful strategy for the design of an adjuvant, which induces CTL responses after s.c. and i.m. administration. In the present studies, CAF09 grafted with 10 mol% DSPE-PEG2000 is the most promising of the tested adjuvants, but additional studies are required to further elucidate the potential of the strategy.

Sunshine, fertility and racial disparities.

This research investigates the effect of sun exposure on fertility, with a special focus on how its effects and consequences for birth outcomes may differ by race. Sun exposure is a key mechanism for obtaining Vitamin D, but this process is inhibited by skin pigmentation. Vitamin D has been linked to male and female fertility and risk of miscarriage, and Vitamin D deficiency is more prevalent among blacks than whites. Using 1989-2004 individual live births data from the Natality Detail Files, county-level, monthly conceptions are estimated as a function of monthly solar insolation, temperature and humidity, as well as month, time and location fixed effects and controls. Insolation has positive, statistically significant effects on fertility for both non-Hispanic blacks and whites, but the effects are stronger and the pattern of effect different for black mothers than white mothers. Poisson estimates from the main model suggest that a 1kWh increase in average daily insolation in the conception month - approximately the difference in sunshine experienced in the typical September vs. October - increases non-Hispanic black conceptions by 1% and non-Hispanic white conceptions by 0.6%. Allowing insolation's effect to differ by maternal characteristic suggests that the racial differences are not being driven by differences in socioeconomic status (SES). Models that allow for more complicated timing of insolation's effect further suggest that insolation pushes black (white) conceptions into the unfavorable (favorable) season of birth. These estimated effects and our decomposition analyses suggest that insolation - and the implied Vitamin D deficiency underlying its effect-helps explain why black conceptions are more likely to display a seasonal pattern that is disadvantageous to birth outcomes.

Induction of Cytotoxic T-Lymphocyte Responses Upon Subcutaneous Administration of a Subunit Vaccine Adjuvanted With an Emulsion Containing the Toll-Like Receptor 3 Ligand Poly(I:C).

There is an unmet medical need for new subunit vaccines that induce cytotoxic T-lymphocyte (CTL) responses to prevent infection with a number of pathogens. However, stimulation of CTL responses via clinically acceptable subcutaneous (s.c.) and intramuscular (i.m.) injection is challenging. Recently, we designed a liposomal adjuvant [cationic adjuvant formulation (CAF)09] composed of the cationic lipid dimethyldioctadecylammonium (DDA) bromide, a synthetic monomycoloyl glycerol analog and polyinosinic:polycytidylic acid, which induce strong CTL responses to peptide and protein antigens after intraperitoneal administration. By contrast, CAF09 does not stimulate CTL responses upon s.c. or i.m. injection because the vaccine forms a depot that remains at the injection site. Hence, we engineered a series of nanoemulsions (CAF24a-c) based on the active components of CAF09. The oil phase consisted of biodegradable squalane, and the surface charge was varied systematically by replacing DDA with zwitterionic distearoylphosphoethanolamine. We hypothesized that the nanoemulsions drain to the lymph nodes to a larger extent than CAF09, upon s.c. co-administration with the model antigen chicken egg ovalbumin (OVA). This results in an increased dose fraction that reaches the draining lymph nodes (dLNs) and subsequently activates cross-presenting dendritic cells (DCs), which can prime CTL responses. Indeed, the nanoemulsions induced antigen-specific CD8+ T-cell responses, which were significantly higher than those stimulated by OVA adjuvanted with CAF09. We explain this by the observed rapid localization of CAF24a in the dLNs and the subsequent association with conventional DCs, which promotes induction of CTL responses. Uptake of CAF24a was not specific for DCs, because CAF24a was also detected with B cells and macrophages. No measurable dose fraction of CAF09 was detected in the dLNs within the study period, and CAF09 formed a depot at the site of injection. Importantly, s.c. vaccination with OVA adjuvanted with CAF24a induced significant levels of specific lysis of antigen-pulsed splenocytes were induced after, which was not observed for OVA adjuvanted with CAF09. Thus, CAF24a is a promising adjuvant for induction of CTL responses upon s.c. and i.m. immunization, and it offers interesting perspectives for the design of vaccines against pathogens for which CTL responses are required to prevent infection.

Systematic Investigation of the Role of Surfactant Composition and Choice of oil: Design of a Nanoemulsion-Based Adjuvant Inducing Concomitant Humoral and CD4+ T-Cell Responses.

PURPOSE: Induction of cell-mediated immune (CMI) responses is crucial for vaccine-mediated protection against difficult vaccine targets, e.g., Chlamydia trachomatis (Ct). Adjuvants are included in subunit vaccines to potentiate immune responses, but many marketed adjuvants stimulate predominantly humoral immune responses. Therefore, there is an unmet medical need for new adjuvants, which potentiate humoral and CMI responses. The purpose was to design an oil-in-water nanoemulsion adjuvant containing a synthetic CMI-inducing mycobacterial monomycoloyl glycerol (MMG) analogue to concomitantly induce humoral and CMI responses. METHODS: The influence of emulsion composition was analyzed using a systematic approach. Three factors were varied: i) saturation of the oil phase, ii) type and saturation of the applied surfactant mixture, and iii) surfactant mixture net charge. RESULTS: The emulsions were colloidally stable with a droplet diameter of 150-250 nm, and the zeta-potential correlated closely with the net charge of the surfactant mixture. Only cationic emulsions containing the unsaturated surfactant mixture induced concomitant humoral and CMI responses upon immunization of mice with a Ct antigen, and the responses were enhanced when squalene was applied as the oil phase. In contrast, emulsions with neutral and net negative zeta-potentials did not induce CMI responses. The saturation degree of the oil phase did not influence the adjuvanticity. CONCLUSION: Cationic, MMG analogue-containing nanoemulsions are potential adjuvants for vaccines against pathogens for which both humoral and CMI responses are needed.

Cigarette Taxes, Smoking-and Exercise?

This research provides the first in-depth analysis of the effect that increased cigarette taxes have on exercise behavior. Smoking may diminish the ability to exercise; individuals may also use exercise to compensate for the harmful health effects of smoking or to avoid gaining weight if they cut back. Our conceptual model highlights these and several other avenues for effect and reveals that the predicted effect of cigarette costs on exercise behavior is theoretically ambiguous. To investigate the relationship empirically, 1994-2012 data from the behavioral risk factor surveillance system are combined with state level cigarette tax rates and other state level variables. Several measures of both smoking and exercise behavior are created and estimated in reduced form models. Our results suggest that both smoking and exercise are reduced by cigarette taxes. However, the effects on exercise may be more complicated as we find that certain groups, such as young adults or those who have recently quit smoking, are affected differently. Our analyses also show that the responsiveness of both smoking and exercise behavior to cigarette costs is much smaller in the 2000s, an era of high-tax increases. Copyright © 2016 John Wiley & Sons, Ltd.

The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8(+) T-cell responses: The immunological consequences of the biodistribution profile.

A prerequisite for vaccine-mediated induction of CD8(+) T-cell responses is the targeting of dendritic cell (DC) subsets specifically capable of cross-presenting antigen epitopes to CD8(+) T cells. Administration of a number of cationic adjuvants via the intraperitoneal (i.p.) route has been shown to result in strong CD8(+) T-cell responses, whereas immunization via e.g. the intramuscular (i.m.) or subcutaneous (s.c.) routes often stimulate weak CD8(+) T-cell responses. The hypothesis for this is that self-drainage of the adjuvant/antigen to the lymphoid organs, which takes place upon i.p. immunization, is required for the subsequent activation of cross-presenting lymphoid organ-resident CD8α(+) DCs. In contrast, s.c. or i.m. immunization usually results in the formation of a depot at the site of injection (SOI), which hinders the self-drainage and targeting of the vaccine to cross-presenting CD8α(+) DCs. We investigated this hypothesis by correlating the biodistribution pattern and the adjuvanticity of the strong CD8(+) T-cell inducing liposomal cationic adjuvant formulation 09 (CAF09), which is composed of dimethyldioctadecylammonium bromide/monomycoloyl glycerol liposomes with polyinosinic:polycytidylic acid electrostatically adsorbed to the surface. Biodistribution studies with radiolabeled CAF09 and a surface-adsorbed model antigen [ovalbumin (OVA)] showed that a significantly larger fraction of the vaccine dose localized in the draining lymph nodes (dLNs) and the spleen 6h after i.p. immunization, as compared to after i.m. immunization. Studies with fluorescently labelled OVA+CAF09 demonstrated a preferential association of OVA+CAF09 to DCs/monocytes, as compared to macrophages and B cells, following i.p. immunization. Administration of OVA+CAF09 via the i.p. route did also result in DC activation, whereas no DC activation could be measured within the same period with unadjuvanted OVA and OVA+CAF09 administered via the s.c. or i.m. routes. In the dLNs, the highest level of activated, cross-presenting CD8α(+) DCs was detected at 24h post immunization, whereas an influx of activated, migrating and cross-presenting CD103(+) DCs to the dLNs could be measured after 48h. This suggests that the CD8α(+) DCs are activated by self-draining OVA+CAF09 in the lymphoid organs, whereas the CD103(+) DCs are stimulated by the OVA+CAF09 at the SOI. These results support the hypothesis that the self-drainage of OVA+CAF09 to the draining LNs is required for the activation of CD8α(+) DCs, while the migratory CD103(+) DCs may play a role in sustaining the subsequent induction of strong CD8(+) T-cell responses.

How Has Elderly Migration Changed in the Twenty-First Century? What the Data Can-and Cannot-Tell Us.

Interstate elderly migration has strong implications for state tax policies and health care systems, yet little is known about how it has changed in the twenty-first century. Its relative rarity requires a large data set with which to construct reliable measures, and the replacement of the U.S. Census long form (CLF) with the American Community Survey (ACS) has made such updates difficult. Two commonly used alternative migration data sources-the Current Population Survey (CPS) and the Statistics of Income (SOI) program of the Internal Revenue Service (IRS)-suffer serious limitations in studying the migration of any subpopulation, including the elderly. Our study informs migration research in the post-2000 era by identifying methodological differences between data sources and devising strategies for reconciling the CLF and ACS. Our investigation focusing on the elderly suggests that the ACS can generate comparable migration data that reveal a continuation of previously identified geographic patterns as well as changes unique to the 2000s. However, its changed definition of residence and survey timing leaves us unable to construct a comparable national migration rate, suggesting that one must use national trends in the smaller CPS to investigate whether elderly migration has increased or decreased in the twenty-first century.

Liposome-Based Adjuvants for Subunit Vaccines: Formulation Strategies for Subunit Antigens and Immunostimulators.

The development of subunit vaccines has become very attractive in recent years due to their superior safety profiles as compared to traditional vaccines based on live attenuated or whole inactivated pathogens, and there is an unmet medical need for improved vaccines and vaccines against pathogens for which no effective vaccines exist. The subunit vaccine technology exploits pathogen subunits as antigens, e.g., recombinant proteins or synthetic peptides, allowing for highly specific immune responses against the pathogens. However, such antigens are usually not sufficiently immunogenic to induce protective immunity, and they are often combined with adjuvants to ensure robust immune responses. Adjuvants are capable of enhancing and/or modulating immune responses by exposing antigens to antigen-presenting cells (APCs) concomitantly with conferring immune activation signals. Few adjuvant systems have been licensed for use in human vaccines, and they mainly stimulate humoral immunity. Thus, there is an unmet demand for the development of safe and efficient adjuvant systems that can also stimulate cell-mediated immunity (CMI). Adjuvants constitute a heterogeneous group of compounds, which can broadly be classified into delivery systems or immunostimulators. Liposomes are versatile delivery systems for antigens, and they can carefully be customized towards desired immune profiles by combining them with immunostimulators and optimizing their composition, physicochemical properties and antigen-loading mode. Immunostimulators represent highly diverse classes of molecules, e.g., lipids, nucleic acids, proteins and peptides, and they are ligands for pattern-recognition receptors (PRRs), which are differentially expressed on APC subsets. Different formulation strategies might thus be required for incorporation of immunostimulators and antigens, respectively, into liposomes, and the choice of immunostimulator should ideally be based on knowledge regarding the specific PRR expression profile of the target APCs. Here, we review state-of-the-art formulation approaches employed for the inclusion of immunostimulators and subunit antigens into liposome dispersion and their optimization towards robust vaccine formulations.

Immunogenicity of HLA Class I and II Double Restricted Influenza A-Derived Peptides.

The aim of the present study was to identify influenza A-derived peptides which bind to both HLA class I and -II molecules and by immunization lead to both HLA class I and class II restricted immune responses. Eight influenza A-derived 9-11mer peptides with simultaneous binding to both HLA-A*02:01 and HLA-DRB1*01:01 molecules were identified by bioinformatics and biochemical technology. Immunization of transgenic HLA-A*02:01/HLA-DRB1*01:01 mice with four of these double binding peptides gave rise to both HLA class I and class II restricted responses by CD8 and CD4 T cells, respectively, whereas four of the double binding peptides did result in HLA-A*02:01 restricted responses only. According to their cytokine profile, the CD4 T cell responses were of the Th2 type. In influenza infected mice, we were unable to detect natural processing in vivo of the double restricted peptides and in line with this, peptide vaccination did not decrease virus titres in the lungs of intranasally influenza challenged mice. Our data show that HLA class I and class II double binding peptides can be identified by bioinformatics and biochemical technology. By immunization, double binding peptides can give rise to both HLA class I and class I restricted responses, a quality which might be of potential interest for peptide-based vaccine development.

Influence of trehalose 6,6'-diester (TDX) chain length on the physicochemical and immunopotentiating properties of DDA/TDX liposomes.

Linking physicochemical characterization to functional properties is crucial for defining critical quality attributes during development of subunit vaccines toward optimal safety and efficacy profiles. We investigated how the trehalose 6,6'-diester (TDX) chain length influenced the physicochemical and immunopotentiating properties of the clinically tested liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and analogues of trehalose-6,6'-dibehenate (TDB). TDB analogues with symmetrically shortened acyl chains [denoted X: arachidate (A), stearate (S), palmitate (P), myristate (Myr) and laurate (L)] were incorporated into DDA liposomes and characterized with respect to size, polydispersity index, charge, thermotropic phase behavior and lipid-lipid interactions. Incorporation of 11 mol% TDX into DDA liposomes significantly decreased the polydispersity index when TDA, TDS, TDP and TDMyr were incorporated, whereas both the initial size and the charge of the liposomes were unaffected. The long-term colloidal stability was only decreased when including TDL in DDA liposomes. The fatty acid length of TDX affected the phase transition of the liposomes, and for the DDA/TDP and DDA/TDS liposomes a homogeneous distribution of the lipids in the bilayer was indicated. The membrane packing was studied further by using the Langmuir monolayer technique. Incorporation of TDS improved the packing of the lipid monolayer, as compared to the other analogues, suggesting the most favorable stability. Finally, immunization of mice with the recombinant tuberculosis fusion antigen Ag85B-ESAT-6-Rv2660c (H56) and the physicochemically most optimal formulations (DDA/TDB, DDA/TDS and DDA/TDP) induced comparable T-cell responses. In conclusion, of the investigated TDB analogues, incorporation of 11 mol% TDS or TDP into DDA liposomes resulted in an adjuvant system with the most favorable physicochemical properties and an immunological profile comparable to that of DDA/TDB.

A stable nanoparticulate DDA/MMG formulation acts synergistically with CpG ODN 1826 to enhance the CD4⁺ T-cell response.

AIM: To combine the dimethyldioctadecyl ammonium/monomycoloyl glycerol (DDA/MMG) liposomal vaccine adjuvant with the Toll-like receptor (TLR) ligands poly(I:C) (TLR3), flagellin (TLR5) or CpG oligodeoxynucleotide 1826 (TLR9) and investigate their physicochemical properties as well as their CD4(+) T-cell-inducing capacity. MATERIALS & METHODS: Formulations were investigated by dynamic light scattering and differential scanning calorimetry. Their CD4(+) T-cell induction with a tuberculosis antigen was analyzed by multiplex cytokine analysis, ELISA and intracellular cytokine staining. RESULTS: DDA/MMG/CpG was the best combination for obtaining increased CD4(+) T-cell responses. However, coformulating CpG and DDA/MMG liposomes led to instability and the formulation was therefore optimized systematically using a design of experiment. CONCLUSION: The nanoparticulate DDA/MMG/CpG adjuvant can be stabilized and synergistically enhances CD4(+) T-cell responses compared with DDA/MMG liposomes.

Fast vaccine design and development based on correlates of protection (COPs).

New and reemerging infectious diseases call for innovative and efficient control strategies of which fast vaccine design and development represent an important element. In emergency situations, when time is limited, identification and use of correlates of protection (COPs) may play a key role as a strategic tool for accelerated vaccine design, testing, and licensure. We propose that general rules for COP-based vaccine design can be extracted from the existing knowledge of protective immune responses against a large spectrum of relevant viral and bacterial pathogens. Herein, we focus on the applicability of this approach by reviewing the established and up-coming COPs for influenza in the context of traditional and a wide array of new vaccine concepts. The lessons learnt from this field may be applied more generally to COP-based accelerated vaccine design for emerging infections.

Induction of CD8+ T-cell responses against subunit antigens by the novel cationic liposomal CAF09 adjuvant.

Vaccines inducing cytotoxic T-cell responses are required to achieve protection against cancers and intracellular infections such as HIV and Hepatitis C virus. Induction of CD8+ T cell responses in animal models can be achieved by the use of viral vectors or DNA vaccines but so far without much clinical success. Here we describe the novel CD8+ T-cell inducing adjuvant, cationic adjuvant formulation (CAF) 09, consisting of dimethyldioctadecylammonium (DDA)-liposomes stabilized with monomycoloyl glycerol (MMG)-1 and combined with the TLR3 ligand, Poly(I:C). Different antigens from tuberculosis (TB10.3, H56), HIV (Gag p24), HPV (E7) and the model antigen ovalbumin were formulated with CAF09 and administering these vaccines to mice resulted in a high frequency of antigen-specific CD8+ T cells. CAF09 was superior in its ability to induce antigen-specific CD8+ T cells as compared to other previously described CTL-inducing adjuvants, CAF05 (DDA/trehalose dibehenate (TDB)/Poly(I:C)), Aluminium/monophosphoryl lipid-A (MPL) and Montanide/CpG/IL-2. The optimal effect was obtained when the CAF09-adjuvanted vaccine was administered by the i.p. route, whereas s.c. administration primed limited CD8+ T-cell responses. The CD4+ T cells induced by CAF09 were mainly of an effector-memory-like phenotype and the CD8+ T cells were highly cytotoxic. Finally, in a mouse therapeutic skin tumor model, the HPV-16 E7 antigen formulated in CAF09 significantly reduced the growth of already established subcutaneous E7-expressing TC-1 tumors in 38% of the mice and in a corresponding prophylactic model 100% of the mice were protected. Thus, CAF09 is a potent new adjuvant which is able to induce CD8+ T-cell responses against several antigens and to enhance the protective efficacy of an E7 vaccine both in a therapeutic and in a prophylactic tumor model.

Cationic liposomal vaccine adjuvants in animal challenge models: overview and current clinical status.

Cationic liposome formulations can function as efficient vaccine adjuvants. However, due to the highly diverse nature of lipids, cationic liposomes have different physical-chemical characteristics that influence their adjuvant mechanisms and their relevance for use in different vaccines. These characteristics can be further manipulated by incorporation of additional lipids or stabilizers, and inclusion of carefully selected immunostimulators is a feasible strategy when tailoring cationic liposomal adjuvants for specific disease targets. Thus, cationic liposomes present a plasticity, which makes them promising adjuvants for future vaccines. This versatility has also led to a vast amount of literature on different experimental liposomal formulations in combination with a wide range of immunostimulators. Here, we have compiled information about the animal challenge models and administration routes that have been used to study vaccine adjuvants based on cationic liposomes and provide an overview of the applicability, progress and clinical status of cationic liposomal vaccine adjuvants.

Cationic liposomes as vaccine adjuvants.

The application of cationic liposomes as vaccine delivery systems and adjuvants has been investigated extensively over the last few decades. However, cationic liposomes are, in general, not sufficiently immunostimulatory, which is why the combination of liposomes with immunostimulating ligands has arisen as a strategy in the development of novel adjuvant systems. Within the last 5 years, two novel adjuvant systems based on cationic liposomes incorporating Toll-like receptor or non-Toll-like receptor immunostimulating ligands have progressed from preclinical testing in smaller animal species to clinical testing in humans. The immune responses that these clinical candidates induce are primarily of the Th1 type for which there is a profound unmet need. Furthermore, a number of new cationic liposome-forming surfactants with notable immunostimulatory properties have been discovered. In this article we review the recent progress on the application of cationic liposomes as vaccine delivery systems/adjuvants.