From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation.

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.

A cross-sectional analysis of publication of pediatric global health abstracts from seven major international conferences.

Research presented at conferences may increase context-specific evidence in low- and middle-income countries (LMICs), where global childhood disease burden is greatest and where massive relative deficits in research persist. Publication of studies presented at conferences is necessary for complete results dissemination. Our objective was to determine the frequency of publication of pediatric global health conference abstracts and to identify factors associated with publication. We conducted a cross-sectional study of abstracts that reported pediatric research conducted in at least one LMIC presented at seven major scientific conferences in 2017, 2018, and 2019. We used PubMed, EMBASE and Google Scholar to search for publications of the results presented as abstracts. We created a Kaplan-Meier curve to determine the cumulative incidence of publications and used predetermined abstract-level factors to create a multivariable Cox proportional hazard model to identify factors associated with time to publication. There were 8,105 abstracts reviewed and 1,433 (17.7%) reported pediatric research conducted in one or more LMICs. The probability of publication of pediatric global health abstracts was 33.6% (95% confidence interval [CI] 31.2-36.1%) at 24 months and 46.6% (95% CI 44.0-49.3%) at 48 months. Abstracts that reported research conducted in East Asia and Pacific (adjusted hazard ratio [aHR] 3.06, 95% CI 1.74-5.24), South Asia (aHR 2.25, 95% CI 1.30-3.91%), and upper-middle-income countries (1.50, 95% CI 1.12-2.02) were published sooner than those that reported research in LMICs in Europe and Central Asia and lower-middle-income countries, respectively. Fewer than half of pediatric global health abstracts were published in peer-reviewed journals up to four years after presentation at international conferences. Efforts are urgently needed to promote the widespread and long-lasting dissemination of pediatric research conducted in LMICs presented as abstracts to provide a more robust evidence base for both clinical care and policy related to child health.

Association of International Editorial Staff With Published Articles From Low- and Middle-Income Countries.

Importance: The association between geographic diversity of medical journal editorial staff and publications reporting research conducted in low- and middle-income countries (LMICs) is unclear. Objective: To examine the association between having editorial staff members affiliated with LMICs and publishing research articles from LMICs in leading biomedical journals. Design, Setting, and Participants: This cross-sectional study included biomedical journals in fields representing the largest disease burden globally from January 1 to December 31, 2020. Websites of the 5 leading journals in general medicine, pediatrics, surgery, obstetrics and gynecology, cancer, cardiovascular diseases, infectious diseases, psychiatry, and nutrition were reviewed to obtain the country affiliations of editorial staff members. To determine article study countries, original research articles in each journal were reviewed through MEDLINE. Editorial staff country affiliations and study country locations were classified according to World Bank income brackets and regions. Exposure: Editorial staff country affiliation. Main Outcomes and Measures: Descriptive statistics of the proportion of editorial staff affiliated with each income bracket and region and Spearman rank correlation coefficients were used to assess the association between the proportion of editorial staff affiliated with LMICs and the proportion of published articles reporting work conducted in these countries. Results: There were 3819 editorial staff members in the 45 included journals: 3637 (95.2%) were affiliated with high-income countries, 140 (3.7%) with upper-middle-income countries, 37 (1.0%) with lower-middle-income countries, and 5 (0.1%) with low-income countries. All 48 editors-in-chief were affiliated with a high-income country. Editorial staff members were mostly affiliated with North American countries (n = 2120 [55.5%]) and European or Central Asian countries (n = 1256 [32.9%]). Of the 10 096 original research articles included in our analysis, 7857 (77.8%) reported research conducted in high-income countries, 1562 (15.5%) reported research conducted in upper-middle-income countries, 507 (5.0%) reported research conducted in lower-middle-income countries, and 170 (1.7%) reported research conducted in low-income countries. Greater editorial staff representation correlated moderately with more published articles reporting research conducted in LMICs (Spearman ρ = 0.51; 95% CI, 0.25-0.70; P < .001). Conclusions and Relevance: In this cross-sectional study, editorial staff in leading biomedical journals were largely composed of individuals affiliated with high-income countries in North America and Europe. A correlation was found between greater editorial staff representation and publication of research focused on LMICs, suggesting that the inclusion of editorial staff affiliated with LMICs may promote the publication of research conducted in those countries.

Development of a TLR7/8 agonist adjuvant formulation to overcome early life hyporesponsiveness to DTaP vaccination.

Infection is the most common cause of mortality early in life, yet the broad potential of immunization is not fully realized in this vulnerable population. Most vaccines are administered during infancy and childhood, but in some cases the full benefit of vaccination is not realized in-part. New adjuvants are cardinal to further optimize current immunization approaches for early life. However, only a few classes of adjuvants are presently incorporated in vaccines approved for human use. Recent advances in the discovery and delivery of Toll-like receptor (TLR) agonist adjuvants have provided a new toolbox for vaccinologists. Prominent among these candidate adjuvants are synthetic small molecule TLR7/8 agonists. The development of an effective infant Bordetella pertussis vaccine is urgently required because of the resurgence of pertussis in many countries, contemporaneous to the switch from whole cell to acellular vaccines. In this context, TLR7/8 adjuvant based vaccine formulation strategies may be a promising tool to enhance and accelerate early life immunity by acellular B. pertussis vaccines. In the present study, we optimized (a) the formulation delivery system, (b) structure, and (c) immunologic activity of novel small molecule imidazoquinoline TLR7/8 adjuvants towards human infant leukocytes, including dendritic cells. Upon immunization of neonatal mice, this TLR7/8 adjuvant overcame neonatal hyporesponsiveness to acellular pertussis vaccination by driving a T helper (Th)1/Th17 biased T cell- and IgG2c-skewed humoral response to a licensed acellular vaccine (DTaP). This potent immunization strategy may represent a new paradigm for effective immunization against pertussis and other pathogens in early life.

mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis.

Regulatory T cells (Tregs) have shown great promise as a means of cellular therapy in a multitude of allo- and auto-immune diseases-due in part to their immunosuppressive potency. Nevertheless, the clinical efficacy of human Tregs in patients has been limited by their poor in vivo homeostasis. To avert apoptosis, Tregs require stable antigenic (CD3ζ/T-cell-receptor-mediated), co-stimulatory (CD28-driven), and cytokine (IL-2-dependent) signaling. Notably, this sequence of signals supports an activated Treg phenotype that includes a high expression of granzymes, particularly granzyme B (GrB). Previously, we have shown that aside from the functional effects of GrB in lysing target cells to modulate allo-immunity, GrB can leak out of the intracellular lysosomal granules of host Tregs, initiating pro-apoptotic pathways. Here, we assessed the role of inhibiting mechanistic target of rapamycin complex 1 (mTORC1), a recently favored drug target in the transplant field, in regulating human Treg apoptosis via GrB. Using ex vivo models of human Treg culture and a humanized mouse model of human skin allotransplantation, we found that by inhibiting mTORC1 using rapamycin, intracytoplasmic expression and functionality of GrB diminished in host Tregs; lowering human Treg apoptosis by in part decreasing the phosphorylation of S6K and c-Jun. These findings support the already clinically validated effects of mTORC1 inhibition in patients, most notably their stabilization of Treg bioactivity and in vivo homeostasis.