31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

New Insights into Neisseria gonorrhoeae (NG): Geographic heterogeneity in Black-White disparities and spatiotemporal trends among US females and the role of azithromycin use for STI treatment in antibiotic resistance

Thesis (Ph.D.)--University of Washington, 2022Gonorrhea (caused by the Neisseria gonorrhoeae (NG) bacterium) is the second most-commonly reported sexually transmitted infection (STI) in the United States (US) and can cause serious, permanent reproductive sequalae in females. Gonorrhea rates have increased rapidly in the US throughout the last 3 decades, while profound racial disparities have stubbornly persisted with non-Hispanic Black (NHB) populations experiencing the greatest burden of disease. In geographic depictions of gonorrhea rates, the US Southeast is highlighted as the area of highest morbidity. Concerningly, NG has developed antimicrobial resistance (AMR) to nearly all drugs historically used for treatment. AMR NG is more common among men who have sex with men (MSM), which may be related to the more frequent use of antibiotics for STI treatment in this population. While racial disparities in gonorrhea rates are well-described, our understanding of variation in the magnitude of these disparities within the US is lacking. Reduction of racial disparities is a core goal of the 2021-2015 US National Strategic Plan for STIs; it is therefore imperative that national and local public health programs know where such disparities are greatest for interventions to have greatest impact. Similarly, national data demonstrating increases in gonorrhea rates among females may obscure informative variation in localized trends. Areas with later or earlier increases in gonorrhea rates, with high or low rates of disease, may share characteristics influential in gonorrhea epidemiology. There is also currently conflicting evidence about the role of individual-level antibiotic use on the development of AMR gonorrhea. A study of Dutch clinic attendees identified an association between AZM use and AZM resistance, while two reviews of surveillance data from the UK found no such association. In this dissertation, we sought to fill these gaps in our knowledge of gonorrhea epidemiology through several related but distinct analyses. First, we examined the geographic variation in county-level gonorrhea rates among NHB and non-Hispanic White (NHW) females using national gonorrhea surveillance data obtained from the US Centers for Disease Control and Prevention. We created a series of maps to depict the spatial distribution of within- and between-race disparities (relative and absolute) in gonorrhea rates. We then used group-based trajectory models to identify and characterize distinct groups of counties with similar trajectories of NG rates in these populations separately. Lastly, we examined the association between individual-level receipt of AZM for sexually transmitted infection treatment and subsequent NG infection with reduced susceptibility to AZM among attendees of the Public Health Seattle-King County Sexual Health Clinic (SHC). We found that nearly all US counties had NHB female gonorrhea rates ≥3x those in NHW females, with NHB females in most highly populated counties experienced ≥9-fold difference in gonorrhea rates. Additionally, NHB females in counties in the south had lower rates of gonorrhea compared to NHB females in the Midwest and West. In our analysis of county-level spatiotemporal gonorrhea trends, we identified 9 distinct gonorrhea trajectories for NHB, 3 of which experienced declines in case rates from 2003-2018; conversely, all 7 identified trajectories among NHW females were characterized by stable or increasing rates of gonorrhea. Furthermore, counties with similar gonorrhea trajectories were sometimes, but not always, in close proximity. Finally, we found evidence for an association between receipt of AZM in the prior 30 days and having an AMR NG infection among SHC attendees. Our first analysis highlights pervasive yet variable racial disparities in gonorrhea; further, these disparities are often greater outside the US south. These findings counter damaging regional stereotypes, provide evidence to refocus prevention efforts to areas of highest disparities, and suggest that monitoring racial disparities can function as an actionable public health metric. Our second analysis confirmed that national data do obscure a highly heterogenous gonorrhea epidemic for both NHW and NHB females. These two exploratory analyses should prompt further analysis into the differential drivers of gonorrhea morbidity. Lastly, our finding of an association between AZM use and AZM-resistance underscore the timeliness of updated STI treatment guidelines that reduce the utilization of AZM in populations at high risk for AMR NG

Cost-effectiveness of rotavirus vaccination in Bolivia from the state perspective

BACKGROUND—In Bolivia, in 2008, the under-five mortality rate is 54 per 1000 live births. Diarrhea causes 15% of these deaths, and 40% of pediatric diarrhea-related hospitalizations are caused by rotavirus illness (RI). Rotavirus vaccination (RV), subsidized by international donors, is expected to reduce morbidity, mortality, and economic burden to the Bolivian state. Estimates of illness and economic burden of RI and their reduction by RV are essential to the Bolivian state’s policies on RV program financing. The goal of this report is to estimate the economic burden of RI and the cost-effectiveness of the RV program. METHODS—To assess treatment costs incurred by the healthcare system, we abstracted medical records from 287 inpatients and 6,751 outpatients with acute diarrhea between 2005 and 2006 at 5 sentinel hospitals in 4 geographic regions. RI prevalence rates were estimated from 4 years of national hospital surveillance. We used a decision-analytic model to assess the potential cost- effectiveness of universal RV in Bolivia. RESULTS—Our model estimates that, in a 5-year birth cohort, Bolivia will incur over US$3 million in direct medical costs due to RI. RV reduces, by at least 60$3.81 per dose and cost-effective below a price of US $194.10 per dose. Diarrheal mortality and hospitalization inputs were the most important drivers of rotavirus vaccine cost-effectiveness. DISCUSSION—Our data will guide Bolivia’s funding allocation for RV as international subsidies change

Cost-effectiveness of rotavirus vaccination in Bolivia from the state perspective

Background: In Bolivia, in 2008, the under-five mortality rate is 54 per 1000 live births. Diarrhea causes 15% of these deaths, and 40% of pediatric diarrhea-related hospitalizations are caused by rotavirus illness (RI). Rotavirus vaccination (RV), subsidized by international donors, is expected to reduce morbidity, mortality, and economic burden to the Bolivian state. Estimates of illness and economic burden of RI and their reduction by RV are essential to the Bolivian state\u27s policies on RV program financing. The goal of this report is to estimate the economic burden of RI and the cost-effectiveness of the RV program. Methods: To assess treatment costs incurred by the healthcare system, we abstracted medical records from 287 inpatients and 6751 outpatients with acute diarrhea between 2005 and 2006 at 5 sentinel hospitals in 4 geographic regions. RI prevalence rates were estimated from 4 years of national hospital surveillance. We used a decision-analytic model to assess the potential cost-effectiveness of universal RV in Bolivia. Results: Our model estimates that, in a 5-year birth cohort, Bolivia will incur over US$3 million in direct medical costs due to RI. RV reduces, by at least 60$3.81 per dose and cost-effective below a price of US$194.10 per dose. Diarrheal mortality and hospitalization inputs were the most important drivers of rotavirus vaccine cost-effectiveness. Discussion: Our data will guide Bolivia\u27s funding allocation for RV as international subsidies change. © 2011 Elsevier Ltd

Comparison of common acute respiratory infection case definitions for identification of hospitalized influenza cases at a population-based surveillance site in Egypt.

BackgroundMultiple case definitions are used to identify hospitalized patients with community-acquired acute respiratory infections (ARI). We evaluated several commonly used hospitalized ARI case definitions to identify influenza cases.MethodsThe study included all patients from a population-based surveillance site in Damanhour, Egypt hospitalized for a broad set of criteria consistent with community acquired ARIs. Naso- and oropharyngeal (NP/OP) swabs were tested for influenza using RT-PCR. Sensitivity, specificity and PPV for influenza identification was compared between the 2014 WHO Severe Acute Respiratory Infection (SARI) definition (fever ≥38°C and cough with onset within 10 days), the 2011 WHO SARI definition (fever ≥38°C and cough with onset within 7 days), the 2006 PAHO SARI definition, the International Emerging Infections Program (IEIP) pneumonia case definition, and the International Management of Childhood Illness (IMCI) case definitions for moderate and severe pneumonia.ResultsFrom June 2009-December 2012, 5768 NP/OP swabs were obtained from 6113 hospitalized ARI patients; 799 (13.9%) were influenza positive. The 2014 WHO SARI case definition captured the greatest number of ARI patients, influenza positive patients and ARI deaths compared to the other case definitions examined. Sensitivity for influenza detection was highest for the 2014 WHO SARI definition with 88.6%, compared to the 2011 WHO SARI (78.2%) the 2006 PAHO SARI (15.8%) the IEIP pneumonia (61.0%) and the IMCI moderate and severe pneumonia (33.8% and 38.9%) case definitions (IMCI applies to ConclusionsOur results support use of the 2014 WHO SARI definition for identifying influenza positive hospitalized SARI cases as it captures the highest proportion of ARI deaths and influenza positive cases. Routine use of this case definition for hospital-based surveillance will provide a solid, globally comparable foundation on which to build needed response efforts for novel pandemic viruses

Etiologic agents of central nervous system infections among febrile hospitalized patients in the country of Georgia.

OBJECTIVES: There is a large spectrum of viral, bacterial, fungal, and prion pathogens that cause central nervous system (CNS) infections. As such, identification of the etiological agent requires multiple laboratory tests and accurate diagnosis requires clinical and epidemiological information. This hospital-based study aimed to determine the main causes of acute meningitis and encephalitis and enhance laboratory capacity for CNS infection diagnosis. METHODS: Children and adults patients clinically diagnosed with meningitis or encephalitis were enrolled at four reference health centers. Cerebrospinal fluid (CSF) was collected for bacterial culture, and in-house and multiplex RT-PCR testing was conducted for herpes simplex virus (HSV) types 1 and 2, mumps virus, enterovirus, varicella zoster virus (VZV), Streptococcus pneumoniae, HiB and Neisseria meningitidis. RESULTS: Out of 140 enrolled patients, the mean age was 23.9 years, and 58% were children. Bacterial or viral etiologies were determined in 51% of patients. Five Streptococcus pneumoniae cultures were isolated from CSF. Based on in-house PCR analysis, 25 patients were positive for S. pneumoniae, 6 for N. meningitidis, and 1 for H. influenzae. Viral multiplex PCR identified infections with enterovirus (n = 26), VZV (n = 4), and HSV-1 (n = 2). No patient was positive for mumps or HSV-2. CONCLUSIONS: Study findings indicate that S. pneumoniae and enteroviruses are the main etiologies in this patient cohort. The utility of molecular diagnostics for pathogen identification combined with the knowledge provided by the investigation may improve health outcomes of CNS infection cases in Georgia