Foundations in Global Health Research Methodologies

This presentation provides an overview of epidemiology and research methodologies, and addresses the following questions: What is epidemiology and translational research? What are standard study designs? How is data collected? How is data analyzed? When to seek IRB approval? How to find a research mentor? How is research funded? Ultimate goals: changes in health‐care practices and public health policies

Epidemic to Endemic or Pandemic Infectious Diseases: Commonalities and Distinctions between Malaria, Ebola and COVID19

This presentation provides an overview of epidemics by discussing malaria, Ebola and COVID-19: definition of terms; examples of diseases, transmission and health impact; diagnostics versus presumptive diagnosis –how to make strategic decisions with limited resources and specific context; how strategies are modified by what we learn -- how fast can we adapt; control, elimination, eradication -- modeling the end game

Foundations in Global Health Research Methodologies: Pre-course information

This pre-course presentation for the Foundations in Global Health Research Methodologies course includes learning objectives and quizzes

The hunt for protective correlates of immunity to Plasmodium falciparum malaria

Determining an immunologic correlate of protection against Plasmodium falciparum malaria has been the holy grail of natural infection studies, and sought after as an endpoint for malaria vaccine trials. An in vitro assay that provides an accurate and precise assessment of protective immunity to malaria would make smaller, short-duration studies feasible, rather than the currently powered study designs that use morbidity or mortality as outcomes. Such a biomarker would be especially desirable in situations where malaria control measures that result in decreases in clinical endpoints and putatively waning protective immunity have been implemented. In an article published in BMC Medicine, Osier and colleagues addressed this problem, and demonstrated that antibodies promoting opsonic phagocytosis of merozoites provide a functional link between antigen-specific responses and protection. Understanding the mechanisms conferring protection against malaria not only improves our knowledge of basic human immunology, but promises to help in the design of an effective malaria vaccine

New gorilla adenovirus vaccine vectors induce potent immune responses and protection in a mouse malaria model

BACKGROUND: A DNA-human Ad5 (HuAd5) prime-boost malaria vaccine has been shown to protect volunteers against a controlled human malaria infection. The potency of this vaccine, however, appeared to be affected by the presence of pre-existing immunity against the HuAd5 vector. Since HuAd5 seroprevalence is very high in malaria-endemic areas of the world, HuAd5 may not be the most appropriate malaria vaccine vector. This report describes the evaluation of the seroprevalence, immunogenicity and efficacy of three newly identified gorilla adenoviruses, GC44, GC45 and GC46, as potential malaria vaccine vectors. RESULTS: The seroprevalence of GC44, GC45 and GC46 is very low, and the three vectors are not efficiently neutralized by human sera from Kenya and Ghana, two countries where malaria is endemic. In mice, a single administration of GC44, GC45 and GC46 vectors expressing a murine malaria gene, Plasmodium yoelii circumsporozoite protein (PyCSP), induced robust PyCSP-specific T cell and antibody responses that were at least as high as a comparable HuAd5-PyCSP vector. Efficacy studies in a murine malaria model indicated that a prime-boost regimen with DNA-PyCSP and GC-PyCSP vectors can protect mice against a malaria challenge. Moreover, these studies indicated that a DNA-GC46-PyCSP vaccine regimen was significantly more efficacious than a DNA-HuAd5-PyCSP regimen. CONCLUSION: These data suggest that these gorilla-based adenovectors have key performance characteristics for an effective malaria vaccine. The superior performance of GC46 over HuAd5 highlights its potential for clinical development

Human monoclonal antibodies to Plasmodium falciparum circumsporozoite protein for transient passive protection of malaria travelers to endemic areas

Plasmodium falciparum, is a protozoa that causes over 214 million cases of Malaria worldwide and the World Health Organization reported an estimated 438,000 deaths attributed to malaria in 2015. Current prevention strategies have reduced malaria cases but they are either costly, have poor efficacy or resistance has begun to develop. There is a global need for an effective pre-exposure prophylaxis treatment. The leading Malaria vaccine candidate is RTS,S which contains a monovalent Plasmodium falciparum circumsporozoite protein (CSP). The goal of this vaccine is to induce anti-CSP antibodies that would block sporozoite invasion of hepatocytes and thereby hinder parasite development into a blood-stage infection that causes malaria morbidity and mortality. Antibodies isolated from individuals who have received the RTS,S vaccine have been shown to prevent infection of hepatocytes, suggesting that CSP antibodies could be used prophylactically. However, phase III trial results of the vaccine have shown underwhelming efficacy in children. Growing resistance to transient protection strategies for travelers and low efficacy in vaccine trials suggest there is a need for a new treatment strategy. The generation of CSP specific human monoclonal antibodies (mAbs) would be useful as prevention especially for individuals that are temporarily exposed to Malaria in endemic regions such as travelers or military personnel. Isolation and production of therapeutic mAbs traditionally utilizes a handful of techniques including antibody engineering, phage display or hybridoma generation from transgenic mice. We have sorted antigen-specific memory B-cells from the peripheral blood of children naturally infected with malaria to isolate CSP-specific memory B-cells. These cells were individually sorted and PCR was performed to amplify antibody variable regions of the B-cell’s antibody mRNA. Samples that produced heavy and light chain antibody sequence were cloned and transiently expressed. We plan to characterize these mAbs for binding and neutralization of CSP to identify functional therapeutic mAbs

Presentation and Treatment Outcomes of Liberian Children Age 5 Years and Under Diagnosed With Severe Malaria

Malaria is endemic in Liberia with a prevalence rate of up to 60% in some regions, and it has been a major cause of death in children under 5 years of age. Prior to the recent Ebola epidemic, we undertook a prospective, hospital-based pilot study at the National Referral Hospital in Monrovia, to characterize the presentation, accuracy of diagnosis, and treatment outcomes of children presenting for treatment of malaria. From June 2013 to May 2014, we recruited children 5 years and under who presented to the JFK Medical Center with suspected malaria. We collected both clinical and laboratory data on admission and on discharge. We enrolled 477 patients with an average age of 1.6 years. Demographic factors associated with testing negative for malaria included regular bed net use and prior treatment for malaria. The most common presenting symptoms of severe malaria in this population were headache and seizures. Of 246 patients admitted and treated for severe malaria, 33% tested negative by rapid diagnostic test and blood smear for malaria. The case fatality rate was higher for the patients who tested negative for malaria (4.9%) versus those who tested positive (0.6%). Three children who tested negative for malaria showed evidence of undiagnosed Salmonella typhi infection. These results suggest that malaria may be overdiagnosed and that the diagnoses of other infectious diseases, which present in a similar fashion, may be neglected. These findings underscore the need to develop rapid diagnostic tests to screen for alternative causes of febrile illness

Sensitive detection of EBV microRNAs across cancer spectrum reveals association with decreased survival in adult acute myelocytic leukemia

Epstein Barr virus (EBV) is the etiologic agent involved in numerous human cancers. After infecting the host, EBV establishes a latent infection, with low levels of messenger RNA (mRNA) and protein expression, evolved to evade immune recognition. Conversely, EBV microRNAs (miRNA) are expressed ubiquitously and abundantly within infected cells. Their role in tumor biology and clinical outcomes across the spectrum of cancer is not fully explained. Here, we applied our bioinformatics pipeline for quantitative EBV miRNA detection to examine sequencing data of 8,955 individual tumor samples across 27 tumor types representing the breadth of cancer. We uncover an association of intermediate levels of viral miRNA with decreased survival in adult acute myeloid leukemia (AML) patients (P = 0.00013). Prognostic modeling of this association suggests that increased EBV miRNA levels represent an independent risk factor for poor patient outcomes. Furthermore, we explore differences in expression between elevated and absent viral miRNA loads in adult AML tumors finding that EBV positivity was associated with proinflammatory signals. Together, given no associations were found for pediatric AML, our analyses suggests EBV positivity has the potential for being a prognostic biomarker and might represent a surrogate measure related to immune impairment in adult patients

Mentoring future Kenyan oncology researchers

This is a summary of the 1st Academic Model Providing Access to Healthcare (AMPATH) Oncology Institute research grant writing workshop organized in collaboration with the Kenya Medical Research Institute (KEMRI) and held in Kisumu, Kenya from January 16th to 18th, 2013. The goal of this meeting was to mentor future Kenyan scientists and prioritize research topics that would lead to improved cancer care and survival for the citizens of Kenya