Bridget Pratt

MHC class I allele frequencies in pigtail macaques of diverse origin

Pigtail macaques (Macaca nemestrina) are an increasingly common primate model for the study of human AIDS. Major Histocompatibility complex (MHC) class I-restricted CD8+ T cell responses are a critical part of the adaptive immune response to HIV-1 in humans and simian immunodeficiency virus (SIV) in macaques; however, MHC class I alleles have not yet been comprehensively characterized in pigtail macaques. The frequencies of ten previously defined alleles (four Mane-A and six Mane-B) were investigated in detail in 109 pigtail macaques using reference strand-mediated conformational analysis (RSCA). The macaques were derived from three separate breeding colonies in the USA, Indonesia and Australia, and allele frequencies were analysed within and between these groups. Mane-A*10, an allele that restricts the immunodominant SIV Gag epitope KP9, was the most common allele, present in 32.1% of the animals overall, with similar frequencies across the three cohorts. Additionally, RSCA identified a new allele (Mane-A*17) common to three Indonesian pigtail macaques responding to the same Gag CD8+ T cell epitope. This broad characterization of common MHC class I alleles in more than 100 pigtail macaques further develops this animal model for the study of virus-specific CD8+ T cell responses.

Health research systems: promoting health equity or economic competitiveness?

International collaborative health research is justifiably expected to help reduce global health inequities. Investment in health policy and systems research in developing countries is essential to this process but, currently, funding for international research is mainly channelled towards the development of new medical interventions. This imbalance is largely due to research legislation and policies used in high-income countries. These policies have increasingly led these countries to invest in health research aimed at boosting national economic competitiveness rather than reducing health inequities. In the United States of America and the United Kingdom of Great Britain and Northern Ireland, the regulation of research has encouraged a model that: leads to products that can be commercialized; targets health needs that can be met by profitable, high-technology products; has the licensing of new products as its endpoint; and does not entail significant research capacity strengthening in other countries. Accordingly, investment in international research is directed towards pharmaceutical trials and product development public-private partnerships for neglected diseases. This diverts funding away from research that is needed to implement existing interventions and to strengthen health systems, i.e. health policy and systems research. Governments must restructure their research laws and policies to increase this essential research in developing countries.

Virus-Specific T-Cell Immunity Correlates with Control of GB Virus B Infection in Marmosets

ABSTRACT GB virus B (GBV-B) is a hepatotropic virus that is closely related to hepatitis C virus (HCV). GBV-B causes acute hepatitis in infected marmosets and tamarins and is therefore a useful small-animal model for the study of HCV. We investigated virus-specific T-cell responses in marmosets infected with GBV-B. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses in the peripheral blood of two marmosets were assessed throughout the course of GBV-B infection. These T-cell responses were directed against the GBV-B nonstructural proteins 3 (NS3), 4A (NS4A), and 5B (NS5B), and their appearance was temporally associated with clearance of viremia. These marmosets were then rechallenged with GBV-B at least 3 months after clearance of the primary infection to determine if the animals were protected from reinfection. There was no detectable viremia following reinfection, although a sharp increase in T-cell responses against GBV-B proteins was observed. Epitope mapping of T-cell responses to GBV-B was performed with liver and blood samples from both marmosets after rechallenge with GBV-B. Three shared, immunodominant T-cell epitopes within NS3 were identified in animals with multiple common major histocompatibility complex class I alleles. IFN-γ ELISPOT responses were also detected in the livers of two marmosets that had resolved a primary GBV-B infection. These responses were high in frequency and were directed against epitopes within GBV-B NS3, NS4A, and NS5B proteins. These results indicate that virus-specific T-cell responses are detectable in the liver and blood of GBV-B-infected marmosets and that the clearance of GBV-B is associated with the appearance of these responses.

Exploitation and community engagement: can community advisory boards successfully assume a role minimising exploitation in international research?

It has been suggested that community advisory boards (CABs) can play a role in minimising exploitation in international research. To get a better idea of what this requires and whether it might be achievable, the paper first describes core elements that we suggest must be in place for a CAB to reduce the potential for exploitation. The paper then examines a CAB established by the Shoklo Malaria Research Unit under conditions common in resource-poor settings - namely, where individuals join with a very limited understanding of disease and medical research and where an existing organisational structure is not relied upon to serve as the CAB. Using the Tak Province Border Community Ethics Advisory Board (T-CAB) as a case study, we assess the extent to which it might be able to take on a role minimising exploitation were it to decide to do so. We investigate whether, after two years in operation, T-CAB is capable of assessing clinical trials for exploitative features and addressing those found to have them. The findings show that, although T-CAB members have gained knowledge and developed capacities that are foundational for one-day taking on a role to reduce exploitation, their ability to critically evaluate studies for the presence of exploitative elements has not yet been strongly demonstrated. In light of this example, we argue that CABs may not be able to perform such a role for a number of years after initial formation, making it an unsuitable responsibility for many short-term CABs.

Evaluating the Capacity of Theories of Justice to Serve as a Justice Framework for International Clinical Research

This article investigates whether or not theories of justice from political philosophy, first, support the position that health research should contribute to justice in global health, and second, provide guidance about what is owed by international clinical research (ICR) actors to parties in low- and middle-income countries. Four theories—John Rawlss theory of justice, the rights-based cosmopolitan theories of Thomas Pogge and Henry Shue, and Jennifer Rugers health capability paradigm—are evaluated. The article shows that three of the four theories require the conduct of health research for justice in global health. The theories help identify the ends of justice to which ICR is to contribute, but they cannot tell us how to organize ICR to promote these ends. Aside from Rugers health capability paradigm, the theories also lack an allocative principle for assigning specific duties to specific actors. This creates difficulties for establishing obligations for certain types of ICR actors.

Governance of Transnational Global Health Research Consortia and Health Equity

Global health research partnerships are increasingly taking the form of consortia of institutions from high-income countries and low- and middle-income countries that undertake programs of research. These partnerships differ from collaborations that carry out single projects in the multiplicity of their goals, scope of their activities, and nature of their management. Although such consortia typically aim to reduce health disparities between and within countries, what is required for them to do so has not been clearly defined. This article takes a conceptual approach to explore how the governance of transnational global health research consortia should be structured to advance health equity. To do so, it applies an account called shared health governance to derive procedural and substantive guidance. A checklist based on this guidance is proposed to assist research consortia determine where their governance practices strongly promote equity and where they may fall short.

JUSTICE IN INTERNATIONAL CLINICAL RESEARCH

Debates about justice in international clinical research problematically conflate two quite different forms of obligation. International research ethics guidelines were intended to describe how to conduct biomedical research in a just manner at the micro or clinical level (within the researcher-participant interaction) but have come to include requirements that are clearly intended to promote justice at the global level. Ethicists have also made a variety of claims regarding what international research should contribute to global justice. This paper argues that the conflation of debates about justice at the micro and macro-levels has not only resulted in the placement of obligations upon the wrong actors but has also served to exclude relevant actors from the ethical picture. Suggestions for who should properly bear macro-level obligations of justice in international clinical research are offered. The paper further contends that, unlike researchers who violate informed consent requirements, no similar type of accountability exists for obligations of global justice, even for those obligation-bearers (incorrectly) identified by current ethics guidelines.

The ethics of health systems research in low- and middle-income countries: A call to action

The increasing conduct of health systems research (HSR) in low- and middle-income countries (LMICs) has not been matched by concurrent work to clarify the fields ethical dimensions. To begin to address this gap, a two-day workshop on the ethics of HSR in LMICs was convened at Johns Hopkins University in June 2013. Participants included health systems researchers, philosophers, lawyers, bioethicists and institutional review board members from Botswana, Uganda, the UK, USA and Zambia. Based on discussions from the workshop, the paper affirms that, while HSR in LMICs raises ethical issues in relation to constructs (i.e. consent, risk, equipoise) common to international clinical research, the nature of the issues that arise often differ between the two fields. Three salient features of HSR and the ethical considerations associated with each of them in LMICs are described to demonstrate this point. Recommendations for institutional review boards’ oversight of HSR in LMICs are presented. Finally, a call is made for further action to develop thinking and guidance around the ethics of HSR in resource-poor settings.

Ancillary Care: From Theory to Practice in International Clinical Research

How international research might contribute to justice in global health has not been substantively addressed by bioethics. This article describes how the provision of ancillary care can link international clinical research to the reduction of global health disparities. It identifies the ancillary care obligations supported by a theory of global justice, showing that Jennifer Ruger’s health capability paradigm requires the delivery of ancillary care to trial participants for a limited subset of conditions that cause severe morbidity and mortality. Empirical research on the Shoklo Malaria Research Unit’s (SMRU) vivax malaria treatment trial was then undertaken to demonstrate whether and how these obligations might be upheld in a resource-poor setting. Our findings show that fulfilment of the ancillary care obligations is feasible where there is commitment from chief investigators and funders and is strongly facilitated by SMRU’s dual role as a research unit and medical non-governmental organization.

Applying a Global Justice Lens to Health Systems Research Ethics: An Initial Exploration

Recent scholarship has considered what, if anything, rich people owe to poor people to achieve justice in global health and the implications of this for international research. Yet this work has primarily focused on international clinical research. Health systems research is increasingly being performed in low and middle income countries and is essential to reducing global health disparities. This paper provides an initial description of the ethical issues related to priority setting, capacity-building, and the provision of post-study benefits that arise during the conduct of such research. It presents a selection of issues discussed in the health systems research literature and argues that they constitute ethical concerns based on their being inconsistent with a particular theory of global justice (the health capability paradigm). Issues identified include the fact that priority setting for health systems research at the global level is often not driven by national priorities and that capacity-building efforts frequently utilize one-size-fits-all approaches.