Adrian Miller

Preexisting CD8+ T-cell immunity to the H7N9 influenza A virus varies across ethnicities

Significance The severity of the novel H7N9 influenza A virus (IAV) and the lack of neutralizing antibodies raise real pandemic concerns. In this scenario, CD8+ T lymphocytes (CTLs) may provide a layer of protection against the H7N9 virus. Our study dissects the extent of preexisting CTL immunity with the potential to respond to H7N9. We identified conserved immunogenic peptides with the capacity to elicit robust CTL responses against any human IAV, including the H7N9 virus, as well as the mutations that abolish CTL recognition. The human leukocyte antigen class I molecules that present these peptides vary in prevalence depending on the ethnicity. Such analyses found that the Alaskan and Australian Indigenous people may be particularly vulnerable to the H7N9 influenza disease. The absence of preexisting neutralizing antibodies specific for the novel A (H7N9) influenza virus indicates a lack of prior human exposure. As influenza A virus–specific CD8+ T lymphocytes (CTLs) can be broadly cross-reactive, we tested whether immunogenic peptides derived from H7N9 might be recognized by memory CTLs established following infection with other influenza strains. Probing across multiple ethnicities, we identified 32 conserved epitopes derived from the nucleoprotein (NP) and matrix-1 (M1) proteins. These NP and M1 peptides are presented by HLAs prevalent in 16–57% of individuals. Remarkably, some HLA alleles (A*0201, A*0301, B*5701, B*1801, and B*0801) elicit robust CTL responses against any human influenza A virus, including H7N9, whereas ethnicities where HLA-A*0101, A*6801, B*1501, and A*2402 are prominent, show limited CTL response profiles. By this criterion, some groups, especially the Alaskan and Australian Indigenous peoples, would be particularly vulnerable to H7N9 infection. This dissection of CTL-mediated immunity to H7N9 thus suggests strategies for both vaccine delivery and development.

Molecular basis for universal HLA-A*0201–restricted CD8+ T-cell immunity against influenza viruses

Significance Influenza is a rapidly spreading acute respiratory infection that causes profound morbidity and mortality. Established CD8+ T-lymphocyte (CTL) immunity directed at conserved viral regions provides protection against distinct influenza A viruses (IAVs). In this study, we show that public T-cell receptors (TCRs) specific for the most prominent human CTL epitope (M158–66 restricted by HLA-A*0201) are capable of recognizing sporadically emerging variant IAVs. We also identify the structural mechanisms that enable promiscuous TCR recognition in this context. Our analysis suggests that preexisting cross-reactive TCRs may limit the spread of newly emerging pandemic IAVs. Memory CD8+ T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide–HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M158 and the hypervariable HLA-B*3501-NP418 antigens. The TCRαβs for HLA-B*3501-NP418+ CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19+ TCRαβ was selected in HLA-A*0201+ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19+ TCR specificity for the WT and mutant M158 peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201+ individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M158. Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.

Challenges faced by Indigenous nursing students and strategies that aided their progress in the course: A descriptive study

Abstract Marked improvements in Indigenous health can be achieved by increasing the participation of Indigenous people in the health professions. Currently in Australia the participation by Indigenous people in the health professions is low and the Indigenous people of Australia continue to have poor health outcomes. This qualitative study utilised interviews with 22 Indigenous students enrolled in undergraduate nursing degrees across Australia, to explore the challenges they faced and uncover the strategies they had found helpful to their progress in the course. The findings indicate that students are challenged by financial hardship, staff insensitivity to cultural issues, discrimination, lack of Indigenous mentors, poor study skills, lack of adequate educational preparation, lack of resources, and ongoing family commitments. Strategies identified as particularly helpful to tenure within the course include specific Indigenous support units, adequate financial support, interested academics, Aboriginal Tertiary Assistance Scheme (ATAS) tutors, support from family and friends, and support from other students.

No one’s discussing the elephant in the room: contemplating questions of research impact and benefit in Aboriginal and Torres Strait Islander Australian health research

BackgroundThere remains a concern that Indigenous Australians have been over-researched without corresponding improvements in their health; this trend is applicable to most Indigenous populations globally. This debate article has a dual purpose: 1) to open a frank conversation about the value of research to Indigenous Australian populations; and 2) to stimulate ways of thinking about potential resolutions to the lack of progress made in the Indigenous research benefit debate.DiscussionCapturing the meaning of research benefit takes the form of ethical value-oriented methodological considerations in the decision-making processes of Indigenous research endeavours. Because research practices come from Western knowledge bases, attaining such positions in research means reconciling both Indigenous and Western knowledge systems to produce new methodologies that guide planning, evaluating and monitoring of research practices as necessary. Increasingly, more sophisticated performance measures have been implemented to ensure academic impact and benefits are captured. Assessing societal and other non-academic impacts and benefits however, has not been accorded corresponding attention. Research reform has only focussed on research translation in more recent years. The research impact debate must take account of the various standards of accountability (to whom), impact priorities (for whom), positive and negative impacts, and biases that operate in describing impact and measuring benefit.SummaryA perennial question in Indigenous research discourse is whether the abundance of research conducted; purportedly to improve health, is justified and benefits Indigenous people in ways that are meaningful and valued by them. Different research stakeholders have different conceptions of the value and nature of research, its conduct, what it should achieve and the kinds of benefits expected. We need to work collaboratively and listen more closely to the voice of Indigenous Australians to better understand, demonstrate and measure health research benefits. The authors conclude that as an imperative, a systematic benefit assessment strategy that includes identification of research priorities and planning, monitoring and evaluation components needs to be developed and implemented across research projects. In Indigenous health research, this will often mean adopting a benefit-led approach by changing the way research is done and preferencing alternative research methodologies. As a point of departure to improving impact and reaching mutually beneficial outcomes for researchers and partners in Indigenous health research, we need to routinise the assessment of benefit from outset of research as one of the standards toward which we work.

Australian Aboriginal and Torres Strait Islander communities and the development of pandemic influenza containment strategies: Community voices and community control

OBJECTIVES To develop culturally appropriate and effective strategies to reduce the risk from pandemic influenza (H1N109) in rural and remote Australian Aboriginal and Torres Strait Islander communities. METHODS Participatory Action Research (PAR) approach that enabled communities and researchers to work together to develop understanding and take action to reduce risk. RESULTS The H1N109 pandemic raised deep concerns and serious issues in all of the Aboriginal and Torres Strait Islander communities involved in this project. The participants expressed distrust and scepticism in relation to current Australian health policies on containment and told the researchers that specific plans for Aboriginal and Torres Strait Islander peoples were needed. Respondents indicated that policies and plans had been developed without respectful engagement with communities. The strong and recurring themes that emerged from the PAR cycles were: the importance of family; ways of life and realities of living in response to influenza; and key messages to government and health services to focus on communication, understanding and respect. CONCLUSION The essential work of reducing risk of pandemic influenza with Aboriginal and Torres Strait Islander communities is not straightforward, but this project has highlighted a number of useful pathways to continue to journey along with communities. A number of strategies to reduce the spread of pandemic influenza in Aboriginal and Torres Strait Islander communities were identified. These strategies would make a good starting point for conversations with communities and health services. In Aboriginal and Torres Strait Islander communities the environment, community structures and traditions vary. Respectful engagement with communities is needed to develop effective policy.

Strongyloides stercoralis: systematic review of barriers to controlling strongyloidiasis for Australian Indigenous communities

Background Strongyloides stercoralis infects human hosts mainly through skin contact with contaminated soil. The result is strongyloidiasis, a parasitic disease, with a unique cycle of auto-infection causing a variety of symptoms and signs, with possible fatality from hyper-infection. Australian Indigenous community members, often living in rural and remote settings, are exposed to and infected with S. stercoralis. The aim of this review is to determine barriers to control of strongyloidiasis. The purpose is to contribute to the development of initiatives for prevention, early detection and effective treatment of strongyloidiasis. Methodology/Principle Findings Systematic search reviewing research published 2012 and earlier was conducted. Research articles discussing aspects of strongyloidiasis, context of infection and overall health in Indigenous Australians were reviewed. Based on the PRISMA statement, the systematic search of health databases, Academic Search Premier, Informit, Medline, PubMed, AMED, CINAHL, Health Source Nursing and Academic was conducted. Key search terms included strongyloidiasis, Indigenous, Australia, health, and community. 340 articles were retrieved with 16 original research articles published between 1969 and 2006 meeting criteria. Review found barriers to control defined across three key themes, (1) health status, (2) socioeconomic status, and (3) health care literacy and procedures. Conclusions/Significance This study identifies five points of intervention: (1) develop reporting protocols between health care system and communities; (2) test all Indigenous Australian patients, immunocompromised patients and those exposed to areas with S. stercoralis; (3) health professionals require detailed information on strongyloidiasis and potential for exposure to Indigenous Australian people; (4) to establish testing and treatment initiatives within communities; and (5) to measure and report prevalence rates specific to communities and to act with initiatives based on these results. By defining barriers to control of strongyloidiasis in Australian Indigenous people, improved outcomes of prevention, treatment of strongyloidiasis and increased health overall are attainable.

Study Protocol - Alcohol Management Plans (AMPs) in remote indigenous communities in Queensland: Their impacts on injury, violence, health and social indicators and their cost-effectiveness

BackgroundIn 2002/03 the Queensland Government responded to high rates of alcohol-related harm in discrete Indigenous communities by implementing alcohol management plans (AMPs), designed to include supply and harm reduction and treatment measures. Tighter alcohol supply and carriage restrictions followed in 2008 following indications of reductions in violence and injury. Despite the plans being in place for over a decade, no comprehensive independent review has assessed to what level the designed aims were achieved and what effect the plans have had on Indigenous community residents and service providers. This study will describe the long-term impacts on important health, economic and social outcomes of Queensland’s AMPs.Methods/DesignThe project has two main studies, 1) outcome evaluation using de-identified epidemiological data on injury, violence and other health and social indicators for across Queensland, including de-identified databases compiled from relevant routinely-available administrative data sets, and 2) a process evaluation to map the nature, timing and content of intervention components targeting alcohol. Process evaluation will also be used to assess the fidelity with which the designed intervention components have been implemented, their uptake and community responses to them and their perceived impacts on alcohol supply and consumption, injury, violence and community health. Interviews and focus groups with Indigenous residents and service providers will be used. The study will be conducted in all 24 of Queensland’s Indigenous communities affected by alcohol management plans.DiscussionThis evaluation will report on the impacts of the original aims for AMPs, what impact they have had on Indigenous residents and service providers. A central outcome will be the establishment of relevant databases describing the parameters of the changes seen. This will permit comprehensive and rigorous surveillance systems to be put in place and provided to communities empowering them with the best credible evidence to judge future policy and program requirements for themselves. The project will inform impending alcohol policy and program adjustments in Queensland and other Australian jurisdictions.The project has been approved by the James Cook University Human Research Ethics Committee (approval number H4967 & H5241).

Towards identification of immune and genetic correlates of severe influenza disease in Indigenous Australians

Indigenous populations, including Indigenous Australians, are highly susceptible to severe influenza disease and the underlying mechanisms are unknown. We studied immune and genetic factors that could predicate severe influenza disease in Indigenous Australians enrolled in the LIFT study: looking into influenza T‐cell immunity. To examine CD8+ T‐cell immunity, we characterised human leukocyte antigen (HLA) profiles. HLA typing confirmed previous studies showing predominant usage of HLA‐A*02:01, 11:01, 24:02, 34:01 and HLA‐B*13:01, 15:21, 40:01/02, 56:01/02 in Indigenous Australians. We identified two new HLA alleles (HLA‐A*02:new and HLA‐B*56:new). Modelling suggests that variations within HLA‐A*02:new (but not HLA‐B56:new) could affect peptide binding. There is a relative lack of known influenza epitopes for the majority of these HLAs, with the exception of a universal HLA‐A*02:01‐M158 epitope and proposed epitopes presented by HLA‐A*11:01/HLA‐A*24:02. To dissect universal CD8+ T‐cell responses, we analysed the magnitude, function and T‐cell receptor (TCR) clonality of HLA‐A*02:01‐M158 +CD8+ T cells. We found comparable IFN‐γ, TNF and CD107a and TCRαβ characteristics in Indigenous and non‐Indigenous Australians, suggesting that the ~15% of Indigenous people that express HLA‐A*02:01 have universal influenza‐specific CD8+ T‐cell immunity. Furthermore, the frequency of an influenza host risk factor, IFITM3‐C/C, was comparable between Indigenous Australians and Europeans, suggesting that expression of this allele does not explain increased disease severity at a population level. Our study indicates a need to identify novel influenza‐specific CD8+ T‐cell epitopes restricted by HLA‐A and HLA‐B alleles prevalent in Indigenous populations for the rational design of universal T‐cell vaccines.

Strongyloidiasis: a case for notification in Australia?

TO THE EDITOR: Hillman and colleagues give an excellent overview of rapid response systems (RRSs).1 There is no doubt that this system of care that matches “the right people — with the right skills and knowledge — with the right patients at the right time” is a vast improvement on the usual traditional hierarchical referral model of care, particularly for patients in acute care hospitals whose condition is deteriorating.

The National Strongyloides Working Group in Australia 10 workshops on: commendations and recommendations

[Extract] Strongyloidiasis, caused by the intestinal helminth Strongyloides stercoralis, is commonly found in developing nations in tropical and subtropical regions. Strongyloidiasis was omitted by the World Health Organization (WHO) as one of the Soil Transmitted Helminths in their Neglected Tropical Diseases Roadmap and can therefore be considered one of the most neglected tropical diseases. Despite its reputation as a disease of developing countries, strongyloidiasis remains an important disease in Australia, particularly for Aboriginal and Torres Strait Islanders, and those living in remote communities.