There 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. Capturing 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. A 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.

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.

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 (M1 _58–66 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.

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.

Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8⁺ T cells to mount robust responses. We elucidate the HLA-A*68:01⁺CD8⁺ T cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP₁₄₅⁺CD8⁺ T cell responses. Dissecting A68/NP₁₄₅⁺CD8⁺ T cells in low vs. medium/high responders reveals that high responding donors have A68/NP₁₄₅⁺CD8⁺ memory T cells with clonally expanded TCRαβs, while low-responders display A68/NP₁₄₅⁺CD8⁺ T cells with predominantly naïve phenotypes and non-expanded TCRαβs. Single-cell index sorting and TCRαβ analyses link expansion of A68/NP₁₄₅⁺CD8⁺ T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8⁺ T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8⁺ T cell compartments in HLA-A*68:01-expressing individuals for establishment of pre-existing protective memory T cell pools.