Principal Research Fellow Research Articles

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine.

The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine. Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The 'beta variant' RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5. These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial. This work was supported by grants from the Medical Research Future Fund (MRFF) (2005846), The Jack Ma Foundation, National Health and Medical Research Council of Australia (NHMRC; 1113293) and Singapore National Medical Research Council (MOH-COVID19RF-003). Individual researchers were supported by an NHMRC Senior Principal Research Fellowship (1117766), NHMRC Investigator Awards (2008913 and 1173871), Australian Research Council Discovery Early Career Research Award (ARC DECRA; DE210100705) and philanthropic awards from IFM investors and the A2 Milk Company.

Familial aggregation of esophageal cancer.

Familial aggregation of esophageal cancer.

Editorial introductions.

Editorial introductions.

Menopause, hysterectomy, menopausal hormone therapy and cause-specific mortality: cohort study of UK Biobank participants.

STUDY QUESTIONWhat is the association between menopausal hormone therapy (MHT) and cause-specific mortality?SUMMARY ANSWERSelf-reported MHT use following early natural menopause, surgical menopause or premenopausal hysterectomy is associated with a lower risk of breast cancer mortality and is not consistently associated with the risk of mortality from cardiovascular disease or other causes.WHAT IS KNOWN ALREADYEvidence from the Women’s Health Initiative randomized controlled trials showed that the use of estrogen alone is not associated with the risk of cardiovascular mortality and is associated with a lower risk of breast cancer mortality, but evidence from the Million Women Study showed that use of estrogen alone is associated with a higher risk of breast cancer mortality.STUDY DESIGN, SIZE, DURATIONCohort study (the UK Biobank), 178 379 women, recruited in 2006–2010.PARTICIPANTS/MATERIALS, SETTING, METHODSPostmenopausal women who had reported age at menopause (natural or surgical) or hysterectomy, and information on MHT and cause-specific mortality. Age at natural menopause, age at surgical menopause, age at hysterectomy and MHT were exposures of interest. Natural menopause was defined as spontaneous cessation of menstruation for 12 months with no previous hysterectomy or oophorectomy. Surgical menopause was defined as the removal of both ovaries prior to natural menopause. Hysterectomy was defined as removal of the uterus before natural menopause without bilateral oophorectomy. The study outcome was cause-specific mortality.MAIN RESULTS AND THE ROLE OF CHANCEAmong the 178 379 women included, 136 790 had natural menopause, 17 569 had surgical menopause and 24 020 had hysterectomy alone. Compared with women with natural menopause at the age of 50–52 years, women with natural menopause before 40 years (hazard ratio (HR): 2.38, 95% CI: 1.64, 3.45) or hysterectomy before 40 years (HR: 1.60, 95% CI: 1.23, 2.07) had a higher risk of cardiovascular mortality but not cancer mortality. MHT use was associated with a lower risk of breast cancer mortality following surgical menopause before 45 years (HR: 0.17, 95% CI: 0.08, 0.36), at 45–49 years (HR: 0.15, 95% CI: 0.07, 0.35) or at ≥50 years (HR: 0.28, 95% CI: 0.13, 0.63), and the association between MHT use and the risk of breast cancer mortality did not differ by MHT use duration (<6 or 6–20 years). MHT use was also associated with a lower risk of breast cancer mortality following natural menopause before 45 years (HR: 0.59, 95% CI: 0.36, 0.95) or hysterectomy before 45 years (HR: 0.49, 95% CI: 0.32, 0.74).LIMITATIONS, REASONS FOR CAUTIONSelf-reported data on age at natural menopause, age at surgical menopause, age at hysterectomy and MHT.WIDER IMPLICATIONS OF THE FINDINGSThe current international guidelines recommend women with early menopause to use MHT until the average age at menopause. Our findings support this recommendation.STUDY FUNDING/COMPETING INTEREST(S)This project is funded by the Australian National Health and Medical Research Council (NHMRC) (grant numbers APP1027196 and APP1153420). G.D.M. is supported by NHMRC Principal Research Fellowship (APP1121844), and M.H. is supported by an NHMRC Investigator Grant (APP1193838). There are no competing interests.TRIAL REGISTRATION NUMBERN/A.

The Role of Child Diets in the Association between Pre-pregnancy Diets and Childhood Behavioral Problems: A Mediation Analysis

ObjectivesTo quantify the mediating role of childhood diets in the association between maternal diets before pregnancy and offspring behavioral problems.MethodsThis study included 1448 mother-child pairs from the Australian longitudinal study on women's health and its sub-study mothers and their children's health. The healthy eating index score was constructed using a semi-quantitative and validated 101-item food-frequency questionnaire. Childhood behavioral problems were assessed using the strengths and difficulties questionnaire. Three dietary patterns were identified using principal component analysis to explore childhood dietary patterns (high fats and sugar; prudent diets; and diary). A causal inference framework for mediation analysis was used to quantify the mediating role of childhood diets in the association between pre-pregnancy diets and the risk of offspring behavioral problems.ResultsWe found a 20% of the total effect of the poor adherence to pre-pregnancy diet quality on the risk of offspring behavioral problems was mediated through childhood high consumptions of fats and sugar. No clear mediating effect through prudent, and diary childhood diets was observed.ConclusionsThis study suggests that childhood high fats and sugar consumption may contribute to the total effects of the pre-pregnancy diets on the risk of childhood behavioral problems.Funding SourcesThe ALSWH is funded by the Australian Government Department of Health. MatCH is funded by the National Health and Medical Research Council (NHMRC) project grant. Dereje Gete is supported by the University of Queensland Research Training Scholarship. Gita Mishra holds the Australian Health and Medical Research Council Principal Research Fellowship.

Listening to the silent struggles of bipolar disorder through sonification of iMoodJournal data.

Listening to the silent struggles of bipolar disorder through sonification of iMoodJournal data.

MTOR-associated Mitochondrial Energy Metabolism Limits Mycobacterium ESX-1-induced Cytotoxicity

Abstract Necrosis of macrophages in the tuberculous granuloma represents a major pathogenic event in tuberculosis. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations were required to prevent mitochondrial damage and death caused specifically by the mycobacterial ESX-1 secretion system. Our finding that the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism may help explain why Mycobacterium tuberculosis, albeit humanity’s most lethal pathogen, only causes disease in a minority of infected individuals. This work was supported by a Wellcome Trust Principal Research Fellowship (103950/Z/14) and an NIH MERIT award (R37 AI054503) (L.R.).

Limitations of the new ISO standard for health and wellness apps

Limitations of the new ISO standard for health and wellness apps

A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2.

BackgroundAs vaccines against SARS-CoV-2 are now being rolled out, a better understanding of immunity to the virus, whether from infection, or passive or active immunisation, and the durability of this protection is required. This will benefit from the ability to measure antibody-based protection to SARS-CoV-2, ideally with rapid turnaround and without the need for laboratory-based testing.MethodsWe have developed a lateral flow POC test that can measure levels of RBD-ACE2 neutralising antibody (NAb) from whole blood, with a result that can be determined by eye or quantitatively on a small instrument. We compared our lateral flow test with the gold-standard microneutralisation assay, using samples from convalescent and vaccinated donors, as well as immunised macaques.FindingsWe show a high correlation between our lateral flow test with conventional neutralisation and that this test is applicable with animal samples. We also show that this assay is readily adaptable to test for protection to newly emerging SARS-CoV-2 variants, including the beta variant which revealed a marked reduction in NAb activity. Lastly, using a cohort of vaccinated humans, we demonstrate that our whole-blood test correlates closely with microneutralisation assay data (specificity 100% and sensitivity 96% at a microneutralisation cutoff of 1:40) and that fingerprick whole blood samples are sufficient for this test.InterpretationTaken together, the COVID-19 NAb-testTM device described here provides a rapid readout of NAb based protection to SARS-CoV-2 at the point of care.FundingSupport was received from the Victorian Operational Infrastructure Support Program and the Australian Government Department of Health. This work was supported by grants from the Department of Health and Human Services of the Victorian State Government; the ARC (CE140100011, CE140100036), the NHMRC (1113293, 2002317 and 1116530), and Medical Research Future Fund Awards (2005544, 2002073, 2002132). Individual researchers were supported by an NHMRC Emerging Leadership Level 1 Investigator Grants (1194036), NHMRC APPRISE Research Fellowship (1116530), NHMRC Leadership Investigator Grant (1173871), NHMRC Principal Research Fellowship (1137285), NHMRC Investigator Grants (1177174 and 1174555) and NHMRC Senior Principal Research Fellowships (1117766 and 1136322). Grateful support was also received from the A2 Milk Company and the Jack Ma Foundation.

Regeneration in the phylogenetic empire: an interview with Peter Currie.

Regeneration in the phylogenetic empire: an interview with Peter Currie.

Substituting serum anti-Müllerian hormone for polycystic ovary morphology increases the number of women diagnosed with polycystic ovary syndrome: a community-based cross-sectional study.

Can serum anti-Müllerian hormone (AMH) replace polycystic ovary morphology (PCOM) determined by ultrasound as a diagnostic component of polycystic ovary syndrome (PCOS)? Despite good correlations between serum AMH and PCOM, the use of a high serum AMH as a proxy for PCOM resulted in the reclassification of PCOS in 5% of study participants, with the main effect being more women identified, although some women previously classified as having PCOS were no longer classified as such. AMH has been proposed as an alternative to PCOM as a diagnostic component of PCOS. Previous studies are limited by poorly defining PCOS, use of infertile women as comparators, measurement of hormones by immunoassay that lack precision in the female range, low-resolution ovarian ultrasound and inconsistent handling and storage of serum samples. This is an Australian cross-sectional study of 163 non-healthcare-seeking women. Serum AMH was measured by both the Ansh picoAMH assay and the Beckman Coulter Access 2 (BA2) assay, in parallel with androgens measured by liquid chromatography-tandem mass spectrometry, in blood samples of women, not pregnant, breast feeding or using systemic steroids, who also underwent high-resolution ovarian ultrasound. PCOS was determined by the Rotterdam criteria with PCOM defined by the Androgen Excess-PCOS Taskforce recommendation of ≥25 follicles in at least one ovary. Cut-off serum concentrations that best identified women as having PCOM were identified by receiver operator characteristic (ROC) curves. A total of 163 women, mean (SD) age 32.5 (5.5) years, who provided a blood sample and had both ovaries visualized on ultrasound were included in the analysis. Women with isolated PCOM had higher median (range) Ansh AMH and BA2 AMH concentrations than those with no PCOS characteristics [56.9 pmol/l (34.6, 104.2) versus 18.7 (3.2, 50.9), P = 0.002 and 38.5 pmol/l (22.2, 100.2) versus 16.7 (3.5, 38.9), P = 0.002, respectively]. An AMH ≥ 44.0 pmol/l, suggested by the ROC curve, identified 80.6% of women with PCOM, falsely identified 15.2% of women without PCOM as having PCOS and had a positive predictive value of 55.6%. The negative predictive value was 94.9%. An AMH BA2 assay cut-off of ≥33.2 pmol/l provided a sensitivity of 80.6%, a specificity of 79.5% and a positive predictive value for PCOM of 48.1%. The negative predictive value was 94.6% for PCOM. When serum AMH was used in the place of PCOM as a diagnostic criterion for PCOS, the Ansh assay resulted in an additional seven women classified as having PCOS and no longer classified one woman as having PCOS. For the BA2 assay, eight additional and two fewer women were classified as having PCOS. Overall, both assays resulted in six more women being classified as having PCOS. Women with functional hypogonadotrophic hypogonadism were not excluded and may have been misclassified as having an oligo-amenorrhoea-PCOM phenotype. As study participants were predominantly Caucasian/White, our findings cannot be generalized to women of other ethnicities. Although serum AMH reflects the number of developing ovarian follicles, the absolute values vary between assays and specific reference ranges for individual assays are required. Irrespective of the assay used, replacing PCOM with serum AMH to diagnose PCOS in a community-based sample altered the number of women classified as having or not having PCOS. Consequently, although overall the risk of women being identified as having PCOS would be increased, some women would no longer be classified as having this condition. The study was supported by the Norman Beischer Research Foundation and the Grollo-Ruzzene Foundation. S.R.D. is an NHMRC Senior Principal Research Fellow (Grant No. 1135843). S.R.D. reports unrelated support that includes grants from the NHMRC Australia, personal fees for educational activities from Besins Healthcare, Abbott Chile, BioFemme and Pfizer Australia, personal Advisory Board/consultancy fees from Theramex, Abbott Laboratories, Astellas, Mayne Pharmaceuticals, Roche Diagnostics, Lawley Pharmaceuticals and Que Oncology and has received institutional grant funding from Que Oncology and Ovoca research. The other authors declare no conflicts of interest. N/A.

Delayed diagnosis of endometriosis disadvantages women in ART: a retrospective population linked data study

Abstract STUDY QUESTION Do the outcomes and use of ART differ between women with and without endometriosis? SUMMARY ANSWER ART use and outcome do not appear to differ for women with and without endometriosis, as long as endometriosis is diagnosed prior to commencing ART. WHAT IS KNOWN ALREADY Approximately 40% of women with endometriosis have infertility and ART is the recommended treatment option for these women. However, diagnosis of endometriosis can be complex and lengthy, and a delay in diagnosis can reduce the likelihood of achieving a live birth. STUDY DESIGN, SIZE, DURATION This retrospective national cohort study used longitudinal self-report data (collected 1996–2018) from women born in 1973–1978 who are participants in the Australian Longitudinal Study on Women’s Health (ALSWH). The study also used linked administrative data on Endometriosis (1970–2018), ART (1996–2020) and births (1996–2018). PARTICIPANTS/MATERIALS, SETTING, METHODS The outcome measures were: age at first ART cycle; use of ART treatments (IVF only; IUI only/and IVF); number of ART cycles (1–3; 4–10; 11–36); and births after first ART (no; yes) (note that births could not be tied to ART). MAIN RESULTS AND THE ROLE OF CHANCE One in three (34.7%, n = 459/1322) women using ART had endometriosis, with 65.6% of these diagnosed before first ART and 34.4% after. Adjusted regression analyses showed women with endometriosis diagnosed before first ART were not significantly different to women without endometriosis on any outcome. However, women with endometriosis diagnosed after first ART were more likely to use IUI (adjusted odds ratio (aOR) 2.14, 95% CI 1.48, 3.09) and do more cycles (11–36 cycles: aOR 4.09, 95% CI 2.41, 6.95), and less likely to report a birth (aOR 0.67, 95% CI 0.45, 0.99), compared to women without endometriosis, despite no significant difference in starting age (coefficient = −0.62, 95% CI −1.36, 0.13). LIMITATIONS, REASONS FOR CAUTION We did not have information on the severity of endometriosis, or the reasons for using ART, which can influence treatment and outcomes. We were not able to reliably link births with ART treatment. Finally, it is possible that some of the women in our ‘no endometriosis’ group did have endometriosis and were unaware of it, although prevalence rates match population estimates. WIDER IMPLICATIONS OF THE FINDINGS These findings support previous studies that have found no difference in outcome of ART for women with endometriosis, but add the new insight that this is only true if endometriosis is diagnosed prior to commencing ART. A delayed diagnosis can create disadvantage during ART treatment. Early recourse to IVF may be advantageous for pregnancy prospects for women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The ALSWH is funded by the Australian Government Department of Health. G.D.M. is supported by an NHMRC Principal Research Fellowship (APP11218449). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

868Harnessing new approaches and contemporary methods for better evidence on housing and health

868Harnessing new approaches and contemporary methods for better evidence on housing and health

Pre-pregnancy Diet Quality Is Associated With Lowering the Risk of Offspring Obesity and Underweight: Finding From a Prospective Cohort Study

Abstract Objectives To examine the association between maternal diet quality before pregnancy and childhood BMI in offspring. Methods We included 1936 mothers with 3391 children from the Australian Longitudinal Study on Women's Health (ALSWH) and the Mothers and their Children's Health study (MatCH). Maternal diet was assessed using a semi-quantitative and validated 101-item food-frequency questionnaire (FFQ). We used the healthy eating index (HEI-2015) score to explore maternal diet quality before pregnancy. Children over 2 years of age were categorized as underweight, normal, overweight, and obese based on age and sex-specific BMI classifications for children. Multinomial logistic regression with cluster-robust standard errors was used for analyses. Results Greater adherence to maternal diet quality before pregnancy was associated with a lower risk of offspring underweight after adjustment for potential confounders, highest vs lowest quartile (RRR = 0.68, 95% CI: 0.49, 0.96). Higher adherence to pre-pregnancy diet quality was also inversely associated with the risk of offspring obesity (RRR = 0.49, 95% CI: 0.24, 0.98). This association was, however, slightly attenuated by pre-pregnancy body mass index (BMI) in the full adjusted model. No significant association was observed between pre-pregnancy diet quality and offspring overweight. Conclusions This study suggests that better adherence to maternal diet quality before pregnancy is associated with a reduced risk of childhood underweight and obesity. Funding Sources The ALSWH is funded by the Australian Government Department of Health. MatCH is funded by the National Health and Medical Research Council (NHMRC) project grant. Dereje Gete is supported by the University of Queensland Research Training Scholarship. Gita Mishra holds the Australian Health and Medical Research Council Principal Research Fellowship.

Use of community-based reference ranges to estimate the prevalence of polycystic ovary syndrome by the recognised diagnostic criteria, a cross-sectional study.

Does the application of reference ranges for sex steroids and the modified Ferriman-Gallwey (mFG) scale established in the community from which the study sample was drawn, combined with the most conservative polycystic ovary morphology (PCOM) criteria to the recognised diagnostic criteria for polycystic ovary syndrome (PCOS) improve the certainty of diagnosis of PCOS in non-healthcare-seeking women? Despite application of the stringent definitions of the elements used to diagnose PCOS in a non-healthcare seeking community-based sample, the risk of diagnostic uncertainty remains. There is heterogeneity in prevalence estimates for PCOS due, in part, to lack of standardisation of the elements comprising the recognised National Institutes of Health (NIH), Rotterdam and Androgen Excess Society (AE-PCOS) diagnostic criteria. The AE-PCOS Society proposed refinements to the definitions of biochemical androgen excess and PCOM that can now be incorporated into these sets of diagnostic criteria to estimate PCOS prevalence. An Australian cross-sectional study of 168 non-healthcare-seeking women. The 168 included women were aged 18-39 years, euthyroid and normoprolactinemic, not recently pregnant, breast feeding or using systemic hormones. Each provided menstrual history and assessment of the mFG, had measurement of sex steroids by liquid chromatography, tandem mass spectrometry, and a pelvic ultrasound. The presence of PCOS was determined using modified (m) NIH, Rotterdam, and AE-PCOS criteria according to AE-PCOS Society recommendations. Overall, 10.1% of the included participants met the mNIH PCOS criteria, which requires the presence of menstrual dysfunction, while 18.5% met the mRotterdam and 17.5% the AE-PCOS criteria, with the latter requiring hyperandrogenism. Eight of the 27 participants with menstrual dysfunction, 10 of 31 women with PCOM, and 39 of 68 women with hyperandrogenism had no other feature of PCOS. Of the 19 participants with hyperandrogenaemia, 10 met the mNIH criteria (52.5%) and 14 met both the mRotterdam and AE-PCOS criteria (78.9%). Women who had the combination of hyperandrogenism and PCOM explained the greatest discrepancy between the mNIH and the other criteria. Clinical androgenisation relied on participant self-assessment, which has been shown to be valid when compared with clinician assessment. The sample size was a function of both the strict inclusion criteria and the requirements of non-healthcare-seeking women having a blood draw and pelvic ultrasound which may have introduced a selection bias. Despite applying stringent cut-offs for serum androgens, the mFG scale and the ovarian follicle count, these criteria remain arbitrary. Accordingly, healthy women may be captured by these criteria, and misidentified as having PCOS, while women with the condition may be missed. Consequently, PCOS remains a diagnosis to be made with care. The study was supported by the Grollo-Ruzzene Foundation. Dr S.R.D. is an NHMRC Senior Principal Research Fellow (Grant no. 1135843). S.R.D. has been paid for developing and delivering educational presentations for Besins Healthcare, BioFemme and Pfizer Australia, has been on Advisory Boards for Theramex, Abbott Laboratories, Mayne Pharmaceuticals and Roche and a consultant to Lawley Pharmaceuticals and Que Oncology and has received has received institutional grant funding for Que Oncology research; there are no other relationships or activities that could appear to have influenced the submitted work. N/A.

Robust and Prototypical Immune Responses Towards Influenza Vaccines in the High-Risk Group of Indigenous Australians

Background: Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. Methods: We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the LIFT-V cohort, and collected blood to define baseline, early (day 7) and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells and antibody profiles, and investigated host factors that could contribute to vaccine responses. Findings:We found robust antibody responses to influenza vaccination induced in Indigenous Australians, with activation profiles of circulating T follicular helper type-1 (cT FH 1) cells at the acute response strongly correlating with total change of antibody vaccine titres induced by vaccination. Formation of influenza-specific haemagglutinin (HA)-binding memory B cells was significantly higher in seroconverters compared to non-seroconverters. Back-boosting of antibodies towards previously circulating influenza strains was observed following influenza vaccination. In-depth antibody characterisation revealed a reduction in IgG3 pre- and post-vaccination in the Indigenous Australian population, potentially linked to the increased frequency of G3m21* allotype. Interpretation: Overall, our data provide the first evidence that Indigenous populations elicit robust, broad and prototypical immune responses following immunisation with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and its subsequent complications. Funding: This work was funded by the Australian National Health and Medical Research Council (NHMRC) Program Grant (#1071916) to KK, NHMRC Project Grant (#1122524) to KK, ST, AM, NHMRC Project Grant (#1141840) to MP, KLF, Clifford Craig Foundation Grant (#145) to KLF, and NHMRC Investigator Grant (#1173871) to KK supported this work. EBC is a NHMRC Peter Doherty Fellow. ST is a NHMRC Career Development Fellow (#1145033). This work is supported by the NHMRC program grant 111 #1149990 (SJK), NHMRC project grant #1162760 (AKW). KK is supported by a NHMRC Senior Research Fellowship (#1102792) and SJK by a NHMRC Senior Principal Research Fellowship (#1136322). LH is supported by the Melbourne International Research Scholarship the Melbourne International Fee Remission Scholarship from The University of Melbourne. CES has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 792532. The Melbourne WHO Collaborating Centre for Reference Research on Influenza is supported by the Australian Government Department of Health. Declaration of Interest: None to declare. Ethical Approval: All experiments were conducted according to the Declaration of Helsinki principles and NHMRC Code of practice and approved by the University of Melbourne Human Research Ethics Committee (#1955465 and #1441452), the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (#2012-1928), and the Tasmanian Human Research Ethics Committee (#H0015460).

High Precursor Frequency and Promiscuity in Αβ T Cell Receptor Pairing Underpin CD8+ T-Cell Responses to an Immunodominant SARS-CoV-2 Nucleocapsid Epitope

T-cell responses to SARS-CoV-2-derived peptide pools have been documented, however it remains largely unclear whether prominent SARS-CoV-2-specific T cell populations originate from naïve or pre-existing memory sets. As HLA-B*07:02-restricted N105-113 epitope (B7/N105) is the most dominant SARS-CoV-2 CD8+ T-cell specificity to date, we dissected CD8+ T-cell responses directed at this epitope by direct ex vivo analyses in peripheral blood mononuclear cells (PBMCs) from acute and convalescent COVID-19 patients, and pre-pandemic PBMCs, tonsils, lungs and spleens. Using peptide-HLA tetramers, immunodominant B7/N105+CD8+ T-cells were detected at a high frequency (∼2.18x10-4) in COVID-19 patients, comparable to the well-established influenza-specific A2/M158+CD8+ T-cell population. Remarkably, frequencies of B7/N105+CD8+ T-cells were also readily detectable in pre-pandemic PBMCs and tonsils (at 6.55x10-5 and 2.76x10-4, respectively), although they mainly displayed a naïve phenotype, indicating a lack of previous cross-reactive exposures. Ex vivo TCRαβ analyses revealed that a diverse TCRαβ repertoire and promiscuity in αβ TCR pairing underlie such high naïve precursor frequencies of B7/N105+CD8+ T-cells. Overall, our study demonstrates that high precursor frequency and plasticity of TCRα-TCRβ pairing underpin immunodominance of SARS-CoV-2-specific B7/N105+CD8+ T-cell responses and advocates for vaccine strategies which include the nucleocapsid protein to elicit immunodominant CD8+ T-cell responses in HLA-B*07:02 individuals.Funding: This work was supported by theClifford Craig Foundation to KLF and KK, NHMRC Leadership Investigator Grant to KK (1173871), NHMRC Program Grant to DLD (#1132975), Research Grants Council of theHong Kong Special Administrative Region, China (#T11-712/19-N) to KK, the Victorian Government (SJK, AKW), MRFF award (#2002073) to SJK and AKW, MRFFAward (#1202445) to KK, NHMRC program grant 1149990 (SJK) and NHMRC project grant 1162760 (AKW). AKW is supported by Emerging Leadership 1 Investigator Grant (#1173433), JAJ by an NHMRC Early Career Fellowship (ECF) (#1123673), KK by NHMRC SeniorResearch Fellowship (1102792), DLD by a NHMRC Principal Research Fellowship(#1137285) and SJK by NHMRC Senior Principal Research Fellowship (#1136322). CES has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532). JR is supported by an ARC Laureate fellowship. JRH and WZ are supported by the Melbourne Research Scholarship from The University of Melbourne. LH is supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS) from The University of Melbourne.Ethical Approval: Experiments conformed to the Declaration of Helsinki Principles and theAustralian National Health and Medical Research Council Code of Practice. Written informed consents were obtained from all blood donors prior to the study. Lung and spleen tissues were obtained from deceased organ donors after written informed consents from the next of kin.Written informed consents were obtained from participants’ parental or guardians for underage tonsil tissue donors. The study was approved by the Alfred Hospital (#280/14), Austin Health (HREC/63201/Austin-2020); the University of Melbourne (#2057366.1, #2056901.1,#2056689, #2056761, #1442952, #1955465, and #1443389), the Australian Red CrossLifeblood (ID 2015#8), the Tasmanian Health and Medical (ID H0017479) and the James Cook University (H7886) Human Research Ethics Committees.

The rebirth of lithium as the archetypal mood stabilizer.

The serendipitous discovery of lithium's efficacy for the treatment of manic excitement dates back to initial observations by the Danish psychologist Carl Lange in 1886 who theorised that patients with manic-depressive illness had "cerebral gout" for which he suggested lithium salts because lithium could dissolve urate stones. Modern use was triggered by Cade in Melbourne in 1949, while its efficacy for the management of manic episodes and for the prophylaxis of both manic and bipolar depressive episodes was empirically confirmed by Mogens Schou in Denmark.

Re: Integrated Immune Dynamics Define Correlates of COVID-19 Severity and Antibody Responses

SARS-CoV-2 causes a spectrum of illness, ranging from asymptomatic to severe COVID-19. As the immunological basis for severity remains ill-defined, we analysed 78 SARS-CoV-2-infected individuals at acute and/or convalescent timepoints, up to 102 days post-symptom onset, quantifying 184 innate and adaptive immunological parameters. Acute COVID-19 in hospitalised patients was associated with high levels of IL-6, IL-18 and IL-10, elevated neutrophil-to-lymphocyte and neutrophil-to-T cell ratios, and high proportions of activated CD38+ neutrophils, CD38+ eosinophils, CD38+ HLA-DRlo monocytes, CD38+CD56dim NK cells, CD38+ γδ T cells, antibody-secreting cells, CD38+ICOS+ circulating T follicular helper (cTFH) cells, CD38+HLA-DR+CD4+ T cells, effector CD27-CD45RA+ and CD38+ CD8+ T cells. During convalescence, elevated seroconversion and neutralising antibodies were prominent and correlated with acute CXCR3+ cTFH cell activation. Strikingly, intensive care unit (ICU) patients with severe COVID-19 displayed higher levels of soluble IL-6R, IL-18, and hyperactivation of innate, adaptive and myeloid compartments than ward patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients during acute and convalescent phases of SARS-CoV-2 infection, and integrate key cellular pathways of complex perturbed immune networks that underpin severe COVID-19, providing important insights into potential biomarkers and immunotherapies.Funding: This work was supported by the Australian National Health and Medical Research Council (NHMRC) Leadership Investigator Grant to KK (#1173871), NHMRC Program Grant to DLD (#1132975), Research Grants Council of the Hong Kong Special Administrative Region, China (#T11-712/19-N) to KK, the Jack Ma Foundation to KK, KS, DIG and AWC, the a2 milk foundation to KS, the Victorian Government MRFF award (#2002073) to SJK, DIG and AKW, MRFF Award (#1202445) to KK, NHMRC program grant 1149990 (SJK), NHMRC project grant 1162760 (AKW), NHMRC Program Grant (#1071916) to KK and DCJ, NHMRC Program Grant (1113293) to DIG, the Merridew Foundation to NJCK. KK is supported by NHMRC Senior Research Fellowship (1102792), DLD by a NHMRC Principal Research Fellowship (#1137285), KS by an NHMRC Investigator grant (#1177174), SYCT by a NHMRC Career Development Fellowship (#1145033), DIG by an NHMRC Senior Principal Research Fellowship (#1117766) and SJK by NHMRC Senior Principal Research Fellowship (#1136322). SRL is supported by an NHMRC program grant (#1149990) and practitioner fellowship (#1135851). LH and WZ are supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS) from The University of Melbourne. XJ is supported by China Scholarship Council-University of Melbourne joint Scholarship. CES has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532). JRH and WZ are supported by the Melbourne Research Scholarship from The University of Melbourne. TMA and FM-W are International Society for Advancement of Cytometry Marylou Ingram Scholars. GHP is supported by the Australian Government Research Training Program (RTP) Scholarship. JAJ is supported by an NHMRC Early Career Fellowship (ECF) (#1123673). EBC. is supported by a NHMRC Peter Doherty Fellowship (#1091516). KK and AC were supported by the University of Melbourne Dame Kate Campbell Fellowship. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. Conflict of Interest: The authors declare no conflict of interest.Ethical Approval: The study was approved by the Alfred Hospital (#280/14), Melbourne Health (HREC/17/MH/53), Monash Health (HREC/15/MonH/64/2016.196), The University of Melbourne (#2056689, #2056761, #1442952, #1955465 and #1443389) and James Cook University (H7886) Human Research Ethics Committees.

Editorial introductions

Editorial introductions