Projecting the economic burden of chronic kidney disease at the patient level (Inside CKD): a microsimulation modelling study.

Background: The growing burden of chronic kidney disease (CKD) places substantial financial pressures on patients, healthcare systems, and society. An understanding of the costs attributed to CKD and kidney replacement therapy (KRT) is essential for evidence-based policy making. Inside CKD maps and projects the economic burden of CKD across 31 countries/regions from 2022 to 2027. Methods: A microsimulation model was developed that generated virtual populations using national demographics, relevant literature, and renal registries for the 31 countries/regions included. Patient-level country/region-specific cost data were extracted via a pragmatic local literature review and under advisement from local experts. Direct cost projections were generated for diagnosed CKD (by age, stage 3a-5), KRT (by modality), cardiovascular complications (heart failure, myocardial infarction, stroke), and comorbidities (hypertension, type 2 diabetes). Findings: For the 31 countries/regions, Inside CKD projected that annual direct costs (US$) of diagnosed CKD and KRT would increase by 9.3% between 2022 and 2027, from $372.0 billion to $406.7 billion. Annual KRT-associated costs were projected to increase by 10.0% from $169.6 billion to $186.6 billion between 2022 and 2027. By 2027, patients receiving KRT are projected to constitute 5.3% of the diagnosed CKD population but contribute 45.9% of the total costs. Interpretation: The economic burden of CKD is projected to increase from 2022 to 2027. KRT contributes disproportionately to this burden. Earlier diagnosis and proactive management could slow disease progression, potentially alleviating the substantial costs associated with later CKD stages. Data presented here can be used to inform healthcare resource allocation and shape future policy. Funding: AstraZeneca.

Dietary Inulin to Improve SARS-CoV-2 Vaccine Response in Kidney Transplant Recipients: The RIVASTIM-Inulin Randomised Controlled Trial.

Kidney transplant recipients are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard two-dose vaccination schedules are typically inadequate to generate protective immunity. Gut dysbiosis, which is common among kidney transplant recipients and known to effect systemic immunity, may be a contributing factor to a lack of vaccine immunogenicity in this at-risk cohort. The gut microbiota modulates vaccine responses, with the production of immunomodulatory short-chain fatty acids by bacteria such as Bifidobacterium associated with heightened vaccine responses in both observational and experimental studies. As SCFA-producing populations in the gut microbiota are enhanced by diets rich in non-digestible fibre, dietary supplementation with prebiotic fibre emerges as a potential adjuvant strategy to correct dysbiosis and improve vaccine-induced immunity. In a randomised, double-bind, placebo-controlled trial of 72 kidney transplant recipients, we found dietary supplementation with prebiotic inulin for 4 weeks before and after a third SARS-CoV2 mRNA vaccine to be feasible, tolerable, and safe. Inulin supplementation resulted in an increase in gut Bifidobacterium, as determined by 16S RNA sequencing, but did not increase in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third vaccination. Dietary fibre supplementation is a feasible strategy with the potential to enhance vaccine-induced immunity and warrants further investigation.

Sex differences in risk of incident microvascular and macrovascular complications: a population-based data-linkage study among 25 713 people with diabetes.

BACKGROUND: The global prevalence of diabetes is similar in men and women; however, there is conflicting evidence regarding sex differences in diabetes-related complications. The aim of this study was to investigate sex differences in incident microvascular and macrovascular complications among adults with diabetes. METHODS: This prospective cohort study linked data from the 45 and Up Study, Australia, to administrative health records. The study sample included 25 713 individuals (57% men), aged ≥45 years, with diabetes at baseline. Incident cardiovascular disease (CVD), eye, lower limb, and kidney complications were determined using hospitalisation data and claims for medical services. Multivariable Cox proportional hazards models were used to assess the association between sex and incident complications. RESULTS: Age-adjusted incidence rates per 1000 person years for CVD, eye, lower limb, and kidney complications were 37, 52, 21, and 32, respectively. Men had a greater risk of CVD (adjusted hazard ratio (aHR) 1.51, 95% CI 1.43 to 1.59), lower limb (aHR 1.47, 95% CI 1.38 to 1.57), and kidney complications (aHR 1.55, 95% CI 1.47 to 1.64) than women, and a greater risk of diabetic retinopathy (aHR 1.14, 95% CI 1.03 to 1.26). Over 10 years, 44%, 57%, 25%, and 35% of men experienced a CVD, eye, lower limb, or kidney complication, respectively, compared with 31%, 61%, 18%, and 25% of women. Diabetes duration (<10 years vs ≥10 years) had no substantial effect on sex differences in complications. CONCLUSIONS: Men with diabetes are at greater risk of complications, irrespective of diabetes duration. High rates of complications in both sexes highlight the importance of targeted complication screening and prevention strategies from diagnosis.

Pretransplant screening for coronary artery disease: data are required before practice change.

Declining rates of peritransplant cardiovascular death, an increasing burden of pretransplant tests, and concerns about the effectiveness of screening candidates for coronary artery disease have led many transplant programs to de-escalate screening protocols. Recent Kidney Disease: Improving Global Outcomes and American Heart Association scientific statements and guidelines neatly summarize current evidence, but also identify areas of need. Here, we argue that key questions should be addressed by adequately powered clinical trials before our long-held screening paradigms are completely rewritten.

ABO Incompatible Kidney Transplantation Without B-cell Depletion is Associated With Increased Early Acute Rejection: A Single-Center Australian Experience.

We performed a single-center retrospective cohort study of 66 consecutive ABO incompatible kidney transplants (ABOiKT) performed without B-cell depleting therapy. Outcomes were compared to an earlier era performed with rituximab (n = 18) and a contemporaneous cohort of ABO compatible live donor transplants (ABOcKT). Acute rejection within 3 months of transplant was significantly more common after rituximab-free ABOiKT compared to ABOiKT with rituximab (OR 8.8, p = 0.04) and ABOcKT (OR 2.9, p = 0.005) in adjusted analyses. Six recipients of rituximab-free ABOiKT experienced refractory antibody mediated rejection requiring splenectomy, and a further two incurred early graft loss with no such episodes amongst ABOiKT with rituximab or ABOcKT cohorts. Patient and graft survival were similar between groups over a median follow-up of 3.1 years. This observational evidence lends strong support to the continued inclusion of rituximab in desensitization protocols for ABOiKT.

Survival after kidney transplantation compared with ongoing dialysis for people over 70 years of age: A matched-pair analysis.

Kidney transplantation offers improved survival and quality of life compared to dialysis for most recipients; however, benefits for elderly patients (>70 years) remain uncertain. Using the Australia and New Zealand Dialysis and Transplant Registry (2009-2019), elderly transplant recipients were matched to a waitlisted dialysis patient by age, cause of end-stage kidney disease, and dialysis duration (paired controls). We censored dialysis patients at the time of transplant. Survival was compared using stratified Cox regression. Elderly transplant recipients (KTRs) (n = 465) were matched to waitlisted pairs. Transplant group mortality initially exceeded dialysis due to excess infection-related deaths (1.9 transplant versus 0.3 dialysis/100 patient-years, P = .03). Beyond month 9, a progressive survival benefit in favor of transplantation was apparent. Over a median follow-up of 1.7 years, mortality was 38% lower for KTRs (95% confidence interval 0.41-0.94, P = .02), and 5-year survival was 80% KTRs vs 53% dialysis (P < .001). Recipients of living and standard criteria donor kidneys acquired immediate survival advantage compared with dialysis, while recipients of expanded criteria donor's kidneys experienced elevated risk of death for the first 17 months. Compared with remaining on dialysis, elderly KTRs incur an increased risk of early posttransplant mortality but thereafter may anticipate progressively superior survival rates.

Nutrition in the Management of Kidney Transplant Recipients.

Kidney transplantation offers patients with end stage kidney disease the best outcomes. Concentration on nutrition is pivotal throughout the transplant life course. Nutritional requirements change during each phase of transplantation, from pretransplant evaluation and wait-time, acute transplantation, maintenance and ultimately declining graft function, and care should be taken to consider each stage. In this article we concentrate on addressing each phase, with additional focus on current hot topics of dysglycaemia management and on the impact of diet on gut microbiome.

Transdermal Magnesium for the Treatment of Peripheral Neuropathy in Chronic Kidney Disease: A Single-Arm, Open-Label Pilot Study.

Introduction: Peripheral neuropathy is common in chronic kidney disease (CKD) and may be multifactorial in origin, resulting from uremia, hyperkalemia, and diabetes. Previous studies have suggested that magnesium plays a crucial role in chronic pain. Studies evaluating magnesium in neuropathy have demonstrated mixed results. Aims: To provide preliminary data on the effectiveness of transdermal magnesium in treating peripheral neuropathy related to CKD. Methods: Twenty participants with advanced CKD were enrolled from a major teaching hospital clinic in Sydney, Australia. Each participant was provided with a spray bottle containing magnesium chloride and instructed to apply five sprays to each limb affected by neuropathy daily for 12 weeks. Participants completed the Neuropathy Total Symptom Score-6 (NTSS-6) every 4 weeks during follow-up. Serum magnesium concentrations were measured at 4-week intervals. Results: Twenty participants were recruited, of which 14 completed the 12-week follow-up period. Mean age was 78.90 years, 80.00% were female and mean estimated glomerular filtration rate was 9.78 mL/min/1.73 m2. With intention to treat analysis (mean [95% confidence interval]), NTSS-6 was significantly reduced at weeks 8 (4.04 [2.43-5.65]) and 12 (4.26 [2.47-6.05]), compared with baseline (6.92 [5.29-8.55]), p < 0.05. Serum magnesium concentration did not change significantly during the study. Conclusion: This pilot study suggests that transdermal magnesium may be beneficial in reducing frequency and severity of peripheral neuropathic symptoms in patients with advanced CKD. Trial Registration: australianclinicaltrials.gov.au. Identifier: ACTRN12621000841875. Date first registered January 7, 2021.

Obesity is Associated With Delayed Graft Function in Kidney Transplant Recipients: A Paired Kidney Analysis.

Obesity is increasingly prevalent among candidates for kidney transplantation. Existing studies have shown conflicting post-transplant outcomes for obese patients which may relate to confounding bias from donor-related characteristics that were unaccounted for. We used ANZDATA Registry data to compare graft and patient survival between obese (BMI >27.5 kg/m2 Asians; >30 kg/m2 non-Asians) and non-obese kidney transplant recipients, while controlling for donor characteristics by comparing recipients of paired kidneys. We selected transplant pairs (2000-2020) where a deceased donor supplied one kidney to an obese candidate and the other to a non-obese candidate. We compared the incidence of delayed graft function (DGF), graft failure and death by multivariable models. We identified 1,522 pairs. Obesity was associated with an increased risk of DGF (aRR = 1.26, 95% CI 1.11-1.44, p < 0.001). Obese recipients were more likely to experience death-censored graft failure (aHR = 1.25, 95% CI 1.05-1.49, p = 0.012), and more likely to die with function (aHR = 1.32, 95% CI 1.15-1.56, p = 0.001), versus non-obese recipients. Long-term patient survival was significantly worse in obese patients with 10- and 15-year survival of 71% and 56% compared to 77% and 63% in non-obese patients. Addressing obesity is an unmet clinical need in kidney transplantation.

Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Short-chain fatty acids directly exert anti-inflammatory responses in podocytes and tubular epithelial cells exposed to high glucose.

Aims: Gut-microbiome derived short-chain fatty acids exert anti-inflammatory effects and delay progression of kidney disease in diabetic nephropathy. The aim of this study was to examine the impact in vivo and in vitro of short-chain fatty acid treatment on cellular pathways involved in the development of experimental diabetic nephropathy. Methods: To determine the effect of short-chain fatty acids in diabetic nephropathy, we compared wildtype, GPR43-/- and GPR109A-/- mice diabetic mice treated with acetate or butyrate and assessed variables of kidney damage. We also examined the impact of short-chain fatty acid treatment on gene expression in renal tubular cells and podocytes under high glucose conditions. Results: Short-chain fatty acid treatment with acetate or butyrate protected wild-type mice against development of diabetic nephropathy, exhibiting less glomerular hypertrophy, hypercellularity and interstitial fibrosis compared to diabetic controls. Acetate and butyrate treatment did not provide the same degree of protection in diabetic GPR43-/- and GPR109A-/- diabetic mice respectively. Consistent with our in vivo results, expression of pro-inflammatory genes in tubular epithelial cells exposed to high glucose were attenuated by acetate and butyrate treatment. Acetate did not reduce inflammatory or fibrotic responses in glucose stimulated GPR43-/- TECs. Butyrate mediated inhibition of pro-fibrotic gene expression in TECs through GPR109A, and in podocytes via GPR43. Conclusion: SCFAs protect against progression of diabetic nephropathy and diminish podocyte and tubular epithelial injury and interstitial fibrosis via direct, GPR-pathway dependent effects on intrinsic kidney cells. GPR43 and GPR109A are critical to short-chain fatty acid mediated reno-protection and have potential to be harnessed as a therapeutic target in diabetic nephropathy.

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

The living kidney donor profile index fails to discriminate allograft survival: implications for its use in kidney paired donation programs.

The inclusion of blood group- and human leukocyte antigen-compatible donor and recipient pairs (CPs) in kidney paired donation (KPD) programs is a novel strategy to increase living donor (LD) transplantation. Transplantation from a donor with a better Living Donor Kidney Profile Index (LKDPI) may encourage CP participation in KPD programs. We undertook parallel analyses using data from the Scientific Registry of Transplant Recipients and the Australia and New Zealand Dialysis and Transplant Registry to determine whether the LKDPI discriminates death-censored graft survival (DCGS) between LDs. Discrimination was assessed by the following: (1) the change in the Harrell C statistic with the sequential addition of variables in the LKDPI equation to reference models that included only recipient factors and (2) whether the LKDPI discriminated DCGS among pairs of prognosis-matched LD recipients. The addition of the LKDPI to reference models based on recipient variables increased the C statistic by only 0.02. Among prognosis-matched pairs, the C statistic in Cox models to determine the association of the LKDPI with DCGS was no better than chance alone (0.51 in the Scientific Registry of Transplant Recipient and 0.54 in the Australia and New Zealand Dialysis and Transplant Registry cohorts). We conclude that the LKDPI does not discriminate DCGS and should not be used to promote CP participation in KPD programs.

Projecting the Epidemiological and Economic Impact of Chronic Kidney Disease Using Patient-Level Microsimulation Modelling: Rationale and Methods of Inside CKD.

INTRODUCTION: Chronic kidney disease (CKD) is a serious condition associated with significant morbidity and healthcare costs. Despite this, early-stage CKD is often undiagnosed, and globally there is substantial variation in the effectiveness of screening and subsequent management. Microsimulations can estimate future epidemiological costs, providing useful insights for clinicians, policymakers and researchers. Inside CKD is a programme designed to analyse the projected prevalence and burden of CKD for countries across the world, and to simulate hypothetical intervention strategies that can then be assessed for potential impact on health and economic outcomes at a national and a global level. METHODS: Inside CKD uses a population-based approach that creates virtual individuals for a given country, with this simulated population progressing through a microsimulation in 1-year increments. A series of data inputs derived from national statistics and key literature defined the likelihood of a change in health state for each individual. Input modules allow for the input of nationally specific demographic and CKD status (including prevalence, diagnosis rates, disease stage and likelihood of renal replacement therapy), disease progression, critical comorbidities, and mortality. Health economics are reflected in cost data and a flexible intervention module allows for the testing of hypothetical policies-such as screening strategies-that may alter disease progression and outcomes. RESULTS: Using input data from the UK as a case study and a 6-year simulation period, Inside CKD estimated a prevalence of 9.2 million individuals (both diagnosed and estimated undiagnosed) with CKD by 2027 and a 5.0% increase in costs for diagnosed CKD and renal replacement therapy. External validation and sensitivity analyses confirmed the observed trends, substantiating the robustness of the microsimulation. CONCLUSIONS: Using a microsimulation approach, Inside CKD extends the reach of current CKD policy analyses by factoring in multiple inputs that reflect national healthcare systems and enable analysis of the effect of multiple hypothetical screening scenarios on disease progression and costs.

Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. Methods: We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. Results: During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. Conclusions: BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin - study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients.

INTRODUCTION: Kidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is suboptimal. Strategies to enhance vaccine efficacy are therefore required. Current evidence supports the role of the gut microbiota in shaping the immune response to vaccination. Gut dysbiosis is common in KTRs and is a potential contributor to impaired COVID-19 vaccine responses. We hypothesise that dietary fibre supplementation will attenuate gut dysbiosis and promote vaccine responsiveness in KTRs. METHODS AND ANALYSIS: Rapamycin and inulin for third-dose vaccine response stimulation-inulin is a multicentre, randomised, prospective, double-blinded, placebo-controlled pilot trial examining the effect of dietary inulin supplementation prior to a third dose of COVID-19 vaccine in KTRs who have failed to develop protective immunity following a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to inulin (active) or maltodextrin (placebo control), administered as 20 g/day of powdered supplement dissolved in water, for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm that achieve in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third dose of COVID-19 vaccine. Secondary outcomes include the safety and tolerability of dietary inulin, the diversity and differential abundance of gut microbiota, and vaccine-specific immune cell populations and responses. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Central Adelaide Local Health Network (CALHN) Human Research Ethics Committee (HREC) (approval number: 2021/HRE00354) and the Sydney Local Health District (SHLD) HREC (approval numbers: X21-0411 and 2021/STE04280). Results of this trial will be published following peer-review and presented at scientific meetings and congresses. TRIAL REGISTRATION NUMBER: ACTRN12621001465842.