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As the COVID‐19 pandemic has progressed, it has become apparent that COVID‐19 vaccination has limited impact on SAR‐CoV‐2 transmission and provides only short‐term protection against acquiring infection, but more robust protection against severe disease and death. As a result, vaccinated people remain susceptible to SARS‐CoV‐2 infection but are less likely to experience severe outcomes. Studies show that immunity derived from the combination of vaccination and natural infection, so‐called hybrid immunity, is superior to that provided by vaccination or natural infection alone. Since most Australian adults have received three or more doses of COVID‐19 vaccines and >70% have also been infected with SARS‐CoV‐2, we now have a population with high levels of hybrid immunity. This was mostly achieved by receiving original Wuhan strain vaccines and then experiencing Omicron strain infections. The original Wuhan strain of SARS‐CoV‐2 has now disappeared and been replaced with Omicron‐lineage variants globally. The predominance of the Omicron strain initially led to the development of bivalent vaccines containing both the Wuhan strain and Omicron variants. Currently, vaccines containing the original Wuhan strain of spike protein are being phased out, and new COVID‐19 vaccines based exclusively on the Omicron strain XBB have become available in Australia. This article explores the question of whether further doses will be required from 2024 onwards and, if so, who should receive them? [ABSTRACT FROM AUTHOR]

Objective: To compare clinician documentation of sepsis for infective presentations in the ED against a formal sepsis pathway in the ED and to assess appropriateness of the initial parenteral antibiotic prescription for adult patients in ED. Methods: A retrospective, clinical audit of adult patients who received at least one parenteral antibiotic in ED over a 10‐week period in 2018. Documented initial clinical impression was compared with an approved sepsis pathway. Antibiotic appropriateness was assessed using National Antimicrobial Prescribing Survey definitions. Assessment was carried out by an infectious diseases pharmacist, with input from an infectious diseases physician. Results: Two hundred and nineteen infective presentations were included in the analysis. There was a discordance between the initial documented clinical impression compared with the classification when a sepsis pathway was applied. An initial documented clinical impression of sepsis and septic shock was present in 38 (60.3%) of the presentations compared to 63 presentations when a formal sepsis pathway was applied as a screening tool. There was a significant difference in the proportion of patients in each diagnostic group (infection, sepsis and septic shock) according to documented clinical impression versus sepsis pathway classification (P = 0.0002). There were 386 prescriptions for antibiotics as part of the initial management. Antibiotic appropriateness for the initial prescription was assessed as 63.7% appropriate, 27.2% inappropriate and 9.1% not assessable. Conclusion: Our observations demonstrate that use of a formal sepsis pathway may improve the screening and early diagnosis of sepsis and septic shock and that there is a need for antibiotic prescribing guidance in the ED. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette‐Guérin (BCG) vaccine could play a role in counteracting the rising prevalence of atopic diseases, through its beneficial off‐target effects. We aimed to determine whether neonatal BCG vaccination reduces the incidence of eczema in infants. Methods: Randomized controlled trial with 1272 infants allocated to receive BCG‐Denmark or no BCG at birth. The primary outcome was the 12‐month incidence of eczema based on 3‐monthly questionnaires. Eczema was also assessed at a 12‐month clinic visit. ClinicalTrial.gov: NCT01906853. Results: The 12‐month eczema incidence was 32.2% in the BCG group compared with 36.6% in the control group (adjusted risk difference (aRD) −4.3%, 95% CI −9.9% to 1.3%, multiple imputation model). In addition, comparing infants in the BCG group with the control group, 15.7% vs. 19.2% had eczema lesions at the 12‐month visit (aRD −3.5%, 95% CI −8.0% to 1.0%); 35.7% vs. 39.0% reported using topical steroids (aRD −3.3, 95% CI −9.2 to 2.7); and 7.3% vs. 10.2% had severe eczema scores (aRD −3.0%, 95% CI −8.8% to 2.7%). In 344 high‐risk infants (two atopic parents), the 12‐month eczema incidence was 35.3% in the BCG group compared with 46.8% in the control group (aRD −11.5%, 95% CI −21.9% to −1.2%; number needed to treat 8.7, 95% CI 4.6 to 83.3). Conclusion: There is insufficient evidence to recommend neonatal BCG vaccination in all infants for the prevention of eczema in the first year of life; however, a modest beneficial effect was observed among high‐risk infants. A single dose of BCG‐Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents. [ABSTRACT FROM AUTHOR]

Objective: CD4+ T cells are critical mediators of immunity to Plasmodium spp. infection, but their characteristics during malarial episodes and immunopathology in naturally infected adults are poorly defined. Flow cytometric analysis of PBMCs from patients with either P. falciparum or P. knowlesi malaria revealed a pronounced population of CD4+ T cells co‐expressing very high levels of CD4 and CD38 we have termed CD4hiCD38hi T cells. We set out to gain insight into the function of these novel cells. Methods: CD4+ T cells from 18 patients with P. falciparum or P. knowlesi malaria were assessed by flow cytometry and sorted into populations of CD4hiCD38hi or CD4norm T cells. Gene expression in the sorted populations was assessed by qPCR and NanoString. Results: CD4hiCD38hi T cells expressed high levels of CD4 mRNA and canonical type 1 regulatory T‐cell (TR1) genes including IL10, IFNG, LAG3 and HAVCR2 (TIM3), and other genes with relevance to cell migration and immunomodulation. These cells increased in proportion to malaria disease severity and were absent after parasite clearance with antimalarials. Conclusion: In naturally infected adults with acute malaria, a prominent population of type 1 regulatory T cells arises that can be defined by high co‐expression of CD4 and CD38 (CD4hiCD38hi) and that correlates with disease severity in patients with falciparum malaria. This study provides fundamental insights into T‐cell biology, including the first evidence that CD4 expression is modulated at the mRNA level. These findings have important implications for understanding the balance between immunity and immunopathology during malaria. [ABSTRACT FROM AUTHOR]

Aim: We investigated the effect of early-life factors, namely sex, delivery mode, feeding method and antibiotic exposure, on antibody responses to routine vaccinations administered during the first year of life.Methods: One and seven months after the primary course of routine vaccines and 1 month after routine vaccines at 12 months of age, antibodies against 26 vaccine antigens were measured in 398 healthy infants. The geometric mean concentration (GMC) of antibodies (adjusted for effect modifiers with multiple linear regression) and the seroprotection rate for each vaccine were compared for each early-life factor.Results: Sex had an influence on GMCs. Antibody concentrations were significantly lower at 7 months of age in females for tetanus and filamentous haemagglutinin and at 13 months of age for pertactin. In contrast, at 13 months of age, antibody concentrations were significantly higher in females for polio type 3, pneumococcal serotype 6A and measles. Sex did not have an influence on seroprotection rates. Delivery mode, feeding method and antibiotic exposure did not exert a substantial influence on vaccine antibody concentrations.Conclusion: There is a difference between males and females in the humoral response to routine vaccinations in the first year of life. [ABSTRACT FROM AUTHOR]

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SUMMARY HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long-term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Placental malaria (PM), a frequent infection of pregnancy, provides an ideal opportunity to investigate the impact on immune development of exposure of the foetal immune system to foreign Ag. We investigated the effect of PM on the regulatory phenotype and function of cord blood cells from healthy Gambian newborns and peripheral blood cells from their mothers, and analyzed for effects on the balance between regulatory and effector responses. Using the gold standard for classifying PM we further distinguished between resolved infection and acute or chronic PM active at the time of delivery. We show that exposure to malarial Ag in utero results in the expansion of malaria-specific FOXP3 Treg and more generalized FOXP3 CD4 Treg in chronic and resolved PM, alongside increased Th1 pro-inflammatory responses (IFN-γ, TNF-α, IFN-γ:IL-10) in resolved PM infection only. These observations demonstrate a clear effect of exposure to malarial Ag in foetal life on the immune environment at birth, with a regulatory response dominating in the newborns with ongoing chronic PM, while those with resolved infection produce both regulatory and inflammatory responses. The findings might explain some of the adverse effects on the health of babies born to women with PM. [ABSTRACT FROM AUTHOR]

Routine vaccination programmes have led to substantial declines in the incidence of most of the target diseases. In these circumstances, vaccine effects beyond those on the target diseases may become evident. Several studies have suggested that certain vaccines may influence mortality in low income settings in ways that cannot be attributed to effects on target diseases. Trials of such 'non-specific' effects are difficult if not impossible to organise; and observational studies of them are prone to serious confounding, because those who do or do not receive vaccines are likely to differ in many ways, some of which relate to their subsequent risk of early death, independent of vaccination. They are also prone to other biases, including the selective loss of vaccination records for children who die. We review these potential sources of bias and suggest what and how data may be collected to optimise the validity of such studies. [ABSTRACT FROM AUTHOR]

Irradiated malaria sporozoites induce better protection than viable untreated sporozoites. We observed early differences between irradiated and viable untreated sporozoites in priming responsesin vivoto a protective CD8 T-cell epitope, pb9, of the circumsporozoite protein ofPlasmodium berghei. Sporozoites were processed for MHC class I presentation by dendritic cells (DC) to prime pb9-specific IFN-γ-producing CD8 T cells. DC pulsed with untreated and irradiated sporozoites were similarly capable of priming central memory T-cell responses, detectable by the IFN-γ cultured ELISPOT assay. However, irradiation significantly enhanced sporozoites’ ability to prime effector T-cell responses detectable by the IFN-γ ex vivoELISPOT assay. Irradiation also enhanced the ability of splenic APC to process and present sporozoites in order to re-stimulate pb9-specific polyclonal and clonal T-cell responses. Sporozoites did not stimulate T cells in the absence of APC. Over-irradiation decreased the sporozoites’ T-cell stimulating capacityin vitroat high parasite doses, which may indicate that an optimal irradiation dose is necessary to induce protective immunity by sporozoite inoculation. The induction of sporozoite-specific CD8 T-cell responses without the need for liver stage infection identifies a potentially important mechanism in the development of pre-erythrocytic immunity. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Objective Methods Results Conclusions and Clinical Relevance The beneficial off‐target effects of Bacille Calmette–Guérin (BCG) vaccination potentially include protection against allergy.In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants.In this randomised controlled trial, 1272 neonates were allocated to BCG‐Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3‐monthly online questionnaires and oral food challenges. Data were analysed by intention‐to‐treat using binary regression. Clinicaltrials.gov (NCT01906853).Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI −1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI −3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration).Neonatal BCG‐Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life. [ABSTRACT FROM AUTHOR]

A COVID-19 pharmacovigilance plan, incorporating key vaccine safety programs developed since 2009 including AusVaxSafety (http://www.ausvaxsafety.org.au) and vaccine safety reporting programs established in states and territories, will ensure real-time monitoring of adverse events. Keywords: COVID-19; Vaccination; Infectious diseases; Respiratory tract infections EN COVID-19 Vaccination Infectious diseases Respiratory tract infections 249 249 1 04/06/21 20210401 NES 210401 Careful planning is required to deliver a safe and effective COVID-19 program Providing a safe and effective coronavirus disease 2019 (COVID-19) vaccination program is required to mitigate against the current and future negative impacts on the health and wellbeing of all Australians from COVID-19. Current COVID-19 vaccine trials include 30 000-50 000 participants, of whom roughly half will receive the vaccine. Developing a COVID-19 vaccine program With over 60 candidates in clinical trials, unprecedented efforts are driving vaccine development. [Extracted from the article]