Potential Cost-Effectiveness of Maternal Influenza Immunisation in Low-Income Countries: An Explorative Modelling Study and Value of Information Analysis to Guide Future Clinical Research.

Maternal influenza immunisation (MII) is recommended for protecting pregnant women and infants under six months of age from severe disease related to influenza. However, few low-income countries have introduced this vaccine. Existing cost-effectiveness studies do not consider potential vaccine non-specific effects (NSE) observed in some settings, such as reductions in preterm birth. A decision tree model was built to examine the potential cost-effectiveness of MII in a hypothetical low-income country compared to no vaccination, considering possible values for NSE on preterm birth in addition to vaccine-specific effects on influenza. We synthesized epidemiological and cost data from low-income countries. All costs were adjusted to 2021 United States dollars (USD). We considered cost-effectiveness thresholds that reflect opportunity costs (USD 188 per disability-adjusted life year averted; range: USD 28-538). Results suggest that even a small (5%) NSE on preterm birth may make MII a cost-effective strategy in these settings. A value of information analysis indicated that acquiring more information on the presence and possible size of NSE of MII could greatly reduce the uncertainty in decision-making on MII. Further clinical research investigating NSE in low-income countries may be of high value to optimise immunisation policy.

COVID-19 vaccination: are more jabs needed or are we now immune?

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?

Factors Associated with Early Versus Late Uptake of the COVID-19 Vaccine during Pregnancy over Time in Australia: A Population-Based Cohort Study.

BACKGROUND: Pregnant women are at an increased risk of hospitalisation, admission to the intensive care unit, mechanical ventilation, and death from SARS-CoV-2 infection. The aim of this study is to determine the predictive factors associated with COVID-19 vaccine uptake during pregnancy over time in a population with a high background uptake of maternal influenza and pertussis vaccination. METHODS: This is a population-based, cohort study of all pregnant women who gave birth in Victoria, Australia between 1 July 2021 and 30 June 2022. Data from the Victorian Perinatal Data Collection were analysed using univariable and multivariable logistic regression. RESULTS: This study reports on 77,719 women who gave birth over a 12 month period, of whom 49,281 (63.4%) received a COVID-19 vaccine, 54,887 (70.6%) received an influenza vaccination and 63,594 (81.8%) received a pertussis vaccine by the time of delivery. Pregnant women aged >30 years (aOR 1.31 CI 1.27, 1.36), who had >=8 antenatal visits (aOR 1.08 CI 1.04, 1.12), and those who received influenza vaccine (aOR 1.23 CI 1.19, 1.28) were more likely to have received a COVID-19 vaccine. Those who smoked (aOR 0.7 CI 0.66, 0.74), were First Nations (aOR 0.83 CI 0.74, 0.93) and those who gave birth in public hospitals (aOR 0.65 CI 0.63, 0.68) were less likely to receive COVID-19 vaccine in the first 12 months of the rollout. CONCLUSION: Maternal age, smoking, parity and Indigenous status were factors associated with delayed and sustained lower coverage, even in a population with background maternal influenza and pertussis coverage of 70.6% and 81.8%, respectively.

Interim results from a phase I randomized, placebo-controlled trial of novel SARS-CoV-2 beta variant receptor-binding domain recombinant protein and mRNA vaccines as a 4th dose booster.

BACKGROUND: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. METHODS: 76 healthy adults aged 18-64 y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45 µg, N = 32), mRNA vaccine (10, 20, or 50 µg, N = 32), or placebo (saline, N = 12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection. Bleeds occurred on days 1 (prior to vaccination), 8, and 29. CLINICALTRIALS: govNCT05272605. FINDINGS: No vaccine-related serious or medically-attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation. INTERPRETATION: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains. FUNDING: Australian Government Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.

The pregnant traveller: An overview of common preventable infections.

Pregnant travellers are often unaware of the various infections that can be acquired during travel and that pregnant people may be at increased risk of severe disease compared to their non-pregnant counterparts. Pregnant people often seek pre-travel counselling from their obstetrician or primary care physicians, who may not be well versed in travel medicine. This paper aims to provide information for maternity care providers regarding important travel-related food, water and mosquito-borne illnesses, including their prevention and treatment methods, equipping maternity care providers to confidently counsel prospective travellers during pregnancy.

Vaccination recommendations for pregnant people travelling overseas.

With international travel on the rise following pandemic restrictions, the number of pregnant travellers is likely to proportionally increase. Recent published data suggest most pregnant travellers seek pre-travel advice from their maternity and primary care providers. With these data, it is important to provide maternity and primary care providers with guidelines and resources to help aid safe, informed, and timely delivery of vaccinations prior to travel. Vaccination for travel during pregnancy is fundamental in mitigating maternal and fetal communicable disease morbidity and mortality. This clinical perspective provides an overview of the indications, safety, and recommendations for pre-travel vaccines in pregnancy.

ATAGI 2023 Annual Statement on Immunisation.

The Australian Technical Advisory Group on Immunisation (ATAGI) 2023 Annual Statement on Immunisation is the third publication in this series. It highlights the key successes, trends and challenges in the use of vaccines and control of vaccine preventable diseases (VPDs) in Australia in 2022. It also signals ATAGI's priority actions for addressing key issues for 2023 and beyond.

CO-Sprout-A Pilot Double-Blinded Placebo-Controlled Randomised Trial of Broccoli Sprout Powder Supplementation for Pregnant Women with COVID-19 on the Duration of COVID-19-Associated Symptoms: Study Protocol.

Since its discovery in late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been estimated to be responsible for at least 769.3 million infections and over 6.95 million deaths. Despite significant global vaccination efforts, there are limited therapies that are considered safe and effective for use in the management of COVID-19 during pregnancy despite the common knowledge that pregnant patients have a much higher risk of adverse outcomes. A bioactive compound found in broccoli sprout-sulforaphane-is a potent inducer of phase-II detoxification enzymes promoting a series of potentially beneficial effects notably as an antioxidant, anti-inflammatory, and anti-viral. A pilot, double-blinded, placebo-controlled randomised trial is to be conducted in Melbourne, Australia, across both public and private hospital sectors. We will assess a commercially available broccoli sprout extract in pregnant women between 20+0 and 36+0 weeks gestation with SARS-CoV-2 infection to investigate (i) the duration of COVID-19 associated symptoms, (ii) maternal and neonatal outcomes, and (iii) biomarkers of infection and inflammation. We plan to enrol 60 outpatient women with COVID-19 irrespective of vaccination status diagnosed by PCR swab or RAT (rapid antigen test) within five days and randomised to 14 days of oral broccoli sprout extract (42 mg of sulforaphane daily) or identical microcrystalline cellulose placebo. The primary outcome of this pilot trial will be to assess the feasibility of conducting a larger trial investigating the duration (days) of COVID-19-associated symptoms using a broccoli sprout supplement for COVID-19-affected pregnancies. Pregnant patients remain an at-risk group for severe disease following infection with SARS-CoV-2 and currently unclear consequences for the offspring. Therefore, this study will assess feasibility of using a broccoli sprout supplement, whilst providing important safety data for the use of sulforaphane in pregnancy.

Unravelling the mechanisms by which chronic hepatitis B infection is associated with an increased risk of gestational diabetes.

An independent association between chronic hepatitis B virus (HBV) and the development of gestational diabetes (GDM) has been reported in the literature. Ethnic background and regional influences have been demonstrated to play a role in the reporting of incidence rates of GDM among women with chronic HBV. The mechanisms behind this association are poorly understood, but evidence suggests an inflammatory basis. Viral factors such as chronic HBV replication, quantifiable by HBV viral load, have been proposed to contribute to the increasing risk of insulin resistance in pregnancy. More research is needed to better characterise the association and determine if any interventions early in pregnancy for women infected with chronic HBV would mitigate the development of GDM.

The Reemergence of Syphilis Among Females of Reproductive Age and Congenital Syphilis in Victoria, Australia, 2010 to 2020: A Public Health Priority.

BACKGROUND: Syphilis notifications in Victoria, Australia, have been increasing over the past decade, with an increase in infectious syphilis (syphilis of less than 2 years in duration) cases in females of reproductive age and an associated reemergence of congenital syphilis (CS). Before 2017, there had been 2 CS cases in the preceding 26 years. This study describes the epidemiology of infectious syphilis among females of reproductive age and CS in Victoria. METHODS: Routine surveillance data provided by mandatory Victorian syphilis case notifications were extracted and grouped into a descriptive analysis of infectious syphilis and CS incidence data from 2010 to 2020. RESULTS: In 2020, infectious syphilis notifications in Victoria were approximately 5 times more than 2010 (n = 289 in 2010 to n = 1440 in 2020), with a more than 7-fold rise among females (n = 25 in 2010 to n = 186 in 2020). Females made up 29% (n = 60 of 209) of Aboriginal and Torres Strait Islander notifications occurring between 2010 and 2020. Between 2017 and 2020, 67% of notifications in females (n = 456 of 678) were diagnosed in low-caseload clinics, at least 13% (n = 87 of 678) of all female notifications were known to be pregnant at diagnosis, and there were 9 CS notifications. CONCLUSIONS: Cases of infectious syphilis in females of reproductive age and CS are on the rise in Victoria, necessitating sustained public health action. Increasing awareness among individuals and clinicians, and health system strengthening, particularly targeting primary care where most females are diagnosed before pregnancy, are required. Treating infections before or promptly during pregnancy and undertaking partner notification and treatment to reduce risk of reinfection are critical to reducing CS cases.

Influenza and pertussis vaccine coverage in pregnancy in Australia, 2016-2021.

Vaccination in pregnancy is the best strategy to reduce complications from influenza or pertussis infection in infants who are too young to be protected directly from vaccination. Pregnant women are also at risk of influenza complications preventable through antenatal vaccination. Both vaccines are funded under the National Immunisation Program for pregnant women in Australia, but coverage is not routinely reported nationally. We reviewed all reported Australian maternal influenza and pertussis vaccine coverage data for the period 2016-2021, to identify gaps and information needs. Maternal influenza vaccine coverage was suboptimal at < 58% for 2016-2018, with higher coverage of 62-75% reported in two states (Victoria and Western Australia) for 2019-2021. Maternal pertussis vaccine coverage from 2016 was generally higher than for influenza at > 70%, with the highest jurisdictional coverage of 89% reported in Western Australia in 2020. Vaccination rates were often suboptimal among First Nations pregnant women and up to 20% lower than among non-First Nations Australian women; while data were limited, coverage was low among culturally and linguistically diverse women and among women of lower socio-economic status. Jurisdictional perinatal data collections were the best source of information on antenatal vaccine coverage but were only available for a minority of the population; a nationally consistent systematic approach is lacking. Timely and comprehensive data are needed to provide feedback to improve maternal vaccination coverage, particularly among groups with higher risk and/or low uptake, and as new vaccines are recommended, including COVID-19 vaccination.

The non-specific effects of maternal immunization on birth outcomes: The evidence, mechanisms, and the implications.

Preterm birth (PTB) and stillbirth remain two of the most important causes of death, morbidity, and disability in childhood. Despite efforts to reduce PTB and stillbirth worldwide, rates of these adverse outcomes remain persistently elevated, independent of income setting. There is an urgent need for more effective interventions to reduce associated neonatal and early childhood morbidity and mortality. Maternal vaccines are a well-established strategy used for prevention of pathogen-specific disease in mothers and infants through transplacental antibody transfer. Beyond these pathogen-specific benefits, some studies have also identified non-specific effects (NSEs) of maternal vaccination protecting against several adverse birth outcomes, including PTB and stillbirth. This paper will review the evidence supporting the NSEs of maternal vaccination on birth outcomes, describe the possible underlying mechanisms, outline the research gaps, and summarize the significance from a global health perspective.

Protective effect of maternal immunization on birth outcomes: A data linkage study.

OBJECTIVE: To explore the impact of maternal immunization on adverse pregnancy outcomes including preterm birth (PTB) and stillbirth. METHODS: The authors performed a data linkage study for women who delivered a singleton baby between January 2017 and May 2021. They used Poisson models to estimate incidence rates of adverse pregnancy outcomes and Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), accounting for the time-dependent nature of the exposure and adjusting for confounders. RESULTS: This study included 10 938 women who received at least one vaccine, and 4029 unvaccinated women. Influenza vaccine was associated with a significant reduction in stillbirth (adjusted HR [aHR], 0.55 [95% CI, 0.33-0.94]), but not in PTB (aHR, 0.92 [95% CI, 0.77-1.10]). Pertussis vaccine was associated with a significant reduction in PTB (aHR, 0.78 [95% CI, 0.64-0.94]) and a similar point estimate for reduction in stillbirth (aHR, 0.59 [95% CI, 0.31-1.10]), although not significant. CONCLUSION: Reductions in PTB and stillbirth associated with maternal immunization suggest possible protective effects beyond pathogen-specific protection. These findings may strengthen justification for scaling up maternal immunization in low-income settings where there remains a high burden of these adverse pregnancy outcomes.

Maternal Vaccination to Prevent Adverse Pregnancy Outcomes: An Underutilized Molecular Immunological Intervention?

Adverse pregnancy outcomes including maternal mortality, stillbirth, preterm birth, intrauterine growth restriction cause millions of deaths each year. More effective interventions are urgently needed. Maternal immunization could be one such intervention protecting the mother and newborn from infection through its pathogen-specific effects. However, many adverse pregnancy outcomes are not directly linked to the infectious pathogens targeted by existing maternal vaccines but rather are linked to pathological inflammation unfolding during pregnancy. The underlying pathogenesis driving such unfavourable outcomes have only partially been elucidated but appear to relate to altered immune regulation by innate as well as adaptive immune responses, ultimately leading to aberrant maternal immune activation. Maternal immunization, like all immunization, impacts the immune system beyond pathogen-specific immunity. This raises the possibility that maternal vaccination could potentially be utilised as a pathogen-agnostic immune modulatory intervention to redirect abnormal immune trajectories towards a more favourable phenotype providing pregnancy protection. In this review we describe the epidemiological evidence surrounding this hypothesis, along with the mechanistic plausibility and present a possible path forward to accelerate addressing the urgent need of adverse pregnancy outcomes.

Azithromycin treatment for short cervix with or without amniotic fluid sludge: A matched cohort study.

BACKGROUND: Preterm birth (PTB) is one of the leading causes of neonatal mortality and morbidity worldwide. A shortened cervix is a recognised risk factor for PTB, and amniotic fluid sludge (AFS) diagnosed on ultrasound may be suggestive of underlying inflammation or infection. AIMS: The aim is to determine if azithromycin, administered in cases of a shortened cervix, results in prolongation of gestation with improvements in neonatal outcomes. MATERIALS AND METHODS: We performed a retrospective cohort study at three tertiary maternity services in Melbourne, Australia, between 2015 and 2020. Women with a singleton pregnancy were included if they had a cervical length of 15 mm or less at 13-24 weeks' gestation, with or without AFS. Exclusion criteria comprised multiple pregnancy, major fetal congenital anomaly, placenta praevia, prelabour premature rupture of membranes, vaginal bleeding and/or clinical signs suggestive of chorioamnionitis at the time of diagnosis of the short cervix. The results of antibiotic treatment with azithromycin were compared to those of no antibiotic treatment. The outcomes of interest were PTB, prelabour premature rupture of membranes (PPROM), chorioamnionitis and neonatal morbidity. RESULTS: A total of 374 women were included in the study, of whom 129 received azithromycin and 245 received no antibiotics. When adjusting for potential confounders, the adjusted risk of PTB overall was higher in the treatment group (adjusted hazard ratio 1.36 (95% confidence interval 1.04-1.77) P = 0.023) with no differences found for PPROM, chorioamnionitis or neonatal morbidity. CONCLUSION: These data do not support the routine use of azithromycin in women with a short cervix, including those with AFS detected on ultrasound.

Quality of life in people living with HIV (the fourth 90) - are we there yet in Australia?

In 2014, UNAIDS outlined the 90-90-90 treatment targets. The "fourth 90" reflects the need to focus on optimising quality of life (HRQoL) in people living with HIV. Using a sample of non-heterosexual males in Melbourne, Australia, we aimed to assess HRQoL differences between HIV-positive and HIV-negative individuals, and identify factors that predict HRQoL both at baseline and after three years of follow up. Clinical information and patient-reported outcomes incorporating the Assessing Quality of Life-6D scale were collected at baseline and at three years. Sixty-two HIV-positive cases (antiretroviral therapy naïve at baseline) and 48 controls were enrolled. Results were compared between cases and controls at baseline, three-year follow-up, and between timepoints. HRQoL was significantly lower in cases compared to controls (83.5 (IQR 77.2-88.6) vs 87.3 (IQR 82.1-91.8), p = 0.022) at baseline, with increased depression and anxiety associated with reduced HRQoL in multivariate analysis. Mental health in cases improved between timepoints (75.0 (IQR 56.3-81.3) to 81.3 (IQR 62.5-81.3), p = 0.0428). No differences between the HRQoL of cases and controls were observed at three years. Increased mental health support may be required at commencement of antiretroviral therapy to enable similar levels of HRQoL between HIV-positive and HIV-negative individuals to be achieved.

The PRotective Effect of Maternal Immunisation on preTerm birth: characterising the Underlying mechanisms and Role in newborn immune function: the PREMITUR study protocol.

Maternal immunisation, a low cost and high efficacy intervention is recommended for its pathogen specific protection. Evidence suggests that maternal immunisation has another significant impact: reduction of preterm birth (PTB), the single greatest cause of childhood morbidity and mortality globally. Our overarching question is: how does maternal immunisation modify the immune system in pregnant women and/or their newborn to reduce adverse pregnancy outcomes and enhance the newborn infant's capacity to protect itself from infectious diseases during early childhood? To answer this question we are conducting a multi-site, prospective observational cohort study collecting maternal and infant biological samples at defined time points during pregnancy and post-partum from nulliparous women. We aim to enrol 400 women and determine the immune trajectory in pregnancy and the impact of maternal immunisation (including influenza, pertussis and/or COVID-19 vaccines) on this trajectory. The results are expected to identify areas that can be targeted for future intervention studies.

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

Anticoagulation in Non-Critically Ill Covid-19 PatientsMcQuilten et al. conducted a randomized clinical trial comparing low-dose, intermediate-dose, low-dose plus aspirin, and therapeutic-dose anticoagulation in patients with Covid-19 of diverse ethnicities in high-, low-, and middle-income countries.