Hearing loss in Australian First Nations children at 6-monthly assessments from age 12 to 36 months: Secondary outcomes from randomised controlled trials of novel pneumococcal conjugate vaccine schedules.

BACKGROUND: In Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations. METHODS AND FINDINGS: In 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size. CONCLUSIONS: In this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01735084 and NCT01174849.

The effectiveness of maternal pertussis vaccination for protecting Aboriginal and Torres Strait Islander infants against infection, 2012-2017: a retrospective cohort study.

OBJECTIVES: To evaluate the effectiveness of maternal pertussis vaccination for preventing pertussis infections in Aboriginal and Torres Strait Islander infants under seven months of age. STUDY DESIGN: Retrospective cohort study; analysis of linked administrative health data. SETTING, PARTICIPANTS: Mother-infant cohort (Links2HealthierBubs) including all pregnant women who gave birth to live infants (gestational age ≥ 20 weeks, birthweight ≥ 400 g) in the Northern Territory, Queensland, and Western Australia during 1 January 2012 - 31 December 2017. MAIN OUTCOME MEASURES: Proportions of women vaccinated against pertussis during pregnancy, rates of pertussis infections among infants under seven months of age, and estimated effectiveness of maternal vaccination for protecting infants against pertussis infection, each by Indigenous status. RESULTS: Of the 19 892 Aboriginal and Torres Strait Islander women who gave birth to live infants during 2012-2017, 7398 (37.2%) received pertussis vaccine doses during their pregnancy, as had 137 034 of 259 526 non-Indigenous women (52.8%; Indigenous v non-Indigenous: adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.62-0.70). The annual incidence of notified pertussis infections in non-Indigenous infants declined from 16.8 (95% CI, 9.9-29) in 2012 to 1.4 (95% CI, 0.3-8.0) cases per 10 000 births in 2017; among Aboriginal and Torres Strait Islander infants, it declined from 47.6 (95% CI, 16.2-139) to 38.6 (95% CI, 10.6-140) cases per 10 000 births. The effectiveness of maternal vaccination for protecting non-Indigenous infants under seven months of age against pertussis infection during 2014-17 was 68.2% (95% CI, 51.8-79.0%); protection of Aboriginal and Torres Strait Islander infants was not statistically significant (36.1%; 95% CI, -41.3% to 71.1%). CONCLUSIONS: During 2015-17, maternal pertussis vaccination did not protect Aboriginal and Torres Strait Islander infants in the NT, Queensland, and WA against infection. Increasing the pertussis vaccination rate among pregnant Aboriginal and Torres Strait Islander women requires culturally appropriate, innovative strategies co-designed in partnership with Indigenous organisations and communities.

Novel Human Parechovirus 3 Diversity, Recombination, and Clinical Impact Across 7 Years: An Australian Story.

BACKGROUND: A novel human parechovirus 3 Australian recombinant (HPeV3-AR) strain emerged in 2013 and coincided with biennial outbreaks of sepsis-like illnesses in infants. We evaluated the molecular evolution of the HPeV3-AR strain and its association with severe HPeV infections. METHODS: HPeV3-positive samples collected from hospitalized infants aged 5-252 days in 2 Australian states (2013-2020) and from a community-based birth cohort (2010-2014) were sequenced. Coding regions were used to conduct phylogenetic and evolutionary analyses. A recombinant-specific polymerase chain reaction was designed and utilized to screen all clinical and community HPeV3-positive samples. RESULTS: Complete coding regions of 54 cases were obtained, which showed the HPeV3-AR strain progressively evolving, particularly in the 3' end of the nonstructural genes. The HPeV3-AR strain was not detected in the community birth cohort until the initial outbreak in late 2013. High-throughput screening showed that most (>75%) hospitalized HPeV3 cases involved the AR strain in the first 3 clinical outbreaks, with declining prevalence in the 2019-2020 season. The AR strain was not statistically associated with increased clinical severity among hospitalized infants. CONCLUSIONS: HPeV3-AR was the dominant strain during the study period. Increased hospital admissions may have been from a temporary fitness advantage and/or increased virulence.

Introduction.

Cholangiocarcinoma (CCA) is a lethal cancer arising in the bile ducts within and just outside the liver. It occurs worldwide and falls into two etiologically defined groups, one related to chronic liver fluke infection and the other not. Liver fluke-related CCA is found in continental Southeast Asia (caused by Opisthorchis viverrini with infection leading to opisthorchiasis), East Asia (Clonorchis sinensis), and Eastern Europe and Russia (Opisthorchis felineus). Both O. viverrini and C. sinensis are classified as group one carcinogens, while recent data from O. felineus suggest the same. In Southeast Asia, an estimated 67.3 million people are at risk of O. viverrini infection and subsequently developing CCA. When the three liver fluke species are considered, an estimated 700 million people are at risk of infection and developing CCA globally. The northeast of Thailand (Isan) is the world's hot spot of liver fluke infection and CCA. Early detection, diagnosis, and surgical intervention/curative treatment of CCA are critical to increase life expectancy and quality of life of people in the region and globally. Despite concentrated recent efforts focusing on a multidisciplinary approach to understand the ecology, epidemiology, biology, public health, and social significance of infection by cancer causing liver flukes, it remains an underestimated and under-resourced public health problem. In addition, it is still believed to be a regional problem without global significance-this is not the case. This book focuses on O. viverrini as the main causative agent of CCA in Southeast Asia, but many aspects detailed in the following chapters also relate to the two other liver fluke species. Our aim is to produce a holistic framework including the basic biology of O. viverrini and its relation to the epidemiology of the disease through diagnosis to treatment, including palliative methods, pathology, and control.

Opisthorchis viverrini Life Cycle, Distribution, Systematics, and Population Genetics.

Opisthorchis viverrini plays a key role as the carcinogenic liver fluke causing bile duct cancer in Southeast Asia. A comprehensive understanding of its life cycle, distribution, systematics, and population genetics is critically important as they underpin the effective development and establishment of future prevention and control programs that center on opisthorchiasis and cholangiocarcinoma. This chapter provides detailed information concerning the basic biology and updated information of O. viverrini related to its host life cycle, transmission route via raw, partially cooked or fermented freshwater cyprinid fish, endemic areas, and the discovery of new foci. Previous sequential studies over the last two decades on the phylogenetic and systematic relationships, genetic variation, and population genetics of O. viverrini as well as its snail intermediate host Bithynia spp. are presented and discussed, which have led to the currently known complex species level systematics and population genetics framework of this host-parasite system. Additionally, further directions for comprehensive research are suggested to provide a more complete understanding of liver fluke, O. viverrini-related cholangiocarcinoma.

Synopsis.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer worldwide. Despite the severity of the disease and its impact on individuals, families, and communities, there remains an overall lack of awareness and interest in this disease. The information contained in the chapters of this book shows that this is indeed a significant public health and socioeconomic problem with varying levels of country-specific awareness. In Southeast Asia liver fluke, O. viverrini related CCA is endemic with the highest incidence worldwide in northeast Thailand, yet it is treatable and preventable. The chapters highlight significant advances in our knowledge of the biology and epidemiology of the O. viverrini species complex, intermediate hosts, systematics, population genetics, and the complexity of the three-host life cycle. A comprehensive conceptual framework has been developed to assist in understanding the complexity of molecular mechanisms of CCA carcinogenesis and cancer development which can result in improvement of targeted CCA therapy. There have been many advances in understanding the pathology of CCA in the biliary tract, including advances in prognosis and molecular pathogenesis. The development of different modalities and their advantages for diagnosis have increased diagnostic accuracy, providing reliable information allowing appropriate treatment and management programs to be selected for each patient. Particularly exciting is the recent development of a urine antigen assay which has revolutionized the diagnostic approach of opisthorchiasis due to its simplicity, the non-invasive nature of sample collection, and its ease of use in field settings. Significant in-roads and advances have been made in the surgical and systemic treatment of CCA patients. Additionally, a sophisticated data collection and analysis system, the Isan Cohort, has been developed and established for the treatment and control of CCA. Importantly, a greater understanding has been made of the social, community, religious, and anthropological issues initiating and sustaining the eating behavior of raw, partially cooked, and/or fermented fresh water fish. Specially designed education programs/curricula, based on currently available multidisciplinary hard data targeting school children, have been introduced since the inception of the Cholangiocarcinoma Screening and Care Program (CASCAP) and the subsequent strategic Fluke Free Thailand Model. The education program is being expanded to other provinces in Thailand and in the near future to other Southeast Asian countries, initially to Lao PDR, where the Fluke Free Lao PDR program has already been implemented. Despite advances that have been made in many disciplines focused on O. viverrini related CCA, raising awareness of CCA at all levels, particularly across endemic regions, is still needed, as is raising the awareness of CCA globally. As parasites and parasite related diseases have no borders, it is critical that an effective common strategic plan is instigated and established between all countries where liver fluke, O. viverrini related CCA is a significant public health problem, thereby increasing the quality of life and life expectancy of millions of people who suffer from this insidious disease.

RAW ATTITUDES: Socio-Cultures, Altered Landscapes, and Changing Perceptions of an Underestimated Disease.

Raw attitudes relate to the food cultures, eating habits, and behaviours of people in relation to the consumption of raw, partially cooked, and fermented freshwater fish dishes, which puts people at risk of Ophistochis viverrini and other parasitic infections. The chapter reviews raw attitudes within the countries and across the borders of the greater Mekong region, particularly northeast Thailand, Lao PDR, Vietnam, and Cambodia. Rather than treat each nation-state as an isolated epidemiological box, the chapter explores transborder complexity in relation to multiple anthropogenic transformations to the landscapes of the region and developmental impacts upon ecosystems and life cycles. Economic projects such as multiple hydropower dams, irrigation schemes, water-diversions, roads, and aquaculture ponds have significant impacts on FTZ life-cycle dynamics. In addition, many ecological changes are transboundary ones, and there are added complications relating human mobility, altered agrarian landscapes, and significant numbers of migrant workers. The chapter also examines public health programmes and educational interventions which are altering perceptions of O. viverrini and cholangiocarcinoma over time. A key argument is the need for transdisciplinary scientific and social science strategies alongside multi-pronged health interventions, such as 'the CASCAP model'. There exist many unknowns and gaps relating to widespread anthropogenic modifications upon life cycles, upon lifestyles, livelihoods, and human behaviours, which require research projects that span socio-economic, ecological, geographical, and public health dynamics of disease.

Epidemiology and Control of Opisthorchis viverrini Infection: Implications for Cholangiocarcinoma Prevention.

It is known that Opisthorchis viverrini (OV) is the most significant risk factor for the development of cholangiocarcinoma (CCA); hence, it is also known as carcinogenic parasite. Effective control and elimination of OV infection should significantly reduce O. viverrini-related CCA. This chapter includes details of the three recently developed innovative tools, namely the Isan cohort database software, an OV-RDT for screening of O. viverrini, and an ultrasound telecommunication system. Past and current control programs, i.e., education, medication, and sanitation were discussed and stressed the need for a comprehensive control program which encompasses primary, secondary, and tertiary patient care programs for confirmation and management of suspected CCA cases. The approach of mathematical modeling for control of OV and CCA was also briefly described. Additionally, we highlighted the current progress toward control of OV and CCA in Thailand and potential for expansion into nearby countries in Southeast Asia.

Inequity of antenatal influenza and pertussis vaccine coverage in Australia: the Links2HealthierBubs record linkage cohort study, 2012-2017.

BACKGROUND: Pregnancy and early infancy are increased risk periods for severe adverse effects of respiratory infections. Aboriginal and/or Torres Strait Islander (respectfully referred to as First Nations) women and children in Australia bear a disproportionately higher burden of respiratory diseases compared to non-Indigenous women and infants. Influenza vaccines and whooping cough (pertussis) vaccines are recommended and free in every Australian pregnancy to combat these infections. We aimed to assess the equity of influenza and/or pertussis vaccination in pregnancy for three priority groups in Australia: First Nations women; women from culturally and linguistically diverse (CALD) backgrounds; and women living in remote areas or socio-economic disadvantage. METHODS: We conducted individual record linkage of Perinatal Data Collections with immunisation registers/databases between 2012 and 2017. Analysis included generalised linear mixed model, log-binomial regression with a random intercept for the unique maternal identifier to account for clustering, presented as prevalence ratios (PR) and 95% compatibility intervals (95%CI). RESULTS: There were 445,590 individual women in the final cohort. Compared with other Australian women (n = 322,848), First Nations women (n = 29,181) were less likely to have received both recommended antenatal vaccines (PR 0.69, 95% CI 0.67-0.71) whereas women from CALD backgrounds (n = 93,561) were more likely to have (PR 1.16, 95% CI 1.10-1.13). Women living in remote areas were less likely to have received both vaccines (PR 0.75, 95% CI 0.72-0.78), and women living in the highest areas of advantage were more likely to have received both vaccines (PR 1.44, 95% CI 1.40-1.48). CONCLUSIONS: Compared to other groups, First Nations Australian families, those living in remote areas and/or families from lower socio-economic backgrounds did not receive recommended vaccinations during pregnancy that are the benchmark of equitable healthcare. Addressing these barriers must remain a core priority for Australian health care systems and vaccine providers. An extension of this cohort is necessary to reassess these study findings.

Having a real say: findings from first nations community panels on pandemic influenza vaccine distribution.

BACKGROUND: Recent deliberations by Australian public health researchers and practitioners produced an ethical framework of how decisions should be made to distribute pandemic influenza vaccine. The outcome of the deliberations was that the population should be considered in two categories, Level 1 and Level 2, with Level 1 groups being offered access to the pandemic influenza vaccine before other groups. However, the public health researchers and practitioners recognised the importance of making space for public opinion and sought to understand citizens values and preferences, especially First Nations peoples. METHODS: We conducted First Nations Community Panels in two Australian locations in 2019 to assess First Nations people's informed views through a deliberative process on pandemic influenza vaccination distribution strategies. Panels were asked to make decisions on priority levels, coverage and vaccine doses. RESULTS: Two panels were conducted with eighteen First Nations participants from a range of ages who were purposively recruited through local community networks. Panels heard presentations from public health experts, cross-examined expert presenters and deliberated on the issues. Both panels agreed that First Nations peoples be assigned Level 1 priority, be offered pandemic influenza vaccination before other groups, and be offered two doses of vaccine. Reasons for this decision included First Nations people's lives, culture and families are important; are at-risk of severe health outcomes; and experience barriers and challenges to accessing safe, quality and culturally appropriate healthcare. We found that communication strategies, utilising and upskilling the First Nations health workforce, and targeted vaccination strategies are important elements in pandemic preparedness and response with First Nations peoples. CONCLUSIONS: First Nations Community Panels supported prioritising First Nations peoples for pandemic influenza vaccination distribution and offering greater protection by using a two-dose full course to fewer people if there are initial supply limitations, instead of one dose to more people, during the initial phase of the vaccine roll out. The methodology and findings can help inform efforts in planning for future pandemic vaccination strategies for First Nations peoples in Australia.

Timing and temporal trends of influenza and pertussis vaccinations during pregnancy in three Australian jurisdictions: The Links2HealthierBubs population-based linked cohort study, 2012-2017.

BACKGROUND: Antenatal inactivated influenza (IIV) and pertussis-containing vaccines (dTpa) offer protection against severe respiratory infections for pregnant women and infants <6 months of age. Both vaccines are recommended in pregnancy; however, little is known about temporal or jurisdictional trends and predictors of uptake. AIMS: To identify gaps and predictors of IIV and/or dTpa vaccinations in Australian pregnancies from 2012 to 2017. MATERIALS AND METHODS: We conducted a probabilistically linked, multi-jurisdictional population-based cohort study, drawing from perinatal data collections and immunisation databases. We used a generalised linear mixed model with a random effect term to account for clustering of multiple pregnancies within mothers, to calculate vaccination uptake, and identify predictors of uptake by maternal demographic, pregnancy, and health characteristics. RESULTS: Of 591 868 unique pregnancies, IIV uptake was 15%, dTpa 27% and 12% received both vaccines. Pertussis vaccinations in First Nations pregnancies were 20% lower than non-Indigenous pregnancies; dTpa was strongly associated with IIV uptake (risk ratio (RR): 8.60, 95% CI 8.48-8.73). This trend was temporally and jurisdictionally consistent. First Nations women were more likely to have had IIV in pregnancy before the introduction of dTpa in the pregnancy program: (RR: 1.48, 95% CI 1.40-1.57), but less likely after dTpa implementation (RR: 0.78, 95% CI 0.76-0.80). CONCLUSIONS: Inequity in vaccine uptake between First Nations and non-Indigenous pregnancies, and dismal rates of vaccination in pregnancy overall need urgent review, particularly before the next influenza pandemic or pertussis outbreak. If antenatal dTpa is driving IIV uptake, changes in antenatal healthcare practices are needed to ensure vaccines are offered equitably and optimally to protect against infection.

Transplacental transfer of RSV antibody in Australian First Nations infants.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection hospitalisations in Aboriginal infants specifically those aged <6 months. Maternally derived RSV antibody (Ab) can protect against severe RSV disease in infancy. However, the efficiency of transplacental transfer of maternal anti-RSV Ab remains unknown in Aboriginal infants. We characterised RSV Ab in Australian First Nations mother-infant pairs (n = 78). We investigated impact of covariates including low birthweight, gestational age (GA), sex of the baby, maternal age and multiparity of the mother on cord to maternal anti-RSV Ab titre ratio (CMTR) using multivariable logistic regression model. All (n = 78) but one infant was born full term (median GA: 39 weeks, interquartile range: 38-40 weeks) and 56% were males. The mean log2 RSV Ab titre was 10.7 (SD± 1.3) in maternal serum and 11.0 (SD ± 1.3) in cord serum at birth; a ratio of 1.02 (SD ± 0.06). One-third of the pairs had a CMTR of <1 indicating impaired transfer. Almost 9% (7/78) of the term infants had cord RSV Ab levels below

Drivers of the summer influenza epidemic in New South Wales, 2018-19.

OBJECTIVES: To assess the extent to which the 2018-19 New South Wales summer influenza epidemic was associated with overseas or domestic travel and with seasonal influenza vaccination status. DESIGN, SETTING: Unmatched case-control study, based on an online survey distributed from the NSW Notifiable Conditions Information Management System (NCIMS) to people for whom mobile phone numbers were available. PARTICIPANTS: A case was defined as a person with notified laboratory-confirmed influenza with onset of illness between 1 December 2018 and 21 March 2019. People with notified pertussis infections (confirmed or probable) were selected as controls. MAIN OUTCOME MEASURES: Notified influenza infection, by travel and contact with unwell overseas travellers in the week before onset of illness and seasonal influenza vaccination status (as the primary exposures). RESULTS: Valid survey responses were provided by 648 of 2806 invited people with notified influenza (23%) and 257 of 796 invited people with notified pertussis (32%). The demographic characteristics of the respondents were similar to those of the source population (7251 cases, 2254 controls). During the first two months of the summer of 2018-19, notified influenza was more likely for people who had travelled overseas or had contact with an ill overseas traveller in the week before symptom onset (adjusted OR [aOR], 6.99; 95% CI, 3.59-13.6), but not during the second two months (aOR, 1.63; 95% CI, 0.79-3.35). Influenza vaccination status was not associated with the likelihood of notified influenza. CONCLUSIONS: Travel-related factors were early drivers of the 2018-19 NSW summer influenza epidemic; local transmission sustained the outbreak despite unfavourable conditions later in summer. Our findings prompted re-evaluation of recommendations for pre-travel vaccination in NSW. The role of travel in out-of-season influenza outbreaks should be considered in other temperate zones.

Population dynamics and diversity of trematode infections in Bithynia siamensis goniomphalos in an irrigated area in northeast Thailand.

Several trematodes including Opisthorchis viverrini utilize Bithynia siamensis goniomphalos as a snail intermediate host in their life cycles. In order to capture a comprehensive range of host­parasite interactions and their transmission dynamic patterns, B. s. goniomphalos were sampled monthly over 4 consecutive years in an irrigated paddy-field habitat in northeast Thailand. Using a standard cercarial shedding method, a high diversity of trematodes (17 types) was recovered. Virgulate xiphidiocercariae were the most prevalent (7.84%) followed by O. viverrini (0.71%). In addition to seasonal and environmental factors, the quantity of irrigation water for rice cultivation correlated with transmission dynamics of trematodes in B. s. goniomphalos. The peak prevalence of all trematode infections combined in the snails shifted from the cool-dry season in 2010­2012 to the hot-dry season in 2013 associated with an increasing quantity of water irrigation. A low frequency of mixed trematode infections was found, indicating that the emergence of virgulate cercariae, but not of O. viverrini, was negatively impacted by the presence of other trematodes in the same snail. Taken together, the observed results suggest that interactions between host and parasite, and hence transmission dynamics, depend on specific characteristics of the parasite and environmental factors including irrigated water for rice cultivation.

Genetic diversity and phylogenetic analyses of ixodid ticks infesting cattle in northeast Thailand: the discovery of Rhipicephalus microplus clade C and the rarely detected R. haemaphysaloides.

In total, 160 ticks infesting cattle in the northeast region of Thailand were collected and used for molecular investigation. Three tick species-Rhipicephalus microplus Canestrini, Rhipicephalus haemaphysaloides Supino and Haemaphysalis bispinosa Neumann-were identified based on morphology and DNA sequences of mitochondrial cytochrome c oxidase subunit 1 (CO1) and 16S ribosomal RNA (16S rRNA). In total, 26 and seven unique haplotypes of the CO1 and 16S rRNA genes, respectively, were recovered. Phylogenetic analysis using the CO1 sequence revealed that the R. microplus from northeastern Thailand were grouped into the previously described clades A and C, whereas the 16S rRNA phylogenetic tree assigned all isolates of R. microplus from Northeast Thailand into the previously described clade B. Clade C of the CO1 phylogenetic tree is a new genetic assemblage recently discovered from India and Malaysia, which has now been detected in our study. The haplotype network also demonstrated that R. microplus is divided into two haplogroups corresponding to the assemblage of the CO1 phylogenetic tree. Our findings strongly support the previous genetic assemblage classification and evidence that R. microplus from Northeast Thailand is a species complex comprising at least two genetic assemblages, i.e., clades A and C. However, further investigation is needed and should involve more comprehensive genetic and morphological analyses and cover a larger part of their distributional range throughout Southeast Asia.

Effectiveness of Meningococcal Vaccines at Reducing Invasive Meningococcal Disease and Pharyngeal Neisseria meningitidis Carriage: A Systematic Review and Meta-analysis.

BACKGROUND: Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, leads to significant morbidity and mortality worldwide. This review aimed to establish the effectiveness of meningococcal vaccines at preventing IMD and N. meningitidis pharyngeal carriage. METHODS: A search within PubMed, Embase, Scopus, and unpublished studies up to 1 February 2020 was conducted. RESULTS: After removal of duplicates, 8565 studies were screened and 27 studies included. Protection was provided by meningococcal C vaccines for group C IMD (odds ratio [OR], 0.13 [95% confidence interval {CI}, .07-.23]), outer membrane vesicle (OMV) vaccines against group B IMD (OR, 0.35 [95% CI, .25-.48]), and meningococcal A, C, W, Y (MenACWY) vaccines against group ACWY IMD (OR, 0.31 [95% CI, .20-.49]). A single time series analysis found a reduction following an infant 4CMenB program (incidence rate ratio, 0.25 [95% CI, .19-.36]). Multivalent MenACWY vaccines did not reduce carriage (relative risk [RR], 0.88 [95% CI, .66-1.18]), unlike monovalent C vaccines (RR, 0.50 [95% CI, .26-.97]). 4CMenB vaccine had no effect on group B carriage (RR, 1.12 [95% CI, .90-1.40]). There was also no reduction in group B carriage following MenB-FHbp vaccination (RR, 0.98 [95% CI, .53-1.79]). CONCLUSIONS: Meningococcal conjugate C, ACWY, and OMV vaccines are effective at reducing IMD. A small number of studies demonstrate that monovalent C conjugate vaccines reduce pharyngeal N. meningitidis carriage. There is no evidence of carriage reduction for multivalent MenACWY, OMV, or recombinant MenB vaccines, which has implications for immunization strategies. CLINICAL TRIALS REGISTRATION: CRD42018082085 (PROSPERO).

Impact of Meningococcal B (4CMenB) Vaccine on Pharyngeal Neisseria meningitidis Carriage Density and Persistence in Adolescents.

BACKGROUND: Higher density of Neisseria meningitidis carriage may be associated with transmission of the meningococcus. Our aim was to establish the impact of meningococcal B (4CMenB) vaccine on N. meningitidis carriage density. METHODS: We compared 4CMenB vaccine to control among 913 South Australian students aged approximately 15-18 years in a cluster randomized trial who had N. meningitidis carriage at 12 months. Oropharyngeal swabs were collected at baseline and 12 months later to detect N. meningitidis carriage. Colony-forming units per milliliter (CFU/mL) were estimated by generating a standard curve that plotted quantitative polymerase chain reaction cycle threshold values against log-normalized CFU. RESULTS: Among the 913 students with N. meningitidis carriage at 12 months, there was no difference in mean carriage density between the vaccinated (n = 434; 3.80 log CFU/mL [standard deviation {SD}, 1.29]) and control group (n = 479; 3.73 log CFU/mL [SD, 1.30]; P = .51). Higher N. meningitidis carriage density at baseline was associated with an increase in the odds of persistent carriage at 12 months (n = 504; odds ratio [OR] per 1.0 log CFU/mL increase in density, 1.36 [95% confidence interval {CI}, 1.17-1.58]; P < .001). Students with baseline carriage who were vaccinated had decreased persistent N. meningitidis carriage at 12 months compared to unvaccinated students (81/260 [31%] vs 105/244 [43%]; OR, 0.60 [95% CI, .40-.90]; P = .01). CONCLUSIONS: 4CMenB vaccine did not reduce carriage density of N. meningitidis 12 months postvaccination, despite increased carriage clearance. Higher carriage density is likely to enable transmission through prolonged periods of population exposure. CLINICAL TRIALS REGISTRATION: NCT03089086.

Levels of pneumococcal conjugate vaccine coverage and indirect protection against invasive pneumococcal disease and pneumonia hospitalisations in Australia: An observational study.

BACKGROUND: There is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children. METHODS AND FINDINGS: Birth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged <5 years, born between 2001 and 2012 in 2 Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD; (2) all-cause pneumonia; and (3) pneumococcal and lobar pneumonia hospitalisation in undervaccinated children. Undervaccinated children received <2 doses of PCV at <12 months of age and no doses at ≥12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph. There were strong inverse associations between PCV coverage and the incidence of PCV7-type IPD (adjusted incidence rate ratio [aIRR] 0.967, 95% confidence interval [CI] 0.958 to 0.975, p-value < 0.001), and pneumonia hospitalisations (all-cause pneumonia: aIRR 0.991 95% CI 0.990 to 0.994, p-value < 0.001) among undervaccinated children. Subgroup analyses for children <4 months old, urban, rural, and Indigenous populations showed similar trends, although effects were smaller for rural and Indigenous populations. Approximately 50% coverage of PCV7 among children <5 years of age was estimated to prevent up to 72.5% (95% CI 51.6 to 84.4) of PCV7-type IPD among undervaccinated children, while 90% coverage was estimated to prevent 95.2% (95% CI 89.4 to 97.8). The main limitations of this study include the potential for differential loss to follow-up, geographical misclassification of children (based on residential address at birth only), and unmeasured confounders. CONCLUSIONS: In this study, we observed substantial indirect protection at lower levels of PCV coverage than previously described-challenging assumptions that high levels of PCV coverage (i.e., greater than 90%) are required. Understanding the association between PCV coverage and indirect protection is a priority since the control of vaccine-type pneumococcal disease is a prerequisite for reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to substantially reduce program costs while maintaining vaccine impact.

Estimation of the force of infection and infectious period of skin sores in remote Australian communities using interval-censored data.

Prevalence of impetigo (skin sores) remains high in remote Australian Aboriginal communities, Fiji, and other areas of socio-economic disadvantage. Skin sore infections, driven primarily in these settings by Group A Streptococcus (GAS) contribute substantially to the disease burden in these areas. Despite this, estimates for the force of infection, infectious period and basic reproductive ratio-all necessary for the construction of dynamic transmission models-have not been obtained. By utilising three datasets each containing longitudinal infection information on individuals, we estimate each of these epidemiologically important parameters. With an eye to future study design, we also quantify the optimal sampling intervals for obtaining information about these parameters. We verify the estimation method through a simulation estimation study, and test each dataset to ensure suitability to the estimation method. We find that the force of infection differs by population prevalence, and the infectious period is estimated to be between 12 and 20 days. We also find that optimal sampling interval depends on setting, with an optimal sampling interval between 9 and 11 days in a high prevalence setting, and 21 and 27 days for a lower prevalence setting. These estimates unlock future model-based investigations on the transmission dynamics of skin sores.

Strongyloides stercoralis seropositivity is not associated with increased symptoms in a remote Aboriginal community.

BACKGROUND: Strongyloides stercoralis is a soil-transmitted helminth, endemic in remote Aboriginal and Torres Strait Islander communities in northern Australia with estimates of prevalences up to 60%. Hyperinfection in the setting of immunosuppression is a rare, but well recognised cause of significant morbidity and mortality. However, the morbidity associated with chronic uncomplicated infection is less well characterised. AIMS: To measure the prevalence of symptoms potentially attributable to S. stercoralis infection and their association with seropositivity. METHODS: This retrospective matched case-control study reviewed records of primary healthcare presentations for symptoms in the 12 months before and after an ivermectin mass drug administration (MDA) in a remote Aboriginal community. RESULTS: One hundred and seventy-five S. stercoralis seropositive cases were matched with 175 seronegative controls. The most frequently reported symptom overall in the 12 months prior to the MDA was cough followed by abdominal pain, weight loss/malnutrition, diarrhoea and pruritis. Seropositive cases were not more likely than matched controls to have symptoms typically attributed to strongyloidiasis. In the seropositive cohort, we found no difference in symptoms in the 12 months before and after an ivermectin MDA despite a reduction in seroprevalence. CONCLUSION: We found no evidence to suggest that S. stercoralis seropositivity was associated with increased symptoms when compared to matched seronegative controls. Treatment with ivermectin did not reduce symptoms in seropositive cases. Without evidence to support that population-based screening or treatment programmes reduce symptoms, the emphasis must remain on identifying and managing those few individuals with immunosuppression that predisposes them to potentially life-threatening hyperinfection.