Doherty Institute - Research Publications

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    Longitudinal Analysis of Group A Streptococcus emm Types and emm Clusters in a High-Prevalence Setting: Relationship between Past and Future Infections.
    Campbell, PT ; Tong, SYC ; Geard, N ; Davies, MR ; Worthing, KA ; Lacey, JA ; Smeesters, PR ; Batzloff, MR ; Kado, J ; Jenney, AWJ ; Mcvernon, J ; Steer, AC (Oxford University Press (OUP), 2020-05-01)
    Group A Streptococcus is a pathogen of global importance, but despite the ubiquity of group A Streptococcus infections, the relationship between infection, colonization, and immunity is still not completely understood. The M protein, encoded by the emm gene, is a major virulence factor and vaccine candidate and forms the basis of a number of classification systems. Longitudinal patterns of emm types collected from 457 Fijian schoolchildren over a 10-month period were analyzed. No evidence of tissue tropism was observed, and there was no apparent selective pressure or constraint of emm types. Patterns of emm type acquisition suggest limited, if any, modification of future infection based on infection history. Where impetigo is the dominant mode of transmission, circulating emm types either may not be constrained by ecological niches or population immunity to the M protein, or they may require several infections over a longer period of time to induce such immunity.
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    A model of population dynamics with complex household structure and mobility: implications for transmission and control of communicable diseases
    Chisholm, RH ; Crammond, B ; Wu, Y ; Bowen, AC ; Campbell, PT ; Tong, SYC ; McVernon, J ; Geard, N (PEERJ INC, 2020-11-03)
    Households are known to be high-risk locations for the transmission of communicable diseases. Numerous modelling studies have demonstrated the important role of households in sustaining both communicable diseases outbreaks and endemic transmission, and as the focus for control efforts. However, these studies typically assume that households are associated with a single dwelling and have static membership. This assumption does not appropriately reflect households in some populations, such as those in remote Australian Aboriginal and Torres Strait Islander communities, which can be distributed across more than one physical dwelling, leading to the occupancy of individual dwellings changing rapidly over time. In this study, we developed an individual-based model of an infectious disease outbreak in communities with demographic and household structure reflective of a remote Australian Aboriginal community. We used the model to compare the dynamics of unmitigated outbreaks, and outbreaks constrained by a household-focused prophylaxis intervention, in communities exhibiting fluid vs. stable dwelling occupancy. We found that fluid dwelling occupancy can lead to larger and faster outbreaks in modelled scenarios, and may interfere with the effectiveness of household-focused interventions. Our findings suggest that while short-term restrictions on movement between dwellings may be beneficial during outbreaks, in the longer-term, strategies focused on reducing household crowding may be a more effective way to reduce the risk of severe outbreaks occurring in populations with fluid dwelling occupancy.
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    Epidemiological consequences of enduring strain-specific immunity requiring repeated episodes of infection
    Chisholm, RH ; Sonenberg, N ; Lacey, JA ; McDonald, MI ; Pandey, M ; Davies, MR ; Tong, SYC ; McVernon, J ; Geard, N ; Lewis, B (PUBLIC LIBRARY SCIENCE, 2020-06-01)
    Group A Streptococcus (GAS) skin infections are caused by a diverse array of strain types and are highly prevalent in disadvantaged populations. The role of strain-specific immunity in preventing GAS infections is poorly understood, representing a critical knowledge gap in vaccine development. A recent GAS murine challenge study showed evidence that sterilising strain-specific and enduring immunity required two skin infections by the same GAS strain within three weeks. This mechanism of developing enduring immunity may be a significant impediment to the accumulation of immunity in populations. We used an agent-based mathematical model of GAS transmission to investigate the epidemiological consequences of enduring strain-specific immunity developing only after two infections with the same strain within a specified interval. Accounting for uncertainty when correlating murine timeframes to humans, we varied this maximum inter-infection interval from 3 to 420 weeks to assess its impact on prevalence and strain diversity, and considered additional scenarios where no maximum inter-infection interval was specified. Model outputs were compared with longitudinal GAS surveillance observations from northern Australia, a region with endemic infection. We also assessed the likely impact of a targeted strain-specific multivalent vaccine in this context. Our model produced patterns of transmission consistent with observations when the maximum inter-infection interval for developing enduring immunity was 19 weeks. Our vaccine analysis suggests that the leading multivalent GAS vaccine may have limited impact on the prevalence of GAS in populations in northern Australia if strain-specific immunity requires repeated episodes of infection. Our results suggest that observed GAS epidemiology from disease endemic settings is consistent with enduring strain-specific immunity being dependent on repeated infections with the same strain, and provide additional motivation for relevant human studies to confirm the human immune response to GAS skin infection.
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    Optimal timing of influenza vaccine during pregnancy: A systematic review and meta-analysis
    Cuningham, W ; Geard, N ; Fielding, JE ; Braat, S ; Madhi, SA ; Nunes, MC ; Christian, LM ; Lin, S-Y ; Lee, C-N ; Yamaguchi, K ; Bisgaard, H ; Chawes, B ; Chao, A-S ; Blanchard-Rohner, G ; Schlaudecker, EP ; Fisher, BM ; McVernon, J ; Moss, R (WILEY, 2019-09-01)
    BACKGROUND: Pregnant women have an elevated risk of illness and hospitalisation from influenza. Pregnant women are recommended to be prioritised for influenza vaccination during any stage of pregnancy. The risk of seasonal influenza varies substantially throughout the year in temperate climates; however, there is limited knowledge of how vaccination timing during pregnancy impacts the benefits received by the mother and foetus. OBJECTIVES: To compare antenatal vaccination timing with regard to influenza vaccine immunogenicity during pregnancy and transplacental transfer to their newborns. METHODS: Studies were eligible for inclusion if immunogenicity to influenza vaccine was evaluated in women stratified by trimester of pregnancy. Haemagglutination inhibition (HI) titres, stratified by trimester of vaccination, had to be measured at either pre-vaccination and within one month post-vaccination, post-vaccination and at delivery in the mother, or in cord/newborn blood. Authors searched PubMed, Scopus, Web of Science and EMBASE databases from inception until June 2016 and authors of identified studies were contacted for additional data. Extracted data were tabulated and summarised via random-effect meta-analyses and qualitative methods. RESULTS: Sixteen studies met the inclusion criteria. Meta-analyses found that compared with women vaccinated in an earlier trimester, those vaccinated in a later trimester had a greater fold increase in HI titres (1.33- to 1.96-fold) and higher HI titres in cord/newborn blood (1.21- to 1.64-fold). CONCLUSIONS: This review provides comparative analysis of the effect of vaccination timing on maternal immunogenicity and protection of the infant that is informative and relevant to current vaccine scheduling for pregnant women.
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    Quantity or quality? Assessing relationships between perceived social connectedness and recorded encounters
    Dias, A ; Geard, N ; Campbell, PT ; Warr, D ; McVernon, J ; Poncela-Casasnovas, J (PUBLIC LIBRARY SCIENCE, 2018-11-29)
    INTRODUCTION: Higher levels of social connectedness are associated with better physical and mental health outcomes, but measures of connectedness are often study specific. Prior research has distinguished between perceived and received (quantifiable) measures of social connectedness, with differing impacts on health, sometimes mediated by place of residence. This analysis investigated the relationship between perceptions of social support/connection and quantifiable measures of social encounters, by neighbourhood, to inform understanding of place-based differences in connectedness and health outcomes. METHODS: Negative binomial regression models were used to determine associations between perceptions of social connectedness (perceived community connections and social involvement) and the number of recorded daily social encounters as a proxy for received support/connectedness. Analyses were undertaken across two Local Government Areas (LGAs) in Melbourne with disparate socio-economic profiles to examine potential modification of social connectedness measures by neighbourhood of residence. RESULTS: Two measures of perceived connectedness had a clear relationship with recorded daily social encounters-feeling a sense of community belonging (RR 1.20 (1.04, 1.37), p = 0.010) and having family or friends close by (RR 1.30 (1.10,1.54), p = 0.002 "neither" compared to "disagree", (RR 1.15 (1.04, 1.26), p = 0.006 "agree" compared to "disagree"). Involvement in a local church, sporting or social club was associated with a greater number of daily social encounters for respondents who participated a few times a year (RR 1.17 (1.05,1.32), p = 0.006) or often (RR 1.23 (1.12,1.36), p<0.001) compared to never. In the less affluent LGA, active contributions to neighbours and community through assistance and volunteering were a frequent driver of social connection. Differences in patterns between the two areas were found with some measures of perception showing stronger relationships with recorded daily encounters in one area but not the other. CONCLUSIONS: These results indicate substantial complexity in the relationship between perceptions of social connectedness and recorded daily social encounters/received connectedness, meaning that one cannot be reliably extrapolated from the other. Drivers of individuals' social connections also varied by area of residence. These findings offer new insights into potential mediators of the association between connectedness and wellbeing.
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    Implications of asymptomatic carriers for infectious disease transmission and control
    Chisholm, RH ; Campbell, PT ; Wu, Y ; Tong, SYC ; McVernon, J ; Geard, N (ROYAL SOC, 2018-02-01)
    For infectious pathogens such as Staphylococcus aureus and Streptococcus pneumoniae, some hosts may carry the pathogen and transmit it to others, yet display no symptoms themselves. These asymptomatic carriers contribute to the spread of disease but go largely undetected and can therefore undermine efforts to control transmission. Understanding the natural history of carriage and its relationship to disease is important for the design of effective interventions to control transmission. Mathematical models of infectious diseases are frequently used to inform decisions about control and should therefore accurately capture the role played by asymptomatic carriers. In practice, incorporating asymptomatic carriers into models is challenging due to the sparsity of direct evidence. This absence of data leads to uncertainty in estimates of model parameters and, more fundamentally, in the selection of an appropriate model structure. To assess the implications of this uncertainty, we systematically reviewed published models of carriage and propose a new model of disease transmission with asymptomatic carriage. Analysis of our model shows how different assumptions about the role of asymptomatic carriers can lead to different conclusions about the transmission and control of disease. Critically, selecting an inappropriate model structure, even when parameters are correctly estimated, may lead to over- or under-estimates of intervention effectiveness. Our results provide a more complete understanding of the role of asymptomatic carriers in transmission and highlight the importance of accurately incorporating carriers into models used to make decisions about disease control.
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    Indigenous Australian household structure: a simple data collection tool and implications for close contact transmission of communicable diseases
    vino, T ; Singh, GR ; Davision, B ; Campbell, PT ; Lydeamore, MJ ; Robinson, A ; McVernon, J ; Tong, SYC ; Geard, N (PEERJ INC, 2017-10-26)
    Households are an important location for the transmission of communicable diseases. Social contact between household members is typically more frequent, of greater intensity, and is more likely to involve people of different age groups than contact occurring in the general community. Understanding household structure in different populations is therefore fundamental to explaining patterns of disease transmission in these populations. Indigenous populations in Australia tend to live in larger households than non-Indigenous populations, but limited data are available on the structure of these households, and how they differ between remote and urban communities. We have developed a novel approach to the collection of household structure data, suitable for use in a variety of contexts, which provides a detailed view of age, gender, and room occupancy patterns in remote and urban Australian Indigenous households. Here we report analysis of data collected using this tool, which quantifies the extent of crowding in Indigenous households, particularly in remote areas. We use these data to generate matrices of age-specific contact rates, as used by mathematical models of infectious disease transmission. To demonstrate the impact of household structure, we use a mathematical model to simulate an influenza-like illness in different populations. Our simulations suggest that outbreaks in remote populations are likely to spread more rapidly and to a greater extent than outbreaks in non-Indigenous populations.
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    Characterising pandemic severity and transmissibility from data collected during first few hundred studies
    Black, AJ ; Geard, N ; McCaw, JM ; McVernon, J ; Ross, JV (ELSEVIER SCIENCE BV, 2017-06-01)
    Early estimation of the probable impact of a pandemic influenza outbreak can assist public health authorities to ensure that response measures are proportionate to the scale of the threat. Recently, frameworks based on transmissibility and severity have been proposed for initial characterization of pandemic impact. Data requirements to inform this assessment may be provided by "First Few Hundred" (FF100) studies, which involve surveillance-possibly in person, or via telephone-of household members of confirmed cases. This process of enhanced case finding enables detection of cases across the full spectrum of clinical severity, including the date of symptom onset. Such surveillance is continued until data for a few hundred cases, or satisfactory characterization of the pandemic strain, has been achieved. We present a method for analysing these data, at the household level, to provide a posterior distribution for the parameters of a model that can be interpreted in terms of severity and transmissibility of a pandemic strain. We account for imperfect case detection, where individuals are only observed with some probability that can increase after a first case is detected. Furthermore, we test this methodology using simulated data generated by an independent model, developed for a different purpose and incorporating more complex disease and social dynamics. Our method recovers transmissibility and severity parameters to a high degree of accuracy and provides a computationally efficient approach to estimating the impact of an outbreak in its early stages.
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    Determining the Best Strategies for Maternally Targeted Pertussis Vaccination Using an Individual-Based Model
    Campbell, PT ; McVernon, J ; Geard, N (OXFORD UNIV PRESS INC, 2017-07-01)
    Rising pertussis incidence has prompted a number of countries to implement maternally targeted vaccination strategies to protect vulnerable infants, but questions remain about the optimal design of such strategies. We simulated pertussis transmission within an individual-based model parameterized to match Australian conditions, explicitly linking infants and their mothers to estimate the effectiveness of alternative maternally targeted vaccination strategies (antenatal delivery vs. postnatal delivery) and the benefit of revaccination over the course of multiple pregnancies. For firstborn infants aged less than 2 months, antenatal immunization reduced annual pertussis incidence by 60%, from 780 per 100,000 firstborn children under age 2 months (interquartile range (IQR), 682-862) to 315 per 100,000 (IQR, 260-370), while postnatal vaccination produced a minimal reduction, with an incidence of 728 per 100,000 (IQR, 628-789). Subsequent infants obtained limited protection from a single antenatal dose, but revaccinating mothers during every pregnancy decreased incidence for these infants by 58%, from 1,878 per 100,000 subsequent children under age 2 months (IQR, 1,712-2,076) to 791 per 100,000 (IQR, 683-915). Subsequent infants also benefited from household-level herd immunity when antenatal vaccination for every pregnancy was combined with a toddler booster dose at age 18 months; incidence was reduced to 626 per 100,000 (IQR, 548-691). Our approach provides useful information to aid consideration of alternative maternally targeted vaccination strategies and can inform development of outcome measures for program evaluation.
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    Who's holding the baby? A prospective diary study of the contact patterns of mothers with an infant
    Campbell, PT ; McVernon, J ; Shrestha, N ; Nathan, PM ; Geard, N (BMC, 2017-09-20)
    BACKGROUND: Models of infectious disease are increasingly utilising empirical contact data to quantify the number of potentially infectious contacts between age groups. While a growing body of data is being collected on contact patterns across many populations, less attention has been paid to the social contacts of young infants. We collected information on the social contacts of primary carers of young infants and investigated their potential for use as a proxy for contacts made by their infant. METHODS: We recruited primary carers of infants under one year of age residing in two geographically, demographically and socioeconomically distinct local government areas of Melbourne, Australia - Boroondara and Hume - including a sub-group of Turkish-speaking participants. Participants recorded their own contacts in a paper diary and noted whether their infant was present or absent. Information collected included times at an address; description of location; and details on people contacted at the location. Descriptive summary measures and distributions of contacts by location type, intensity, day of contact and by age are reported. RESULTS: Of the 226 participants recruited, 220 completed diaries were returned. Participant contact patterns were similar across all groups, with respect to the types of locations, intensity and day of contact, with some variation in the number of unique daily contacts. The infant was present at around 85% of locations at which the primary carer contacted other individuals. The majority of contacts occurring when the infant was present were in Own Home (32%), Retail and Hospitality (18%) and Transport (18%) settings. The mean daily number of unique contacts by infants was estimated as 9.1, 8.7 and 6.5 in Boroondara, Hume (English) and Hume (Turkish), respectively, with a similar age distribution across each of our surveyed groups. CONCLUSIONS: Our demonstration that contact patterns of mothers with infants are reasonably robust to socioeconomic and cultural differences is a step forward in modelling infectious disease transmission. With infants spending most of their time in the company of their mother, contact patterns of mothers are a useful proxy measure of infant contact patterns. The age distribution of contacts made by infants estimated in this study may be used to supplement population-wide contact information commonly used in infectious disease transmission models.