Patricia Therese Campbell

Increased Population Prevalence of Low Pertussis Toxin Antibody Levels in Young Children Preceding a Record Pertussis Epidemic in Australia

Background Cross-sectional serosurveys using IgG antibody to pertussis toxin (IgG-PT) are increasingly being used to estimate trends in recent infection independent of reporting biases. Methods/Principal Findings We compared the age-specific seroprevalence of various levels of IgG-PT in cross-sectional surveys using systematic collections of residual sera from Australian diagnostic laboratories in 1997/8, 2002 and 2007 with reference to both changes in the pertussis vaccine schedule and the epidemic cycle, as measured by disease notifications. A progressive decline in high-level (≥62.5 EU/ml) IgG-PT prevalence from 19% (95% CI 16–22%) in 1997/98 to 12% (95% CI 11–14%) in 2002 and 5% (95% CI 4–6%) in 2007 was consistent with patterns of pertussis notifications in the year prior to each collection. Concomitantly, the overall prevalence of undetectable (<5 EU/ml) levels increased from 17% (95% CI 14–20%) in 1997/98 to 38% (95% CI 36–40%) in 2007 but among children aged 1–4 years, from 25% (95% CI 17–34%) in 1997/98 to 62% (95% CI 56–68%) in 2007. This change followed withdrawal of the 18-month booster dose in 2003 and preceded record pertussis notifications from 2008 onwards. Conclusions/Significance Population seroprevalence of high levels of IgG-PT is accepted as a reliable indicator of pertussis disease activity over time within and between countries with varying diagnostic practices, especially in unimmunised age groups. Our novel findings suggest that increased prevalence of undetectable IgG-PT is an indicator of waning immunity useful for population level monitoring following introduction of acellular vaccines and/or schedule changes.

Defining long-term drivers of pertussis resurgence, and optimal vaccine control strategies.

Pertussis resurgence has been reported from several developed countries with long-standing immunisation programs. Among these, Australia in 2003 discontinued an 18 months (fourth) booster dose in favour of an adolescent (fifth) dose. We developed a model to evaluate determinants of resurgence in Australia and alternative vaccine strategies for mitigation. Novel characteristics of our model included the use of seroepidemiologic data for calibration, and broad investigation of variables relevant to transmission of, and protection against, pertussis. We simulated multiple parameter combinations, retaining those consistent with observed data for subsequent use in predictive models comparing alternative vaccination schedules. Reproducing the early control of pertussis followed by late resurgence observed in Australia required natural immunity to last decades longer than vaccine-acquired immunity, with mean duration exceeding 50 years in almost 90% of simulations. Replacement of the dose at 18 months with an adolescent dose in 2003 resulted in a 40% increase in infections in the age group 18-47 months by 2013. A six dose strategy (2, 4, 6, 18 months, 4 and 15 years) yielded a reduction in infection incidence (pre-school 43%, infants 8%) greater than any alternative strategies considered for timing of five administered doses. Our finding that natural immunity drives long-term trends in pertussis cycles is relevant to a range of pertussis strategies and provides the necessary context in which to consider maternal vaccination. Comparatively short-lived vaccine-acquired immunity requires multiple boosters over the first two decades of life to maximise reduction in infections.

The seroepidemiology of pertussis in NSW: fluctuating immunity profiles related to changes in vaccination schedules

The pertussis epidemic experienced in NSW in 2008-2009 was likely to be in part due to changes in diagnostic practice since 2007, which amplified disease notifications. We used population-based seroepidemiology as a less biased means of interpreting age-specific pertussis infection patterns in NSW from three serosurveys undertaken in 1997-98 (during an epidemic), 2002 (post-epidemic) and 2007 (inter-epidemic), using a standardised pertussis toxin IgG enzyme-linked immunosorbent assay (ELISA). There was a decrease in the proportion of high anti-pertussis toxin IgG titres (>62.5ELISAUnits/mL) across all age groups in the 2007 serosurvey compared to the previous two serosurveys. In the 2007 serosurvey, the proportion of undetectable (<5ELISAUnits/mL) anti-pertussis toxin IgG titres increased in many age groups. The seroepidemiological profiles of the three serosurveys demonstrate fluctuating immunity profiles related to changes in vaccination schedules.

Influence of Population Demography and Immunization History on the Impact of an Antenatal Pertussis Program

Background. Antenatal pertussis vaccination is being considered as a means to reduce the burden of infant pertussis in low- and middle-income countries (LMICs), but its likely impact in such settings is yet to be quantified. Methods. An individual-based model was used to simulate the demographic structure and dynamics of a population with characteristics similar to those of LMICs. Transmission of pertussis within this population was simulated to capture the incidence of infection in (1) the absence of vaccination; (2) with a primary course only (three doses of diphtheria, tetanus, and pertussis vaccines [DTP3] commencing in 1985, 1995, or 2005 at 20%, 50%, or 80% coverage); and (3) with the addition of an antenatal pertussis program. Results. Modeled annual incidence averaged over the period 2015–2024 reduced with increasing DTP3 coverage, regardless of the year childhood vaccination commenced. Over the same period, the proportion of infants born with passive protection did not change substantially compared with the prevaccination situation, regardless of DTP3 coverage and start year. We found minimal impact of antenatal vaccination on infection in all infants when mothers were eligible for a single antenatal dose. When mothers were eligible for multiple antenatal doses, incidence in infants aged 0–2 months was reduced by around 30%. This result did not hold for the full 0- to 1-year age group, for whom antenatal vaccination did not reduce infection levels. Conclusions. While antenatal vaccination could potentially reduce infant mortality in LMICs, broader gains at the population level are likely to be achieved by focusing efforts on increasing DTP3 coverage.

Pertussis models to inform vaccine policy

Pertussis remains a challenging public health problem with many aspects of infection, disease and immunity poorly understood. Initially controlled by mass vaccination, pertussis resurgence has occurred in some countries with well-established vaccination programs, particularly among adolescents and young adults. Several studies have used mathematical models to investigate drivers of pertussis epidemiology and predict the likely impact of different vaccination strategies. We reviewed a number of these models to evaluate their suitability to answer questions of public health importance regarding optimal vaccine scheduling. We critically discuss the approaches adopted and the impact of chosen model structures and assumptions on study conclusions. Common limitations were a lack of contemporary, population relevant data for parameterization and a limited understanding of the relationship between infection and disease. We make recommendations for future model development and suggest epidemiologic data collections that would facilitate efforts to reduce uncertainty and improve the robustness of model-derived conclusions.

Whole genome sequencing reveals extensive community-level transmission of group A Streptococcus in remote communities

Impetigo is common in remote Indigenous children of northern Australia, with the primary driver in this context being Streptococcus pyogenes [or group A Streptococcus (GAS)]. To reduce the high burden of impetigo, the transmission dynamics of GAS must be more clearly elucidated. We performed whole genome sequencing on 31 GAS isolates collected in a single community from children in 11 households with ⩾2 GAS-infected children. We aimed to determine whether transmission was occurring principally within households or across the community. The 31 isolates were represented by nine multilocus sequence types and isolates within each sequence type differed from one another by only 0-3 single nucleotide polymorphisms. There was evidence of extensive transmission both within households and across the community. Our findings suggest that strategies to reduce the burden of impetigo in this setting will need to extend beyond individual households, and incorporate multi-faceted, community-wide approaches.

Who’s holding the baby? A prospective diary study of the contact patterns of mothers with an infant

BackgroundModels 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.MethodsWe 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.ResultsOf 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.ConclusionsOur 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.

Scabies and risk of skin sores in remote Australian Aboriginal communities: A self-controlled case series study

Background Skin sores caused by Group A streptococcus (GAS) infection are a major public health problem in remote Aboriginal communities. Skin sores are often associated with scabies, which is evident in scabies intervention programs where a significant reduction of skin sores is seen after focusing solely on scabies control. Our study quantifies the strength of association between skin sores and scabies among Aboriginal children from the East Arnhem region in the Northern Territory. Methods and results Pre-existing datasets from three published studies, which were conducted as part of the East Arnhem Healthy Skin Project (EAHSP), were analysed. Aboriginal children were followed from birth up to 4.5 years of age. Self-controlled case series design was used to determine the risks, within individuals, of developing skin sores when infected with scabies versus when there was no scabies infection. Participants were 11.9 times more likely to develop skin sores when infected with scabies compared with times when no scabies infection was evident (Incidence Rate Ratio (IRR) 11.9; 95% CI 10.3–13.7; p<0.001), and this was similar across the five Aboriginal communities. Children had lower risk of developing skin sores at age ≤1 year compared to at age >1 year (IRR 0.8; 95% CI 0.7–0.9). Conclusion The association between scabies and skin sores is highly significant and indicates a causal relationship. The public health importance of scabies in northern Australia is underappreciated and a concerted approach is required to recognise and eliminate scabies as an important precursor of skin sores.

A biological model of scabies infection dynamics and treatment informs mass drug administration strategies to increase the likelihood of elimination.

Infections with Sarcoptes scabiei, or scabies, remain common in many disadvantaged populations. Mass drug administration (MDA) has been used in such settings to achieve a rapid reduction in infection and transmission, with the goal of eliminating the public health burden of scabies. While prevalence has been observed to fall substantially following such an intervention, in some instances resurgence of infection to baseline levels has occurred over several years. To explore the biology underpinning this phenomenon, we have developed a theoretical model of scabies life-cycle and transmission dynamics in a homogeneously mixing population, and simulate the impact of mass drug treatment strategies acting on egg and mite life cycle stages (ovicidal) or mites alone (non-ovicidal). In order to investigate the dynamics of the system, we first define and calculate the optimal interval between treatment doses. We calculate the probability of eradication as a function of the number of optimally-timed successive treatment doses and the number of years over which a program is run. For the non-ovicidal intervention, we first show that at least two optimally-timed doses are required to achieve eradication. We then demonstrate that while more doses over a small number of years provides the highest chance of eradication, a similar outcome can be achieved with fewer doses delivered annually over a longer period of time. For the ovicidal intervention, we find that doses should be delivered as close together as possible. This work provides a platform for further research into optimal treatment strategies which may incorporate heterogeneity of transmission, and the interplay between MDA and enhancement of continuing scabies surveillance and treatment strategies.

Turnover of Village Chickens Undermines Vaccine Coverage to Control HPAI H5N1.

Highly pathogenic avian influenza (HPAI) subtype H5N1 remains an enzootic disease of village chickens in Indonesia, posing ongoing risk at the animal–human interface. Previous modelling showed that the fast natural turnover of chicken populations might undermine herd immunity after vaccination, although actual details of how this effect applies to Indonesias village chicken population have not been determined. We explored the turnover effect in Indonesias scavenging and mixed populations of village chickens using an extended Leslie matrix model parameterized with data collected from village chicken flocks in Java region, Indonesia. Population dynamics were simulated for 208 weeks; the turnover effect was simulated for 16 weeks after vaccination in two ‘best case’ scenarios, where the whole population (scenario 1), or birds aged over 14 days (scenario 2), were vaccinated. We found that the scavenging and mixed populations have different productive traits. When steady‐state dynamics are reached, both populations are dominated by females (54.5%), and ‘growers’ and ‘chicks’ represent the most abundant age stages with 39% and 38% in the scavenging, and 60% and 25% in the mixed population, respectively. Simulations showed that the population turnover might reduce the herd immunity below the critical threshold that prevents the re‐emergence of HPAI H5N1 4–8 weeks (scavenging) and 6–9 weeks (mixed population) after vaccination in scenario 1, and 2–6 weeks (scavenging) and 4–7 weeks (mixed population) after vaccination in scenario 2. In conclusion, we found that Indonesias village chicken population does not have a unique underlying population dynamic and therefore, different turnover effects on herd immunity may be expected after vaccination; nonetheless, our simulations carried out in best case scenarios highlight the limitations of current vaccine technologies to control HPAI H5N1. This suggests that the improvements and complementary strategies are necessary and must be explored.