Constructing an ethical framework for priority allocation of pandemic vaccines.

BACKGROUND: Allocation of scarce resources during a pandemic extends to the allocation of vaccines when they eventually become available. We describe a framework for priority vaccine allocation that employed a cross-disciplinary approach, guided by ethical considerations and informed by local risk assessment. METHODS: Published and grey literature was reviewed, and augmented by consultation with key informants, to collate past experience, existing guidelines and emerging strategies for pandemic vaccine deployment. Identified ethical issues and decision-making processes were also included. Concurrently, simulation modelling studies estimated the likely impacts of alternative vaccine allocation approaches. Assembled evidence was presented to a workshop of national experts in pandemic preparedness, vaccine strategy, implementation and ethics. All of this evidence was then used to generate a proposed ethical framework for vaccine priorities best suited to the Australian context. FINDINGS: Published and emerging guidance for priority pandemic vaccine distribution differed widely with respect to strategic objectives, specification of target groups, and explicit discussion of ethical considerations and decision-making processes. Flexibility in response was universally emphasised, informed by real-time assessment of the pandemic impact level, and identification of disproportionately affected groups. Model outputs aided identification of vaccine approaches most likely to achieve overarching goals in pandemics of varying transmissibility and severity. Pandemic response aims deemed most relevant for an Australian framework were: creating and maintaining trust, promoting equity, and reducing harmful outcomes. INTERPRETATION: Defining clear and ethically-defendable objectives for pandemic response in context aids development of flexible and adaptive decision support frameworks and facilitates clear communication and engagement activities.

Priority allocation of pandemic influenza vaccines in Australia - Recommendations of 3 community juries.

BACKGROUND: Pandemic planning has historically been oriented to respond to an influenza virus, with vaccination strategy being a key focus. As the current COVID-19 pandemic plays out, the Australian government is closely monitoring progress towards development of SARS-CoV2 vaccines as a definitive intervention. However, as in any pandemic, initial supply will likely be exceeded by demand due to limited manufacturing output. METHODS: We convened community juries in three Australian locations in 2019 to assess public acceptability and perceived legitimacy of influenza pandemic vaccination distribution strategies. Preparatory work included literature reviews on pandemic vaccine allocation strategies and on vaccine allocation ethics, and simulation modelling studies. We assumed vaccine would be provided to predefined priority groups. Jurors were then asked to recommend one of two strategies for distributing remaining early doses of vaccine: directly vaccinate people at higher risk of adverse outcomes from influenza; or indirectly protect the general population by vaccinating primary school students, who are most likely to spread infection. RESULTS: Thirty-four participants of diverse backgrounds and ages were recruited through random digit dialling and topic-blinded social media advertising. Juries heard evidence and arguments supporting different vaccine distribution strategies, and questioned expert presenters. All three community juries supported prioritising school children for influenza vaccination (aiming for indirect protection), one by 10-2 majority and two by consensus. Justifications included that indirect protection benefits more people and is likely to be more publicly acceptable. CONCLUSIONS: In the context of an influenza pandemic, informed citizens were not opposed to prioritising groups at higher risks of adverse outcomes, but if resources and epidemiological conditions allow, achieving population benefits should be a strategic priority. These insights may inform future SARS-CoV-2 vaccination strategies.

Prior exposure to immunogenic peptides found in human influenza A viruses may influence the age distribution of cases with avian influenza H5N1 and H7N9 virus infections.

The epidemiology of H5N1 and H7N9 avian viruses of humans infected in China differs despite both viruses being avian reassortants that have inherited six internal genes from a common ancestor, H9N2. The median age of infected populations is substantially younger for H5N1 virus (26 years) compared with H7N9 virus (63 years). Population susceptibility to infection with seasonal influenza is understood to be influenced by cross-reactive CD8+ T cells directed towards immunogenic peptides derived from internal viral proteins which may provide some level of protection against further influenza infection. Prior exposure to seasonal influenza peptides may influence the age-related infection patterns observed for H5N1 and H7N9 viruses. A comparison of relatedness of immunogenic peptides between historical human strains and the two avian emerged viruses was undertaken for a possible explanation in the differences in age incidence observed. There appeared to be some relationship between past exposure to related peptides and the lower number of H5N1 virus cases in older populations, however the relationship between prior exposure and older populations among H7N9 virus patients was less clear.

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.

Calculation of the age of the first infection for skin sores and scabies in five remote communities in northern Australia.

Prevalence of skin sores and scabies in remote Australian Aboriginal communities remains unacceptably high, with Group A Streptococcus (GAS) the dominant pathogen. We aim to better understand the drivers of GAS transmission using mathematical models. To estimate the force of infection, we quantified the age of first skin sores and scabies infection by pooling historical data from three studies conducted across five remote Aboriginal communities for children born between 2001 and 2005. We estimated the age of the first infection using the Kaplan-Meier estimator; parametric exponential mixture model; and Cox proportional hazards. For skin sores, the mean age of the first infection was approximately 10 months and the median was 7 months, with some heterogeneity in median observed by the community. For scabies, the mean age of the first infection was approximately 9 months and the median was 8 months, with significant heterogeneity by the community and an enhanced risk for children born between October and December. The young age of the first infection with skin sores and scabies reflects the high disease burden in these communities.

Influenza as a trigger for cardiovascular disease: An investigation of serotype, subtype and geographic location.

BACKGROUND: Seasonal peaks of influenza and cardiovascular disease tend to coincide. Many excess deaths may be triggered by influenza, and the severity of this effect may vary with the virulence of the circulating influenza strain and host susceptibility. We aimed to explore the association between hospital admissions for influenza and/or pneumonia (IP) and acute myocardial infarction (AMI) or ischaemic heart disease (IHD) in Queensland, Australia, taking into account temporal and spatial variation of influenza virus type and subtype in 2007, 2008 and 2009. METHODS: This ecological study at Statistical Subdivision level (SSD, n=38) used linked patient-level data. For each study year, Standardized Morbidity Ratios (SMRs) were calculated for hospital admissions with diagnoses of IP, AMI and IHD. We investigated the associations between IP and AMI or IHD using spatial autoregressive modelling, adjusting for socio-demographic factors. RESULTS: Spatial autocorrelation was detected in SMRs, possibly reflecting underlying social and behavioural risk factors, but consistent with infectious disease spread. SMRs for IP were consistently predictive of SMRs for AMI and IHD when adjusted for socioeconomic status, population density and per cent Indigenous population (coefficient: 0.707, 95% confidence interval (CI): 0.318 - 1.096; 0.553, 0.222 - 0.884; 0.598, 0.307 - 0.888 and 1.017, 0.711 - 1.323; 0.650, 0.342 - 0.958; 1.031, 0.827 - 1.236) in 2007, 2008 and 2009, respectively. CONCLUSIONS: This ecological study provides further evidence that severe respiratory infections may trigger the onset of cardiovascular events, implicating the influenza virus as a contributing factor.

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 Indonesia's village chicken population have not been determined. We explored the turnover effect in Indonesia's 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 Indonesia's 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.

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.

Quantifying differences in the epidemic curves from three influenza surveillance systems: a nonlinear regression analysis.

Influenza surveillance enables systematic collection of data on spatially and demographically heterogeneous epidemics. Different data collection mechanisms record different aspects of the underlying epidemic with varying bias and noise. We aimed to characterize key differences in weekly incidence data from three influenza surveillance systems in Melbourne, Australia, from 2009 to 2012: laboratory-confirmed influenza notified to the Victorian Department of Health, influenza-like illness (ILI) reported through the Victorian General Practice Sentinel Surveillance scheme, and ILI cases presenting to the Melbourne Medical Deputising Service. Using nonlinear regression, we found that after adjusting for the effects of geographical region and age group, characteristics of the epidemic curve (including season length, timing of peak incidence and constant baseline activity) varied across the systems. We conclude that unmeasured factors endogenous to each surveillance system cause differences in the disease patterns recorded. Future research, particularly data synthesis studies, could benefit from accounting for these differences.

The influence of changing host immunity on 1918-19 pandemic dynamics.

The sociological and biological factors which gave rise to the three pandemic waves of Spanish influenza in England during 1918-19 are still poorly understood. Symptom reporting data available for a limited set of locations in England indicates that reinfection in multiple waves occurred, suggesting a role for loss of infection-acquired immunity. Here we explore the role that changes in host immunity, driven by a combination of within-host factors and viral evolution, may play in explaining weekly mortality data and wave-by-wave symptomatic attack-rates available for a subset of English cities. Our results indicate that changes in the phenotype of the pandemic virus are likely required to explain the closely spaced waves of infection, but distinguishing between the detailed contributions of viral evolution and changing adaptive immune responses to transmission rates is difficult given the dearth of sero-epidemiological and virological data available even for more contemporary pandemics. We find that a dynamical model in which pre-pandemic protection in older "influenza-experienced" cohorts is lost rapidly prior to the second wave provides the best fit to the mortality and symptom reporting data. Best fitting parameter estimates for such a model indicate that post-infection protection lasted of order months, while other statistical analyses indicate that population-age was inversely correlated with overall mortality during the herald wave. Our results suggest that severe secondary waves of pandemic influenza may be triggered by viral escape from pre-pandemic immunity, and thus that understanding the role of heterosubtypic or cross-protective immune responses to pandemic influenza may be key to controlling the severity of future influenza pandemics.

Pandemic controllability: a concept to guide a proportionate and flexible operational response to future influenza pandemics.

The 2009 H1N1 influenza pandemic posed challenges for governments worldwide. Strategies designed to limit community transmission, such as antiviral deployment, were largely ineffective due to both feasibility constraints and the generally mild nature of disease, resulting in incomplete case ascertainment. Reviews of national pandemic plans have identified pandemic impact, primarily linked to measures of transmissibility and severity, as a key concept to incorporate into the next generation of plans. While an assessment of impact provides the rationale under which interventions may be warranted, it does not directly provide an assessment on whether particular interventions may be effective. Such considerations motivate our introduction of the concept of pandemic controllability. For case-targeted interventions, such as antiviral treatment and post-exposure prophylaxis, we identify the visibility and transmissibility of a pandemic as the key drivers of controllability. Taking a case-study approach, we suggest that high-impact pandemics, for which control is most desirable, are likely uncontrollable with case-targeted interventions. Strategies that do not rely on the identification of cases may prove relatively more effective. By introducing a pragmatic framework for relating the assessment of impact to the ability to mitigate an epidemic (controllability), we hope to address a present omission identified in pandemic response plans.

Likely effectiveness of pharmaceutical and non-pharmaceutical interventions for mitigating influenza virus transmission in Mongolia.

OBJECTIVE: To assess the likely benefit of the interventions under consideration for use in Mongolia during future influenza pandemics. METHODS: A stochastic, compartmental patch model of susceptibility, exposure, infection and recovery was constructed to capture the key effects of several interventions--travel restrictions, school closure, generalized social distancing, quarantining of close contacts, treatment of cases with antivirals and prophylaxis of contacts--on the dynamics of influenza epidemics. The likely benefit and optimal timing and duration of each of these interventions were assessed using Latin-hypercube sampling techniques, averaging across many possible transmission and social mixing parameters. FINDINGS: Timely interventions could substantially alter the time-course and reduce the severity of pandemic influenza in Mongolia. In a moderate pandemic scenario, early social distancing measures decreased the mean attack rate from around 10% to 7-8%. Similarly, in a severe pandemic scenario such measures cut the mean attack rate from approximately 23% to 21%. In both moderate and severe pandemic scenarios, a suite of non-pharmaceutical interventions proved as effective as the targeted use of antivirals. Targeted antiviral campaigns generally appeared more effective in severe pandemic scenarios than in moderate pandemic scenarios. CONCLUSION: A mathematical model of pandemic influenza transmission in Mongolia indicated that, to be successful, interventions to prevent transmission must be triggered when the first cases are detected in border regions. If social distancing measures are introduced at this stage and implemented over several weeks, they may have a notable mitigating impact. In low-income regions such as Mongolia, social distancing may be more effective than the large-scale use of antivirals.

Incorporating population dynamics into household models of infectious disease transmission.

Most household models of disease transmission assume static household distributions. Although this is a reasonable simplification for assessing vaccination strategies at a single point in time or over the course of an outbreak, it has considerable drawbacks for assessing long term vaccination policies or for predicting future changes in immunity. We demonstrate that household models that include births, deaths and movement between households can show dramatically different patterns of infection and immunity to static population models. When immunity is assumed to be life-long, the pattern of births by household size is the key driver of infection, suggesting that the influx of susceptibles has most impact on infection risk in the household. In a comparison of 12 countries, we show that both the crude birth rate and the mean household size affect the risk of infection in households.

Seroprevalence of 2009 pandemic influenza A(H1N1) virus in Australian blood donors, October - December 2009.

Assessment of the severity of disease due to the 2009 pandemic influenza A(H1N1) in Australian states and territories has been hampered by the absence of denominator data on population exposure. We compared antibody reactivity to the pandemic virus using haemagglutination inhibition assays performed on plasma specimens taken from healthy adult blood donors (older than 16 years) before and after the influenza pandemic that occurred during the southern hemisphere winter. Pre-influenza season samples (April ­ May 2009, n=496) were taken from donation collection centres in North Queensland (in Cairns and Townsville); post-outbreak specimens (October ­ November 2009, n=779) were from donors at seven centres in five states. Using a threshold antibody titre of 40 as a marker of recent infection, we observed an increase in the influenza-seropositive proportion of donors from 12% to 22%, not dissimilar to recent reports of influenza A(H1N1)-specific immunity in adults from the United Kingdom. No significant differences in seroprevalence were observed between Australian states, although the ability to detect minor variations was limited by the sample size. On the basis of these figures and national reporting data, we estimate that approximately 0.23% of all individuals in Australia exposed to the pandemic virus required hospitalisation and 0.01% died. The low seroprevalence reported here suggests that some degree of prior immunity to the virus, perhaps mediated by broadly reactive T-cell responses to conserved influenza viral antigens, limited transmission among adults and thus constrained the pandemic in Australia.

Understanding the impact of Hib conjugate vaccine on transmission, immunity and disease in the United Kingdom.

A rise in invasive Haemophilus influenzae type b (Hib) infections occurred 8 years after vaccine introduction in the United Kingdom. Aspects of Hib vaccine delivery unique to the United Kingdom have been implicated. The authors developed a fully age-structured deterministic susceptible-infected-resistant-susceptible mathematical model, expressed as a set of partial differential equations, to better understand the causes of declining vaccine effectiveness. We also investigated the consequences of the vaccine's impact on reducing Hib transmission for maintenance of immunity. Our findings emphasized the importance of maintaining high post-immunization antibody titres among age groups at greatest risk of invasive infections. In keeping with UK population-based estimates, low direct efficacy of immunological memory against disease was found, cautioning against over-reliance on evidence of priming alone as a correlate of population protection. The contribution of herd immunity to disease control was reinforced. Possible intervention strategies will be explored in subsequent work.

Host and environmental factors associated with Hib in England, 1998-2002.

BACKGROUND: Declining effectiveness of the UK's Hib vaccine programme was observed between 1998 and 2002. OBJECTIVE: To provide insight into non-vaccine factors contributing to ongoing Hib disease in England after immunisation. DESIGN: Postal questionnaire study, matched case-control design. SETTING: Health Protection Agency Centre for Infections, England. PATIENTS: Cases were children born after 1 January 1993 presenting with confirmed Hib infection in England between the start of 1998 and end of 2002, regardless of vaccination status. Controls were matched by date of birth and region. MAIN OUTCOME MEASURES: Odds ratios were calculated to assess the impact of host and environmental variables on disease risk. RESULTS: Increased disease risk was noted among children with frequent antibiotic use (adjusted OR (AOR) (trend) 1.51 (95% CI 1.06 to 2.13); p = 0.02) and from sole-parent households (AOR 2.56 (95% CI 1.24 to 5.29); p = 0.01). These two risk factors were further related to each other, consistent with previously reported associations between infection and social deprivation. In fully immunised children, receipt of all three doses of the primary course as an acellular pertussis-containing combination vaccine (DTaP-Hib) increased the risk of vaccine failure (OR 2.88 (95% CI 0.99 to 8.37), p = 0.01). Day care attendance between 2 and 5 years of age was linked with a dose-dependent reduction in risk (AOR (trend) 0.79 (95% CI 0.66 to 0.93); p = 0.01), possibly because of natural boosting of immunity. CONCLUSIONS: The association noted between invasive infection and social deprivation in this and other studies is concerning and merits further investigation. The importance of ongoing surveillance of vaccine-preventable diseases to allow nested studies of this kind was reinforced.

Model answers or trivial pursuits? The role of mathematical models in influenza pandemic preparedness planning.

The panzootic of H5N1 influenza in birds has raised concerns that the virus will mutate to spread more readily in people, leading to a human pandemic. Mathematical models have been used to interpret past pandemics and outbreaks, and to thus model possible future pandemic scenarios and interventions. We review historical influenza outbreak and transmission data, and discuss the way in which modellers have used such sources to inform model structure and assumptions. We suggest that urban attack rates in the 1918-1919 pandemic were constrained by prior immunity, that R(0) for influenza is higher than often assumed, and that control of any future pandemic could be difficult in the absence of significant prior immunity. In future, modelling assumptions, parameter estimates and conclusions should be tested against as many relevant data sets as possible. To this end, we encourage researchers to access FluWeb, an on-line influenza database of historical pandemics and outbreaks.

Changes in the epidemiology of epiglottitis following introduction of Haemophilus influenzae type b (Hib) conjugate vaccines in England: a comparison of two data sources.

Paediatric cases of epiglottitis declined markedly in England following the introduction of safe effective immunization against Haemophilus influenzae type b (Hib). With the recently described resurgence in Hib infections, a corresponding rise in the number of presentations of clinical epiglottitis in children was observed, although numbers were still well below those reported prior to vaccine availability. This was seen both in microbiology reports and hospital admissions data for England. In keeping with the more diverse aetiology of epiglottitis in adults, Hib vaccination had minimal impact on hospital presentations with upper airway infections in those aged 15 years and over, which showed an overall increasing trend over 10 years. The need for a high index of suspicion to allow early diagnosis of this life-threatening clinical presentation is reinforced.

Long-term impact of vaccination on Haemophilus influenzae type b (Hib) carriage in the United Kingdom.

A recent resurgence in serious infections due to Haemophilus influenzae type b (Hib) has been observed in the United Kingdom. More information on Hib transmission in the population is required in order to better understand the mechanism of this increase. The Public Health Laboratory Service (subsumed into the Health Protection Agency since April 2004) conducted four cross-sectional studies of asymptomatic oropharyngeal Hib carriage in children attending day-care nurseries in England and Wales in 1992, 1994, 1997 and 2002. These demonstrated a marked reduction in the prevalence of Hib colonization over time since vaccine introduction (3.98% in 1992; 0.70% in 1994; 0% in 1997; 0% in 2002), which did not explain the increase in invasive disease reports from 1999 onwards. We believe that a reduction in antibody levels over the first 5 years of life in immunized children in recent years has fuelled the rise in reported cases in the absence of an obvious increase in transmission.