The role of a hepatitis C virus vaccine:modelling the benefits alongside direct-acting antiviral treatments

BACKGROUND: Hepatitis C virus (HCV) elimination is being seriously considered globally. Current elimination models require a combination of highly effective HCV treatment and harm reduction, but high treatment costs make such strategies prohibitively expensive. Vaccines should play a key role in elimination but their best use alongside treatments is unclear. For three vaccines with different efficacies we used a mathematical model to estimate the additional reduction in HCV prevalence when vaccinating after treatment; and to identify in which settings vaccines could most effectively reduce the number of treatments required to achieve fixed reductions in HCV prevalence among people who inject drugs (PWID). METHODS: A deterministic model of HCV transmission among PWID was calibrated for settings with 25, 50 and 75% chronic HCV prevalence among PWID, stratified by high-risk or low-risk PWID. For vaccines with 30, 60 or 90% efficacies, different rates of treatment and vaccination were introduced. We compared prevalence reductions achieved by vaccinating after treatment to prevent reinfection and vaccinating independently of treatment history in the community; and by allocating treatments and vaccinations to specific risk groups and proportionally across risk groups. RESULTS: Vaccinating after treatment was minimally different to vaccinating independently of treatment history, and allocating treatments and vaccinations to specific risk groups was minimally different to allocating them proportionally across risk groups. Vaccines with 30 or 60% efficacy provided greater additional prevalence reduction per vaccination in a setting with 75% chronic HCV prevalence among PWID than a 90% efficacious vaccine in settings with 25 or 50% chronic HCV prevalence among PWID. CONCLUSIONS: Vaccinating after treatment is an effective and practical method of administration. In settings with high chronic HCV prevalence among PWID, even modest coverage with a low-efficacy vaccine could provide significant additional prevalence reduction beyond treatment alone, and would likely reduce the cost of achieving prevalence reduction targets

Timing of Mycobacterium tuberculosis exposure explains variation in BCG effectiveness: A systematic review and meta-analysis

Rationale The heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure. Methods We updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context. Main results Of 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings with longer follow-up showed no protection, sometimes with higher case rates in the vaccinated than the controls in the later follow-up period. Conclusions The most plausible explanatory hypothesis for these results is that BCG protects against TB that results from exposure shortly after vaccination. However, we found no evidence of protection when exposure occurs later from vaccination, which would be of greater importance in trials in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection observed for many years thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines with repeated exposure to Mycobacterium tuberculosis or other pathogens

Model-Informed Risk Assessment and Decision Making for an Emerging Infectious Disease in the Asia-Pacific Region

Background: Effective response to emerging infectious disease (EID) threats relies on health care systems that can detect and contain localised outbreaks before they reach a national or international scale. The Asia-Pacific region contains low and middle income countries in which the risk of EID outbreaks is elevated and whose health care systems may require international support to effectively detect and respond to such events. The absence of comprehensive data on populations, health care systems and disease characteristics in this region makes risk assessment and decisions about the provision of such support challenging.\ud \ud Methodology/principal findings: We describe a mathematical modelling framework that can inform this process by integrating available data sources, systematically explore the effects of uncertainty, and provide estimates of outbreak risk under a range of intervention scenarios. We illustrate the use of this framework in the context of a potential importation of Ebola Virus Disease into the Asia-Pacific region. Results suggest that, across a wide range of plausible scenarios, preemptive interventions supporting the timely detection of early cases provide substantially greater reductions in the probability of large outbreaks than interventions that support health care system capacity after an outbreak has commenced.\ud \ud Conclusions/significance: Our study demonstrates how, in the presence of substantial uncertainty about health care system infrastructure and other relevant aspects of disease control, mathematical models can be used to assess the constraints that limited resources place upon the ability of local health care systems to detect and respond to EID outbreaks in a timely and effective fashion. Our framework can help evaluate the relative impact of these constraints to identify resourcing priorities for health care system support, in order to inform principled and quantifiable decision making

Studies Needed to Address Public Health Challenges of the 2009 H1N1 Influenza Pandemic: Insights from Modeling

In light of the 2009 influenza pandemic and potential future pandemics, Maria Van Kerkhove and colleagues anticipate six public health challenges and the data needed to support sound public health decision making.The authors acknowledge support from the Bill & Melinda Gates Foundation (MDVK, CF, NMF); Royal Society (CF); Medical Research Council (MDVK, CF, PJW, NMF); EU FP7 programme (NMF); UK Health Protection Agency (PJW); US National Institutes of Health Models of Infectious Disease Agent Study program through cooperative agreement 1U54GM088588 (ML); NIH Director's Pioneer Award, DP1-OD000490-01 (DS); EU FP7 grant EMPERIE 223498 (DS); the Wellcome Trust (DS); 3R01TW008246-01S1 from Fogerty International Center and RAPIDD program from Fogerty International Center with the Science & Technology Directorate, Department of Homeland Security (SR); and the Institut de Veille Sanitaire Sanitaire funded by the French Ministry of Health (J-CD). The funders played no role in the decision to submit the article or in its preparation

Strategic investment in tuberculosis control in the Republic of Bulgaria

As Bulgaria transitions away from Global Fund grant, robust estimates of the comparative impact of the various response strategies under consideration are needed to ensure sustained effectiveness of the tuberculosis (TB) programme. We tailored an established mathematical model for TB control to the epidemic in Bulgaria to project the likely outcomes of seven intervention scenarios. Under existing programmatic conditions projected forward, the country's targets for achieving TB elimination in the coming decades will not be achieved. No interventions under consideration were predicted to accelerate the baseline projected reduction in epidemiological indicators significantly. Discontinuation of the 'Open Doors' program and activities of non-governmental organisations would result in a marked exacerbation of the epidemic (increasing incidence in 2035 by 6-8% relative to baseline conditions projected forward). Changing to a short course regimen for multidrug-resistant TB (MDR-TB) would substantially decrease MDR-TB mortality (by 21.6% in 2035 relative to baseline conditions projected forward). Changing to ambulatory care for eligible patients would not affect TB burden but would be markedly cost-saving. In conclusion, Bulgaria faces important challenges in transitioning to a primarily domestically-financed TB programme. The country should consider maintaining currently effective programs and shifting towards ambulatory care to ensure program sustainability

Estimating the long-term effects of mass screening for latent and active tuberculosis in the Marshall Islands

BACKGROUND: Ambitious population-based screening programmes for latent and active tuberculosis (TB) were implemented in the Republic of the Marshall Islands in 2017 and 2018. METHODS: We used a transmission dynamic model of TB informed by local data to capture the Marshall Islands epidemic's historical dynamics. We then used the model to project the future epidemic trajectory following the active screening interventions, as well as considering a counterfactual scenario with no intervention. We also simulated future scenarios including periodic interventions similar to those previously implemented, to assess their ability to reach the End TB Strategy targets and TB pre-elimination in the Marshall Islands. RESULTS: The screening activities conducted in 2017 and 2018 were estimated to have reduced TB incidence and mortality by around one-third in 2020, and are predicted to achieve the End TB Strategy milestone of 50% incidence reduction by 2025 compared with 2015. Screening interventions had a considerably greater impact when latent TB screening and treatment were included, compared with active case finding alone. Such combined programmes implemented at the national level could achieve TB pre-elimination around 2040 if repeated every 2 years. CONCLUSIONS: Our model suggests that it would be possible to achieve TB pre-elimination by 2040 in the Marshall Islands through frequent repetition of the same interventions as those already implemented in the country. It also highlights the importance of including latent infection testing in active screening activities

Transmission Dynamics of Methicillin-Resistant Staphylococcus aureus in a Medical Intensive Care Unit in India

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a global pathogen and an important but seldom investigated cause of morbidity and mortality in lower and middle-income countries where it can place a major burden on limited resources. Quantifying nosocomial transmission in resource-poor settings is difficult because molecular typing methods are prohibitively expensive. Mechanistic statistical models can overcome this problem with minimal cost. We analyse the transmission dynamics of MRSA in a hospital in south India using one such approach and provide conservative estimates of the organism's economic burden. Methods and Findings: Fifty months of MRSA infection data were collected retrospectively from a Medical Intensive Care Unit (MICU) in a tertiary hospital in Vellore, south India. Data were analysed using a previously described structured hidden Markov model. Seventy-two patients developed MRSA infections and, of these, 49 (68%) died in the MICU. We estimated that 4.2% (95%CI 1.0, 19.0) of patients were MRSA-positive when admitted, that there were 0.39 MRSA infections per colonized patient month (0.06, 0.73), and that the ward-level reproduction number for MRSA was 0.42 (0.08, 2.04). Anti-MRSA antibiotic treatment costs alone averaged $124/patient, over three times the monthly income of more than 40% of the Indian population. Conclusions: Our analysis of routine data provides the first estimate of the nosocomial transmission potential of MRSA in India. The high levels of transmission estimated underline the need for cost-effective interventions to reduce MRSA transmission in hospital settings in low and middle income countries. © 2011 Christopher et al

Assessing a 12-month course of oral alendronate for adults with avascular necrosis of the hip: MANTIS RCT with internal pilot

Background People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition. Objectives The aim of the Managing Avascular Necrosis Treatments: an Interventional Study (MANTIS) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis. Design This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase. Setting Eight secondary care NHS hospitals across the UK. Participants Planned trial size – 280 adult patients with avascular necrosis. Intervention Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months. Main outcomes The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome). Results Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet. Limitations This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease. Future work This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease. Conclusions The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip. Trial registration The trial is registered as ISRCTN14015902. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 43. See the NIHR Journals Library website for further project information

Independent measurement of the total active B8 solar neutrino flux using an array of He3 proportional counters at the Sudbury Neutrino Observatory

The Sudbury Neutrino Observatory (SNO) used an array of 3He proportional counters to measure the rate of neutral-current interactions in heavy water and precisely determined the total active (νx) 8B solar neutrino flux. This technique is independent of previous methods employed by SNO. The total flux is found to be 5.54-0.31+0.33(stat)-0.34+0.36(syst)×106  cm-2 s-1, in agreement with previous measurements and standard solar models. A global analysis of solar and reactor neutrino results yields Δm2=7.59-0.21+0.19×10-5  eV2 and θ=34.4-1.2+1.3 degrees. The uncertainty on the mixing angle has been reduced from SNO’s previous results