The public health impact and cost-effectiveness of the R21/Matrix-M malaria vaccine: a mathematical modelling study.

BACKGROUND: The R21/Matrix-M vaccine has demonstrated high efficacy against Plasmodium falciparum clinical malaria in children in sub-Saharan Africa. Using trial data, we aimed to estimate the public health impact and cost-effectiveness of vaccine introduction across sub-Saharan Africa. METHODS: We fitted a semi-mechanistic model of the relationship between anti-circumsporozoite protein antibody titres and vaccine efficacy to data from 3 years of follow-up in the phase 2b trial of R21/Matrix-M in Nanoro, Burkina Faso. We validated the model by comparing predicted vaccine efficacy to that observed over 12-18 months in the phase 3 trial. Integrating this framework within a mathematical transmission model, we estimated the cases, malaria deaths, and disability-adjusted life-years (DALYs) averted and cost-effectiveness over a 15-year time horizon across a range of transmission settings in sub-Saharan Africa. Cost-effectiveness was estimated incorporating the cost of vaccine introduction (dose, consumables, and delivery) relative to existing interventions at baseline. We report estimates at a median of 20% parasite prevalence in children aged 2-10 years (PfPR2-10) and ranges from 3% to 65% PfPR2-10. FINDINGS: Anti-circumsporozoite protein antibody titres were found to satisfy the criteria for a surrogate of protection for vaccine efficacy against clinical malaria. Age-based implementation of a four-dose regimen of R21/Matrix-M vaccine was estimated to avert 181 825 (range 38 815-333 491) clinical cases per 100 000 fully vaccinated children in perennial settings and 202 017 (29 868-405 702) clinical cases per 100 000 fully vaccinated children in seasonal settings. Similar estimates were obtained for seasonal or hybrid implementation. Under an assumed vaccine dose price of US$3, the incremental cost per clinical case averted was $7 (range 4-48) in perennial settings and $6 (3-63) in seasonal settings and the incremental cost per DALY averted was $34 (29-139) in perennial settings and $30 (22-172) in seasonal settings, with lower cost-effectiveness ratios in settings with higher PfPR2-10. INTERPRETATION: Introduction of the R21/Matrix-M malaria vaccine could have a substantial public health benefit across sub-Saharan Africa. FUNDING: The Wellcome Trust, the Bill & Melinda Gates Foundation, the UK Medical Research Council, the European and Developing Countries Clinical Trials Partnership 2 and 3, the NIHR Oxford Biomedical Research Centre, and the Serum Institute of India, Open Philanthropy.

Modeling resource allocation strategies for insecticide-treated bed nets to achieve malaria eradication.

Large reductions in the global malaria burden have been achieved, but plateauing funding poses a challenge for progressing towards the ultimate goal of malaria eradication. Using previously published mathematical models of Plasmodium falciparum and Plasmodium vivax transmission incorporating insecticide-treated nets (ITNs) as an illustrative intervention, we sought to identify the global funding allocation that maximized impact under defined objectives and across a range of global funding budgets. The optimal strategy for case reduction mirrored an allocation framework that prioritizes funding for high-transmission settings, resulting in total case reductions of 76% and 66% at intermediate budget levels, respectively. Allocation strategies that had the greatest impact on case reductions were associated with lesser near-term impacts on the global population at risk. The optimal funding distribution prioritized high ITN coverage in high-transmission settings endemic for P. falciparum only, while maintaining lower levels in low-transmission settings. However, at high budgets, 62% of funding was targeted to low-transmission settings co-endemic for P. falciparum and P. vivax. These results support current global strategies to prioritize funding to high-burden P. falciparum-endemic settings in sub-Saharan Africa to minimize clinical malaria burden and progress towards elimination, but highlight a trade-off with 'shrinking the map' through a focus on near-elimination settings and addressing the burden of P. vivax.

Long-term vaccination strategies to mitigate the impact of SARS-CoV-2 transmission: A modelling study.

BACKGROUND: Vaccines have reduced severe disease and death from Coronavirus Disease 2019 (COVID-19). However, with evidence of waning efficacy coupled with continued evolution of the virus, health programmes need to evaluate the requirement for regular booster doses, considering their impact and cost-effectiveness in the face of ongoing transmission and substantial infection-induced immunity. METHODS AND FINDINGS: We developed a combined immunological-transmission model parameterised with data on transmissibility, severity, and vaccine effectiveness. We simulated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and vaccine rollout in characteristic global settings with different population age-structures, contact patterns, health system capacities, prior transmission, and vaccine uptake. We quantified the impact of future vaccine booster dose strategies with both ancestral and variant-adapted vaccine products, while considering the potential future emergence of new variants with modified transmission, immune escape, and severity properties. We found that regular boosting of the oldest age group (75+) is an efficient strategy, although large numbers of hospitalisations and deaths could be averted by extending vaccination to younger age groups. In countries with low vaccine coverage and high infection-derived immunity, boosting older at-risk groups was more effective than continuing primary vaccination into younger ages in our model. Our study is limited by uncertainty in key parameters, including the long-term durability of vaccine and infection-induced immunity as well as uncertainty in the future evolution of the virus. CONCLUSIONS: Our modelling suggests that regular boosting of the high-risk population remains an important tool to reduce morbidity and mortality from current and future SARS-CoV-2 variants. Our results suggest that focusing vaccination in the highest-risk cohorts will be the most efficient (and hence cost-effective) strategy to reduce morbidity and mortality.

Estimating long-term vaccine effectiveness against SARS-CoV-2 variants: a model-based approach.

With the ongoing evolution of the SARS-CoV-2 virus updated vaccines may be needed. We fitted a model linking immunity levels and protection to vaccine effectiveness data from England for three vaccines (Oxford/AstraZeneca AZD1222, Pfizer-BioNTech BNT162b2, Moderna mRNA-1273) and two variants (Delta, Omicron). Our model reproduces the observed sustained protection against hospitalisation and death from the Omicron variant over the first six months following dose 3 with the ancestral vaccines but projects a gradual waning to moderate protection after 1 year. Switching the fourth dose to a variant-matched vaccine against Omicron BA.1/2 is projected to prevent nearly twice as many hospitalisations and deaths over a 1-year period compared to administering the ancestral vaccine. This result is sensitive to the degree to which immunogenicity data can be used to predict vaccine effectiveness and uncertainty regarding the impact that infection-induced immunity (not captured here) may play in modifying future vaccine effectiveness.

Modeling the Impact of a Highly Potent Plasmodium falciparum Transmission-Blocking Monoclonal Antibody in Areas of Seasonal Malaria Transmission.

Transmission-blocking interventions can play an important role in combating malaria worldwide. Recently, a highly potent Plasmodium falciparum transmission-blocking monoclonal antibody (TB31F) was demonstrated to be safe and efficacious in malaria-naive volunteers. Here we predict the potential public health impact of large-scale implementation of TB31F alongside existing interventions. We developed a pharmaco-epidemiological model, tailored to 2 settings of differing transmission intensity with already established insecticide-treated nets and seasonal malaria chemoprevention interventions. Community-wide annual administration (at 80% coverage) of TB31F over a 3-year period was predicted to reduce clinical incidence by 54% (381 cases averted per 1000 people per year) in a high-transmission seasonal setting, and 74% (157 cases averted per 1000 people per year) in a low-transmission seasonal setting. Targeting school-aged children gave the largest reduction in terms of cases averted per dose. An annual administration of the transmission-blocking monoclonal antibody TB31F may be an effective intervention against malaria in seasonal malaria settings.

Modelling the relative cost-effectiveness of the RTS,S/AS01 malaria vaccine compared to investment in vector control or chemoprophylaxis.

BACKGROUND: The World Health Organization has recommended a 4-dose schedule of the RTS,S/AS01 (RTS,S) vaccine for children in regions of moderate to high P. falciparum transmission. Faced with limited supply and finite resources, global funders and domestic malaria control programs will need to examine the relative cost-effectiveness of RTS,S and identify target areas for vaccine implementation relative to scale-up of existing interventions. METHODS: Using an individual-based mathematical model of P. falciparum, we modelled the cost-effectiveness of RTS,S across a range of settings in sub-Saharan Africa, incorporating various rainfall patterns, insecticide-treated net (ITN) use, treatment coverage, and parasite prevalence bands. We compare age-based and seasonal RTS,S administration to increasing ITN usage, switching to next generation ITNs in settings experiencing insecticide-resistance, and introduction of seasonal malaria chemoprevention (SMC) in areas of seasonal transmission. RESULTS: For RTS,S to be the most cost-effective intervention option considered, the maximum cost per dose was less than $9.30 USD in 90.9% of scenarios. Nearly all (89.8%) values at or above $9.30 USD per dose were in settings with 60% established bed net use and / or with established SMC, and 76.3% were in the highest PfPR2-10 band modelled (40%). Addition of RTS,S to strategies involving 60% ITN use, increased ITN usage or a switch to PBO nets, and SMC, if eligible, still led to significant marginal case reductions, with a median of 2,653 (IQR: 1,741 to 3,966) cases averted per 100,000 people annually, and 82,270 (IQR: 54,034 to 123,105) cases averted per 100,000 fully vaccinated children (receiving at least three doses). CONCLUSIONS: Use of RTS,S results in reductions in malaria cases and deaths even when layered upon existing interventions. When comparing relative cost-effectiveness, scale up of ITNs, introduction of SMC, and switching to new technology nets should be prioritized in eligible settings.

Modelling the impact of vaccine hesitancy in prolonging the need for Non-Pharmaceutical Interventions to control the COVID-19 pandemic.

Background: Vaccine hesitancy - a delay in acceptance or refusal of vaccines despite availability - has the potential to threaten the successful roll-out of SARS-CoV-2 vaccines globally. In this study, we aim to understand the likely impact of vaccine hesitancy on the control of the COVID-19 pandemic. Methods: We modelled the potential impact of vaccine hesitancy on the control of the pandemic and the relaxation of non-pharmaceutical interventions (NPIs) by combining an epidemiological model of SARS-CoV-2 transmission with data on vaccine hesitancy from population surveys. Results: Our simulations suggest that the mortality over a 2-year period could be up to 7.6 times higher in countries with high vaccine hesitancy compared to an ideal vaccination uptake if NPIs are relaxed. Alternatively, high vaccine hesitancy could prolong the need for NPIs to remain in place. Conclusions: While vaccination is an individual choice, vaccine-hesitant individuals have a substantial impact on the pandemic trajectory, which may challenge current efforts to control COVID-19. In order to prevent such outcomes, addressing vaccine hesitancy with behavioural interventions is an important priority in the control of the COVID-19 pandemic.

Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: A mathematical modelling analysis.

The worldwide endeavour to develop safe and effective COVID-19 vaccines has been extraordinary, and vaccination is now underway in many countries. However, the doses available in 2021 are likely to be limited. We extend a mathematical model of SARS-CoV-2 transmission across different country settings to evaluate the public health impact of potential vaccines using WHO-developed target product profiles. We identify optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We find that the health impact of SARS-CoV-2 vaccination depends on the cumulative population-level infection incidence when vaccination begins, the duration of natural immunity, the trajectory of the epidemic prior to vaccination, and the level of healthcare available to effectively treat those with disease. Within a country we find that for a limited supply (doses for < 20% of the population) the optimal strategy is to target the elderly. However, with a larger supply, if vaccination can occur while other interventions are maintained, the optimal strategy switches to targeting key transmitters to indirectly protect the vulnerable. As supply increases, vaccines that reduce or block infection have a greater impact than those that prevent disease alone due to the indirect protection provided to high-risk groups. Given a 2 billion global dose supply in 2021, we find that a strategy in which doses are allocated to countries proportional to population size is close to optimal in averting deaths and aligns with the ethical principles agreed in pandemic preparedness planning.

Database of epidemic trends and control measures during the first wave of COVID-19 in mainland China.

OBJECTIVES: In this data collation study, we aimed to provide a comprehensive database describing the epidemic trends and responses during the first wave of coronavirus disease 2019 (COVID-19) throughout the main provinces in China. METHODS: From mid-January to March 2020, we extracted publicly available data regarding the spread and control of COVID-19 from 31 provincial health authorities and major media outlets in mainland China. Based on these data, we conducted descriptive analyses of the epidemic in the six most-affected provinces. RESULTS: School closures, travel restrictions, community-level lockdown, and contact tracing were introduced concurrently around late January but subsequent epidemic trends differed among provinces. Compared with Hubei, the other five most-affected provinces reported a lower crude case fatality ratio and proportion of critical and severe hospitalised cases. From March 2020, as the local transmission of COVID-19 declined, switching the focus of measures to the testing and quarantine of inbound travellers may have helped to sustain the control of the epidemic. CONCLUSIONS: Aggregated indicators of case notifications and severity distributions are essential for monitoring an epidemic. A publicly available database containing these indicators and information regarding control measures is a useful resource for further research and policy planning in response to the COVID-19 epidemic.

Risk Factors Associated With Postendoscopic Mucosal Resection Bleeding in Patients With Cirrhosis: A Retrospective Multicenter Cohort Study.

BACKGROUND AND AIM: There is limited data regarding the safety of endoscopic mucosal resection (EMR) in the cirrhotic population. Our study aimed to evaluate the safety of colonoscopic EMR in cirrhosis. MATERIALS AND METHODS: This was a retrospective review of cirrhotics who underwent colonic EMR at 8 Cleveland Clinic Centers between January 1, 2006, and December 31, 2018. Patient data including polyp details and complications occurring within 30 days of the procedure were noted. Univariable and multivariable logistic regression analyses were conducted to find risk factors for post-EMR bleeding. RESULTS: A total of 238 patients who underwent EMR were included. There were 145 males (60.9%) and the mean age was 61.9±8.6 years. Immediate and delayed bleeding, and postpolypectomy syndrome rates were 9.2%, 5.8%, and 1.3%, respectively. Significant risk factors for postpolypectomy bleeding were: increased age (P=0.001), procedure duration >37 minutes (P=0.001), antiplatelet use within 5 days (P=0.023), and lesion diameter >15 mm (P=0.004). Multivariable analysis revealed independent predictors of procedure-related bleeding: age above 65 years [odds ratio (OR) 2.14, P=0.044], antiplatelet use within 5 days (OR 2.42, P=0.047), right colon polyp (OR 3.51, P=0.001), and lesion diameter >15 mm (OR 3.22, P=0.003). CONCLUSIONS: EMR in cirrhotics has an acceptable bleeding risk. Age above 65 years, right colon polyp, polyp size >15 mm, and use of antiplatelets within 5 days are independent risk factors for bleeding.