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Background: A recent clinical trial of seasonal RTS,S/AS01E (RTS,S) vaccination showed that vaccination was non-inferior to seasonal malaria chemoprevention (SMC) in preventing clinical malaria. The combination of these two interventions provided significant additional protection against clinical and severe malaria outcomes. Impact projections of this novel approach to RTS,S vaccination in seasonal transmission settings for longer time frames and across a range of epidemiological settings are needed to inform policy recommendations. Methods: We used a mathematical model of malaria transmission to assess the potential impact of an age-based or seasonally targeted RTS,S vaccination schedule in seasonal transmission settings in both the absence and presence of SMC. Estimates of cases and deaths averted in a population of 100,000 children aged 0-5 years were calculated over a 15-year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2–10-year-olds and over two West African seasonality archetypes. Findings: Seasonally targeting RTS,S resulted in greater absolute reductions in malaria cases and deaths compared to an age-based strategy, averting between 32%-100% more clinical cases dependent on seasonality and transmission intensity. We predict that adding seasonally targeted RTS,S to SMC would reduce clinical incidence by up to an additional 36%-56% in children under five compared with SMC alone. Transmission season duration was a key determinant of intervention impact, with the advantage of adding RTS,S to SMC predicted to be smaller with shorter transmission seasons. Interpretation: RTS,S vaccination in seasonal settings could be a valuable additional tool to existing interventions, with seasonal delivery maximising impact relative to an age-based approach. Decisions surrounding deployment strategies of RTS,S in such settings will need to consider the local and regional variations in seasonality, current levels of other interventions and potential achievable RTS,S coverage. Funding: UK Medical Research Council, UK Foreign Commonwealth & Development Office, The Wellcome Trust and The Royal society.

Infection by Taenia solium poses a major burden across endemic countries. The World Health Organization (WHO) 2021–2030 Neglected Tropical Diseases roadmap has proposed that 30% of endemic countries achieve intensified T. solium control in hyperendemic areas by 2030. Understanding geographical variation in age-prevalence profiles and force-of-infection (FoI) estimates will inform intervention designs across settings. Human taeniasis (HTT) and human cysticercosis (HCC) age-prevalence data from 16 studies in Latin America, Africa and Asia were extracted through a systematic review. Catalytic models, incorporating diagnostic performance uncertainty, were fitted to the data using Bayesian methods, to estimate rates of antibody (Ab)-seroconversion, infection acquisition and Ab-seroreversion or infection loss. HCC FoI and Ab-seroreversion rates were also estimated across 23 departments in Colombia from 28,100 individuals. Across settings, there was extensive variation in all-ages seroprevalence. Evidence for Ab- seroreversion or infection loss was found in most settings for both HTT and HCC and for HCC Ab- seroreversion in Colombia. The average duration until humans became Ab-seropositive/infected decreased as all-age (sero)prevalence increased. There was no clear relationship between the average duration humans remain Ab-seropositive and all-age seroprevalence. Marked geographical heterogeneity in T. solium transmission rates indicate the need for setting- specific intervention strategies to achieve the WHO goals.

Vaccines have played a central role in mitigating severe disease and death from COVID-19 in the past 12 months. However, efficacy wanes over time and this loss of protection will be compounded by the emergence of the Omicron variant. By fitting an immunological model to population-level vaccine effectiveness data, we estimate that neutralizing antibody titres for Omicron are reduced by 4.5-fold (95% CrI 3.1–7.1) compared to the Delta variant. This is predicted to result in a drop in vaccine efficacy against severe disease (hospitalisation) from 96.5% (95% CrI 96.1%–96.8%) against Delta to 80.1% (95% CrI 76.3%–83.2%) against Omicron for the Pfizer-BioNTech booster by 60 days post boost if NAT decay at the same rate following boosting as following the primary course, and from 97.6% (95% CrI 97.4%-97.9%) against Delta to 85.9% (95% CrI 83.1%-88.3%) against Omicron if NAT decay at half the rate observed after the primary course. Integrating this immunological model within a model of SARS-CoV-2 transmission, we show that booster doses will be critical to mitigate the impact of future Omicron waves in countries with high levels of circulating virus. They will also be needed in “zero-COVID” countries where there is little prior infection-induced immunity in order to open up safely. Where dose supply is limited, targeting boosters to the highest risk groups to ensure continued high protection in the face of waning immunity is of greater benefit than giving these doses as primary vaccination to younger age-groups. In all scenarios it is likely that health systems will be stretched. It may be essential, therefore, to maintain and/or reintroduce NPIs to mitigate the worst impacts of the Omicron variant as it replaces the Delta variant. Ultimately, Omicron variant-specific vaccines are likely to be required.

Infection with the pork tapeworm (Taenia solium) is responsible for a substantial global burden of disease, not only restricted to its impact on human health, but also resulting in a considerable economic burden to smallholder pig farmers due to pig cysticercosis infection. The life-cycle, parasitology and immunology of T. solium are complex, involving pigs(the intermediate host, harbouring the larval metacestode stage), humans(the definitive host, harbouring the adult tapeworm, in addition to acting as accidental intermediate hosts) and the environment (the source of infection with eggs/proglottids). We review the parasitology, immunology, and epidemiology of the infection associated with each of the T. solium life-cycle stages, including the pre-adult/adult tapeworm responsible for human taeniasis; post-oncosphere and cysticercus associated with porcine and human cysticercosis, and the biological characteristics of eggs in the environment. We discuss the burden associated, in endemic settings, with neurocysticercosis (NCC) in humans, and the broader cross-sectoral economic impact associated both with NCC and porcine cysticercosis, the latter impacting food-value chains. Existing tools for diagnostics and control interventions that target different stages of the T. solium transmission cycle are reviewed and their limitations discussed. Currently, no national T. solium control programmes have been established in endemic areas, with further work required to identify optimal strategies according to epidemiological setting. There is increasing evidence suggesting that cross-sectoral interventions which target the parasite in both the human and pig host provide the most effective approaches for achieving control and ultimately elimination. We discuss future avenues for research on T. soliumto support the attainement of the goals proposed in the revised World Health Organization neglected tropical diseases roadmap for 2021–2030adopted at the 73rdWorld Health Assembly in November 2020

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 extended 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 identified optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We found 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

There is a trade-off between the education sector and other economic sectors in the control of SARS-Cov-2 transmission. Here we integrate a dynamic model of SARS-CoV-2 transmission with a 63-sector economic model reflecting sectoral heterogeneity in transmission and economic interdependence between sectors. We identify COVID-19 control strategies which optimize economic production while keeping schools and universities operational and constraining infections such that emergency hospital capacity is not exceeded. The model estimates an economic gain of between £163bn and £205bn for the United Kingdom compared to a blanket lockdown of non-essential activity over six months, depending on hospital capacity. Sectors identified as potential priorities for closure are contact-intensive and/or less economically productive.

The infection fatality ratio (IFR) is a key statistic for estimating the burden of coronavirus disease 2019 (COVID-19) and has been continuously debated throughout the current pandemic. Previous estimates have relied on data early in the epidemic, or have not fully accounted for uncertainty in serological test characteristics and delays from onset of infection to seroconversion, death, and antibody waning. After screening 175 studies, we identified 10 representative antibody surveys to obtain updated estimates of the IFR using a modelling framework that addresses the limitations listed above. We inferred serological test specificity from regional variation within serosurveys, which is critical for correctly estimating the cumulative proportion infected when seroprevalence is still low. We find that age-specific IFRs follow an approximately log-linear pattern, with the risk of death doubling approximately every eight years of age. Using these age-specific estimates, we estimate the overall IFR in a typical low-income country, with a population structure skewed towards younger individuals, to be 0.23% (0.14-0.42 95% prediction interval range). In contrast, in a typical high income country, with a greater concentration of elderly individuals, we estimate the overall IFR to be 1.15% (0.78-1.79 95% prediction interval range). We show that accounting for seroreversion, the waning of antibodies leading to a negative serological result, can slightly reduce the IFR among serosurveys conducted several months after the first wave of the outbreak, such as Italy. In contrast, uncertainty in test false positive rates combined with low seroprevalence in some surveys can reconcile apparently low crude fatality ratios with the IFR in other countries. Unbiased estimates of the IFR continue to be critical to policymakers to inform key response decisions. It will be important to continue to monitor the IFR as new treatments are introduced. The code for reproducing these results are available as a R Research Compendium on Github: `mrc-ide/reestimate_covidIFR_analysis`.

Background The RTS,S/AS01 malaria vaccine is currently being piloted in three African countries. We sought to identify whether vaccination could reach additional children who are at risk from malaria but do not currently have access to, or use, core malaria interventions. Methods Using data from household surveys we calculated the overlap between malaria intervention coverage and childhood vaccination (diphtheria-tetanus-pertussis dose 3, DTP3) uptake in 20 African countries with at least one first administrative level unit with Plasmodium falciparum parasite prevalence greater than 10%. We used multilevel logistic regression to explore patterns of overlap by demographic and socioeconomic variables. We also estimated the public health impact of delivering RTS,S/AS01 to those children who do not use an insecticide-treated net (ITN) but who received the DTP3 vaccine. Results Uptake of DTP3 was higher than malaria intervention coverage in most countries. Overall, 34% of children did not use ITNs and received DTP3, while 35% of children used ITNs and received DTP3, although this breakdown varied by country. We estimated that there are 33 million children in these 20 countries who do not use an ITN. Of these, 23 million (70%) received the DTP3 vaccine. Vaccinating those 23 million children who receive DTP3 but do not use an ITN could avert an estimated 9.7 million clinical malaria cases each year. An additional 10.8 million cases could be averted by vaccinating those 24 million children who receive the vaccine and use an ITN. Children who had access to or used an ITN were 9 to 13% more likely to reside in rural areas compared to those who had neither intervention regardless of vaccination status. Mothers’ education status was a strong predictor of intervention uptake and was positively associated with use of ITNs and vaccination uptake and negatively associated with having access to an ITN but not using it. Wealth was also a strong predictor of intervention coverage. Conclusions Childhood vaccination to prevent malaria has the potential to reduce inequity in access to existing malaria interventions and could substantially reduce the childhood malaria burden in sub-Saharan Africa, even in regions with lower existing DTP3 coverage. Competing Interest Statement The authors have declared no competing interest.

Several SARS-CoV-2 vaccine candidates are now in late-stage trials, with efficacy and safety results expected by the end of 2020. Even under optimistic scenarios for manufacture and delivery, the doses available in 2021 are likely to be limited. Here we identify optimal vaccine allocation strategies within and between countries to maximise health (avert deaths) under constraints on dose supply. We extended an existing mathematical model of SARS-CoV-2 transmission across different country settings to model the public health impact of potential vaccines, using a range of target product profiles developed by the World Health Organization. We show that as supply increases, vaccines that reduce or block infection – and thus transmission – in addition to preventing disease have a greater impact than those that prevent disease alone, due to the indirect protection provided to high-risk groups. We further demonstrate that the health impact of vaccination will depend on the cumulative infection incidence in the population when vaccination begins, the duration of any naturally acquired immunity, the likely trajectory of the epidemic in 2021 and the level of healthcare available to effectively treat those with disease. Within a country, we find that for a limited supply (doses for

The COVID-19 pandemic has resulted in substantial mortality worldwide. However, to date, countries in the Middle East and Africa have reported substantially lower mortality rates than in Europe and the Americas. One hypothesis is that these countries have been ‘spared’, but another is that deaths have been under-ascertained (deaths that have been unreported due to any number of reasons, for instance due to limited testing capacity). However, the scale of under-ascertainment is difficult to assess with currently available data. In this analysis, we estimate the potential under-ascertainment of COVID-19 mortality in Damascus, Syria, where all-cause mortality data has been reported between 25th July and 1st August. We fit a mathematical model of COVID-19 transmission to reported COVID-19 deaths in Damascus since the beginning of the pandemic and compare the model-predicted deaths to reported excess deaths. Exploring a range of different assumptions about under-ascertainment, we estimate that only 1.25% of deaths (sensitivity range 1% - 3%) due to COVID-19 are reported in Damascus. Accounting for under-ascertainment also corroborates local reports of exceeded hospital bed capacity. To validate the epidemic dynamics inferred, we leverage community-uploaded obituary certificates as an alternative data source, which confirms extensive mortality under-ascertainment in Damascus between July and August. This level of under-ascertainment suggests that Damascus is at a much later stage in its epidemic than suggested by surveillance reports, which have repo. We estimate that 4,340 (95% CI: 3,250 - 5,540) deaths due to COVID-19 in Damascus may have been missed as of 2nd September 2020. Given that Damascus is likely to have the most robust surveillance in Syria, these findings suggest that other regions of the country could have experienced similar or worse mortality rates due to COVID-19.

Background: COVID-19 has the potential to cause substantial disruptions to health services, including by cases overburdening the health system or response measures limiting usual programmatic activities. We aimed to quantify the extent to which disruptions in services for human immunodeficiency virus (HIV), tuberculosis (TB) and malaria in low- and middle-income countries with high burdens of those disease could lead to additional loss of life. Methods: We constructed plausible scenarios for the disruptions that could be incurred during the COVID-19 pandemic and used established transmission models for each disease to estimate the additional impact on health that could be caused in selected settings. Findings: In high burden settings, HIV-, TB- and malaria-related deaths over five years may increase by up to 10%, 20% and 36%, respectively, compared to if there were no COVID-19 pandemic. We estimate the greatest impact on HIV to be from interruption to antiretroviral therapy, which may occur during a period of high health system demand. For TB, we estimate the greatest impact is from reductions in timely diagnosis and treatment of new cases, which may result from any prolonged period of COVID-19 suppression interventions. We estimate that the greatest impact on malaria burden could come from interruption of planned net campaigns. These disruptions could lead to loss of life-years over five years that is of the same order of magnitude as the direct impact from COVID-19 in places with a high burden of malaria and large HIV/TB epidemics. Interpretation: Maintaining the most critical prevention activities and healthcare services for HIV, TB and malaria could significantly reduce the overall impact of the COVID-19 pandemic. Funding: Bill & Melinda Gates Foundation, The Wellcome Trust, DFID, MRC

The impact of the COVID-19 pandemic in low-income settings is likely to be more severe due to limited healthcare capacity. Within these settings, however, there exists unfair or avoidable differences in health among different groups in society – health inequities – that mean that some groups are particularly at risk from the negative direct and indirect consequences of COVID-19. The structural determinants of these are often reflected in differences by income strata, with the poorest populations having limited access to preventative measures such as handwashing. Their more fragile income status will also mean that they are likely to be employed in occupations that are not amenable to social-distancing measures, thereby further reducing their ability to protect themselves from infection. Furthermore, these populations may also lack access to timely healthcare on becoming ill. We explore these relationships by using large-scale household surveys to quantify the differences in handwashing access, occupation and hospital access with respect to wealth status in low-income settings. We use a COVID-19 transmission model to demonstrate the impact of these differences. Our results demonstrate clear trends that the probability of death from COVID-19 increases with increasing poverty. On average, we estimate a 32.0% (2.5th-97.5th centile 8.0%-72.5%) increase in the probability of death in the poorest quintile compared to the wealthiest quintile from these three factors alone. We further explore how risk mediators and the indirect impacts of COVID-19 may also hit these same disadvantaged and vulnerable the hardest. We find that larger, inter-generational households that may hamper efforts to protect the elderly if social distancing are associated with lower-income countries and, within LMICs, lower wealth status. Poorer populations are also more susceptible to food security issues - with these populations having the highest levels under-nourishment whilst also being most dependent on their own food production. We show that timing of the COVID-19 epidemic in low-resource settings has the potential to interrupt planting and harvesting seasons for staple crops, thereby accentuating this vulnerability. These enhanced risks and key vulnerabilities – alongside the broader concerns surrounding displaced or conflict-affected populations - demonstrate the challenges that the most marginalised populations face during the ongoing COVID-19 pandemic.

The COVID-19 pandemic is likely to severely interrupt health systems in Sub-Saharan Africa (SSA) over the coming weeks and months. Approximately 90% of malaria deaths occur in this region of the world, with an estimated 380,000 deaths from malaria in 2018. Much of the gain made in malaria control over the last decade has been due to the distribution of long-lasting insecticide treated nets (LLINs). Many SSA countries planned to distribute these in 2020. We used COVID-19 and malaria transmission models to understand the likely impact that disruption to these distributions, alongside other core health services, could have on the malaria burden. Results indicate that if all malaria-control activities are highly disrupted then the malaria burden in 2020 could more than double that in the previous year, resulting in large malaria epidemics across the region. These will depend on the course of the COVID-19 epidemic and how it interrupts local health system. Our results also demonstrate that it is essential to prioritise the LLIN distributions either before or as soon as possible into local COVID-19 epidemics to mitigate this risk. Additional planning to ensure other malaria prevention activities are continued where possible, alongside planning to ensure basic access to antimalarial treatment, will further minimise the risk of substantial additional malaria mortality.

COVID-19 has the potential to cause disruptions to health services in different ways; through the health system becoming overwhelmed with COVID-19 patients, through the intervention used to slow transmission of COVID-19 inhibiting access to preventative interventions and services, and through supplies of medicine being interrupted. We aim to quantify the extent to which such disruptions in services for HIV, TB and malaria in high burden low- and middle-income countries could lead to additional loss of life. In high burden settings, HIV, TB and malaria related deaths over 5 years may be increased by up to 10%, 20% and 36%, respectively, compared to if there were no COVID-19 epidemic. We estimate the greatest impact on HIV to be from interruption to ART, which may occur during a period of high or extremely high health system demand; for TB, we estimate the greatest impact is from reductions in timely diagnosis and treatment of new cases, which may result from a long period of COVID-19 suppression interventions; for malaria, we estimate that the greatest impact could come from reduced prevention activities including interruption of planned net campaigns, through all phases of the COVID-19 epidemic. In high burden settings, the impact of each type of disruption could be significant and lead to a loss of life-years over five years that is of the same order of magnitude as the direct impact from COVID-19 in places with a high burden of malaria and large HIV/TB epidemics. Maintaining the most critical prevention activities and healthcare services for HIV, TB and malaria could significantly reduce the overall impact of the COVID-19 epidemic.