Epke A. Le Rutte

New malaria vaccine development builds on groundbreaking recommendations and roll-out of two approved pre-erythrocytic vaccines (PEVs); RTS,S/AS01 and R21/Matrix-M. Whilst these vaccines are effective in reducing childhood malaria within yearly routine immunization programs or seasonal vaccination, there is little evidence on how different PEV efficacies, durations of protection, and spacing between doses influence the potential to avert uncomplicated and severe childhood malaria. Mainly, lacking understanding of the required vaccine properties and delivery strategies that lead to an effective childhood vaccine with multi-year protection. We used an individual-based model of malaria transmission informed by trial data to quantify trade-offs between PEV performance properties and impact across different endemicities, deployment schedules, and coverage levels. We found that deploying a vaccine with 90% initial efficacy against infection, with a six to 12-month half-life duration of protection, co-administered with a blood-stage drug, followed by yearly boosters, results in 60–80% yearly incidence reduction, consistent with seasonal RTS,S and R21 trials. Halting vaccination after five years, leads to sustained protection of at least a 35% incidence reduction in children less than six years in the 12 months following cessation in settings where PfPR_2–10< 30%. Increasing the half-life duration to 12–18 months or reaching more children provides the same health impact with lower vaccine efficacy. Without a booster (fourth dose), high efficacy against infection (>90%) and longer half-life duration (>12 months) are required to sustain impact beyond primary vaccination, averting up to half the preceding year’s burden. The contribution of each property to the overall impact varies by setting and clinical endpoint, indicating that public health goals should dictate key vaccine performance criteria. Overall, our findings support the need for well-defined target product profiles for long duration vaccines linking priority use cases of where, how, and to whom to deploy new malaria vaccines, to maximize public health impact.

New malaria vaccine development builds on groundbreaking recommendations and roll-out of two approved pre-erythrocytic vaccines (PEVs); RTS,S/AS01 and R21/MM. Whilst these vaccines are effective in reducing childhood malaria within yearly routine immunization programs or seasonal vaccination, there is little evidence on how different PEV efficacies, durations of protection, and spacing between doses influence the potential to avert uncomplicated and severe childhood malaria. Mainly, lacking understanding of the required vaccine properties and delivery strategies that lead to an effective childhood vaccine with multi-year protection. We used an individual-based model of malaria transmission informed by trial data to quantify trade-offs between PEV performance properties and impact across different endemicities, deployment schedules, and coverage levels. We found that deploying a vaccine with 90% initial efficacy, with a six to 12-month half-life duration of protection, co-administered with a blood-stage drug, followed by yearly boosters, results in 60-80% yearly incidence reduction, consistent with seasonal RTS,S and R21 trials. Halting vaccination after five years, leads to sustained protection of at least a 35% incidence reduction in children Pf PR _2-10 90%) and longer half-life duration (>12 months) are required to sustain impact beyond primary vaccination, averting up to half the preceding year’s burden. The contribution of each property to the overall impact varies by setting and clinical endpoint, indicating that public health goals should dictate key vaccine performance criteria. Overall, our findings support the need for well-defined target product profiles for long duration vaccines linking priority use cases of where, how, and to whom to deploy new malaria vaccines, to maximize public health impact.

Background Vaccinations have reduced severe burden of COVID-19 and allowed for lifting of non-pharmaceutical interventions. However, with immunity waning alongside emergence of more transmissible variants of concern, vaccination strategies must be examined. Methods Here we apply a SARS-CoV-2 transmission model to identify preferred frequency, timing, and target groups for vaccine boosters to reduce public health burden and health systems risk. We estimated new infections and hospital admissions averted over 2 years through annual or biannual boosting of those eligible (those who received doses one and two) who are (1) most vulnerable (60+ or living with comorbidities) or (2) those 5+, at universal (98% of eligible) or lower coverage (85% of those 50+ or with comorbidities and 50% of 5–49 year olds) representing moderate vaccine fatigue and/or hesitancy. We simulated three emerging variant scenarios: (1) no new variants; (2) 25% more infectious and immune-evading Omicron-level severity variants emerge annually and become dominant; (3) emerge biannually. We further explored the impact of varying seasonality, variant immune-evading capacity, infectivity, severity, timing, and vaccine infection blocking assumptions. Results To reduce COVID-19-related hospitalisations over the next 2 years, boosters should be provided for all those eligible annually 3–4 months ahead of peak winter whether or not new variants of concern emerge. Only boosting those most vulnerable is unlikely to ensure reduced stress on health systems. Moreover, boosting all eligible better protects those most vulnerable than only boosting the vulnerable group. Conversely, while this strategy may not ensure reduced stress on health systems, as an indication of cost-effectiveness, per booster dose more hospitalisations could be averted through annual boosting of those most vulnerable versus all eligible, since those most vulnerable are more likely to seek hospital care once infected, whereas increasing to biannual boosting showed diminishing returns. Results were robust when key model parameters were varied. However, we found that the more frequently variants emerge, the less the effect boosters will have, regardless of whether administered annually or biannually. Conclusions Delivering well-timed annual COVID-19 vaccine boosters to all those eligible, prioritising those most vulnerable, can reduce infections and hospital admissions. Findings provide model-based evidence for decision-makers to plan for administering COVID-19 boosters ahead of winter 2022–2023 to help mitigate the health burden and health system stress.

Background: Vaccinations have reduced severe burden of COVID-19 and allowed for lifting of non-pharmaceutical interventions. However, with immunity waning alongside emergence of more transmissible variants of concern, vaccination strategies must be examined. Methods: Here we apply a SARS-CoV-2 transmission model to identify preferred frequency, timing, and target groups for vaccine boosters to minimise public health burden and health systems risk. We estimated new infections and hospital admissions averted over two-years through annual or biannual boosting of those eligible (those who received doses one and two) who are 1) most vulnerable (60+ or persons with comorbidities) or 2) those 5+, at universal (98% of eligible) or lower coverage (85% of those 50+ or with comorbidities and 50% of 5−49-year-olds who are eligible) representing moderate vaccine fatigue and/or hesitancy. We simulated three emerging variant scenarios: 1) no new variants; 2) 25% more infectious and immune-evading, Omicron-level severity, variants emerge annually and become dominant; and 3) emerge biannually. We further explored the impact of varying seasonality, variant severity, timing, immune evasion, and infectivity, and vaccine infection blocking assumptions. Results: To minimise COVID-19-related hospitalisations over the next two years, boosters should be provided for all those eligible annually three-four months ahead of peak winter whether or not new variants of concern emerge. Only boosting those most vulnerable is unlikely to ensure reduced stress on health systems. Moreover, boosting all eligible protects those most vulnerable more than only boosting the vulnerable group. Conversely, more hospitalisations could be averted per booster dose through annual boosting of those most vulnerable versus all eligible, an indication of cost-effectiveness. Whereas increasing to biannual boosting showed diminishing returns. Results were robust when key model parameters were varied. However, we found that the more frequently variants emerge, the less the effect boosters will have, regardless of whether administered annually or biannually. Conclusions: Well-timed and targeted vaccine boosters preferencing vulnerable, and if possible, all those eligible to receive boosters, can minimise infections and hospital admissions. Findings provide model-based evidence for decision-makers to plan for administering COVID-19 boosters ahead of winter 2022−2023 to help mitigate the health burden and health system stress.

Background: In line with the movement restrictions and physical distancing essential for the control of the global COVID-19 pandemic, the World Health Organization (WHO) recommended postponement of all neglected tropical disease (NTD) control activities which involve community-based surveys, active case-finding and mass drug administration (MDA) in April 2020. Following revised guidance later in 2020, and after interruptions to NTD programmes of varying lengths, NTD programmes have gradually restarted in the context of an ongoing pandemic. However ongoing challenges and service gaps have been reported. This study aimed to evaluate the potential impact of the programmatic interruptions and strategies to mitigate this impact. Methods: For seven of the NTDs, namely soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis, trachoma, visceral leishmaniasis and human African trypanosomiasis, we used mathematical transmission models to simulate the impact of programme interruptions on the dynamics of each of these diseases in different endemic settings. We also explored the potential benefit of implementing mitigation strategies, primarily in terms of minimising the delays to control targets. Findings: We demonstrate that the impact of the COVID-19 induced interruption in terms of delay to achieving elimination goals may in some cases be much longer than the duration of the interruption. For schistosomiasis, onchocerciasis, trachoma and visceral leishmaniasis a mean delay of two to three years for a one-year interruption is predicted in areas of highest prevalence. We also show that these delays can largely be mitigated by measures such as additional MDA or enhanced case-finding. Interpretation: The COVID-19 pandemic has brought infectious disease control to the forefront of global consciousness. As we enter the third year of the pandemic, it is essential that the NTDs, so long neglected in terms of research and financial support, are not overlooked, and remain a priority in health service planning and funding. Funding: This work was supported by the NTD Modelling Consortium, funded by the Bill & Melinda Gates Foundation (OPP1184344). JT and MGB acknowledge funding from the Medical Research Council (MRC) Centre for Global Infectious Disease Analysis (MR/R015600/1), jointly funded by the UK MRC and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the European and Developing Countries Clinical Trials Partnership (EDCTP2) programme supported by the European Union. Declaration of Interest: All authors declare no competing interests.

Summary: SARS-CoV-2 variant Omicron (B.1.1.529) was classified as a variant of concern (VOC) on November 26, 2021. (1, 2) The infectivity, severity, and immune evasion properties of Omicron relative to the Delta variant would determine 1) the probability of dominant future transmission, and 2) the impact on disease burden. (3, 4) Here we apply individual-based transmission model OpenCOVID to identify thresholds for Omicron’s or any VOC’s potential future dominance, impact on health, and risk to health systems; and identify for which combinations of viral properties, current interventions would be sufficient to control transmission. We show that, with first-generation SARS-CoV-2 vaccines (5) and limited physical distancing in place, the threshold for Omicron’s future dominance was primarily be driven by its degree of infectivity. However, we identified that a VOC’s potential dominance will not necessarily lead to increased public health burden. Expanded vaccination, that includes a third-dose for adults and child vaccination strategies, was projected to have the biggest public health benefit for a highly infective, highly severe VOC with low immune evasion capacity. However, a highly immune evading variant that becomes dominant would likely require alternative measures for control, such as strengthened physical distancing measures, novel treatments, and second-generation vaccines. These findings provide quantitative guidance to decision-makers at a critical time while Omicron’s properties are being assessed and preparedness for new VOC’s is eminent. (6) We emphasize the importance of both genomic and population epidemiological surveillance.

The development of vaccines against one or all forms of human leishmaniasis remains hampered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 300–830 million doses for a vaccine preventing visceral leishmaniasis and 557–1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years ~160,000 doses for prevention and ~7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.