Aurélien Cavelan

Background: The recommendation of the RTS,S/AS01 malaria vaccine for use in children in moderate to high transmission areas by the WHO in 2021 provided another crucial tool in reducing malaria morbidity and mortality. As countries introduce the RTS,S vaccine, there is an interest in exploring vaccination schedules that align with existing routine health touch points and to optimize vaccine coverage. Methods: This study used OpenMalaria, an individual-based, stochastic model of malaria transmission and disease progression, to assess the impact of different vaccination timing schedules and coverage on uncomplicated malaria cases, severe malaria cases, and malaria-related deaths across different archetypal transmission settings. We ran simulations comparing fourth dose protection against infection and timings at six-, nine-, 12-, 15- and 18-month intervals following the primary series, including exploring ranges of plausible protection assumptions for many of the dose timings. Results: The primary series substantially reduces the malaria burden across transmission settings, regardless of timing of the fourth dose. While the number of cases averted varies by baseline prevalence, our modelling suggests that the primary series is responsible for around 54-93% of the total clinical and severe cases averted across transmission archetypes in perennial settings. Additionally, a fourth dose of the vaccine could avert additional 9-46% malaria cases and 7-41% severe cases in addition to the primary series alone. We find potential flexibility in timing this dose, especially when focused on 6 to 12 months following the primary series. Conclusions: In addition to the primary series, use of a fourth dose of the RTS,S vaccine can be tailored to country specific context and linked to existing health touch points to ensure adequate coverage of this dose. In particular, a fourth dose delivered between 15- and 21-months of age with high population coverage will likely avert the largest proportion of cases of clinical malaria, severe malaria, and deaths in perennial settings, across transmission intensities. Trial registration: N/A

Background: Malaria transmission exhibits significant heterogeneity within communities, with small proportions of individuals experiencing disproportionate mosquito exposure. Methods: This study addresses critical knowledge gaps in characterising and modelling this heterogeneity. Parameterising Bayesian hierarchical models to field data from Burkina Faso, we compared gamma and lognormal distributions for describing heterogeneity in mosquito biting rates. We then implemented this heterogeneity in an individual-based stochastic modelling platform, OpenMalaria, to assess its impact on transmission dynamics. Findings: The gamma distribution was found to better describe the field data, compared to the lognormal distribution. When heterogeneity is introduced to malaria transmission simulations, both prevalence and incidence levels generally decrease across all age groups. Additionally, heterogeneity shifts disease burden towards younger age cohorts and alters the fundamental relationships between entomological inoculation rate and prevalence/incidence. The integration of appropriate heterogeneity distributions into transmission models substantially improved their ability to reproduce field-observed age-incidence curves. Interpretation: Our findings highlight the importance of accounting for heterogeneous exposure when modelling malaria transmission, particularly in low-transmission and elimination settings where heterogeneity may be more pronounced.

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.

Antigens of Plasmodium falciparum targeted by most current and future vaccines are generally not conserved. There are limited studies estimating the risk of parasite selection with vaccines. We adapted an individual-based model of malaria to assess which conditions favour genotypes having some degree of vaccine resistance and estimate the impact of resistance spread on vaccine effectiveness. Even parasite genotypes with low degrees of vaccine resistance are likely to spread relatively quickly if vaccines are implemented in children and even faster in a broader population. However, only highly resistant genotypes could strongly reduce vaccine effectiveness. These results highlight that it is essential to understand the degree to which genotypes exhibit reduced sensitivity to vaccines and monitor genotype frequency and vaccine effectiveness along with vaccine deployment. If some genotypes exhibit reduced efficacy to vaccines, our results further suggest that polyvalent or combination vaccines should be considered to limit resistance spread.

This paper investigates the optimal number of processors to execute a parallel job, whose speedup profile obeys Amdahl's law, on a large-scale platform subject to fail-stop and silent errors. We combine the traditional checkpointing and rollback recovery strategies with verification mechanisms to cope with both error sources. We provide an exact formula to express the execution overhead incurred by a periodic checkpointing pattern of length T and with P processors, and we give first-order approximations for the optimal values T* and P* as a function of the individual processor failure rate λind. A striking result is that P* is of the order λ _ind ^-1/4 if the checkpointing cost grows linearly with the number of processors, and of the order λ _ind ^-1/3 if the checkpointing cost stays bounded for any P. We conduct an extensive set of simulations to support the theoretical study. The results confirm the accuracy of first-order approximation under a wide range of parameter settings.