Role of seasonal importation and genetic drift on selection for drug-resistant genotypes of Plasmodium falciparum in high-transmission settings.

Historically Plasmodium falciparum has followed a pattern of drug resistance first appearing in low-transmission settings before spreading to high-transmission settings. Several features of low-transmission regions are hypothesized as explanations: higher chance of symptoms and treatment seeking, better treatment access, less within-host competition among clones and lower rates of recombination. Here, we test whether importation of drug-resistant parasites is more likely to lead to successful emergence and establishment in low-transmission or high-transmission periods of the same epidemiological setting, using a spatial, individual-based stochastic model of malaria and drug-resistance evolution calibrated for Burkina Faso. Upon controlling for the timing of importation of drug-resistant genotypes and examination of key model variables, we found that drug-resistant genotypes imported during the low-transmission season were (i) more susceptible to stochastic extinction due to the action of genetic drift, and (ii) more likely to lead to establishment of drug resistance when parasites are able to survive early stochastic loss due to drift. This implies that rare importation events are more likely to lead to establishment if they occur during a high-transmission season, but that constant importation (e.g. neighbouring countries with high levels of resistance) may produce a greater risk during low-transmission periods.

Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum.

Delaying and slowing antimalarial drug resistance evolution is a priority for malaria-endemic countries. Until novel therapies become available, the mainstay of antimalarial treatment will continue to be artemisinin-based combination therapy (ACT). Deployment of different ACTs can be optimized to minimize evolutionary pressure for drug resistance by deploying them as a set of co-equal multiple first-line therapies (MFT) rather than rotating therapies in and out of use. Here, we consider one potential detriment of MFT policies, namely, that the simultaneous deployment of multiple ACTs could drive the evolution of different resistance alleles concurrently and that these resistance alleles could then be brought together by recombination into double-resistant or triple-resistant parasites. Using an individual-based model, we compare MFT and cycling policies in malaria transmission settings ranging from 0.1% to 50% prevalence. We define a total risk measure for multi-drug resistance (MDR) by summing the area under the genotype-frequency curves (AUC) of double- and triple-resistant genotypes. When prevalence ≥ 1%, total MDR risk ranges from statistically similar to 80% lower under MFT policies than under cycling policies, irrespective of whether resistance is imported or emerges de novo. At 0.1% prevalence, there is little statistical difference in MDR risk between MFT and cycling.

Influenza vaccination allocation in tropical settings under constrained resources.

Influenza virus seasonality, synchronicity, and vaccine supply differ substantially between temperate and tropical settings, and optimal vaccination strategy may differ on this basis. Most national vaccine recommendations focus on high-risk groups, elderly populations, and healthcare workers despite previous analyses demonstrating broad benefits to vaccinating younger high-contact age groups. Here, we parameterized an age-structured non-seasonal asynchronous epidemiological model of influenza virus transmission for a tropical low-income setting. We evaluated timing and age allocation of vaccines across vaccine supplies ranging from 10% to 90% using decade-based age groups. Year-round vaccination was beneficial when comparing to vaccination strategies focused on a particular time of year. When targeting a single age-group for vaccine prioritization, maximum vaccine allocation to the 10-19 high-contact age group minimized annual influenza mortality for all but one vaccine supply. When evaluating across all possible age allocations, optimal strategies always allocated a plurality of vaccines to school-age children (10-19). The converse however was not true as not all strategies allocating a plurality to children aged 10-19 minimized mortality. Allocating a high proportion of vaccine supply to the 10-19 age group is necessary but not sufficient to minimize annual mortality as distribution of remaining vaccine doses to other age groups also needs to be optimized. Strategies focusing on indirect benefits (vaccinating children) showed higher variance in mortality outcomes than strategies focusing on direct benefits (vaccinating the elderly). However, the indirect benefit approaches showed lower mean mortality and lower minimum mortality than vaccination focused on the elderly.

Global risk of selection and spread of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions.

In the thirteen years since the first report of pfhrp2-deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reported pfhrp2/3 gene deletions. Due to a high prevalence of pfhrp2/3 deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs, that target pan-specific-pLDH or P. falciparum specific-pLDH alone of in combination with HRP2. However, manufacturing of alternative RDTs has not been brought to scale and there are no WHO prequalified combination tests that use Pf-pLDH instead of HRP2 for P. falciparum detection. For these reasons, the continued spread of pfhrp2/3 deletions represents a growing public health crisis that threatens efforts to control and eliminate P. falciparum malaria. National malaria control programmes, their implementing partners and test developers desperately seek pfhrp2/3 deletion data that can inform their immediate and future resource allocation. In response, we use a mathematical modelling approach to evaluate the global risk posed by pfhrp2/3 deletions and explore scenarios for how deletions will continue to spread in Africa. We incorporate current best estimates of the prevalence of pfhrp2/3 deletions and conduct a literature review to estimate model parameters known to impact the selection of pfhrp2/3 deletions for each malaria endemic country. We identify 20 countries worldwide to prioritise for surveillance and future deployment of alternative RDT, based on quickly selecting for pfhrp2/3 deletions once established. In scenarios designed to explore the continued spread of deletions in Africa, we identify 10 high threat countries that are most at risk of deletions both spreading to and subsequently being rapidly selected for. If HRP2-based RDTs continue to be relied on for malaria case management, we predict that the major route for pfhrp2 deletions to spread is south out from the current hotspot in the Horn of Africa, moving through East Africa over the next 20 years. We explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, we identify three countries that have not yet switched RDTs (Senegal, Zambia and Kenya) that are robustly identified as high risk for pfhrp2/3 deletions. These results provide a refined and updated prediction model for the emergence of pfhrp2/3 deletions in an effort to help guide pfhrp2/3 policy and prioritise future surveillance efforts and innovation.

Role of Seasonal Importation and Random Genetic Drift on Selection for Drug-Resistant Genotypes of Plasmodium falciparum in High Transmission Settings.

Historically Plasmodium falciparum has followed a pattern of drug resistance first appearing in low transmission settings before spreading to high transmission settings. Several features of low-transmission regions are hypothesized as explanations: higher chance of symptoms and treatment seeking, better treatment access, less within-host competition among clones, and lower rates of recombination. Here, we test whether importation of drug-resistant parasites is more likely to lead to successful emergence and establishment in low-transmission or high-transmission periods of the same epidemiological setting, using a spatial, individual-based stochastic model of malaria and drug-resistance evolution calibrated for Burkina Faso. Upon controlling for the timing of importation of drug-resistant genotypes and examination of key model variables, we found that drug-resistant genotypes imported during the low transmission season were, (1) more susceptible to stochastic extinction due to the action of random genetic drift, and (2) more likely to lead to establishment of drug resistance when parasites are able to survive early stochastic loss due to drift. This implies that rare importation events are more likely to lead to establishment if they occur during a high-transmission season, but that constant importation (e.g., neighboring countries with high levels of resistance) may produce a greater risk during low-transmission periods.

A combination of annual and nonannual forces drive respiratory disease in the tropics.

INTRODUCTION: It is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics is less well understood. In this study, we aimed to characterise the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City, Vietnam. METHODS: We monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodic signals in the system. We evaluated the contribution of these periodic signals to predicting ILI and influenza patterns through lognormal and gamma hurdle models. RESULTS: During 10 years of community surveillance, 66 799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected, 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI 8.8% to 9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC=183) compared with all annual covariates (ΔAIC=263) in lognormal regression. Near-annual signals were observed for PCR-confirmed influenza but were not consistent over time or across influenza (sub)types. The explanatory power of climate factors for ILI and influenza virus trends was weak. CONCLUSION: Our study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers, with influenza dynamics showing near-annual periodicities. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.

Modeling policy interventions for slowing the spread of artemisinin-resistant pfkelch R561H mutations in Rwanda.

Artemisinin combination therapies (ACTs) are highly effective at treating uncomplicated Plasmodium falciparum malaria, but the emergence of the new pfkelch13 R561H mutation in Rwanda, associated with delayed parasite clearance, suggests that interventions are needed to slow its spread. Using a Rwanda-specific spatial calibration of an individual-based malaria model, we evaluate 26 strategies aimed at minimizing treatment failures and delaying the spread of R561H after 3, 5 and 10 years. Lengthening ACT courses and deploying multiple first-line therapies (MFTs) reduced treatment failures after 5 years when compared to the current approach of a 3-d course of artemether-lumefantrine. The best among these options (an MFT policy) resulted in median treatment failure counts that were 49% lower and a median R561H allele frequency that was 0.15 lower than under baseline. New approaches to resistance management, such as triple ACTs or sequential courses of two different ACTs, were projected to have a larger impact than longer ACT courses or MFT; these were associated with median treatment failure counts in 5 years that were 81-92% lower than the current approach. A policy response to currently circulating artemisinin-resistant genotypes in Africa is urgently needed to prevent a population-wide rise in treatment failures.

Newly identified lineages of porcine hemagglutinating encephalomyelitis virus exhibit respiratory phenotype.

Swine pathogens have a long history of zoonotic transmission to humans, occasionally leading to sustained outbreaks or pandemics. Through a retrospective epidemiological study of swine populations in China, we describe novel lineages of porcine hemagglutinating encephalomyelitis virus (PHEV) complex coronaviruses (CoVs) that cause exclusively respiratory symptoms with no signs of the neurological symptoms typically associated with classical PHEV infection. Through large-scale epidemiological surveillance, we show that these novel lineages have circulated in at least eight provinces in southeastern China. Phylogenetic and recombination analyses of twenty-four genomes identified two major viral lineages causing respiratory symptoms with extensive recombination within them, between them, and between classical PHEV and the novel respiratory variant PHEV (rvPHEV) lineages. Divergence times among the sampled lineages in the PHEV virus complex date back to 1886-1958 (mean estimate 1928), with the two major rvPHEV lineages separating approximately 20 years later. Many rvPHEV viruses show amino acid substitutions at the carbohydrate-binding site of hemagglutinin esterase (HE) and/or have lost the cysteine required for HE dimerization. This resembles the early adaptation of human CoVs, where HE lost its hemagglutination ability to adapt to growth in the human respiratory tract. Our study represents the first report of the evolutionary history of rvPHEV circulating in swine and highlights the importance of characterizing CoV diversity and recombination in swine to identify pathogens with outbreak potential that could threaten swine farming.

Benefits of near-universal vaccination and treatment access to manage COVID-19 burden in the United States.

BACKGROUND: As we continue the fourth year of the COVID-19 epidemic, SARS-CoV-2 infections still cause high morbidity and mortality in the United States. During 2020-2022, COVID-19 was one of the leading causes of death in the United States and by far the leading cause among infectious diseases. Vaccination uptake remains low despite this being an effective burden reducing intervention. The development of COVID-19 therapeutics provides hope for mitigating severe clinical outcomes. This modeling study examines combined strategies of vaccination and treatment to reduce the burden of COVID-19 epidemics over the next decade. METHODS: We use a validated mathematical model to evaluate the reduction of incident cases, hospitalized cases, and deaths in the United States through 2033 under various levels of vaccination and treatment coverage. We assume that future seasonal transmission patterns for COVID-19 will be similar to those of influenza virus and account for the waning of infection-induced immunity and vaccine-induced immunity in a future with stable COVID-19 dynamics. Due to uncertainty in the duration of immunity following vaccination or infection, we consider three exponentially distributed waning rates, with means of 365 days (1 year), 548 days (1.5 years), and 730 days (2 years). We also consider treatment failure, including rebound frequency, as a possible treatment outcome. RESULTS: As expected, universal vaccination is projected to eliminate transmission and mortality. Under current treatment coverage (13.7%) and vaccination coverage (49%), averages of 81,000-164,600 annual reported deaths, depending on duration of immunity, are expected by the end of this decade. Annual mortality in the United States can be reduced below 50,000 per year with 52-80% annual vaccination coverage and below 10,000 annual deaths with 59-83% annual vaccination coverage, depending on duration of immunity. Universal treatment reduces hospitalizations by 88.6% and deaths by 93.1% under current vaccination coverage. A reduction in vaccination coverage requires a comparatively larger increase in treatment coverage in order for hospitalization and mortality levels to remain unchanged. CONCLUSIONS: Adopting universal vaccination and universal treatment goals in the United States will likely lead to a COVID-19 mortality burden below 50,000 deaths per year, a burden comparable to that of influenza virus.

Preventing antimalarial drug resistance with triple artemisinin-based combination therapies.

Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance. Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use. We show that introduction of TACTs could significantly delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs, and improving the chances of malaria elimination. We conclude that immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.

Antimalarial mass drug administration in large populations and the evolution of drug resistance.

Mass drug administration (MDA) with antimalarials has been shown to reduce prevalence and interrupt transmission in small populations, in populations with reliable access to antimalarial drugs, and in populations where sustained improvements in diagnosis and treatment are possible. In addition, when MDA is effective it eliminates both drug-resistant parasites and drug-sensitive parasites, which has the long-term benefit of extending the useful therapeutic life of first-line therapies for all populations, not just the focal population where MDA was carried out. However, in order to plan elimination measures effectively, it is necessary to characterize the conditions under which failed MDA could exacerbate resistance. We use an individual-based stochastic model of Plasmodium falciparum transmission to evaluate this risk for MDA using dihydroartemisinin-piperaquine (DHA-PPQ), in populations where access to antimalarial treatments may not be uniformly high and where re-importation of drug-resistant parasites may be common. We find that artemisinin-resistance evolution at the kelch13 locus can be accelerated by MDA when all three of the following conditions are met: (1) strong genetic bottlenecking that falls short of elimination, (2) re-importation of artemisinin-resistant genotypes, and (3) continued selection pressure during routine case management post-MDA. Accelerated resistance levels are not immediate but follow the rebound of malaria cases post-MDA, if this is allowed to occur. Crucially, resistance is driven by the selection pressure during routine case management post-MDA and not the selection pressure exerted during the MDA itself. Second, we find that increasing treatment coverage post-MDA increases the probability of local elimination in low-transmission regions (prevalence < 2%) in scenarios with both low and high levels of drug-resistance importation. This emphasizes the importance of planning for and supporting high coverage of diagnosis and treatment post-MDA.

Repeatability and timing of tropical influenza epidemics.

Much of the world experiences influenza in yearly recurring seasons, particularly in temperate areas. These patterns can be considered repeatable if they occur predictably and consistently at the same time of year. In tropical areas, including southeast Asia, timing of influenza epidemics is less consistent, leading to a lack of consensus regarding whether influenza is repeatable. This study aimed to assess repeatability of influenza in Vietnam, with repeatability defined as seasonality that occurs at a consistent time of year with low variation. We developed a mathematical model incorporating parameters to represent periods of increased transmission and then fitted the model to data collected from sentinel hospitals throughout Vietnam as well as four temperate locations. We fitted the model for individual (sub)types of influenza as well as all combined influenza throughout northern, central, and southern Vietnam. Repeatability was evaluated through the variance of the timings of peak transmission. Model fits from Vietnam show high variance (sd = 64-179 days) in peak transmission timing, with peaks occurring at irregular intervals and throughout different times of year. Fits from temperate locations showed regular, annual epidemics in winter months, with low variance in peak timings (sd = 32-57 days). This suggests that influenza patterns are not repeatable or seasonal in Vietnam. Influenza prevention in Vietnam therefore cannot rely on anticipation of regularly occurring outbreaks.

Using compartmental models and Particle Swarm Optimization to assess Dengue basic reproduction number R 0 for the Republic of Panama in the 1999-2022 period.

Nowadays, the ability to make data-driven decisions in public health is of utmost importance. To achieve this, it is necessary for modelers to comprehend the impact of models on the future state of healthcare systems. Compartmental models are a valuable tool for making informed epidemiological decisions, and the proper parameterization of these models is crucial for analyzing epidemiological events. This work evaluated the use of compartmental models in conjunction with Particle Swarm Optimization (PSO) to determine optimal solutions and understand the dynamics of Dengue epidemics. The focus was on calculating and evaluating the rate of case reproduction, R 0 , for the Republic of Panama. Three compartmental models were compared: Susceptible-Infected-Recovered (SIR), Susceptible-Exposed-Infected-Recovered (SEIR), and Susceptible-Infected-Recovered Human-Susceptible-Infected Vector (SIR Human-SI Vector, SIR-SI). The models were informed by demographic data and Dengue incidence in the Republic of Panama between 1999 and 2022, and the susceptible population was analyzed. The SIR, SEIR, and SIR-SI models successfully provided R 0 estimates ranging from 1.09 to 1.74. This study provides, to the best of our understanding, the first calculation of R 0 for Dengue outbreaks in the Republic of Panama.

A combination of annual and nonannual forces drive respiratory disease in the tropics.

Background: It is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics remains elusive. In this study, we aimed to characterize the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City (HCMC), Vietnam. Methods: We monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodicities in the system. We evaluated the contribution of these periodicities to predicting ILI and influenza patterns through lognormal and gamma hurdle models. Findings: During ten years of community surveillance, 66,799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI: 8.8%-9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC = 183) compared to all annual covariates (ΔAIC = 263). Near-annual signals were observed for PCR-confirmed influenza but were not consistent along in time or across influenza (sub)types. Interpretation: Our study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples.

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

Elasticity and substitutability of food demand and emerging disease risk on livestock farms.

Disease emergence in livestock is a product of environment, epidemiology and economic forces. The environmental factors contributing to novel pathogen emergence in humans have been studied extensively, but the two-way relationship between farm microeconomics and outbreak risk has received comparably little attention. We introduce a game-theoretic model where farmers produce and sell two goods, one of which (e.g. pigs, poultry) is susceptible to infection by a pathogen. We model market and epidemiological effects at both the individual farm level and the community level. We find that in the case of low demand elasticity for livestock meat, the presence of an animal pathogen causing production losses can lead to a bistable system where two outcomes are possible: (i) successful disease control or (ii) maintained disease circulation, where farmers slaughter their animals at a low rate, face substantial production losses, but maintain large herds because of the appeal of high meat prices. Our observations point to the potentially critical effect of price elasticity of demand for livestock products on the success or failure of livestock disease control policies. We show the potential epidemiological benefits of (i) policies aimed at stabilizing livestock product prices, (ii) subsidies for alternative agricultural activities during epidemics, and (iii) diversifying agricultural production and sources of proteins available to consumers.

Benefits of near-universal vaccination and treatment access to manage COVID-19 burden in the United States.

Background: As we enter the fourth year of the COVID-19 pandemic, SARS-CoV-2 infections still cause high morbidity and mortality in the United States. During 2020-2022, COVID-19 was one of the leading causes of death in the United States and by far the leading cause among infectious diseases. Vaccination uptake remains low despite this being an effective burden reducing intervention. The development of COVID-19 therapeutics provides hope for mitigating severe clinical outcomes. This modeling study examines combined strategies of vaccination and treatment to reduce the burden of COVID-19 epidemics over the next decade. Methods: We use a validated mathematical model to evaluate the reduction of incident cases, hospitalized cases, and deaths in the United States through 2033 under various levels of vaccination and treatment coverage. We assume that future seasonal transmission patterns for COVID-19 will be similar to those of influenza virus. We account for the waning of infection-induced immunity and vaccine-induced immunity in a future with stable COVID-19 dynamics. Due to uncertainty in the duration of immunity following vaccination or infection, we consider two exponentially-distributed waning rates, with means of 365 days (one year) and 548 days (1.5 years). We also consider treatment failure, including rebound frequency, as a possible treatment outcome. Results: As expected, universal vaccination is projected to eliminate transmission and mortality. Under current treatment coverage (13.7%) and vaccination coverage (49%), averages of 89,000 annual deaths (548-day waning) and 120,000 annual deaths (365-day waning) are expected by the end of this decade. Annual mortality in the United States can be reduced below 50,000 per year with >81% annual vaccination coverage, and below 10,000 annual deaths with >84% annual vaccination coverage. Universal treatment reduces hospitalizations by 88% and deaths by 93% under current vaccination coverage. A reduction in vaccination coverage requires a comparatively larger increase in treatment coverage in order for hospitalization and mortality levels to remain unchanged. Conclusions: Adopting universal vaccination and universal treatment goals in the United States will likely lead to a COVID-19 mortality burden below 50,000 deaths per year, a burden comparable to that of influenza virus.

Seroprotection against tetanus in southern Vietnam.

BACKGROUND: Ongoing tetanus cases and sporadic outbreaks of vaccine-preventable diseases associated with routine vaccination programmes remain problems in many low and middle-income countries, including Vietnam. With no human-to-human transmission or natural immunity, tetanus antibody levels indicate both individual risk of tetanus and gaps in vaccination programmes. METHODS: To investigate gaps in immunity to tetanus in Vietnam, a country with a historically high level of tetanus vaccination coverage, tetanus antibodies were measure by ELISA from samples selected from a long-term serum bank, established for the purposes of general-population seroepidemiological investigations in southern Vietnam. Samples were selected from 10 provinces, focussing on age-groups targeted by national vaccination programmes for infants and pregnant women (Expanded Programme on Immunization, EPI, and Maternal and Neonatal Tetanus, MNT). RESULTS: Antibodies were measured from a total of 3864 samples. Highest tetanus antibody concentrations occurred in children under 4 years old, over 90 % of whom had protective levels. Approximately 70 % of children aged 7-12 years had protective antibody concentrations although there was variation among provinces. For infants and children, there were no significant differences in tetanus protection between males and females, but for adults aged 20-35 years, in five of the ten provinces surveyed, protection against tetanus was higher in females (p < 0.05) who are eligible for booster doses under the MNT programme. In seven of ten provinces, antibody concentrations were inversely related to age (p < 0.01) and protection of older individuals was generally low. CONCLUSION: Widespread immunity to tetanus toxoid is seen in infants and young children consistent with the high coverage rates reported for diptheria tetanus toxoid and pertussis (DTP) in Vietnam. However, the lower antibody concentrations seen in older children and men suggest reduced immunity to tetanus in populations not targeted by EPI and MNT programmes.

National-scale simulation of human movement in a spatially coupled individual-based model of malaria in Burkina Faso.

Malaria due to the Plasmodium falciparum parasite remains a threat to human health despite eradication efforts and the development of anti-malarial treatments, such as artemisinin combination therapies. Human movement and migration have been linked to the propagation of malaria on national scales, highlighting the need for the incorporation of human movement in modeling efforts. Spatially couped individual-based models have been used to study how anti-malarial resistance evolves and spreads in response to drug policy changes; however, as the spatial scale of the model increases, the challenges associated with modeling of movement also increase. In this paper we discuss the development, calibration, and validation of a movement model in the context of a national-scale, spatial, individual-based model used to study the evolution of drug resistance in the malaria parasite.

Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin.

Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population, and how this heterogeneity affects virus evolution. Here we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of the A/Hong Kong/45/2019 (H3N2) and A/Perth/16/2009 (H3N2) strains affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that fixed in influenza variants after 2020 cause the greatest escape from sera from younger individuals. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups, and suggest approaches to understand how this heterogeneous selection shapes viral evolution.