Publications by authors named "Maciej F Boni"

78 Publications

An open dataset of genome variation in 7,000 worldwide samples.

Wellcome Open Res 2021 24;6:42. Epub 2021 Feb 24.

Medical Research Council Unit The Gambia, at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
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http://dx.doi.org/10.12688/wellcomeopenres.16168.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008441PMC
February 2021

Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen.

PLoS Biol 2021 03 12;19(3):e3001115. Epub 2021 Mar 12.

MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.

Virus host shifts are generally associated with novel adaptations to exploit the cells of the new host species optimally. Surprisingly, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has apparently required little to no significant adaptation to humans since the start of the Coronavirus Disease 2019 (COVID-19) pandemic and to October 2020. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, our analysis detects evidence for significant positive episodic diversifying selection acting at the base of the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor about 1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. While an undiscovered "facilitating" intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus.
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http://dx.doi.org/10.1371/journal.pbio.3001115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990310PMC
March 2021

Optimal SARS-CoV-2 vaccine allocation using real-time seroprevalence estimates in Rhode Island and Massachusetts.

medRxiv 2021 Jan 15. Epub 2021 Jan 15.

As three SARS-CoV-2 vaccines come to market in Europe and North America in the winter of 2020-2021, distribution networks will be in a race against a major epidemiological wave of SARS-CoV-2 that began in autumn 2020. Rapid and optimized vaccine allocation is critical during this time. With 95% efficacy reported for two of the vaccines, near-term public health needs require that distribution is prioritized to the elderly, health-care workers, teachers, essential workers, and individuals with co-morbidities putting them at risk of severe clinical progression. Here, we evaluate various age-based vaccine distributions using a validated mathematical model based on current epidemic trends in Rhode Island and Massachusetts. We allow for varying waning efficacy of vaccine-induced immunity, as this has not yet been measured. We account for the fact that known COVID-positive cases may not be included in the first round of vaccination. And, we account for current age-specific immune patterns in both states. We find that allocating a substantial proportion ( 75%) of vaccine supply to individuals over the age of 70 is optimal in terms of reducing total cumulative deaths through mid-2021. As we do not explicitly model other high mortality groups, this result on vaccine allocation applies to all groups at high risk of mortality if infected. Our analysis confirms that for an easily transmissible respiratory virus, allocating a large majority of vaccinations to groups with the highest mortality risk is optimal. Our analysis assumes that health systems during winter 2020-2021 have equal staffing and capacity to previous phases of the SARS-CoV-2 epidemic; we do not consider the effects of understaffed hospitals or unvaccinated medical staff. Vaccinating only seronegative individuals avoids redundancy in vaccine use on individuals that may already be immune, and will result in 1% to 2% reductions in cumulative hospitalizations and deaths by mid-2021. Assuming high vaccination coverage ( 28%) and no major relaxations in distancing, masking, gathering size, or hygiene guidelines between now and spring 2021, our model predicts that a combination of vaccination and population immunity will lead to low or near-zero transmission levels by the second quarter of 2021.
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http://dx.doi.org/10.1101/2021.01.12.21249694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814845PMC
January 2021

Poultry farmer response to disease outbreaks in smallholder farming systems in southern Vietnam.

Elife 2020 08 25;9. Epub 2020 Aug 25.

Center for Infectious Diseases Dynamics, The Pennsylvania State University, University Park, United States.

Avian influenza outbreaks have been occurring on smallholder poultry farms in Asia for two decades. Farmer responses to these outbreaks can slow down or accelerate virus transmission. We used a longitudinal survey of 53 small-scale chicken farms in southern Vietnam to investigate the impact of outbreaks with disease-induced mortality on harvest rate, vaccination, and disinfection behaviors. We found that in small broiler flocks (≤16 birds/flock) the estimated probability of harvest was 56% higher when an outbreak occurred, and 214% higher if an outbreak with sudden deaths occurred in the same month. Vaccination and disinfection were strongly and positively correlated with the number of birds. Small-scale farmers - the overwhelming majority of poultry producers in low-income countries - tend to rely on rapid sale of birds to mitigate losses from diseases. As depopulated birds are sent to markets or trading networks, this reactive behavior has the potential to enhance onward transmission.
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http://dx.doi.org/10.7554/eLife.59212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505654PMC
August 2020

Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic.

Nat Microbiol 2020 11 28;5(11):1408-1417. Epub 2020 Jul 28.

MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.

There are outstanding evolutionary questions on the recent emergence of human coronavirus SARS-CoV-2 including the role of reservoir species, the role of recombination and its time of divergence from animal viruses. We find that the sarbecoviruses-the viral subgenus containing SARS-CoV and SARS-CoV-2-undergo frequent recombination and exhibit spatially structured genetic diversity on a regional scale in China. SARS-CoV-2 itself is not a recombinant of any sarbecoviruses detected to date, and its receptor-binding motif, important for specificity to human ACE2 receptors, appears to be an ancestral trait shared with bat viruses and not one acquired recently via recombination. To employ phylogenetic dating methods, recombinant regions of a 68-genome sarbecovirus alignment were removed with three independent methods. Bayesian evolutionary rate and divergence date estimates were shown to be consistent for these three approaches and for two different prior specifications of evolutionary rates based on HCoV-OC43 and MERS-CoV. Divergence dates between SARS-CoV-2 and the bat sarbecovirus reservoir were estimated as 1948 (95% highest posterior density (HPD): 1879-1999), 1969 (95% HPD: 1930-2000) and 1982 (95% HPD: 1948-2009), indicating that the lineage giving rise to SARS-CoV-2 has been circulating unnoticed in bats for decades.
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http://dx.doi.org/10.1038/s41564-020-0771-4DOI Listing
November 2020

Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2.

Mol Biol Evol 2020 09;37(9):2706-2710

Division of Infection & Immunity, University College London, London, United Kingdom.

Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia's inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited.
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http://dx.doi.org/10.1093/molbev/msaa178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454803PMC
September 2020

Evidence of significant natural selection in the evolution of SARS-CoV-2 in bats, not humans.

bioRxiv 2020 May 29. Epub 2020 May 29.

RNA viruses are proficient at switching to novel host species due to their fast mutation rates. Implicit in this assumption is the need to evolve adaptations in the new host species to exploit their cells efficiently. However, SARS-CoV-2 has required no significant adaptation to humans since the pandemic began, with no observed selective sweeps to date. Here we contrast the role of positive selection and recombination in the in horseshoe bats to SARS-CoV-2 evolution in humans. While methods can detect some evidence for positive selection in SARS-CoV-2, we demonstrate these are mostly due to recombination and sequencing artefacts. Purifying selection is also substantially weaker in SARS-CoV-2 than in the related bat . In comparison, our results show evidence for positive, specifically episodic selection, acting on the bat virus lineage SARS-CoV-2 emerged from. This signature of selection can also be observed among synonymous substitutions, for example, linked to ancestral CpG depletion on this bat lineage. We show the bat virus RmYN02 has recombinant CpG content in Spike pointing to coinfection and evolution in bats without involvement of other species. Our results suggest the non-human progenitor of SARS-CoV-2 was capable of human-human transmission as a consequence of its natural evolution in bats.
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http://dx.doi.org/10.1101/2020.05.28.122366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302214PMC
May 2020

Serology for SARS-CoV-2: Apprehensions, opportunities, and the path forward.

Sci Immunol 2020 05;5(47)

Division of Infectious Diseases, University of Utah School of Medicine, Salt Lake City, UT, USA

Serological testing for SARS-CoV-2 has enormous potential to contribute to COVID-19 pandemic response efforts. However, the required performance characteristics of antibody tests will critically depend on the use case (individual-level vs. population-level).
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http://dx.doi.org/10.1126/sciimmunol.abc6347DOI Listing
May 2020

Using NS1 flavivirus protein microarray to infer past infecting dengue virus serotype and number of past dengue virus infections in Vietnamese individuals.

J Infect Dis 2020 Jan 22. Epub 2020 Jan 22.

Oxford University Clinical Research Unit, Wellcome Trust Asia Program, Ho Chi Minh City, Vietnam.

The use of multiplex microarray assays, in which antibodies are measured against multiple related antigens, is gaining increased focus for use in seroepidemiological studies to infer past transmission. We assess the performance of a flavivirus microarray assay for determining past dengue virus infection history in a dengue-endemic setting, Vietnam. We tested the microarray on samples from 1 and 6 months post-infection from DENV-infected patients (infecting serotype determined using RT-PCR during acute infection, past primary and secondary infection assessed using PRNT 6 months post-infection). Binomial models developed to discriminate past primary from secondary infection using the PMA titres had high AUC (0.90-0.97) and accuracy (0.84-0.86). Multinomial models developed to identify the most recent past infecting serotype using PMA titres performed well in those with past primary (average test-set κ=0.85, accuracy=0.92), but not those with past secondary infection (κ=0.24, accuracy=0.45). Our results suggests that the microarray will be useful in sero-epidemiological studies aimed at classifying the past infection history of individuals (past primary vs secondary and serotype of past primary infections) and thus inferring past transmission intensity of dengue virus in dengue-endemic settings. Future work to validate these models should be undertaken in different transmission settings and with samples later after infection.
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http://dx.doi.org/10.1093/infdis/jiaa018DOI Listing
January 2020

Game theory of vaccination and depopulation for managing livestock diseases and zoonoses on small-scale farms.

Epidemics 2020 03 3;30:100370. Epub 2019 Oct 3.

Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA 16802, USA.

Livestock producers adapt their farm management to epidemiological risks in different ways, through veterinary interventions but also by modulating their farm size and the removal rate of animals. The objective of this theoretical study was to elucidate how these behavioral adaptations may affect the epidemiology of highly-pathogenic avian influenza in domestic poultry and the outcome of the implemented control policies. We studied a symmetric population game where the players are broiler poultry farmers at risk of infection and where the between-farms disease transmission is both environmental and mediated by poultry trade. Three types of farmer behaviors were modelled: vaccination, depopulation, and cessation of poultry farming. We found that the transmission level of the disease through trade networks has strong qualitative effects on the system's epidemiological-economic equilibria. In the case of low trade-based transmission, when the monetary cost of infection is high, depopulation behavior can maintain a stable disease-free equilibrium. In addition, vaccination behavior can lead to eradication by private incentives alone - an outcome not seen for human diseases. In a scenario of high trade-based transmission, depopulation behavior has perverse epidemiological effects as it accelerates the spread of disease via poultry trade. In this situation, state interventions should focus on making vaccination technologies available at a low price rather than penalizing infected farms.
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http://dx.doi.org/10.1016/j.epidem.2019.100370DOI Listing
March 2020

Serological inference of past primary and secondary dengue infection: implications for vaccination.

J R Soc Interface 2019 07 31;16(156):20190207. Epub 2019 Jul 31.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

Owing to the finding that Dengvaxia (the only licensed dengue vaccine to date) increases the risk of severe illness among seronegative recipients, the World Health Organization has recommended screening individuals for their serostatus prior to vaccination. To decide whether and how to carry out screening, it is necessary to estimate the transmission intensity of dengue and to understand the performance of the screening method. In this study, we inferred the annual force of infection (FOI; a measurement of transmission intensity) of dengue virus in three locations in Vietnam: An Giang (FOI = 0.04 for the below 10 years age group and FOI = 0.20 for the above 10 years age group), Ho Chi Minh City (FOI = 0.12) and Quang Ngai (FOI = 0.05). In addition, we show that using a quantitative approach to immunoglobulin G (IgG) levels (measured by indirect enzyme-linked immunosorbent assays) can help to distinguish individuals with primary exposures (primary seropositive) from those with secondary exposures (secondary seropositive). We found that primary-seropositive individuals-the main targets of the vaccine-tend to have a lower IgG level, and, thus, they have a higher chance of being misclassified as seronegative than secondary-seropositive cases. However, screening performance can be improved by incorporating patient age and transmission intensity into the interpretation of IgG levels.
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http://dx.doi.org/10.1098/rsif.2019.0207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685028PMC
July 2019

Poultry population dynamics and mortality risks in smallholder farms of the Mekong river delta region.

BMC Vet Res 2019 Jun 17;15(1):205. Epub 2019 Jun 17.

Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, Millenium Sciences Complex, Pollock road, University Park, PA, 16802, USA.

Background: Poultry farming is widely practiced by rural households in Vietnam and the vast majority of domestic birds are kept on small household farms. However, smallholder poultry production is constrained by several issues such as infectious diseases, including avian influenza viruses whose circulation remains a threat to public health. This observational study describes the demographic structure and dynamics of small-scale poultry farms of the Mekong river delta region.

Method: Fifty three farms were monitored over a 20-month period, with farm sizes, species, age, arrival/departure of poultry, and farm management practices recorded monthly.

Results: Median flock population sizes were 16 for chickens (IQR: 10-40), 32 for ducks (IQR: 18-101) and 11 for Muscovy ducks (IQR: 7-18); farm size distributions for the three species were heavily right-skewed. Muscovy ducks were kept for long periods and outdoors, while chickens and ducks were farmed indoors or in pens. Ducks had a markedly higher removal rate (broilers: 0.14/week; layer/breeders: 0.05/week) than chickens and Muscovy ducks (broilers: 0.07/week; layer/breeders: 0.01-0.02/week) and a higher degree of specialization resulting in a substantially shorter life span. The rate of mortality due to disease did not differ much among species, with birds being less likely to die from disease at older ages, but frequency of disease symptoms differed by species. Time series of disease-associated mortality were correlated with population size for Muscovy ducks (Kendall's coefficient τ = 0.49, p-value < 0.01) and with frequency of outdoor grazing for ducks (τ = 0.33, p-value = 0.05).

Conclusion: The study highlights some challenges to disease control in small-scale multispecies poultry farms. The rate of interspecific contact and overlap between flocks of different ages is high, making small-scale farms a suitable environment for pathogens circulation. Muscovy ducks are farmed outdoors with little investment in biosecurity and few inter-farm movements. Ducks and chickens are more at-risk of introduction of pathogens through movements of birds from one farm to another. Ducks are farmed in large flocks with high turnover and, as a result, are more vulnerable to disease spread and require a higher vaccination coverage to maintain herd immunity.
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http://dx.doi.org/10.1186/s12917-019-1949-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580564PMC
June 2019

Sero-Prevalence Surveillance to Predict Vaccine-Preventable Disease Outbreaks; A Lesson from the 2014 Measles Epidemic in Northern Vietnam.

Open Forum Infect Dis 2019 Mar 24;6(3):ofz030. Epub 2019 Jan 24.

Oxford University Clinical Research Unit, Wellcome Trust Asia Programme, Hanoi, Vietnam.

Background: During the first half of 2014, a severe outbreak of measles occurred in northern Vietnam, causing 15 033 confirmed cases and 146 deaths.

Methods: To evaluate the population-level seroprevalence of protection against measles in the period before the outbreak, we made use of an existing age-stratified serum bank, collected over the year before the outbreak, between November 2012 and December 2013, from 4 sites across the country (Hanoi, Hue, Dak Lak, and Ho Chi Minh City). Data from the UNICEF's Multiple Indicator Clustered Surveys (MICS), carried out in Vietnam during the first quarter of 2014, were used to assess the vaccine coverage in 6 ecological regions of Vietnam.

Results: Results revealed a large discrepancy between levels of protection, as estimated from the serology and vaccine coverage estimated by UNICEF's MICS. Variation in seroprevalence across locations and age groups corresponded with reported numbers of measles cases, most of which were among the 0-2-year-old age group and in the northern part of the country.

Conclusions: Our study presents a strong case in favor of a serosurveillance sentinel network that could be used to proactively tune vaccination policies and other public health interventions.
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http://dx.doi.org/10.1093/ofid/ofz030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405937PMC
March 2019

Multilocus sequence typing of Cryptococcus neoformans var. grubii from Laos in a regional and global context.

Med Mycol 2018 Oct 19. Epub 2018 Oct 19.

Oxford University Clinical Research Unit, Vietnam.

Cryptococcosis causes approximately 180 000 deaths each year in patients with human immunodeficiency virus (HIV). Patients with other forms of immunosuppression are also at risk, and disease is increasingly recognized in apparently immunocompetent individuals. Cryptococcus neoformans var. grubii, responsible for the majority of cases, is distributed globally. We used the consensus ISHAM Multilocus sequence typing (MLST) scheme to define the population structure of clinical C. neoformans var. grubii isolates from Laos (n = 81), which we placed into the global context using published MLST data from other countries (total N = 1047), including a reanalysis of 136 Vietnamese isolates previously reported. We observed a phylogeographical relationship in which the Laotian population was similar to its neighbor Thailand, being dominated (83%) by Sequence Types (ST) 4 and 6. This phylogeographical structure changed moving eastwards, with Vietnam's population consisting of an admixture of isolates dominated by the ST4/ST6 (35%) and ST5 (48%) lineages. The ST5 lineage is the predominant ST reported from China and East Asia, where it accounts for >90% of isolates. Analysis of genetic distance (Fst) between different populations of C. neoformans var. grubii supports this intermediate structure of the Vietnamese population. The pathogen and host diversity reported from Vietnam provide the strongest epidemiological evidence of the association between ST5 and HIV-uninfected patients. Regional anthropological genetic distances suggest diversity in the C. neoformans var. grubii population across Southeast Asia is driven by ecological rather than human host factors. Where the ST5 lineage is present, disease in HIV-uninfected patients is to be expected.
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http://dx.doi.org/10.1093/mmy/myy105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581559PMC
October 2018

Modeling tuberculosis dynamics with the presence of hyper-susceptible individuals for Ho Chi Minh City from 1996 to 2015.

BMC Infect Dis 2018 Oct 1;18(1):494. Epub 2018 Oct 1.

Wellcome Trust Major Overseas Programme, Hospital for Tropical Diseases, Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.

Background: The depletion of CD4 cell is the underlying reason for TB hyper-susceptibility among people with HIV. Consequently, the trend of TB dynamics is usually hidden by the HIV outbreak.

Methods: Here, we aim to evaluate the trend of TB dynamics quantitatively by a simple mathematical model using the known prevalence of hyper-susceptible individuals in the population. In order to estimate the parameters governing transmission we fit this model in a maximum likelihood framework to both reported TB cases and data from samples tested with Interferon Gamma Assay from Ho Chi Minh City - a city with high TB transmission and strong synchronization between HIV/AIDS and TB dynamics.

Results: Our results show that TB transmission in HCMC has been declining among people without HIV; we estimate a 18% (95% CI: 9-25%) decline in the transmission parameter between 1996 and 2015. Furthermore, we show that co-infected patients have limited contribution to the transmission process. For hyper-susceptible individuals, our model suggests that the risk of a new active TB infection occurring is significantly higher than the risk of relapsed active TB, while this is not the case for people without hyper-susceptibility.

Conclusions: The increase of TB notifications in Ho Chi Minh City from 1996 to 2008 is evitable when, as occurred, the number of hyper-susceptible individuals increased faster than the decrease of TB transmission rate. The sharp decrease in TB notifications observed in this city from 2008 to 2015 is the combined result of the decrease of TB transmission rate and the decrease of hyper-susceptible individuals in the population. For hyper-susceptible individuals, we propose that the reason for the reduced relapsed active TB risk is HIV treatment delay. According to HIV treatment guidelines issued by Vietnam's Ministry of Health, hyper-susceptible individuals usually have to wait until their CD4 cell count falls under 350 cells/μl to start ART. Once patients begin ART, they will remain on ART for the rest of their life and thus have greater protection against relapses of TB. We therefore hypothesize that the delay in using ART imposes considerable TB burden on HCMC despite the declining transmission process.
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http://dx.doi.org/10.1186/s12879-018-3383-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167874PMC
October 2018

The Estimates of the Health and Economic Burden of Dengue in Vietnam.

Trends Parasitol 2018 10 9;34(10):904-918. Epub 2018 Aug 9.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address:

Dengue has been estimated to cause a substantial health and economic burden in Vietnam. The most recent studies have estimated that it is responsible for 39884 disability-adjusted life years (DALYs) annually, representing an economic burden of US$94.87 million per year (in 2016 prices). However, there are alternative burden estimates that are notably lower. This variation is predominantly due to differences in how the number of symptomatic dengue cases is estimated. Understanding the methodology of these burden calculations is vital when interpreting health economic analyses of dengue. This review aims to provide an overview of the health and economic burden estimates of dengue in Vietnam. We also highlight important research gaps for future studies.
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http://dx.doi.org/10.1016/j.pt.2018.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192036PMC
October 2018

Nonannual seasonality of influenza-like illness in a tropical urban setting.

Influenza Other Respir Viruses 2018 11 21;12(6):742-754. Epub 2018 Aug 21.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

Background: In temperate and subtropical climates, respiratory diseases exhibit seasonal peaks in winter. In the tropics, with no winter, peak timings are irregular.

Methods: To obtain a detailed picture of influenza-like illness (ILI) patterns in the tropics, we established an mHealth study in community clinics in Ho Chi Minh City (HCMC). During 2009-2015, clinics reported daily case numbers via SMS, with a subset performing molecular diagnostics for influenza virus. This real-time epidemiology network absorbs 6000 ILI reports annually, one or two orders of magnitude more than typical surveillance systems. A real-time online ILI indicator was developed to inform clinicians of the daily ILI activity in HCMC.

Results: From August 2009 to December 2015, 63 clinics were enrolled and 36 920 SMS reports were received, covering approximately 1.7M outpatient visits. Approximately 10.6% of outpatients met the ILI case definition. ILI activity in HCMC exhibited strong nonannual dynamics with a dominant periodicity of 206 days. This was confirmed by time series decomposition, stepwise regression, and a forecasting exercise showing that median forecasting errors are 30%-40% lower when using a 206-day cycle. In ILI patients from whom nasopharyngeal swabs were taken, 31.2% were positive for influenza. There was no correlation between the ILI time series and the time series of influenza, influenza A, or influenza B (all P > 0.15).

Conclusion: This suggests, for the first time, that a nonannual cycle may be an essential driver of respiratory disease dynamics in the tropics. An immunological interference hypothesis is discussed as a potential underlying mechanism.
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http://dx.doi.org/10.1111/irv.12595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185894PMC
November 2018

Projected costs associated with school-based screening to inform deployment of Dengvaxia: Vietnam as a case study.

Trans R Soc Trop Med Hyg 2018 Aug;112(8):369-377

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

Background: After new analysis, Sanofi Pasteur now recommends their dengue vaccine (Dengvaxia) should only be given to individuals previously infected with dengue and the World Health Organization's recommendations regarding its use are currently being revised. As a result, the potential costs of performing large-scale individual dengue screening and/or dengue serosurveys have become an important consideration for decision making by policymakers in dengue-endemic areas.

Methods: We used an ingredients-based approach to estimate the financial costs for conducting both a school-based dengue serosurvey and school-based individual dengue screening within a typical province in Vietnam, using an existing commercial indirect immunoglobulin G enzyme-linked immunosorbent assay kit. This costing is hypothetical and based on estimates regarding the resources that would be required to perform such activities.

Results: We estimated that performing a school-based individual screening of 9-year-olds would cost US$9.25 per child tested or US$197,827 in total for a typical province. We also estimated that a school-based serosurvey would cost US$10,074, assuming one class from each of the grades that include 8- to 11-year-olds are sampled at each of the 12 selected schools across the province.

Conclusions: The study indicates that using this vaccine safely on a large-scale will incur noteworthy operational costs. It is crucial that these be considered in future cost-effectiveness analyses informing how and where the vaccine is deployed.
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http://dx.doi.org/10.1093/trstmh/try057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092611PMC
August 2018

The decline of malaria in Vietnam, 1991-2014.

Malar J 2018 Jun 7;17(1):226. Epub 2018 Jun 7.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

Background: Despite the well-documented clinical efficacy of artemisinin-based combination therapy (ACT) against malaria, the population-level effects of ACT have not been studied thoroughly until recently. An ideal case study for these population-level effects can be found in Vietnam's gradual adoption of artemisinin in the 1990s.

Methods And Results: Analysis of Vietnam's national annual malaria reports (1991-2014) revealed that a 10% increase in artemisinin procurement corresponded to a 32.8% (95% CI 27.7-37.5%) decline in estimated malaria cases. There was no consistent national or regional effect of vector control on malaria. The association between urbanization and malaria was generally negative and sometimes statistically significant.

Conclusions: The decline of malaria in Vietnam can largely be attributed to the adoption of artemisinin-based case management. Recent analyses from Africa showed that insecticide-treated nets had the greatest effect on lowering malaria prevalence, suggesting that the success of interventions is region-specific. Continuing malaria elimination efforts should focus on both vector control and increased access to ACT.
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http://dx.doi.org/10.1186/s12936-018-2372-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992833PMC
June 2018

Primary care influenza-like illness surveillance in Ho Chi Minh City, Vietnam 2013-2015.

Influenza Other Respir Viruses 2018 09 7;12(5):623-631. Epub 2018 Jul 7.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

Background: Year-round transmission of influenza has been detected in Vietnam through both national surveillance and other epidemiological studies. Understanding the demographic and clinical features of influenza-like illness (ILI) presenting to primary care in urban Vietnam is vital to understand these transmission dynamics.

Methods: An observational study of patients with ILI in Ho Chi Minh City, Vietnam, was conducted between August 2013 and November 2015 in a mix of public and private primary care settings. Molecular testing for influenza A and influenza B and 12 other respiratory viruses was performed.

Results: A total of 1152 ILI patients were recruited. 322 and 136 subjects tested positive for influenza A and influenza B, respectively. 193 subjects tested positive for another respiratory virus; most commonly rhinovirus and parainfluenza virus 3. Influenza was detected in 81% of the 116 study weeks. Three peaks of influenza activity were detected; an H3N2 peak April-June 2014, an influenza B peak July-December 2014, and a mixed H3N2 and H1N1 peak March-September 2015. Subjects recruited from private clinics were more likely to have higher income and to have reported previous influenza vaccination. Antibiotic use was common (50.3%) despite limited evidence of bacterial infection.

Conclusion: Influenza in southern Vietnam has complex transmission dynamics including periods of intense influenza activity of alternating types and subtypes. Broadening surveillance from hospital to the community in tropical settings is feasible and a valuable for improving our understanding of the global spread and evolution of the virus.
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http://dx.doi.org/10.1111/irv.12574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086852PMC
September 2018

Evidence of previous but not current transmission of chikungunya virus in southern and central Vietnam: Results from a systematic review and a seroprevalence study in four locations.

PLoS Negl Trop Dis 2018 02 9;12(2):e0006246. Epub 2018 Feb 9.

Mathematical Modelling Department, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

Background: Arbovirus infections are a serious concern in tropical countries due to their high levels of transmission and morbidity. With the outbreaks of chikungunya (CHIKV) in surrounding regions in recent years and the fact that the environment in Vietnam is suitable for the vectors of CHIKV, the possibility of transmission of CHIKV in Vietnam is of great interest. However, information about CHIKV activity in Vietnam remains limited.

Methodology: In order to address this question, we performed a systematic review of CHIKV in Vietnam and a CHIKV seroprevalence survey. The seroprevalence survey tested for CHIKV IgG in population serum samples from individuals of all ages in 2015 from four locations in Vietnam.

Principal Findings: The four locations were An Giang province (n = 137), Ho Chi Minh City (n = 136), Dak Lak province (n = 137), and Hue City (n = 136). The findings give us evidence of some CHIKV activity: 73/546 of overall samples were seropositive (13.4%). The age-adjusted seroprevalences were 12.30% (6.58-18.02), 13.42% (7.16-19.68), 7.97% (3.56-12.38), and 3.72% (1.75-5.69) in An Giang province, Ho Chi Minh City, Dak Lak province, and Hue City respectively. However, the age-stratified seroprevalence suggests that the last transmission ended around 30 years ago, consistent with results from the systematic review. We see no evidence for on-going transmission in three of the locations, though with some evidence of recent exposure in Dak Lak, most likely due to transmission in neighbouring countries. Before the 1980s, when transmission was occurring, we estimate on average 2-4% of the population were infected each year in HCMC and An Giang and Hue (though transmision ended earlier in Hue). We estimate lower transmission in Dak Lak, with around 1% of the population infected each year.

Conclusion: In conclusion, we find evidence of past CHIKV transmission in central and southern Vietnam, but no evidence of recent sustained transmission. When transmission of CHIKV did occur, it appeared to be widespread and affect a geographically diverse population. The estimated susceptibility of the population to chikungunya is continually increasing, therefore the possibility of future CHIKV transmission in Vietnam remains.
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http://dx.doi.org/10.1371/journal.pntd.0006246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823466PMC
February 2018

Towards malaria elimination in Savannakhet, Lao PDR: mathematical modelling driven strategy design.

Malar J 2017 Nov 28;16(1):483. Epub 2017 Nov 28.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Background: The number of Plasmodium falciparum malaria cases around the world has decreased substantially over the last 15 years, but with the spread of resistance against anti-malarial drugs and insecticides, this decline may not continue. There is an urgent need to consider alternative, accelerated strategies to eliminate malaria in countries like Lao PDR, where there are a few remaining endemic areas. A deterministic compartmental modelling tool was used to develop an integrated strategy for P. falciparum elimination in the Savannakhet province of Lao PDR. The model was designed to include key aspects of malaria transmission and integrated control measures, along with a user-friendly interface.

Results: Universal coverage was the foundation of the integrated strategy, which took the form of the deployment of community health workers who provided universal access to early diagnosis, treatment and long-lasting insecticidal nets. Acceleration was included as the deployment of three monthly rounds of mass drug administration targeted towards high prevalence villages, with the addition of three monthly doses of the RTS,S vaccine delivered en masse to the same high prevalence sub-population. A booster dose of vaccine was added 1 year later. The surveillance-as-intervention component of the package involved the screening and treatment of individuals entering the simulated population.

Conclusions: In this modelling approach, the sequential introduction of a series of five available interventions in an integrated strategy was predicted to be sufficient to stop malaria transmission within a 3-year period. These interventions comprised universal access to early diagnosis and adequate treatment, improved access to long-lasting insecticidal nets, three monthly rounds of mass drug administration together with RTS,S vaccination followed by a booster dose of vaccine, and screening and treatment of imported cases.
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http://dx.doi.org/10.1186/s12936-017-2130-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706414PMC
November 2017

Improved Algorithmic Complexity for the 3SEQ Recombination Detection Algorithm.

Mol Biol Evol 2018 01;35(1):247-251

Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Identifying recombinant sequences in an era of large genomic databases is challenging as it requires an efficient algorithm to identify candidate recombinants and parents, as well as appropriate statistical methods to correct for the large number of comparisons performed. In 2007, a computation was introduced for an exact nonparametric mosaicism statistic that gave high-precision P values for putative recombinants. This exact computation meant that multiple-comparisons corrected P values also had high precision, which is crucial when performing millions or billions of tests in large databases. Here, we introduce an improvement to the algorithmic complexity of this computation from O(mn3) to O(mn2), where m and n are the numbers of recombination-informative sites in the candidate recombinant. This new computation allows for recombination analysis to be performed in alignments with thousands of polymorphic sites. Benchmark runs are presented on viral genome sequence alignments, new features are introduced, and applications outside recombination analysis are discussed.
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http://dx.doi.org/10.1093/molbev/msx263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850291PMC
January 2018

A8 The epidemiology and evolution of influenza A/H1N1 and A/H3N2 virus from 2010 to 2015, in Ho Chi Minh City, Vietnam.

Virus Evol 2017 Mar 5;3(Suppl 1). Epub 2017 Mar 5.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

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http://dx.doi.org/10.1093/ve/vew036.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565979PMC
March 2017

No Evidence of On-farm Circulation of Avian Influenza H5 Subtype in Ca Mau Province, Southern Vietnam, March 2016 - January 2017.

PLoS Curr 2017 May 5;9. Epub 2017 May 5.

Department of Biology, Pennsylvania State University, University Park, PA, USA; Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

Background: Subtype H5N1 avian influenza viruses, both high pathogenicity and low pathogenicity, have been enzootic in Vietnam since 2001.  The viruses are readily identified at live bird markets, but virus prevalence on smallholder poultry is typically zero or very low.  If the true direction of the viral transmission chain is farm to market, it is unknown why farm prevalence should be low when market prevalence is moderate to high.

Methods: We established a cohort of 50 smallholder poultry farms in Ca Mau province in the Mekong Delta region of Vietnam.  From March 2016 to January 2017, we collected naso-pharyngeal and cloacal samples from 156 ducks and 96 chickens.  In addition, 126 environmental samples were collected.  Samples were assayed for H5 subtype influenza by real-time RT-PCR. Results/Discussion: None of the 378 collected samples were positive for H5 influenza.  This is likely to mean that circulation of subtype H5 influenza viruses was low in Ca Mau in 2016.  Detection of avian influenza on smallholder poultry farms is necessary to determine the directionality and association between farm prevalence and market prevalence of avian influenza viruses.  Larger farm-level studies should be planned as these will be critical for determining the presence and strength of this association.
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http://dx.doi.org/10.1371/currents.outbreaks.c816d7333370d68f8a0da33f69168986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501696PMC
May 2017

Structure of general-population antibody titer distributions to influenza A virus.

Sci Rep 2017 07 20;7(1):6060. Epub 2017 Jul 20.

Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Seroepidemiological studies aim to understand population-level exposure and immunity to infectious diseases. Their results are normally presented as binary outcomes describing the presence or absence of pathogen-specific antibody, despite the fact that many assays measure continuous quantities. A population's natural distribution of antibody titers to an endemic infectious disease may include information on multiple serological states - naiveté, recent infection, non-recent infection, childhood infection - depending on the disease in question and the acquisition and waning patterns of immunity. In this study, we investigate 20,152 general-population serum samples from southern Vietnam collected between 2009 and 2013 from which we report antibody titers to the influenza virus HA1 protein using a continuous titer measurement from a protein microarray assay. We describe the distributions of antibody titers to subtypes 2009 H1N1 and H3N2. Using a model selection approach to fit mixture distributions, we show that 2009 H1N1 antibody titers fall into four titer subgroups and that H3N2 titers fall into three subgroups. For H1N1, our interpretation is that the two highest-titer subgroups correspond to recent and historical infection, which is consistent with 2009 pandemic attack rates. Similar interpretations are available for H3N2, but right-censoring of titers makes these interpretations difficult to validate.
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http://dx.doi.org/10.1038/s41598-017-06177-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519701PMC
July 2017

Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam.

PLoS Negl Trop Dis 2017 Jun 14;11(6):e0005628. Epub 2017 Jun 14.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme Viet Nam, Ho Chi Minh City, Vietnam.

The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher's exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109 cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.
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http://dx.doi.org/10.1371/journal.pntd.0005628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484541PMC
June 2017

K13 Propeller Mutations in Plasmodium falciparum Populations in Regions of Malaria Endemicity in Vietnam from 2009 to 2016.

Antimicrob Agents Chemother 2017 04 24;61(4). Epub 2017 Mar 24.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.

The spread of artemisinin-resistant compromises the therapeutic efficacy of artemisinin combination therapies (ACTs) and is considered the greatest threat to current global initiatives to control and eliminate malaria. This is particularly relevant in Vietnam, where dihydroartemisinin-piperaquine (DP) is the recommended ACT for infection. The propeller domain gene of K13, a molecular marker of artemisinin resistance, was successfully sequenced in 1,060 isolates collected at 3 malaria hot spots in Vietnam between 2009 and 2016. Eight K13 propeller mutations (Thr474Ile, Tyr493His, Arg539Thr, Ile543Thr, Pro553Leu, Val568Gly, Pro574Leu, and Cys580Tyr), including several that have been validated to be artemisinin resistance markers, were found. The prevalences of K13 mutations were 29% (222/767), 6% (11/188), and 43% (45/105) in the Binh Phuoc, Ninh Thuan, and Gia Lai Provinces of Vietnam, respectively. Cys580Tyr became the dominant genotype in recent years, with 79.1% (34/43) of isolates in Binh Phuoc Province and 63% (17/27) of isolates in Gia Lai Province carrying this mutation. K13 mutations were associated with reduced ring-stage susceptibility to dihydroartemisinin (DHA) and prolonged parasite clearance An analysis of haplotypes flanking K13 suggested the presence of multiple strains with the Cys580Tyr mutation rather than a single strain expanding across the three sites.
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http://dx.doi.org/10.1128/AAC.01578-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365681PMC
April 2017

Tetanus in Southern Vietnam: Current Situation.

Am J Trop Med Hyg 2017 Jan 7;96(1):93-96. Epub 2016 Nov 7.

Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.

In Vietnam, there are no accurate data on tetanus incidence to allow assessment of disease burden or vaccination program efficacy. We analyzed age structure of 786 tetanus cases admitted to a tertiary referral center in Vietnam for three separate years during an 18-year period to examine the impact of tetanus prevention programs, namely the Expanded Program on Immunization (EPI) and the Maternal and Neonatal Tetanus (MNT) initiative. Most cases were born before the initiation of EPI. Median age increased from 33 (interquartile range: 20-52) in 1994, to 46 (32-63) in 2012 (P < 0.001). Birth-year distribution was unchanged, indicating the same birth cohorts presented with tetanus in 1994, 2003, and 2012. Enzyme-linked immunosorbent assay measurements in 90 men and 90 women covered by MNT but not EPI showed 73.3% (95% confidence interval [CI]: 62.9-82.1%) of women had anti-tetanus antibody compared with 24.4% (95% CI: 15.9-34.7%) of men, indicating continued tetanus vulnerability in older men in Vietnam.
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http://dx.doi.org/10.4269/ajtmh.16-0470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239717PMC
January 2017