Dr Ricardo J Aguas

Research Area: Bioinformatics & Stats (inc. Modelling and Computational Biology)
Technology Exchange: Bioinformatics and Computational biology
Scientific Themes: Immunology & Infectious Disease and Tropical Medicine & Global Health
Keywords: Malaria, Intervention strategy optimisation, Influenza, Antigenic evolution and Pathogen population structure
The first two principal components of the PCA undertaken using (a) SARS coronavirus complete spike protein nucleotide sequences, and (b) nucleotides selected by the RFA. Viral groups, defined by host species and season, are represented by ellipses of different colours: Human patient samples from 2002/2003 collected in early, mid and late epidemic phase are HP03E (green), HP03M (purple) and HP03L (yellow); 2004 Human samples are labelled HP04 (black); palm civets samples collected in 2003 and 2004 are labelled PC03 (blue) and PC04 (red); bat samples are labelled BT (magenta).

The first two principal components of the PCA undertaken using (a) SARS coronavirus complete spike ...

Superimposed 2-dimensional antigenic maps generated from predicted antigenic distances (in colour) using a machine learning algorithm to establish an explicit genotype to phenotype map; and from HI titre data (in grey).

Superimposed 2-dimensional antigenic maps generated from predicted antigenic distances (in colour) ...

Individual based model simulations of a mass drug administration (MDA) in 800 villages with different malaria epidemiological initial conditions. Left - 1 MDA set; Right - 2 MDA sets.

Individual based model simulations of a mass drug administration (MDA) in 800 villages with ...

Malaria transmission dynamics and optimizing intervention planning.

I have been developing a fully dynamic transmission model to simulate targeted malaria elimination strategies (METF) currently undergoing in SE Asia. The model is to be calibrated to the METF transmission settings and run in real time to explore options for study design. It will also be used as a bridge to scale up by projecting the impact of large scale strategy options for larger populations with an additional cost element.

Genotype to phenotype mapping

Moving away from genome scan methods used for human GWAS (ultimately inappropriate for the short highly polymorphic genomes of RNA viruses), I have done some work demonstrating the potential of multi-class machine learning algorithms in inferring the functional genetic changes associated with phenotypic change (e.g. a virus crossing the species barrier). These methods allow to uncover a set of features/insights that ultimately could be quite relevant in understanding viral transmission across host species:

  • They show that even distantly related viruses within a viral family share highly conserved genetic signatures of host specificity;
  • Reinforce how fitness landscapes of host adaptation are shaped by host phylogeny;
  • Highlight the evolutionary trajectories of RNA viruses in rapid expansion and under great evolutionary pressure.

These methods can serve as rigorous tools of emergence potential assessment, specifically in scenarios where rapid host classification of newly emerging viruses can be more important than identifying putative functional sites.

Name Department Institution Country
Professor Lisa J White Tropical Medicine Oxford University, Bangkok Thailand
Professor Richard J Maude Tropical Medicine Oxford University, Bangkok Thailand
Professor Yoel Lubell Tropical Medicine Oxford University, Bangkok Thailand
Pitzer VE, Aguas R, Riley S, Loeffen WLA, Wood JLN, Grenfell BT. 2016. High turnover drives prolonged persistence of influenza in managed pig herds. J R Soc Interface, 13 (119), pp. 20160138-20160138. | Show Abstract | Read more

Pigs have long been hypothesized to play a central role in the emergence of novel human influenza A virus (IAV) strains, by serving as mixing vessels for mammalian and avian variants. However, the key issue of viral persistence in swine populations at different scales is ill understood. We address this gap using epidemiological models calibrated against seroprevalence data from Dutch finishing pigs to estimate the 'critical herd size' (CHS) for IAV persistence. We then examine the viral phylogenetic evidence for persistence by comparing human and swine IAV. Models suggest a CHS of approximately 3000 pigs above which influenza was likely to persist, i.e. orders of magnitude lower than persistence thresholds for IAV and other acute viruses in humans. At national and regional scales, we found much stronger empirical signatures of prolonged persistence of IAV in swine compared with human populations. These striking levels of persistence in small populations are driven by the high recruitment rate of susceptible piglets, and have significant implications for management of swine and for overall patterns of genetic diversity of IAV.

Lessler J, Salje H, Van Kerkhove MD, Ferguson NM, Cauchemez S, Rodriquez-Barraquer I, Hakeem R, Jombart T, Aguas R, Al-Barrak A et al. 2016. Estimating the Severity and Subclinical Burden of Middle East Respiratory Syndrome Coronavirus Infection in the Kingdom of Saudi Arabia. Am J Epidemiol, 183 (7), pp. 657-663. | Show Abstract | Read more

Not all persons infected with Middle East respiratory syndrome coronavirus (MERS-CoV) develop severe symptoms, which likely leads to an underestimation of the number of people infected and an overestimation of the severity. To estimate the number of MERS-CoV infections that have occurred in the Kingdom of Saudi Arabia, we applied a statistical model to a line list describing 721 MERS-CoV infections detected between June 7, 2012, and July 25, 2014. We estimated that 1,528 (95% confidence interval (CI): 1,327, 1,883) MERS-CoV infections occurred in this interval, which is 2.1 (95% CI: 1.8, 2.6) times the number reported. The probability of developing symptoms ranged from 11% (95% CI: 4, 25) in persons under 10 years of age to 88% (95% CI: 72, 97) in those 70 years of age or older. An estimated 22% (95% CI: 18, 25) of those infected with MERS-CoV died. MERS-CoV is deadly, but this work shows that its clinical severity differs markedly between groups and that many cases likely go undiagnosed.

Slater HC, Ross A, Ouédraogo AL, White LJ, Nguon C, Walker PGT, Ngor P, Aguas R, Silal SP, Dondorp AM et al. 2015. Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies. Nature, 528 (7580), pp. S94-101. | Show Abstract | Read more

Mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of Plasmodium falciparum malaria. However, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. We estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using polymerase chain reaction if treatment levels are high and screening is conducted during the dry season. Along with other factors, such as coverage, choice of drug, timing of the intervention, importation of infections, and seasonality, the sensitivity of the diagnostic can play a part in increasing the chance of interrupting transmission.

Ferguson NM, Kien DTH, Clapham H, Aguas R, Trung VT, Chau TNB, Popovici J, Ryan PA, O'Neill SL, McGraw EA et al. 2015. Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti. Sci Transl Med, 7 (279), pp. 279ra37. | Show Abstract | Read more

Dengue is the most common arboviral infection of humans and is a public health burden in more than 100 countries. Aedes aegypti mosquitoes stably infected with strains of the intracellular bacterium Wolbachia are resistant to dengue virus (DENV) infection and are being tested in field trials. To mimic field conditions, we experimentally assessed the vector competence of A. aegypti carrying the Wolbachia strains wMel and wMelPop after challenge with viremic blood from dengue patients. We found that wMelPop conferred strong resistance to DENV infection of mosquito abdomen tissue and largely prevented disseminated infection. wMel conferred less resistance to infection of mosquito abdomen tissue, but it did reduce the prevalence of mosquitoes with infectious saliva. A mathematical model of DENV transmission incorporating the dynamics of viral infection in humans and mosquitoes was fitted to the data collected. Model predictions suggested that wMel would reduce the basic reproduction number, R0, of DENV transmission by 66 to 75%. Our results suggest that establishment of wMelPop-infected A. aegypti at a high frequency in a dengue-endemic setting would result in the complete abatement of DENV transmission. Establishment of wMel-infected A. aegypti is also predicted to have a substantial effect on transmission that would be sufficient to eliminate dengue in low or moderate transmission settings but may be insufficient to achieve complete control in settings where R0 is high. These findings develop a framework for selecting Wolbachia strains for field releases and for calculating their likely impact.

Dorigatti I, Aguas R, Donnelly CA, Guy B, Coudeville L, Jackson N, Saville M, Ferguson NM. 2015. Modelling the immunological response to a tetravalent dengue vaccine from multiple phase-2 trials in Latin America and South East Asia. Vaccine, 33 (31), pp. 3746-3751. | Show Abstract | Read more

BACKGROUND: The most advanced dengue vaccine candidate is a live-attenuated recombinant vaccine containing the four dengue viruses on the yellow fever vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the vaccine. METHODS: We analyse the immunogenicity data collected in five phase-2 trials of the CYD-TDV vaccine. We provide a descriptive analysis of the aggregated datasets and fit the observed post-vaccination PRNT50 titres against the four dengue (DENV) serotypes using multivariate regression models. RESULTS: We find that the responses to CYD-TDV are principally predicted by the baseline immunological status against DENV, but the trial is also a significant predictor. We find that the CYD-TDV vaccine generates similar titres against all serotypes following the third dose, though DENV4 is immunodominant after the first dose. CONCLUSIONS: This study contributes to a better understanding of the immunological responses elicited by CYD-TDV. The recent availability of phase-3 data is a unique opportunity to further investigate the immunogenicity and efficacy of the CYD-TDV vaccine, especially in subjects with different levels of pre-existing immunity against DENV. Modelling multiple immunological outcomes with a single multivariate model offers advantages over traditional approaches, capturing correlations between response variables, and the statistical method adopted in this study can be applied to a variety of infections with interacting strains.

Aguas R, Ferguson NM. 2013. Feature selection methods for identifying genetic determinants of host species in RNA viruses. PLoS Comput Biol, 9 (10), pp. e1003254. | Show Abstract | Read more

Despite environmental, social and ecological dependencies, emergence of zoonotic viruses in human populations is clearly also affected by genetic factors which determine cross-species transmission potential. RNA viruses pose an interesting case study given their mutation rates are orders of magnitude higher than any other pathogen--as reflected by the recent emergence of SARS and Influenza for example. Here, we show how feature selection techniques can be used to reliably classify viral sequences by host species, and to identify the crucial minority of host-specific sites in pathogen genomic data. The variability in alleles at those sites can be translated into prediction probabilities that a particular pathogen isolate is adapted to a given host. We illustrate the power of these methods by: 1) identifying the sites explaining SARS coronavirus differences between human, bat and palm civet samples; 2) showing how cross species jumps of rabies virus among bat populations can be readily identified; and 3) de novo identification of likely functional influenza host discriminant markers.

Gomes MGM, Aguas R, Lopes JS, Nunes MC, Rebelo C, Rodrigues P, Struchiner CJ. 2012. How host heterogeneity governs tuberculosis reinfection? Proc Biol Sci, 279 (1737), pp. 2473-2478. | Show Abstract | Read more

Recurrent episodes of tuberculosis (TB) can be due to relapse of latent infection or exogenous reinfection, and discrimination is crucial for control planning. Molecular genotyping of Mycobacterium tuberculosis isolates offers concrete opportunities to measure the relative contribution of reinfection in recurrent disease. Here, a mathematical model of TB transmission is fitted to data from 14 molecular epidemiology studies, enabling the estimation of relevant epidemiological parameters. Meta-analysis reveals that rates of reinfection after successful treatment are higher than rates of new TB, raising an important question about the underlying mechanism. We formulate two alternative mechanisms within our model framework: (i) infection increases susceptibility to reinfection or (ii) infection affects individuals differentially, thereby recruiting high-risk individuals to the group at risk for reinfection. The second mechanism is better supported by the fittings to the data, suggesting that reinfection rates are inflated through a population phenomenon that occurs in the presence of heterogeneity in individual risk of infection. As a result, rates of reinfection are higher when measured at the population level even though they might be lower at the individual level. Finally, differential host recruitment is modulated by transmission intensity, being less pronounced when incidence is high.

van Noort SP, Águas R, Ballesteros S, Gomes MGM. 2012. The role of weather on the relation between influenza and influenza-like illness. J Theor Biol, 298 pp. 131-137. | Show Abstract | Read more

Influenza epidemics, enabled by viral antigenic drift, occur invariably each winter in temperate climates. However, attempts to correlate the magnitude of virus change and epidemic size have been unsatisfactory. The incidence of influenza is not typically measured directly, but rather derived from the incidence of influenza-like illness (ILI), a clinical syndrome. Weather factors have been shown to influence the manifestation of influenza-like symptoms. We fitted an influenza transmission model to time series of influenza-like illness as monitored from 2003 to 2010 by two independent symptomatic surveillance systems (Influenzanet and EISN) in three European countries. By assuming that seasonality only acts upon the manifestation of symptoms, the model shows a significant correlation between the absolute humidity and temperature at the time of infection, and the proportion of influenza infections fulfilling the clinical ILI case definition, the so-called ILI factor. When a weather-dependent ILI factor is included in the model, the epidemic size of influenza-like illness becomes dependent not only on the susceptibility of the population at the beginning of the epidemic season but also on the weather conditions during which the epidemic unfolds. The combination reduces season-to-season variation in epidemic size and, interestingly, leads to a non-monotonic trend whereby the largest ILI epidemic occurs for moderate initial susceptibility.

Aguas R, Ferreira MU, Gomes MGM. 2012. Modeling the effects of relapse in the transmission dynamics of malaria parasites. J Parasitol Res, 2012 pp. 921715. | Show Abstract | Read more

Often regarded as "benign," Plasmodium vivax infections lay in the shadows of the much more virulent P. falciparum infections. However, about 1.98 billion people are at risk of both parasites worldwide, stressing the need to understand the epidemiology of Plasmodium vivax, particularly under the scope of decreasing P. falciparum prevalence and ecological interactions between both species. Two epidemiological observations put the dynamics of both species into perspective: (1) ACT campaigns have had a greater impact on P. falciparum prevalence. (2) Complete clinical immunity is attained at younger ages for P. vivax, under similar infection rates. We systematically compared two mathematical models of transmission for both Plasmodium species. Simulations suggest that an ACT therapy combined with a hypnozoite killing drug would eliminate both species. However, P. vivax elimination is predicted to be unstable. Differences in age profiles of clinical malaria can be explained solely by P. vivax's ability to relapse, which accelerates the acquisition of clinical immunity and serves as an immunity boosting mechanism. P. vivax transmission can subsist in areas of low mosquito abundance and is robust to drug administration initiatives due to relapse, making it an inconvenient and cumbersome, yet less lethal alternative to P. falciparum.

Aguas R, Lourenço JML, Gomes MGM, White LJ. 2009. The impact of IPTi and IPTc interventions on malaria clinical burden - in silico perspectives. PLoS One, 4 (8), pp. e6627. | Show Abstract | Read more

BACKGROUND: Clinical management of malaria is a major health issue in sub-Saharan Africa. New strategies based on intermittent preventive treatment (IPT) can tackle disease burden by simultaneously reducing frequency of infections and life-threatening illness in infants (IPTi) and children (IPTc), while allowing for immunity to build up. However, concerns as to whether immunity develops efficiently in treated individuals, and whether there is a rebound effect after treatment is halted, have made it imperative to define the effects that IPTi and IPTc exert on the clinical malaria scenario. METHODS AND FINDINGS: Here, we simulate several schemes of intervention under different transmission settings, while varying immunity build up assumptions. Our model predicts that infection risk and effectiveness of acquisition of clinical immunity under prophylactic effect are associated to intervention impact during treatment and follow-up periods. These effects vary across regions of different endemicity and are highly correlated with the interplay between the timing of interventions in age and the age dependent risk of acquiring an infection. However, even when significant rebound effects are predicted to occur, the overall intervention impact is positive. CONCLUSIONS: IPTi is predicted to have minimal impact on the acquisition of clinical immunity, since it does not interfere with the occurrence of mild infections, thus failing to reduce the underlying force of infection. On the contrary, IPTc has a significant potential to reduce transmission, specifically in areas where it is already low to moderate.

White NJ, Pongtavornpinyo W, Maude RJ, Saralamba S, Aguas R, Stepniewska K, Lee SJ, Dondorp AM, White LJ, Day NPJ. 2009. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance. Malar J, 8 (1), pp. 253. | Show Abstract | Read more

BACKGROUND: Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. METHODS: The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. RESULTS: Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. CONCLUSION: Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women). Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence.

White LJ, Maude RJ, Pongtavornpinyo W, Saralamba S, Aguas R, Van Effelterre T, Day NPJ, White NJ. 2009. The role of simple mathematical models in malaria elimination strategy design. Malar J, 8 (1), pp. 212. | Show Abstract | Read more

BACKGROUND: Malaria has recently been identified as a candidate for global eradication. This process will take the form of a series of national eliminations. Key issues must be considered specifically for elimination strategy when compared to the control of disease. Namely the spread of drug resistance, data scarcity and the adverse effects of failed elimination attempts. Mathematical models of various levels of complexity have been produced to consider the control and elimination of malaria infection. If available, detailed data on malaria transmission (such as the vector life cycle and behaviour, human population behaviour, the acquisition and decay of immunity, heterogeneities in transmission intensity, age profiles of clinical and subclinical infection) can be used to populate complex transmission models that can then be used to design control strategy. However, in many malaria countries reliable data are not available and policy must be formed based on information like an estimate of the average parasite prevalence. METHODS: A simple deterministic model, that requires data in the form of a single estimate of parasite prevalence as an input, is developed for the purpose of comparison with other more complex models. The model is designed to include key aspects of malaria transmission and integrated control. RESULTS: The simple model is shown to have similar short-term dynamic behaviour to three complex models. The model is used to demonstrate the potential of alternative methods of delivery of controls. The adverse effects on clinical infection and spread of resistance are predicted for failed elimination attempts. Since elimination strategies present an increased risk of the spread of drug resistance, the model is used to demonstrate the population level protective effect of multiple controls against this very serious threat. CONCLUSION: A simple model structure for the elimination of malaria is suitable for situations where data are sparse yet strategy design requirements are urgent with the caveat that more complex models, populated with new data, would provide more information, especially in the long-term.

Maude RJ, Pontavornpinyo W, Saralamba S, Aguas R, Yeung S, Dondorp AM, Day NPJ, White NJ, White LJ. 2009. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J, 8 (1), pp. 31. | Show Abstract | Read more

BACKGROUND: Artemisinin combination therapy (ACT) is now the recommended first-line treatment for falciparum malaria throughout the world. Initiatives to eliminate malaria are critically dependent on its efficacy. There is recent worrying evidence that artemisinin resistance has arisen on the Thai-Cambodian border. Urgent containment interventions are planned and about to be executed. Mathematical modeling approaches to intervention design are now integrated into the field of malaria epidemiology and control. The use of such an approach to investigate the likely effectiveness of different containment measures with the ultimate aim of eliminating artemisinin-resistant malaria is described. METHODS: A population dynamic mathematical modeling framework was developed to explore the relative effectiveness of a variety of containment interventions in eliminating artemisinin-resistant malaria in western Cambodia. RESULTS: The most effective intervention to eliminate artemisinin-resistant malaria was a switch of treatment from artemisinin monotherapy to ACT (mean time to elimination 3.42 years (95% CI 3.32-3.60 years). However, with this approach it is predicted that elimination of artemisinin-resistant malaria using ACT can be achieved only by elimination of all malaria. This is because the various forms of ACT are more effective against infections with artemisinin-sensitive parasites, leaving the more resistant infections as an increasing proportion of the dwindling parasite population. CONCLUSION: Containment of artemisinin-resistant malaria can be achieved by elimination of malaria from western Cambodia using ACT. The "last man standing" is the most resistant and thus this strategy must be sustained until elimination is truly achieved.

Aguas R, White LJ, Snow RW, Gomes MGM. 2008. Prospects for malaria eradication in sub-Saharan Africa. PLoS One, 3 (3), pp. e1767. | Show Abstract | Read more

BACKGROUND: A characteristic of Plasmodium falciparum infections is the gradual acquisition of clinical immunity resulting from repeated exposures to the parasite. While the molecular basis of protection against clinical malaria remains unresolved, its effects on epidemiological patterns are well recognized. Accumulating epidemiological data constitute a valuable resource that must be intensively explored and interpreted as to effectively inform control planning. METHODOLOGY/PRINCIPAL FINDING: Here we apply a mathematical model to clinical data from eight endemic regions in sub-Saharan Africa. The model provides a quantitative framework within which differences in age distribution of clinical disease are assessed in terms of the parameters underlying transmission. The shorter infectious periods estimated for clinical infections induce a regime of bistability of endemic and malaria-free states in regions of mesoendemic transmission. The two epidemiological states are separated by a threshold that provides a convenient measure for intervention design. Scenarios of eradication and resurgence are simulated. CONCLUSIONS/SIGNIFICANCE: In regions that support mesoendemic transmission, intervention success depends critically on reducing prevalence below a threshold which separates endemic and malaria-free regimes.

Aguas R, Gonçalves G, Gomes MGM. 2006. Pertussis: increasing disease as a consequence of reducing transmission. Lancet Infect Dis, 6 (2), pp. 112-117. | Show Abstract | Read more

Since the 1980s, the occurrence of pertussis cases in developed countries has increased and shifted towards older age groups. This resurgence follows 30 years of intense mass vaccination, and has been attributed primarily to three factors: (1) more effective diagnosis of the disease, (2) waning of vaccine-induced immunity, and (3) loss of vaccine efficacy due to the emergence of new Bordetella pertussis strains. Here we develop and analyse a mathematical model to assess the plausibility of these hypotheses. We consider that exposure to B pertussis through natural infection or vaccination induces an immune response that prevents severe disease but does not fully prevent mild infections. We also assume that these protective effects are temporary due to waning of immunity. These assumptions, describing the mode of action of adaptive immunity, are combined with a standard transmission model. Two distinct epidemiological scenarios are detected: under low transmission, most infections lead to severe disease; under high transmission, mild infections are frequent, boosting clinical immunity and maintaining low levels of severe disease. The two behaviours are separated by a reinfection threshold in transmission. As a result, the highest incidence of severe disease is expected to occur at intermediate transmission intensities--near the reinfection threshold--suggesting that pertussis resurgence may be induced by a reduction in transmission, independently of vaccination. The model is extended to interpret the outcomes of current control measures and explore scenarios for future interventions.

Gonçalves G, Machado E, Gouveia E, Santos MA, Castro L, Aguas R, Gomes G. 2005. Resurgence of pertussis in northern Portugal: two severe cases in very young children. Euro Surveill, 10 (6), pp. E050623.3.

Aguas R, Ferguson NM. 2013. Feature selection methods for identifying genetic determinants of host species in RNA viruses. PLoS Comput Biol, 9 (10), pp. e1003254. | Show Abstract | Read more

Despite environmental, social and ecological dependencies, emergence of zoonotic viruses in human populations is clearly also affected by genetic factors which determine cross-species transmission potential. RNA viruses pose an interesting case study given their mutation rates are orders of magnitude higher than any other pathogen--as reflected by the recent emergence of SARS and Influenza for example. Here, we show how feature selection techniques can be used to reliably classify viral sequences by host species, and to identify the crucial minority of host-specific sites in pathogen genomic data. The variability in alleles at those sites can be translated into prediction probabilities that a particular pathogen isolate is adapted to a given host. We illustrate the power of these methods by: 1) identifying the sites explaining SARS coronavirus differences between human, bat and palm civet samples; 2) showing how cross species jumps of rabies virus among bat populations can be readily identified; and 3) de novo identification of likely functional influenza host discriminant markers.

Aguas R, White LJ, Snow RW, Gomes MGM. 2008. Prospects for malaria eradication in sub-Saharan Africa. PLoS One, 3 (3), pp. e1767. | Show Abstract | Read more

BACKGROUND: A characteristic of Plasmodium falciparum infections is the gradual acquisition of clinical immunity resulting from repeated exposures to the parasite. While the molecular basis of protection against clinical malaria remains unresolved, its effects on epidemiological patterns are well recognized. Accumulating epidemiological data constitute a valuable resource that must be intensively explored and interpreted as to effectively inform control planning. METHODOLOGY/PRINCIPAL FINDING: Here we apply a mathematical model to clinical data from eight endemic regions in sub-Saharan Africa. The model provides a quantitative framework within which differences in age distribution of clinical disease are assessed in terms of the parameters underlying transmission. The shorter infectious periods estimated for clinical infections induce a regime of bistability of endemic and malaria-free states in regions of mesoendemic transmission. The two epidemiological states are separated by a threshold that provides a convenient measure for intervention design. Scenarios of eradication and resurgence are simulated. CONCLUSIONS/SIGNIFICANCE: In regions that support mesoendemic transmission, intervention success depends critically on reducing prevalence below a threshold which separates endemic and malaria-free regimes.

Aguas R, Gonçalves G, Gomes MGM. 2006. Pertussis: increasing disease as a consequence of reducing transmission. Lancet Infect Dis, 6 (2), pp. 112-117. | Show Abstract | Read more

Since the 1980s, the occurrence of pertussis cases in developed countries has increased and shifted towards older age groups. This resurgence follows 30 years of intense mass vaccination, and has been attributed primarily to three factors: (1) more effective diagnosis of the disease, (2) waning of vaccine-induced immunity, and (3) loss of vaccine efficacy due to the emergence of new Bordetella pertussis strains. Here we develop and analyse a mathematical model to assess the plausibility of these hypotheses. We consider that exposure to B pertussis through natural infection or vaccination induces an immune response that prevents severe disease but does not fully prevent mild infections. We also assume that these protective effects are temporary due to waning of immunity. These assumptions, describing the mode of action of adaptive immunity, are combined with a standard transmission model. Two distinct epidemiological scenarios are detected: under low transmission, most infections lead to severe disease; under high transmission, mild infections are frequent, boosting clinical immunity and maintaining low levels of severe disease. The two behaviours are separated by a reinfection threshold in transmission. As a result, the highest incidence of severe disease is expected to occur at intermediate transmission intensities--near the reinfection threshold--suggesting that pertussis resurgence may be induced by a reduction in transmission, independently of vaccination. The model is extended to interpret the outcomes of current control measures and explore scenarios for future interventions.

2789