Integrating Transgenic Vector Manipulation with Clinical Interventions to Manage Vector-Borne Diseases

<div><p>Many vector-borne diseases lack effective vaccines and medications, and the limitations of traditional vector control have inspired novel approaches based on using genetic engineering to manipulate vector populations and thereby reduce transmission. Yet both the short- and long-term epidemiological effects of these transgenic strategies are highly uncertain. If neither vaccines, medications, nor transgenic strategies can by themselves suffice for managing vector-borne diseases, integrating these approaches becomes key. Here we develop a framework to evaluate how clinical interventions (i.e., vaccination and medication) can be integrated with transgenic vector manipulation strategies to prevent disease invasion and reduce disease incidence. We show that the ability of clinical interventions to accelerate disease suppression can depend on the nature of the transgenic manipulation deployed (e.g., whether vector population reduction or replacement is attempted). We find that making a specific, individual strategy highly effective may not be necessary for attaining public-health objectives, provided suitable combinations can be adopted. However, we show how combining only partially effective antimicrobial drugs or vaccination with transgenic vector manipulations that merely temporarily lower vector competence can amplify disease resurgence following transient suppression. Thus, transgenic vector manipulation that cannot be sustained can have adverse consequences—consequences which ineffective clinical interventions can at best only mitigate, and at worst temporarily exacerbate. This result, which arises from differences between the time scale on which the interventions affect disease dynamics and the time scale of host population dynamics, highlights the importance of accounting for the potential delay in the effects of deploying public health strategies on long-term disease incidence. We find that for systems at the disease-endemic equilibrium, even modest perturbations induced by weak interventions can exhibit strong, albeit transient, epidemiological effects. This, together with our finding that under some conditions combining strategies could have transient adverse epidemiological effects suggests that a relatively long time horizon may be necessary to discern the efficacy of alternative intervention strategies.</p></div

Transient effects on incidence of combining transgenic vector manipulation with antimicrobial medications of varying efficacies.

<p>(A-B) results for transgenic manipulation aimed at population replacement. (C-D) The same analysis for the case when transgenic manipulation aims at population reduction. Panel (A) assumes <i>α</i> = 10⁻²; panel (B) assumes <i>ρ</i> = (<i>U</i>^⋆ + <i>V</i>^⋆). Panels (B, D) assume an additional medication-induced recovery rate that is 10% of the natural recovery rate for all simulations, but vary <i>α</i> (B) or the time <i>τ</i>_<i>m</i> until releases stop (D). The vertical dotted-dashed line represents the point in time where resistance arises or releases end.</p

Unsustainable transgenic interventions. The epidemiological effects of integrating a vaccine-based intervention strategy with transgenic vector manipulation over a 10-year time horizon when the effects of the transgenic strategy are unsustainable.

<p>Here, and in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004695#pcbi.1004695.g006" target="_blank">Fig 6</a>, resistance arises (or, in the case of population reduction, transgenic releases end) two thirds of the way into a transgenic manipulation regime unless noted otherwise. For the case of population replacement, we model initial invasion of the resistant pathogen by having a single vector carrying the mutant resistant pathogen appear at <i>t</i> = <i>τ</i>_<i>R</i>; in this, and in subsequent figures, the parameter values other than <i>G</i>(<i>t</i>) are modeled to be the same for vectors and hosts infected with the resistant pathogen. (A) The total number of cases (cumulative incidence) relative to the total number of cases without any public health management program when transgenic vector manipulation aims at population replacement. (B) The total number of cases relative to the total number of cases without any public health management program when transgenic vector manipulation aims at reducing vector recruitment. (C-D) The maximum total number of cases, relative to the same quantity without intervention, when the vaccination fraction is low (i.e., evaluated at the time point <i>T</i>_<i>H</i> where is maximized). In contrast to other figures, panels (C) and (D) illustrate the total number of cases at a given point in time rather than the total number of cases over the 10-year time horizon, with the white region of the plots corresponding to regions where the total number of cases with the intervention is always below the incidence in the absence of an intervention. We note that when a relatively small fraction of new hosts are vaccinated, abruptly ending a population reduction program can cause transient oscillations, leading to the nonlinearities apparent in panels (B,D). Panels (E-F) illustrate how the total number of cases can temporarily increase relative to no intervention if transgenic population replacement is unsustainable, although over much longer time horizons eventually falls below one. Panel (E) shows how vaccination can maintain a lower total number of cases relative to the situation in the absence of interventions, but still results in an increase in the total number of cases as vector competence recovers. In panel (F), 5% of new hosts are effectively vaccinated, but the decline <i>G</i>(<i>t</i>) in vector competence is not sustainable.</p

Epidemiological effects of integrating clinical interventions with transgenic manipulation over a 10-year time horizon.

<p>All panels on the left-hand side depict results for transgenic vector manipulation that aims at population replacement, while panels on the right-hand side depict results for transgenic vector manipulation aiming at population reduction. All panels describe the total number of cases (cumulative incidence) over the time horizon relative to the same quantity in the absence of any public health management programs (; see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004695#pcbi.1004695.e019" target="_blank">Eq (5)</a>.) Panels (A-B) show the effect on when no antimicrobial medication is administered in addition to a vaccination program. In (C-D), the medication-induced recovery rate is 1/30 per day, which is 20% of the natural recovery rate.</p

Time <i>t</i>_<i>s</i> to suppression.

<p>Time <i>t</i>_<i>s</i> to suppression.</p

Illustrative time series for the effects of applying only a transgenic vector manipulation strategy.

<p>In this, and in subsequent figures, <i>β</i> = −10, which corresponds to <i>G</i>(0) = 0.99995. (A) The effects on the total number of cases (i.e., cumulative incidence) up until time <i>t</i> for transgenic population replacement where the parameter <i>α</i> reflects how quickly a vector competent population is replaced through transgenic vector manipulation. A value of <i>α</i> governing the decline in vector competence of 10⁻¹ per day corresponds to a program that takes approximately 0.4 years to reduce vector competence by 99%, while a value of 2.5 × 10⁻³ corresponds to a program that takes approximately 16 years to reduce vector competence by 99%. (B) The effects on the type reproductive number over time of the different transgenic population replacement strategies. (C) The effects on the total number of cases of transgenic vector manipulation that reduces recruitment of vectors across release ratios. We note that if the transgenic strategy acts on vector recruitment, its effects on vector poulation size are mediated by the effects of other demographic processes (such as density-independent mortality and density dependence). Whereas, when the transgenic strategy aims at population replacement, the effects of the transgenic strategies are proportional to reductions in vector competence. (D) The effects on the type reproductive number over time of the different transgenic population reduction strategies.</p

Illustrative time series for the effects of applying a single clinical intervention strategy.

<p>Here, and in subsequent figures, in the absence of any intervention the type reproductive number <i>T</i>_<i>R</i> at the disease-free equilibrium is ≈ 4.56; note, however, that at the disease-endemic equilibrium, the effective type reproductive number is one. Here, and in subsequent figures, the solid grey line represents the total number of cases or the effective type reproductive number in the absence of any management strategy. (A) The effects of an antimicrobial medication that renders infectious hosts recovered at different rates on the total number of cases. The natural recovery rate is 1/6 ≈ 0.17 per day. We highlight that even a very weak effect from antimicrobial medications (0.01; approximately 5% of the background natural recovery rate) can cause large transient fluctuations at the disease-endemic equilibrium. The type reproductive number at the disease-free equilibrium is below one when the medication-induced recovery rate is above 0.63 per day. (B) The effects of an antimicrobial medication with different recovery rates on the effective type reproductive number at a given point in time. (C) The effects of vaccinating a fraction <i>ϵ</i> of newborns on the total number of cases and (D) the effective type reproductive number at a given point in time. In this, and in subsequent figures, the cumulative incidence relative to no intervention over time is defined as the running aggregate (see the main text for details).</p

The effect of immigration on the frequency of adult females carrying an anti-pathogen gene two years after releases end under a point-source release of adult male transgenic mosquitoes with weekly releases of (A) 80 males released per site, with the anti-pathogen gene carrying a fitness cost, (B) 80 males released per site, with no fitness cost, (C) 160 males released per site, with the anti-pathogen gene carrying a fitness cost, and (D) 160 males released per site, with no fitness cost.

<p>These release numbers represent values that resulted in relatively low (80 males per site each week) and high (160 males released per site each week) levels of variability across replicate simulations in the frequencies of the anti-pathogen gene (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081860#pone-0081860-g005" target="_blank">Fig. 5A</a>). We focused our analysis of the effects of immigration on release numbers where population extinction never occurred. These release numbers correspond to total release numbers of approximately 1 million (A–B) to 2 million (C–D) transgenic adult males over a single year. Only gravid wild-type females are assumed to migrate into the system. Although removing the fitness cost can reduce the impact of immigration, increasing the number of mosquitoes released amplifies the ability of immigration to counteract the replacement strategy. With immigration, none of the model runs result in extinction across the simulated region. As in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081860#pone-0081860-g004" target="_blank">figures 4</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081860#pone-0081860-g006" target="_blank">6</a>, each model run represents a different, randomized spatial configuration of sites.</p

Parameter values calibrated to Iquitos, Peru. For details, see [21].

<p>Parameter values calibrated to Iquitos, Peru. For details, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081860#pone.0081860-Legros2" target="_blank">[21]</a>.</p

Feasible Introgression of an Anti-pathogen Transgene into an Urban Mosquito Population without Using Gene-Drive

<div><p>Background</p><p>Introgressing anti-pathogen constructs into wild vector populations could reduce disease transmission. It is generally assumed that such introgression would require linking an anti-pathogen gene with a selfish genetic element or similar technologies. Yet none of the proposed transgenic anti-pathogen gene-drive mechanisms are likely to be implemented as public health measures in the near future. Thus, much attention now focuses instead on transgenic strategies aimed at mosquito population suppression, an approach generally perceived to be practical. By contrast, aiming to replace vector competent mosquito populations with vector incompetent populations by releasing mosquitoes carrying a single anti-pathogen gene without a gene-drive mechanism is widely considered impractical.</p><p>Methodology/Principal Findings</p><p>Here we use Skeeter Buster, a previously published stochastic, spatially explicit model of <i>Aedes aegypti</i> to investigate whether a number of approaches for releasing mosquitoes with only an anti-pathogen construct would be efficient and effective in the tropical city of Iquitos, Peru. To assess the performance of such releases using realistic release numbers, we compare the transient and long-term effects of this strategy with two other genetic control strategies that have been developed in <i>Ae. aegypti</i>: release of a strain with female-specific lethality, and a strain with both female-specific lethality and an anti-pathogen gene. We find that releasing mosquitoes carrying only an anti-pathogen construct can substantially decrease vector competence of a natural population, even at release ratios well below that required for the two currently feasible alternatives that rely on population reduction. Finally, although current genetic control strategies based on population reduction are compromised by immigration of wild-type mosquitoes, releasing mosquitoes carrying only an anti-pathogen gene is considerably more robust to such immigration.</p><p>Conclusions/Significance</p><p>Contrary to the widely held view that transgenic control programs aimed at population replacement require linking an anti-pathogen gene to selfish genetic elements, we find releasing mosquitoes in numbers much smaller than those considered necessary for transgenic population reduction can result in comparatively rapid and robust population replacement. In light of this non-intuitive result, directing efforts to improve rearing capacity and logistical support for implementing releases, and reducing the fitness costs of existing recombinant technologies, may provide a viable, alternative route to introgressing anti-pathogen transgenes under field conditions.</p></div