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Genetically-Modified Mosquitoes for Malaria Control:

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Requirements to be Considered Before Field Releases Yeya T. Touré and Bart G.J. Knols*

Abstract

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he technical feasibility of the development of transgenic mosquitoes highly refractory to (rodent) malaria parasites has been demonstrated in the laboratory. Following this proof of principle, genetic control of vectors could have an important role to play in the interruption of transmission of human malarias, if the main developmental and implementation challenges are adequately addressed. These include the establishment of a proof of efficacy and safety for humans and the environment in carefully controlled and contained environments. Prior approval by authorized biosafety, regulatory, and ethical review bodies needs to be obtained before experimental releases. In addition, there is the need to ensure the public and the media that this process is desirable, feasible and can be accomplished safely. Moreover, an appropriate implementation and capacity building plan would increase the chances of making this approach a control method applicable for public health purposes. Analysis of current and anticipated future views of a variety of critical stakeholders enables the provision of a framework that facilitates the transition of research findings from the laboratory to the field. A coordinating mechanism to closely monitor and guide this transition process will be instrumental in furthering developments to fully evaluate the public health potential of this approach.

Introduction

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Mortality and morbidity from malaria remain high despite a global commitment to its control.1,2 Several reasons including poor implementation of interventions, development and spread of resistance of parasites to antimalarial drugs and of vectors to insecticides, besides insufficient human resources, have been shown to contribute to this high disease burden.3 Malaria prevention relies mainly on vector control/personal protection measures and chemoprophylaxis. The vector control methods mostly used are indoor residual spraying of insecticides and the use of insecticide-treated bednets or curtains. In many settings, these strategies face implementation and sustainability problems.4 As the actual control methods and strategies are being applied for malaria prevention, it is crucial to continuously look forward for their improvement and for the development of new and innovative ones. In this regard, on the basis of the progress made in molecular biology and in biotechnology (e.g., genetic modification of Drosophila5), it was thought that the time is ripe *Corresponding Author: Bart G.J. Knols—International Atomic Energy Agency (IAEA), Agency’s Laboratories in Seibersdorf, Seibersdorf, Austria, E-mail: [email protected]

Genetically Modified Mosquitoes for Malaria Control, edited by Christophe Boëte. ©2005 Eurekah.com.

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to explore the feasibility of interrupting malaria parasite transmission through the genetic modification of its vectors.6 The technical feasibility of the development of transgenic mosquitoes with impaired ability to transmit (rodent) malaria parasites has been demonstrated in the laboratory. Anopheles gambiae (Giles) has been genetically modified and Anopheles stephensi (Liston) was made highly refractory to Plasmodium berghei growth and transmission.8 These achievements open an avenue for potential contribution of genetic modification of vectors to malaria control. However, challenges about the complete development of the method, its implementation and public concerns remain to be addressed and should provide an evidence base for policy decision, which would facilitate this approach to become a tool for use in public health for malaria control. Consequently, lessons are to be learned from the genetically-modified food debate9 and previous genetic control trials of vectors in El Salvador10 and India.11 Here we analyse the issues and challenges to be considered before field releases and highlight how these could be addressed.

Developmental Challenges

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The biotechnological challenges about the development of the control method include issues such as developing and evaluating appropriate effector gene constructs, devising and testing suitable gene driving systems, assessing the spread of the foreign genes and fitness impacts on mosquitoes. In addition, a much more challenging undertaking is to provide a proof of efficacy and safety for humans and the environment of the method under laboratory and semi-field conditions. A major concern about the development of transgenic mosquitoes for malaria control is represented by unexpected biological changes, which could affect their transmission capabilities. The transgenic mosquitoes must remain comparable to their field counterparts with the only difference that they would have gained the ability to prevent malarial infections. But in addition, they would not be expected to be able to transmit other pathogens such as filarial worms or (arbo)viruses. In order to address these issues and reassure the public, studies need to be conducted on the efficacy, bio-safety and risk/benefit evaluation through long-term efforts to clarify the scientific uncertainties under different experimental conditions.12-14 This activity is best undertaken in partnership between researchers from developed countries and from disease-endemic countries.15 In addition, the participation of the public and the media is also highly recommended. A sound basis for collection of data on vector biology, ecology, behaviour and genetics addressing efficacy and safety in the field would also need to be provided.16 Moreover, there is the need to develop criteria to identify and prepare the field sites earmarked for anticipated releases. There should be prior environmental and health studies for site selection, and based on these data the most appropriate sites should be chosen. Guidelines and principles would need to be developed on the design and performance of efficacy and minimum risk field research. Criteria and test methods for environmental monitoring are also required. An appropriate safety assessment and management would represent a sound basis for policy decision. Its conduct would need the identification of scientific principles and practices for undertaking safe laboratory experiments and field trials with genetically-modified mosquitoes following Good Developmental Practices (GDP). 18-19 In addition, it needs to include mechanisms to provide the public with information about the bio-safety assessment results and ensure the information reaches the communities and decision-making bodies.

Public Concerns and Implementation Challenges Important achievements have been made in biotechnologies, which could potentially be used for malaria control. However, the public in general and particularly in disease-endemic countries (DECs) is not sufficiently informed about the potential and the process of development of new technologies such as genetically-modified mosquitoes. This information

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gap affects the capability of the public and policy makers alike to fully judge the efficacy and safety of genetically-modified mosquitoes for humans and the environment and to make informed decisions about their implementation for malaria control. Currently, the public in disease-endemic countries, as future end users of this approach, are insufficiently involved in the adoption process with the imminent risk that it may ultimately use its power to reject it. Consequently, mechanisms need to be developed for information exchange, for addressing public concerns and for using standardized regulations world wide in a coordinated manner.20 As a first step, it is necessary to set up mechanisms for improved communication, provision of adequate means for information dissemination and collaboration between the researchers, the public and the media. An adequate translation of scientific knowledge to the public and the media is highly desirable. The information should be openly provided as broadly as possible in a reciprocal process.14 This procedure would ensure an appropriate flow of information exchange and feedback, which would result in raising public awareness, addressing concerns about potential environmental and human health risks and building public confidence in the scientific results. It will also provide means to the public to be sufficiently knowledgeable to make informed decisions about the merits of deploying such programmes in their communities. Another necessary step would be to bring all parties together on common ground that can lead to objective, scientific, legal, ethical and social-based decisions by policy makers, whilst bearing in mind that most people may not trust the scientific efficacy and risk analyses. Ethical, legal and social issues (ELSI) of the use of genetically-modified mosquitoes need to be fully addressed in order for the community at large to adhere to the principle of their potential implementation. For this to be achieved, it would be necessary to integrate with the scientific studies those legal, ethical and social factors that are relevant to the use of genetically-modified mosquitoes and ensure that all parties with legitimate concerns have mechanisms for including their input into the proposed genetic control programmes. In addition, it is necessary to engage the end-users in the choice of sites and plans for deployment, in clear and legally-appropriate concepts of informed consent, in promoting an understanding of the real measures of success for the programmes. Moreover, consent should be obtained from the communities involved and the mechanisms to obtain individual and group consent need to be specifically developed for public health interventions based on genetic vector control concepts. The data should be made open to all so that it can benefit from global expertise and develop an international consensus.14 The safety assessment plan during the implementation phase would need to establish the development of science-based evidence for policy and procedures for the assessment and management of potential risks. Moreover, it will aim at minimizing the potential adverse human and environmental consequences. More specifically, it will have to anticipate detrimental effects that might follow the release of genetically-modified mosquitoes during experimentation. It would also need to design monitoring systems for the early detection and evaluation of adverse outcomes, and plan interventions strategies, so that new information can be gathered and interpreted to avert and if necessary remedy adverse health or environmental effects.21 Guidelines are needed for assessing dispersal, contingency measures and site rehabilitation. The approval of the implementation plan of genetically-modified vectors as a control strategy should be based on a proof of efficacy and safety properly established and approved by authorized bio-safety regulatory and ethical review bodies before any experimental release.12-14 The information necessary for legal and regulatory approvals should be gathered and should include a complete documentation for bio-safety and ethical review. The requirements necessary for national and local authorities’ approvals should also be addressed. The development of guidelines and regulatory procedures would help the researchers and the countries to define a common ground to deal with the issues about the processes for potential approval of the implementation of genetically-modified mosquito-based vector control.

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Capacity and Partnership Building and Coordination Mechanisms

Conclusion

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In order for DECs to be fully involved in undertaking the evaluation and potential implementation of genetically-modified mosquitoes as a control tool, there is the need to enhance their capacity, build partnership and set up a coordination mechanism. Investigators would need to receive funding for research and training to undertake activities for collecting data on the vector biology, ecology, genetics and behavioural ecology of the vectors. They would need to be trained for monitoring and managing safety procedures for human health and for the environment, for evaluating risk/benefits and for managing regulatory and ethical principles. DECs need to be helped to create and manage institutional/national bio-safety and ethical review boards. There would also be the need for promoting South-South and North-South research collaboration based on well-defined ethical and scientific standards.22 The complexity of issues related to genetically-modified mosquito development and implementation requires a multi-disciplinary effort, which would need an international coordinating board. It will focus on the broader dissemination of scientific progress to stakeholders, the facilitation of collaborative efforts and partnership strengthening within and beyond the scientific community and the mobilization of financial resources for the funding of developmental and implementation plans. The technical feasibility of genetically-modified mosquitoes highly refractory to rodent malaria parasites has been demonstrated under laboratory conditions. However, there are developmental and implementation challenges to be addressed before this method can be used as a public health tool. The public perception about the use of genetically-modified mosquitoes varies from fear and refusal to hope and concerns, because of uncertainties and information gap. For this reason, there is a need for careful and thorough assessment of efficacy and safety and addressing properly the public concerns before possible implementation. There is the need to provide adequate means for information dissemination, communication and collaboration between the researchers, the public and the media such to raise awareness and address concerns about possible environmental and human health risks. Ethical, legal and social issues of the use of genetically-modified mosquitoes need to be fully addressed in order for the community at large to appreciate value and endorse the principle of their potential implementation. The implementation of GMM needs public acceptance and appropriate plans for monitoring and managing potential risks over time under well defined regulatory, capacity building and coordination mechanisms. A meeting, jointly-organised by WHO/TDR, IAEA, NIAID and Frontis (Wageningen University, The Netherlands), held in Nairobi in July 2004, focused on the above issues and developed the following seven recommendations:15

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1. Genetic modification of insects could be used to control vector-borne diseases, yet will depend on solving several critical components of the approach, i.e., - Optimising currently available transformation systems; - Identification of additional endogenous and/or artificial effector genes, conditional lethals and novel phenotypes; - Identification of tissue-specific promoters for such systems. 2. Develop techniques for driving effector genes that interfere with disease transmission into wild insect populations, i.e. - Research on the genetic stability of effector and drive mechanisms and their associated fitness costs. 3. Studies on vector field populations with respect to potential future releases of genetically-modified mosquitoes, i.e., - Understanding male mosquito biology and particularly the factors affecting mating and competitiveness under field conditions;

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- Development of models to define threshold levels in terms of system efficacy in order to attain maximum epidemiological impact in both spatial and temporal dimensions; - Characterisation of field sites and field populations that should include the establishment of relationships between transmission intensity and disease outcome. Development of processes dealing with the ethical, legal and social issues (ELSI) of the use of genetically-modified mosquitoes, i.e., - Any genetically-modified mosquito approach must result in a predictable and positive public health outcome; - Development of guidelines and principles for minimum-risk field research that includes environmental risk management. Enhanced involvement of scientists and institutes in DECs. As frontline stakeholders in this endeavour, the roles and responsibilities of DEC scientists should increase and be based on equitable partnership development. Inclusion of genetically-modified mosquitoes in disease control programmes, i.e., research that focuses on the inclusion of genetically-modified mosquito approaches within the broader framework of malaria vector control. Integration of genetically-modified mosquitoes into integrated vector management (IVM) programmes will need to be considered. Coordinating and follow-up mechanism for genetically-modified mosquito research and implementation. Considering the complexity and multi-disciplinary nature of this endeavour, the establishment of a coordinating board was recommended. This board should oversee research developments and drive the broader dissemination of research results to stakeholders and facilitate collaborative research and partnership strengthening within and beyond the scientific community.

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