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Regulation of genetically engineered (GE) mosquitoes as a public well being device: a public well being ethics evaluation | Globalization and Well being

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Regulation of genetically engineered (GE) mosquitoes as a public well being device: a public well being ethics evaluation | Globalization and Well being

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In recent years, different types of genetically engineered (GE) mosquitoes have been proposed as public health measures against the high incidence of mosquito-borne diseases in regions of the global South. GE mosquitoes are intended to either change features of or suppress the population of their wildtype counterpart so that they cannot act as disease vectors. However, uncertainties as well as risks for humans and ecosystems are entailed by the open-release and even uncaged field trials of the GE mosquitoes (see, for instance, [1,2,3]). This article provides a public health ethics analysis of the efforts of the US Food and Drug Administration (FDA) to evaluate the risks of a proposed (uncaged) field trial in Key Haven, Florida of the OX513A GE Aedes aegypti mosquito.Footnote 1

Specifically, this paper evaluates the FDA’s 2016 Environmental (Risk) Assessment [41] of the proposed open release experimental project to determine whether it qualifies as a realistic risk assessment. The criterion of realistic risk assessment differentiates between risk evaluations that do and those that do not offer relevant information about how a proposed public health tool will perform under real world conditions. A risk evaluation of a potential public health measure that does not mirror the actual conditions under which the product will be used may have questionable epistemic and public health value, and thereby, ethical worth. This paper proposes that the criterion of realistic risk assessment should be used to evaluate the risk assessments of uncaged field trials of GE mosquitoes conducted by any regulatory agency.

The case is made that the FDA’s Environmental (Risk) Assessment [41] of the proposed uncaged field trial of the OX513A GE mosquito does not meet the realistic risk assessment criterion. The field trial site is not an area where Aedes aegypti-borne diseases are endemic. So, the uncaged experimental research project would not provide information about how the OX513A GE Aedes aegypti mosquito would function in regions where there is a high prevalence of those diseases.

By evaluating the FDA’s Environmental (Risk) Assessment of the proposed uncaged field trial of the OX513A GE mosquito in Key Haven Florida, this paper means to ask the larger question why the sponsors of the bio-technology have sought to conduct uncaged field trials of their patented bio-products in the US. The US does not have a high incidence of mosquito-borne diseases. During 2004–2016, four US states had the highest reported incidence of mosquito-borne diseases; California had 9254 cases, New York had 7167 cases, Texas had 6649 cases, and Florida had 3822 cases [4]. To state the obvious, in the US there is not a significant incidence of mosquito-borne diseases relative to regions of the global South where mosquito-borne diseases are endemic.

This paper also analyzes the episodic outbreaks of dengue, an Aedes aegypti-transmitted infection, in Puerto Rico. During 2004–2016, the US territory had 80,534 reported cases of mosquito-borne diseases [4]. It is an instance of the type of real-world conditions under which there is a (relatively) high incidence of Aedes aegypti-borne infections and it serves as a telling comparison to the proposed field trial site of Key Haven, Florida. In Puerto Rico, economic and political factors play an important role in determining the incidence of that Aedes aegypti-transmitted infections. So, the question must be asked whether there is ethical warrant for efforts to use patented high-tech ‘solutions’ that carry considerable uncertainty and risks for humans and ecosystems to ‘solve’ public health problems that disproportionately affect economically and politically marginalized populations in regions of the global South.

Additionally, this paper argues that in the interest of conducting a realistic risk assessment, the FDA should have evaluated the possible impact of the OX513A GE Aedes aegypti mosquitoes establishing colonies in areas with marginalized populations who have limited or no access to health care.Footnote 2 The World Health Organization (WHO) in part classifies mosquito-borne diseases as neglected diseases because the populations disproportionately affected by them tend to be politically and economically marginalized [5]. Undocumented farmworkers are discussed as an example of a marginalized population who have limited access to health care in the US and who could be affected by the uncaged release of GE mosquitoes. It is argued that the FDA ought to have considered the possible impact of the uncaged fields trial of the OX513A GE mosquitoes on them. That possibility needs to be examined because tetracycline is used in farms and if the OX513A GE Aedes aegypti mosquitoes are released near farms (or inadvertently transported to them) and if they find tetracycline in sufficient quantities there, the GE mosquitoes might be able to survive over multiple generations. That could have implications for undocumented farmworkers who have limited access to health care.

Next, the justification for this project is discussed. It is argued that this paper’s evaluation of the FDA’s risk assessment of the proposed uncaged field trial matters. The regulatory agency is considered a global standard setter. Neoliberal philanthropies that seek to ‘solve’ public health problems of the global South by means of patented high-tech innovations (such as GE mosquitoes) could use the FDA’s risk assessment to advance their ends. They could use it to urge other countries to permit uncaged field trials and use (of different kinds) of GE mosquitoes in their territories.Footnote 3 If patented GE mosquitoes get uptake among global health governance actors as tools for reducing the incidence of mosquito-borne disease in regions of the global South, it could mean substantial profits for those who own the patents for them even though the bio-technologies present significant uncertainties and risks for humans and ecosystems.

Following the discussion of the ‘framing’ of patented GE mosquitoes as the solution to mosquito-borne diseases in the South, key features of the OX513A GE Aedes aegypti mosquito are outlined. It provides background information for this paper’s analysis of the FDA’s Environmental (Risk) Assessment of the uncaged field trail of the OX513A GE mosquito in Key Haven, Florida [41].

The FDA’s risk assessment of GE mosquitoes and global health governance

The socio-political and economic conditions of individuals and groups affects their health and diseases status [6]. Whether the risk assessments of products conducted by regulatory agencies approximate actual conditions under which they will be used especially matters in the case of products that are intended to act as interventions for public health problems that disproportionately affect the poor, such as mosquito-borne diseases. This ethics analysis argues that if ineffective public health interventions are adopted on the basis of epistemically weak risk evaluations by regulatory agencies, there could be substantial public health and ethical costs for that population.

On the international stage, the US FDA is regarded as a regulatory standard setter, with various countries adopting its criteria and methods for evaluating pharmaceuticals [7]. So, the FDA’s decision to approve the uncaged field trial of a GE mosquito could have international significance. Proponents of the GE mosquito could use it to argue that other countries should permit uncaged field trials of different types of GE mosquitoes in their territories and employ the same parameters that the FDA used. This would be a particular concern with respect to low-income countries that do not have the well-funded and well-resourced regulatory agencies of high-income countries. Regulatory agencies of many countries are under pressure to harmonize their regulatory approaches. The strongest push to harmonize comes from the World Trade Organization, the Organization for Economic Co-operation and Development, and countries that espouse strong patent regimes (see, for instance, [8]).

The FDA’s approval of the OX513A GE Aedes aegypti mosquito as a public health tool could make it (and other kinds of patented GE mosquitoes) appealing to the Global Health Investment Fund and other such social finance enterprises that aim to ‘solve’ the public health problems of the global South poor by means of patented products. To understand the normative commitments of such ventures and their efforts to solve the public health problems of the global South poor, it is useful to examine their ideological underpinnings. They appear to be a mix of neoliberalism and neo-colonialism.

Neoliberal-philanthropic enterprises

Neoliberalism does not have a uniform form nor is it reproduced uniformly over time and contexts [9,10,11]. Rhetoric that disparages government intervention in the economy, lobbying for regulations that are pro-corporate interests, and valorization of the (mythical) bootstrapping, enterprising individual are some of the key practices of neoliberalism. But it is generally understood that not all of those features are present in each case of neoliberalism and no specific characteristic is common to all instances of neoliberalism [11].

However, some features do occur in many instantiations of the ideology. The tendency to construe the democratic state as a moral and practical failure is one such characteristic of neoliberalism. According to it, the democratic state is an unfair and inefficient allocator of social goods and services that discourages individuals from acting as self-sufficient, enterprising risk takers [12].

Some powerful non-state actors committed to capitalism or neoliberalism believe they can do better than the democratic state [13,14,15,16]. Thus, they have chosen to take on some of the roles of the state motivated by the conviction that they can be just, efficient, and effective [14, 16].

However, they are neither chosen by the populations whose lives they impact to take on those roles nor are they accountable to them. The lack of accountability does not seem to be viewed as an ethical or political problem by proponents of neoliberalism. So, while the ideology evinces commitment to the principle of moral equality of all persons, its norms, policies, and practices are inconsistent with it. The failure to recognize this inconsistency is an epistemic problem with neoliberalism that has ethical and political dimensions.

The rise of neoliberalism has also given birth to neoliberal-philanthropic schemes.Footnote 4 Those enterprises aim to assume some of the functions of the state by providing for the needs of the poorer segments of the polity. They are based on neoliberal business principles and their proponents appear to see no ethical tension in serving the interests of their supporters (including funders) as they seek to attend to their philanthropic mission.Footnote 5

Social (public health) finance enterprises can be classified as a sub-category of neoliberal philanthropic endeavors.Footnote 6 While the financially and politically powerful organizations voluntarily take on some of the roles of the state, they do not consider themselves accountable to the populations whose problems they seek to solve nor are they chosen by them to take on that responsibility [17]. In general, social finance enterprises are predicated on the assumption that charitable giving should ‘work’ for the investors in their organizations by generating profits for them [17].

Neoliberal-philanthropic public health initiatives that focus on the global South tend to see it from a neo-colonial perspective. Mirroring the policies and practices of colonial public health schemes, they retain for themselves key decision-making power, even as they seek to solve the public health problems of the South (see, for instance, [18,19,20]). They appear to regard state actors (including national public health agencies) of the global South as corrupt, inefficient, and ineffective, and themselves as virtuous, effective, and efficient benefactors of the global South poor. Thus, they tend to retain decision-making power for themselves [19]. However, it is an open question whether such enterprises can realize their ambition of solving the public health problems of the global South poor, such as the high incidence of mosquito-borne diseases. In part because that goal may be at odds with their ambition of producing profits for their investors or benefitting their funders and supporters [21, 22].Footnote 7

The Global Health Investment Fund (GHIF) qualifies as a form of social(public health) finance enterprise. With the aim of generating profits for its investors, GHIF invests in patented interventions aimed at solving public health problems that disproportionately impact socio-economically marginalized populations in the global South ([23]: S311). In 2014, the Fund’s website stated that its goal was to help “bring about significant improvements in the treatment and prevention of disease, and in family planning, and the reduction of maternal and child mortality (in poorer countries), along with the prospect of a net financial return for investors” ([24], quoted in [23]: S311).

Mosquito-borne diseases that disproportionately affect young children of poor families in regions of the global South are within the scope of the GHIF’s mission. GE mosquitoes as a patented public health intervention could be of considerable interest to GHIF and its investors. For instance, the Oxitec GE mosquito was expected to cost the Brazilian city of Piracicaba (with a population of 391,449) an estimated US $1.1 million during a two-year period at the cost of US $10 per person in the target area (50% of the cost was supposed to financed by the city’s current mosquito control budget; Oxitec was expected to cover some part of the cost [25]). As the GE mosquito is a patented product, presumably it would have to be re-licensed every season [26]. Another study suggested that the price of the GE mosquito for use in an urban area with a population of 50,000 would be an estimated US $1.9 million in the first year and US $384,000 each following year [27]. So, if those numbers are anything to go by, presumably, the patented GE mosquitoes could bring substantial returns for their investors.

The initial eleven investors in the GHIF, included the Bill and Melinda Gates Foundation, JP Morgan Chase, the World Bank, Merck, Pfizer Foundation, and GlaxoSmithKline ([23]: S311). The possibility that patented GE mosquitoes could receive the GHIF’s endorsement and support should not be dismissed out of hand. The Gates Foundation, a key investor in the GHIF, has funded Target Malaria in the amount of US $75 million [28]. That initiative is using techniques of modern biotechnology to develop GE mosquitoes with intentionally altered heritable traits (albeit of a different kind than the OX513A GE Aedes aegypti mosquito that was proposed for the uncaged field trial in Key Haven, Florida). Target Malaria aims to use its GE mosquitoes to wipe out malaria in regions of sub-Saharan Africa [28]. A 2016 MIT Technology Review article notes that “[t] he Gates Foundation has said it no longer believes that malaria can be wiped out without a (GE mosquito with) gene drive.Footnote 8 ‘You can’t walk around with a bed net on you all the time. That’s not going to eliminate malaria,’ says (Fil) Randazzo (deputy director of the Foundation). With a (GE mosquito with) gene drive, ‘human behavior change is not required’” [29].

The sentiments of key Gates Foundation personnel should be taken seriously. The Foundation is a part of the GHIF and it is a powerful global health governance actor. It plays a crucial role in deciding which health care interventions should be adopted and funded for the poor of low-income countries [13, 30, 31]. As the use of GE mosquitoes as a public health tool has the support of a key global health governance actor, and given the credence internationally afforded to the FDA as a regulatory authority, the agency’s risk assessment of the OX513A GE Aedes aegypti mosquito as a potential public health tool could have a wide-ranging impact. Therefore, this ethics analysis argues that regulatory agencies have an epistemic, public health, and ethical duty to adopt a policy of conducting realistic risk assessments of bio-technologies that are meant to serve as public health measures. To provide a context for this paper’s analysis, next, key features of mosquito-borne diseases and the OX513A GE Aedes aegypti mosquito are briefly described.

The OX513A GE Aedes aegypti mosquito

Mosquito-borne diseases (in conjunction with other vector-borne diseases) take an enormous toll on the poor in subtropical and tropical regions. The vulnerability of those populations to vector-borne diseases is partly determined by a complex of socio-political- economic-ecological factors, including global warming and capital-led deforestation ([6, 32], vi [13, 33,34,35]). Histories and cultures, including the affected population’s stance on risks from mosquitoes, also play a role in determining their vulnerability (see, for instance, [36]).

However, some proponents of GE mosquitoes construe the disproportionate incidence of those diseases among the socio-economically marginalized as a primarily, if not wholly, biological phenomenon that must be solved by means of high-tech interventions (see, for instance, [37]). Their stance is in keeping with a long tradition of certain global health governance actors biologizing the high incidence of infectious diseases among the poor of the global South and advocating purely technical solutions for them [8, 13, 38].

Developed by Oxitec Ltd. (Oxford Insect Technologies), the OX513A GE Aedes aegypti mosquito is meant to reduce the population of its wild-type counterpart. The Aedes aegypti mosquito is the main vector of the yellow fever virus, dengue viruses, chikungunya virus, and Zika virus [39]. Aedes aegypti mosquitoes are found in tropical and subtropical regions and tend to establish their habitats in or near human dwellings. They have been inadvertently transported around the globe by humans and Aedes aegypti sub-species are associated with specific regions [40]. Female Aedes aegypti mosquitoes bite (human and non-human) animals and transmit organisms that may cause illness; male mosquitoes do not bite animals ([41], p.16).

The genetic modification of the Oxitec OX513A GE Aedes aegypti mosquitoes includes a heritable synthetic genetic sequence that makes them dependent on tetracycline ([41], p.22). It is expected that when male OX513A GE Aedes aegypti mosquitoes (that are released in the wild during field trials or open-releases) mate with their female wildtype counterpart, approximately 95% of the resulting progeny will inherit the tetracycline dependency trait such that they are not expected to survive to adulthood in environments that do not have sufficient amounts of that chemical ([42], p.13). The assumption is that with periodic releases of additional batches of male OX513A GE Aedes aegypti mosquitoes, which mate with their wildtype female counterpart, the population of the wildtype Aedes aegypti in the target environment will decrease over time because their progeny will not be viable in environments that do not have tetracycline [41]. That is expected to result in a decline in the incidence of dengue and other diseases transmitted by that strain of mosquito.

While Oxitec’s plan was to release only male OX513A GE Aedes aegypti mosquito during the uncaged field trial in Key Haven, it estimated that .2% of the released GE mosquitoes could be females as the sex sorting system used to differentiate between male and female GE mosquitoes had deficiencies ([42] pg.34). So female GE mosquitoes (with the ability to transmit organisms that could cause infections in humans) could be accidentally released. To get a sense of those percentages, it is useful to consider the actual number of OX513A GE mosquitoes that would have been released during the proposed uncaged Key Haven field trial. During the 22 months long experimental research project, Oxitec anticipated releasing in the trial site at least 14 million mosquitoes ([41], p.39). That means if the field trial had been conducted, then it was possible that over time approximately 28,704 female GE Aedes aegypti mosquitoes could have been inadvertently released. If they had found sufficient tetracycline in the environment, presumably, they and their GE progeny could have survived, established habitats, and the female GE mosquitoes and the female GE progeny of female or male GE mosquitoes could have acted as disease vectors.

Although the uncaged field trial of the OX513A GE Aedes aegypti mosquito in Key Haven, Florida was greenlighted by the FDA, it was not conducted because the local population objected [43]. However, this paper’s ethics analysis of the FDA’s risk assessment of the proposed field trial matters because, first, it identifies serious shortcomings with the agency’s risk evaluation, and second, it may have relevance for other proposed uncaged field trials of GE mosquitoes in various countries including the US. In 2020, two uncaged field trials in Florida and Texas of a different GE Aedes aegypti mosquito (OX5034)Footnote 9 were approved by the US Environmental Protection Agency (EPA).Footnote 10 An estimated 508,560,000 male OX5034 GE Aedes aegypti mosquito are to be released as part of uncaged field trials in Florida, and approximately 249,600,000 male OX5034 GE Aedes aegypti mosquito are to be released in Texas for an uncaged experimental field research project [44], p. 5. It is beyond the scope of this paper to address the question whether the EPA’s risk assessment qualified as a realistic risk assessment. However, as argued earlier, it is a criterion by which the EPA’s decision to authorize the uncaged field trials of the OX5034 GE mosquito should be evaluated.

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