Easing heartworm via ‘Friendly Mosquito’

The goal of the Friendly Mosquito project is prevention: it is always better to prevent a disease than treat a patient already infected

Friendly Mosquitoes do not pose a threat to humans or the environment, as confirmed by the U.S. Food and Drug Administration in 2016 and by the EPA in 2020. Images courtesy Oxitec
Figure 1: Friendly Mosquitoes do not pose a threat to humans or the environment, as confirmed by the U.S. Food and Drug Administration in 2016 and by the EPA in 2020.
Images courtesy Oxitec

There is a high stakes drama—like something out of a Hemingway novel—playing out on a small island chain in the southernmost continental states. Ripe with emotions and legal sparring, an environmental conflict is transpiring in the Conch Republic, more commonly known as the Florida Keys.

At issue is an experimental release of what is known as the “Friendly Mosquito,” a genetically modified version of the yellow fever mosquito (Aedes aegypti) (Figure 1).

A. aegypti is an invasive, exotic species in the island chain, consisting of 43 islands connected by 42 bridges and spans approximately 120 miles long. The Florida Keys, which is the origination of Highway U.S. 1, connecting the entire east coast up to the tip of Maine, is at the northernmost boundary of the Caribbean. As such, its year-round hot and humid climate is the perfect location for pesky mosquitoes.

Although A. aegypti only makes up about four percent of the mosquito population in the Keys, it is responsible for virtually all the vector-borne disease transmission. A. aegypti mosquitoes transmit dengue, Zika, chikungunya, yellow fever, and other diseases in people, and heartworm disease in our animal family.

In 2020, there were 67 reported cases of dengue just in the Keys alone (not including the south Florida mainland). Although actual numbers are not recorded for animals, American Heartworm Society (AHS) incidence maps indicate there are, on average, 26 to 50 cases of heartworm disease in dogs per clinic per year. There are about a dozen veterinary facilities in the Keys, equating to between 300 to 600 cases of pet heartworm annually.

Existing methods of controlling A. aegypti, such as applying chemical insecticides, have failed to stop the spread of disease. This is partly because A. aegypti has developed resistance to insecticides, rendering many common chemicals less effective at killing this mosquito. A new technology needed to be developed.

The partnership

Key in this controversy is the Florida Keys Mosquito Control District (FKMCD), which is considered one of the largest and most sophisticated facilities of its type in the United States. The FKMCD is tasked with mosquito control year-round in the island chain, with the summer rainy season being its busiest time. There are multiple native species of mosquitoes claiming home to the Keys, but most of which are not disease vectors.

The mosquito control authorities work continuously to reduce these pests, including the A. aegypti mosquito. Historically, however, this species has been difficult to control with the tools available, so FKMCD management started looking for novel, safe, and effective ways to manage the mosquito populations.

About a decade ago, the FKMCD reached out to Oxitec, an American-owned, private research company based out of the U.K. Oxitec is a developer of biological solutions to control pests transmitting disease, destroying crops, and harming livestock. They have 10-plus years of successful global regulatory decisions, releases, and positive technical opinions (Figure 2).

The nexus of this pairing was a combination of an outbreak of dengue in the Keys in 2009-2010 and the attendance of key FKMCD staff at a mosquito control conference where Oxitec was discussing a current project using genetically modified mosquitoes (GMM) in the Caymans. When the FKMCD learned of this new, environmentally safe technology, they invited Oxitec to pilot its technology in the Keys.

Figure 2: More than 10 years of successful global regulatory decisions, releases, and positive technical opinions.
Figure 2: More than 10 years of successful global regulatory decisions, releases, and positive technical opinions.

The mission

Andrea Leal, executive director of FKMCD, explains, “Our primary mission is to protect residents in the Florida Keys from all mosquitoes, including the disease-transmitting A. aegypti. The FKMCD remains committed to seeking out environmentally friendly and targeted tools to protect our residents and to preserve our wildlife.”

The goal of the Friendly Mosquito project is prevention. It is always better to prevent a disease than treat a patient, human or animal, already infected. Remove the vector, remove the disease threat.

Several human mosquito-borne diseases are vectored by A. aegypti, with dengue being at the forefront in the Keys. There have been multiple cases of locally acquired disease, recently centered in Key Largo.

Annually up to 400 million people get infected with dengue worldwide. Approximately 100 million people get sick from infection, and 22,000 die from severe dengue. Dengue is caused by one of any of four related viruses: dengue virus 1, 2, 3, and 4. Consequently, a person can be infected with a dengue virus as many as four times in his or her lifetime.

People infected with dengue can have symptoms anywhere from mild to severe. Mild cases of dengue typically last two to seven days and resemble more or less a common cold with aches and pains. Most people recover from the mild form with no to minimal intervention in about a week.

About five percent of individuals infected with dengue will develop severe symptoms, such as shock, internal bleeding, and death. People who have been exposed to dengue, recover, and then get reinfected with another of the four viral types are more likely to develop severe dengue.

There is no evidence dengue and several other human mosquito-borne viral diseases infect dogs, but A. aegypti is a vector for heartworm disease in our pets, specifically dogs, cats, and ferrets. When the A. aegypti bites a heartworm-infected dog, it ingests microfilaria. Inside the mosquito the heartworm larvae develop from the L1-L3 stage in 10 to 14 days.

When the infected mosquito then bites a naïve host animal, the L3 is passed on and continues development to L4, and, ultimately, the mature adult heartworm, which takes approximately six to seven months. When caught in time, heartworm infections can be treated; if left unattended, heartworm in pets can lead to heart failure and death.

The solution

Figure 3: Oxitec’s “just add water” mosquito box.
Figure 3: Oxitec’s “just add water” mosquito box.

The Friendly Mosquito project, conducted jointly by the FKMCD and Oxitec, finally kicked off after a decade of planning, public engagement, and regulatory scrutiny.

The project has received required approvals from federal and state regulators, including approval by the U.S. Environmental Protection Agency (EPA) and the Florida Department of Agriculture and Consumer Services (FDACS), as well as support from the U.S. Centers for Disease Control (CDC).

A non-binding referendum in 2016 showed Monroe County (the Florida Keys) residents overwhelmingly supported Oxitec’s technology, with 31 of 33 precincts voting in favor of the Friendly Mosquito project.

In August 2020, the FKMCD board of commissioners approved moving forward with the pilot project to release a test batch at various locations throughout the island chain.

The concept behind the project is simple (Table 1): only female A. aegypti bite and spread disease. Oxitec has developed genetically modified (GM) male A. aegypti possessing a “kill gene,” which prevents female larvae from developing into adult mosquitoes. When the GM male offspring are released, they will mate with the wild population of female mosquitoes, but only their male offspring will develop into adults. These new males continue mating with more wild females when they mature, passing on the altered gene and ultimately reducing the breeding population of A. aegypti.

The mosquito eggs are produced in a facility in the U.K. To produce the males, the females have to be able to develop and breed. The “kill gene” is suppressed in the presence of tetracycline. When the eggs containing the “kill gene” are oviposited, they are rehydrated using water containing tetracycline, allowing the captive females to hatch, mature, and ultimately produce more eggs. For each batch of eggs (which, by nature, contain an equal number of male and female mosquitoes) exposed to water without tetracycline, the “kill gene” in the female offspring is activated, ensuring only the males would develop into adult mosquitoes.

The controversy

Environmentalists are concerned about the GMO mosquitos being released into the environmentally sensitive Florida Keys. They have fears about what these mosquitos may do to the environment, including the native fauna. Importantly, several individuals have expressed concern these mosquitoes will introduce tetracycline into the environment, thus possibly promoting the production of “tetracycline resistant” bacteria. Of prime concern by the project’s opponents is the feeling local residents are being used as “guinea pigs” in this experiment, and have expressed major concerns about being bitten by GMO mosquitoes.

The facts

Only male mosquitoes are released. Therefore, there is no risk of any people or animals being bitten by one of these GMO mosquitoes and no risk of transmission of disease.

The insects are released from custom “Friendly Mosquito” boxes (Figure 3). Inside each box are mosquito eggs and mosquito food. Once in place, the box is filled halfway with plain water. In approximately two weeks, the non-biting male mosquitoes emerge.

The males are introduced into the environment in specified areas where the numbers and results can be closely monitored. Oxitec has inserted a gene in the mosquitoes designed to emit a fluorescent glow when examined under a microscope equipped with a special filter, so when they are captured, they can be easily identified and counted. Once the process has been validated, more mosquitoes will be released at other locations in the future.

Oxitec’s just-add-water “Friendly Mosquito” technology was successfully proven in the state of São Paulo, Brazil, in 2019. After 13 weeks of treatment, the technology suppressed more than 90 percent of A. aegypti. In May 2020, Oxitec received full biosafety approval for this technology from Brazil’s national biosafety regulatory authority, CTNBio after demonstrating the technology’s full safety to human health and the environment.

Independent research found community support for the project in Brazil was overwhelmingly high, with 94 percent of residents surveyed in favor of Oxitec’s mosquito technology and its use in their neighborhoods.

In April 2021, The Wellcome Trust awarded Oxitec $6.8 million in funding to further progress scaling of its A. aegypti technology.

The goal is this project will demonstrate the genetically modified mosquitos can be used as a standalone control program or as part of an integrated pest management plan to suppress A. aegypti in the Florida Keys in a safe way for humans, animals, and the environment.

TABLE 1: FRIENDLY MOSQUITO FUN FACTS

  • Friendly Mosquitoes do not bite.
  • Friendly Mosquitoes are safe, non-toxic, and self-limiting.
  • Non-biting male mosquitoes emerge from just-add-water boxes to mate with biting females. The female offspring of these encounters cannot survive. As the number of biting females in the population declines, the overall population declines.
  • Friendly Mosquitoes do not pose a threat to humans or the environment, as confirmed by the U.S. Food and Drug Administration in 2016 and by the EPA in 2020.
  • More than one billion Friendly Mosquitoes have been produced for release worldwide, with no negative impacts.
  • More than 100 scientific studies and peer-reviewed papers have been published about Oxitec’s technology; many can be found on Oxitec’s website.
  • Friendly Mosquito field pilot projects are small, designed to demonstrate their ability to combat invasive pest female (biting) A. aegypti relative to untreated control areas, as well as other operational and performance-related features.
  • No tetracycline is used with Friendly Mosquito deployed in Florida.

There are more than 100 independent peer reviewed research papers supporting the technology. More references and resources can be found at www.keysmosquitoproject.com and www.oxitec.com.

Douglas R. Mader, MS, DVM, Diplomate ABVP (canine/feline), Diplomate, ABVP (reptile/amphibian), Diplomate, ECZM (herpetology), Fellow, Royal Society of Medicine, received his DVM from the University of California, Davis in 1986. In addition, he completed a residency in primate and zoo animal medicine. He is a consulting veterinarian for the Monroe County Sheriff’s Zoo, the Key West Aquarium, Dynasty Marine, the Sea Turtle Hospital, the Everglades Alligator Farm, and the Theater of the Sea. Dr. Mader is an internationally acclaimed lecturer and is on the review boards of several scientific journals. He has published numerous articles in scientific and veterinary journals, national magazines, and, is an author-editor and co-editor of three textbooks on reptile medicine and surgery.

Dr. Mader is on the Independent Advisory Board of the FKMCD-Oxitec Mosquito Project.

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