Genetically Engineered Mosquitoes: A Vector Control Technology for Reducing Virus Transmission

Genetically Engineered Mosquitoes: A Vector Control Technology for Reducing Virus Transmission

Updated September 8, 2020
Genetically Engineered Mosquitoes: A Vector Control
Technology for Reducing Virus Transmission
Background
As much as 7% of Americans live in areas where the cold
In February 2016, the World Health Organization (WHO)
might not kill off the mosquito in the winter, leaving them
declared Zika virus a “public health emergency of
vulnerable year round.
international concern.” WHO defines such a public health
emergency (1) to constitute a public health risk to other
No vaccine exists for Zika, although the U.S. Food and
states through the international spread of disease and (2) to
Drug Administration (FDA) has approved several
potentially require a coordinated international response.
diagnostic tests for detecting Zika virus antibodies.
This definition implies a situation that is serious, unusual,
Mosquito control and bite prevention are the first lines of
or unexpected; carries implications for public health beyond
defense. Conventional control methods such as truck and
the affected state’s national border; and may require
aerial spraying are only moderately effective (30%-50%) in
immediate international action.
reducing mosquito populations, in part owing to the
resistance the mosquitoes have developed to common
While only about one out of five persons infected with Zika
insecticides and to the limited area in which Aedes aegypti
virus exhibit even the common symptoms of mild fever,
mosquitoes circulate (100-200 yards from where the larvae
rash, and joint pain, the U.S. Centers for Disease Control
emerge). Aedes aegypti mosquitoes also tend to favor house
and Prevention (CDC) confirmed that Zika-infected
interiors where spraying/fogging is not practical. Strategic
pregnant women were at risk for delivering babies with
placement of several low-cost autocidal gravid ovitraps
microcephaly, a birth defect of the cerebral cortex where a
(which mimic breeding sites) in house interiors can reduce
baby’s head is smaller than expected based on sex and age.
the Aedes aegypti population by about 50%.
Zika virus triggered outbreaks in 33 countries and
OX513A Genetically Engineered Mosquitoes
territories, although confirmed cases linking Zika virus to
In this environment, the creation of a genetically engineered
babies with birth defects were initially seen in only Brazil
(GE) Aedes aegypti mosquito by the British firm Oxitec in
and French Polynesia. Several countries also reported a
2002, known as OX513A, generated significant interest
spike in cases of Guillain-Barré syndrome, a neurological
among public health officials. Developed originally to
syndrome also believed to be an effect of the virus in some
suppress the incidence of dengue fever, OX513A was seen
victims.
as a promising technology to reduce the incidence of Zika
virus transmission by reducing the population of
A Mosquito-Borne Virus
mosquitoes. Oxitec is owned by Maryland-based Intrexon
Zika virus (so named for the Zika forest in Uganda, where it
Corporation.
was first identified in monkeys in 1947) is a mosquito-
borne flavivirus that has rapidly infected human populations
Oxitec’s OX513A mosquitoes were engineered with a
in Latin America and the Caribbean, including in the U.S.
synthetic genetic sequence encoding a tetracycline-
territories of Puerto Rico, the U.S. Virgin Islands, and
repressible transcriptional activator (tTAV) that leads to the
American Samoa. In April 2016, over 400 cases in the
death of most of the mosquitoes carrying the trait. If
United States were confirmed, each acquired through either
tetracycline is present (as it is during the mosquito rearing
travel to areas where the mosquito vectors for Zika virus
in the laboratory), then tTAV is repressed and the larvae
circulate or sexual contact with people who had traveled to
can develop and reach adulthood. When the gene is passed
such areas. As of 2019, no cases of local transmission of
on to the mosquito’s offspring, they die before reaching
Zika virus have been confirmed in the contiguous United
adulthood. Each mosquito is also engineered with a
States and its territories.
fluorescent marker permitting effective monitoring of
larvae to assess the effectiveness of control. The fluorescent
The first outbreak of Zika virus outside Africa, Asia, and
marker is visible in all OX5213A offspring using a special
the Pacific Islands occurred in Brazil in May 2015. The
microscope. The male mosquitoes, which do not bite or
virus is spread predominantly by the female Aedes aegypti
spread the virus, are reared in laboratories and then released
mosquito (and to a less effective extent by Aedes
to mate with wild Aedes aegypti female mosquitoes.
albopictus), an aggressive day-biter that is also a vector for
Since only the females bite, releasing millions of OX513A
yellow fever, dengue, and chikungunya. Aedes aegypti
males to mate with wild females would then produce larvae
mosquitoes are non-native to the United States. A model
that die. This would reduce the population of Aedes aegypti
created by Toronto researchers found that approximately
mosquitoes, thereby, reducing the risk of Zika virus
63% of the U.S. population lives in areas where Zika virus
transmission to humans. This approach targets only the
might spread during seasonally warm months if mosquitoes
Aedes aegypti mosquitoes that can spread disease, because
in the United States were to become vectors of Zika virus.
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Genetically Engineered Mosquitoes: A Vector Control Technology for Reducing Virus Transmission
the OX513A males produce offspring only with their own
This review team examined Oxitec’s and independent
species.
collaborators published evidence from their Brazil and
Cayman Islands field trials and other data on safety studies.
Adult males with Oxitec’s lethal transgene survive in the
FDA found the probability negligible that the release of
environment for only about a week. The OX513A
OX513A male mosquitoes would result in toxic or
mosquitoes also have the advantage of repressing
allergenic effects in humans or other animals. “Almost all
populations of Aedes aegypti mosquitoes that carry
of the OX513A mosquitoes released for the investigational
insecticide resistance genes. According to peer-reviewed
field trial will be male, and male mosquitoes do not bite
studies, of the more than 150 million OX513A mosquitoes
humans or other animals. They are therefore not expected to
released in field trials, no effects on other species have been
have any direct impacts on human or animal health.” FDA
observed, no evolution of resistance to the lethal transgene
also found that the “probability that the release or rearing of
has been seen, and there has been no mating with non-target
OX513A mosquitoes would have adverse impacts on the
mosquitoes detected.
ecosystem is largely negligible” and that the “probability of
According to peer-reviewed studies, release of OX513A
OX513A mosquitoes and their progeny persisting and
males in the Cayman Islands in 2010 led to 90%
establishing at the proposed trial site or spreading beyond
suppression of the wild Aedes aegypti population. Isolated
its boundaries is extremely unlikely.”
field demonstrations in Brazil achieved similarly successful
With the FONSI, Oxitec planned field testing in Key
results after six to nine months. In 2011, Oxitec conducted a
Haven, FL, in collaboration with the Florida Keys Mosquito
sustained series of OX513A field releases in Itaberaba,
Control District. However, the Florida Keys Environmental
Brazil. Normal mosquito control continued during the field
Coalition and others petitioned the Florida Commissioner
study as public health agents continued to destroy breeding
of Agriculture and Consumer Services to halt any field
sites and treat homes with larvicide. According to peer-
testing of the OX513A mosquitoes in the state. The Florida
reviewed studies, the Aedes aegypti population was reduced
Keys Mosquito Control Board did not approve the trial
by over 90% in a year based on data from multiple
release, instead putting it on a November 2016 ballot as a
locations.
non-binding referendum. The Key Haven neighborhood
Brazil’s National Biosafety Commission approved country-
rejected the proposed release.
wide use of OX513A in 2014, making Brazil the first
country to approve the commercial use of the OX513A
Oxitec’s Second-Generation GE Mosquito
mosquitoes. A year later, the OX513A mosquitoes were
With local opposition to the planned release, Oxitec
released in the Brazilian city of Piracicaba, and in January
withdrew its application for an EUP. Oxitec researchers
2016, Oxitec announced plans to scale up the program and
subsequently developed a second-generation GE mosquito.
expand its OX513A production capacity. Panama also field
EPA granted an EUP to Oxitec in May 2020 to test the
tested the OX513A mosquitoes in 2014.
efficacy of this second-generation GE mosquito expressing
the tTAV-OX5034 protein. EPA regulates the GE mosquito
In 2016, Brazil’s National Health Surveillance Agency
as a biopesticide under the Federal Insecticide, Fungicide,
granted Oxitec a temporary registration to deploy the GE
and Rodenticide Act (7 U.S.C §136c).
mosquitoes throughout the country. WHO issued a positive
recommendation in support of the OX513A mosquitoes. In
Unlike the first-generation mosquito, eggs of the second-
addition, the Pan-American Health Organization
generation mosquito produce only males, thus reducing the
subsequently provided technical support for countries that
risk of accidental female release. Instead of raising
wish to implement the OX513A mosquitoes.
modified mosquitoes to adulthood before releasing them
Some researchers raised questions about the OX513A
into the wild, the second-generation mosquitoes can be
mosquitoes’ fitness for breeding and whether the males
distributed as eggs in boxes. A box containing eggs can be
could evolve resistance to the lethal gene. Males are
placed in a back yard and filled with water, after which the
mechanically sorted in the laboratory, resulting in less than
males hatch. When the male mosquitoes emerge, they fly
0.01% females accidently released. This could lead to a
away into the neighborhood to mate. The previous proposed
small but temporary increase in the number of biting
method required adult mosquitoes to be raised near the test
mosquitoes.
site and then released via the use of a specially equipped
van. With the first generation, released males mated with a
Environmental Assessment of GE Mosquitoes
female in the wild, and all of the offspring—male and
Oxitec applied for an Experimental Use Permit (EUP) to
female—would die. With the second generation, only the
field test the OX513A mosquitoes in the Florida Keys in
females are targeted. Male progeny survive, carrying the
2011. In 2012, the Key West City Commission passed a
lethal gene to its offspring, which are male only.
resolution objecting to the release of the OX513A
mosquitoes. The FDA Center for Veterinary Medicine
In June, the Center for Food Safety (CFS) filed a notice of
conducted an Environmental Assessment of OX513A under
intent to sue unless EPA revokes Oxitec’s EUP to test the
its Investigational New Animal Drug regulatory process. In
second-generation mosquito in Monroe County, FL, and
2016, FDA published its Preliminary Finding of No
Harris County, TX. CFS’s notice charges that the EUP is a
Significant Impact (FONSI) for proposed field testing the
violation of Section 7 of the Endangered Species Act.
OX513A. After a 60-day comment period, FDA published
its final Environmental Assessment and associated FONSI,
Tadlock Cowan, Analyst in Natural Resources and Rural
which allowed Oxitec to begin field trials.
Development
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Genetically Engineered Mosquitoes: A Vector Control Technology for Reducing Virus Transmission

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