Promising nonvaccine approaches to controlling dengue

SAN DIEGO – In the aftermath of the latest somewhat disappointing report on the effort to develop a dengue vaccine, novel nonvaccine approaches aimed at curbing this rapidly growing public health problem are drawing renewed attention, Eva Harris, Ph.D., declared at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

These promising nonvaccine tools fall into several categories: vector control using genetically modified mosquitoes, development of new and better insecticides, and communitywide nonpesticide-based source reduction programs, explained Dr. Harris, professor of infectious diseases and vaccinology and director of the Center for Global Public Health at the University of California, Berkeley.

Many dengue experts, Dr. Harris among them, were disappointed in the recently reported long-term results of several large clinical trials of the candidate dengue vaccine furthest along in the developmental pipeline. The Sanofi Pasteur vaccine, known as CYD-TDV, is due for review and potential registration by the World Health Organization next year. The latest results show favorable safety but suboptimal efficacy. On the plus side, the data showed that children aged 9-16 years continued to benefit 3-4 years after vaccination. There was, however, a disturbing finding: children younger than 9 years of age at vaccination had an increased risk of hospitalization for dengue when they were naturally infected in the third year following vaccination (N Engl J Med. 2015;373[13]:1195-206).

In an accompanying editorial titled “A Candidate Dengue Vaccine Walks a Tightrope,” Dr. Cameron P. Simmons called the latter finding “a particularly unwelcome outcome” that, if not due to chance, raises the possibility that immunization of young children elicits only transient antibody-mediated immunity. As their antibody titers wane over time, these vaccinated children may, through sensitization, be predisposed to clinical dengue infections that are sufficiently serious to warrant hospitalization. It’s possible, but unproved, that booster doses of the vaccine might circumvent this problem, he added.

“The bumpy road to a vaccine-based solution for dengue continues,” observed Dr. Simmons of the University of Melbourne (N Engl J Med. 2015;373[13]:1263-4).

Dr. Harris noted that two other vaccines, one sponsored by the National Institutes of Health and the other by Takeda, are due to start large, long-term phase-III clinical trials in the next few months. And Merck and GlaxoSmithKline have next-generation vaccines in phase-I studies. But possible consideration of any of these vaccines for regulatory approval is a long ways off, and her focus at ICAAC 2015 was on nonvaccine solutions.

She and her coinvestigators recently published positive results of their landmark randomized controlled trial of a pesticide-free, community-based mobilization program for dengue prevention known as the Camino Verde, or Green Way (BMJ. 2015;351:h3267).

The impetus for this program was recognition of the shortcomings of current dengue control efforts, which rely heavily upon massive use of the organophosphate pesticide temephos (Abate) in household water containers where the mosquito vectors breed. The pesticide program hasn’t prevented ongoing rapid growth of the dengue pandemic. Moreover, the associated human toxicity and negative environmental effects are a mounting concern.

Camino Verde is a nonchemical alternative approach in which facilitators run intervention design groups in neighborhoods to inform community leaders and other residents about the scope of their local dengue mosquito problem based upon entomologic survey results and then help develop consensus regarding community-specific programs for chemical-free prevention of mosquito reproduction. Popular options included introduction of fish into water storage containers, cleanup campaigns targeting abandoned tires and other standing-water sources, and scrubbing and covering water tanks. Allowing each participating site to select its own interventions encouraged strong community support, Dr. Harris explained.

The prospective Camino Verde study involved nearly 19,000 households with more than 85,000 residents in Nicaragua and Mexico. Clusters of households were randomized to continuation of the temephos-based, government-run dengue control program with or without adding on the Camino Verde intervention.

Among the key findings: There was a 30% lower risk of serologic infection with dengue virus among children from intervention sites, as well as a 25% reduction in dengue illness among people of all ages. The numbers needed to treat were 30 for a reduced risk of infection in children and 71 for a lower risk of illness. Investigators also documented a 44% reduction in houses containing Aedes aegypti larvae or pupae in Camino Verde–participating sites, compared with control communities.

This study provides the first-ever solid serologic evidence that a pesticide-free community mobilization effort has a positive impact on dengue infection. The logical next step is for governments in dengue-endemic countries to adopt such an approach, she said.

At least three different strategies of genetic modification of dengue-vector mosquitoes are being pursued in an effort to reduce dengue transmission. All show promise as partial solutions, in Dr. Harris’ view.

Release of sterile transgenic A. aegypti males over the course of a year in a Brazilian suburb resulted in a 95% reduction in the size of the local A. aegypti population, compared with an adjacent control area (PLoS Negl Trop Dis. 2015;9[7]:e0003864). Investigators at Colorado State University in Fort Collins have developed a transgenic strain of A. aegypti males carrying a dominant lethal gene resulting in next-generation flightless females that can’t mate or avoid predators (Proc Natl Acad Sci U S A. 2011;108[12]:4772-5).

In another approach, an international collaborative group has performed field-release trials of A. aegypti mosquitoes deliberately infected with a strain of the intracellular bacterium Wolbachia, which renders the insects resistant to dengue virus infection. The group’s mathematical modeling suggested widespread adoption of this approach would reduce dengue virus transmission by 66%-75%. The investigators predicted this would be sufficient to eliminate dengue in low- or moderate-transmission areas but probably wouldn’t accomplish complete control in the highest-risk areas (Sci Transl Med. 2015;7[279]:279ra37).

Dr. Harris reported that the Camino Verde trial was funded by the UBS Optimus Foundation. She reported having no financial conflicts of interest.

[email protected]

SAN DIEGO – In the aftermath of the latest somewhat disappointing report on the effort to develop a dengue vaccine, novel nonvaccine approaches aimed at curbing this rapidly growing public health problem are drawing renewed attention, Eva Harris, Ph.D., declared at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

These promising nonvaccine tools fall into several categories: vector control using genetically modified mosquitoes, development of new and better insecticides, and communitywide nonpesticide-based source reduction programs, explained Dr. Harris, professor of infectious diseases and vaccinology and director of the Center for Global Public Health at the University of California, Berkeley.

Many dengue experts, Dr. Harris among them, were disappointed in the recently reported long-term results of several large clinical trials of the candidate dengue vaccine furthest along in the developmental pipeline. The Sanofi Pasteur vaccine, known as CYD-TDV, is due for review and potential registration by the World Health Organization next year. The latest results show favorable safety but suboptimal efficacy. On the plus side, the data showed that children aged 9-16 years continued to benefit 3-4 years after vaccination. There was, however, a disturbing finding: children younger than 9 years of age at vaccination had an increased risk of hospitalization for dengue when they were naturally infected in the third year following vaccination (N Engl J Med. 2015;373[13]:1195-206).

In an accompanying editorial titled “A Candidate Dengue Vaccine Walks a Tightrope,” Dr. Cameron P. Simmons called the latter finding “a particularly unwelcome outcome” that, if not due to chance, raises the possibility that immunization of young children elicits only transient antibody-mediated immunity. As their antibody titers wane over time, these vaccinated children may, through sensitization, be predisposed to clinical dengue infections that are sufficiently serious to warrant hospitalization. It’s possible, but unproved, that booster doses of the vaccine might circumvent this problem, he added.

“The bumpy road to a vaccine-based solution for dengue continues,” observed Dr. Simmons of the University of Melbourne (N Engl J Med. 2015;373[13]:1263-4).

Dr. Harris noted that two other vaccines, one sponsored by the National Institutes of Health and the other by Takeda, are due to start large, long-term phase-III clinical trials in the next few months. And Merck and GlaxoSmithKline have next-generation vaccines in phase-I studies. But possible consideration of any of these vaccines for regulatory approval is a long ways off, and her focus at ICAAC 2015 was on nonvaccine solutions.

She and her coinvestigators recently published positive results of their landmark randomized controlled trial of a pesticide-free, community-based mobilization program for dengue prevention known as the Camino Verde, or Green Way (BMJ. 2015;351:h3267).

The impetus for this program was recognition of the shortcomings of current dengue control efforts, which rely heavily upon massive use of the organophosphate pesticide temephos (Abate) in household water containers where the mosquito vectors breed. The pesticide program hasn’t prevented ongoing rapid growth of the dengue pandemic. Moreover, the associated human toxicity and negative environmental effects are a mounting concern.

Camino Verde is a nonchemical alternative approach in which facilitators run intervention design groups in neighborhoods to inform community leaders and other residents about the scope of their local dengue mosquito problem based upon entomologic survey results and then help develop consensus regarding community-specific programs for chemical-free prevention of mosquito reproduction. Popular options included introduction of fish into water storage containers, cleanup campaigns targeting abandoned tires and other standing-water sources, and scrubbing and covering water tanks. Allowing each participating site to select its own interventions encouraged strong community support, Dr. Harris explained.

The prospective Camino Verde study involved nearly 19,000 households with more than 85,000 residents in Nicaragua and Mexico. Clusters of households were randomized to continuation of the temephos-based, government-run dengue control program with or without adding on the Camino Verde intervention.

Among the key findings: There was a 30% lower risk of serologic infection with dengue virus among children from intervention sites, as well as a 25% reduction in dengue illness among people of all ages. The numbers needed to treat were 30 for a reduced risk of infection in children and 71 for a lower risk of illness. Investigators also documented a 44% reduction in houses containing Aedes aegypti larvae or pupae in Camino Verde–participating sites, compared with control communities.

This study provides the first-ever solid serologic evidence that a pesticide-free community mobilization effort has a positive impact on dengue infection. The logical next step is for governments in dengue-endemic countries to adopt such an approach, she said.

At least three different strategies of genetic modification of dengue-vector mosquitoes are being pursued in an effort to reduce dengue transmission. All show promise as partial solutions, in Dr. Harris’ view.

Release of sterile transgenic A. aegypti males over the course of a year in a Brazilian suburb resulted in a 95% reduction in the size of the local A. aegypti population, compared with an adjacent control area (PLoS Negl Trop Dis. 2015;9[7]:e0003864). Investigators at Colorado State University in Fort Collins have developed a transgenic strain of A. aegypti males carrying a dominant lethal gene resulting in next-generation flightless females that can’t mate or avoid predators (Proc Natl Acad Sci U S A. 2011;108[12]:4772-5).

In another approach, an international collaborative group has performed field-release trials of A. aegypti mosquitoes deliberately infected with a strain of the intracellular bacterium Wolbachia, which renders the insects resistant to dengue virus infection. The group’s mathematical modeling suggested widespread adoption of this approach would reduce dengue virus transmission by 66%-75%. The investigators predicted this would be sufficient to eliminate dengue in low- or moderate-transmission areas but probably wouldn’t accomplish complete control in the highest-risk areas (Sci Transl Med. 2015;7[279]:279ra37).

Dr. Harris reported that the Camino Verde trial was funded by the UBS Optimus Foundation. She reported having no financial conflicts of interest.

[email protected]

SAN DIEGO – In the aftermath of the latest somewhat disappointing report on the effort to develop a dengue vaccine, novel nonvaccine approaches aimed at curbing this rapidly growing public health problem are drawing renewed attention, Eva Harris, Ph.D., declared at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

These promising nonvaccine tools fall into several categories: vector control using genetically modified mosquitoes, development of new and better insecticides, and communitywide nonpesticide-based source reduction programs, explained Dr. Harris, professor of infectious diseases and vaccinology and director of the Center for Global Public Health at the University of California, Berkeley.

Many dengue experts, Dr. Harris among them, were disappointed in the recently reported long-term results of several large clinical trials of the candidate dengue vaccine furthest along in the developmental pipeline. The Sanofi Pasteur vaccine, known as CYD-TDV, is due for review and potential registration by the World Health Organization next year. The latest results show favorable safety but suboptimal efficacy. On the plus side, the data showed that children aged 9-16 years continued to benefit 3-4 years after vaccination. There was, however, a disturbing finding: children younger than 9 years of age at vaccination had an increased risk of hospitalization for dengue when they were naturally infected in the third year following vaccination (N Engl J Med. 2015;373[13]:1195-206).

In an accompanying editorial titled “A Candidate Dengue Vaccine Walks a Tightrope,” Dr. Cameron P. Simmons called the latter finding “a particularly unwelcome outcome” that, if not due to chance, raises the possibility that immunization of young children elicits only transient antibody-mediated immunity. As their antibody titers wane over time, these vaccinated children may, through sensitization, be predisposed to clinical dengue infections that are sufficiently serious to warrant hospitalization. It’s possible, but unproved, that booster doses of the vaccine might circumvent this problem, he added.

“The bumpy road to a vaccine-based solution for dengue continues,” observed Dr. Simmons of the University of Melbourne (N Engl J Med. 2015;373[13]:1263-4).

Dr. Harris noted that two other vaccines, one sponsored by the National Institutes of Health and the other by Takeda, are due to start large, long-term phase-III clinical trials in the next few months. And Merck and GlaxoSmithKline have next-generation vaccines in phase-I studies. But possible consideration of any of these vaccines for regulatory approval is a long ways off, and her focus at ICAAC 2015 was on nonvaccine solutions.

She and her coinvestigators recently published positive results of their landmark randomized controlled trial of a pesticide-free, community-based mobilization program for dengue prevention known as the Camino Verde, or Green Way (BMJ. 2015;351:h3267).

The impetus for this program was recognition of the shortcomings of current dengue control efforts, which rely heavily upon massive use of the organophosphate pesticide temephos (Abate) in household water containers where the mosquito vectors breed. The pesticide program hasn’t prevented ongoing rapid growth of the dengue pandemic. Moreover, the associated human toxicity and negative environmental effects are a mounting concern.

Camino Verde is a nonchemical alternative approach in which facilitators run intervention design groups in neighborhoods to inform community leaders and other residents about the scope of their local dengue mosquito problem based upon entomologic survey results and then help develop consensus regarding community-specific programs for chemical-free prevention of mosquito reproduction. Popular options included introduction of fish into water storage containers, cleanup campaigns targeting abandoned tires and other standing-water sources, and scrubbing and covering water tanks. Allowing each participating site to select its own interventions encouraged strong community support, Dr. Harris explained.

The prospective Camino Verde study involved nearly 19,000 households with more than 85,000 residents in Nicaragua and Mexico. Clusters of households were randomized to continuation of the temephos-based, government-run dengue control program with or without adding on the Camino Verde intervention.

Among the key findings: There was a 30% lower risk of serologic infection with dengue virus among children from intervention sites, as well as a 25% reduction in dengue illness among people of all ages. The numbers needed to treat were 30 for a reduced risk of infection in children and 71 for a lower risk of illness. Investigators also documented a 44% reduction in houses containing Aedes aegypti larvae or pupae in Camino Verde–participating sites, compared with control communities.

This study provides the first-ever solid serologic evidence that a pesticide-free community mobilization effort has a positive impact on dengue infection. The logical next step is for governments in dengue-endemic countries to adopt such an approach, she said.

At least three different strategies of genetic modification of dengue-vector mosquitoes are being pursued in an effort to reduce dengue transmission. All show promise as partial solutions, in Dr. Harris’ view.

Release of sterile transgenic A. aegypti males over the course of a year in a Brazilian suburb resulted in a 95% reduction in the size of the local A. aegypti population, compared with an adjacent control area (PLoS Negl Trop Dis. 2015;9[7]:e0003864). Investigators at Colorado State University in Fort Collins have developed a transgenic strain of A. aegypti males carrying a dominant lethal gene resulting in next-generation flightless females that can’t mate or avoid predators (Proc Natl Acad Sci U S A. 2011;108[12]:4772-5).

In another approach, an international collaborative group has performed field-release trials of A. aegypti mosquitoes deliberately infected with a strain of the intracellular bacterium Wolbachia, which renders the insects resistant to dengue virus infection. The group’s mathematical modeling suggested widespread adoption of this approach would reduce dengue virus transmission by 66%-75%. The investigators predicted this would be sufficient to eliminate dengue in low- or moderate-transmission areas but probably wouldn’t accomplish complete control in the highest-risk areas (Sci Transl Med. 2015;7[279]:279ra37).

Dr. Harris reported that the Camino Verde trial was funded by the UBS Optimus Foundation. She reported having no financial conflicts of interest.

[email protected]