In the Journals

Dengue vaccine shows full protection in human challenge model

A dengue vaccine currently in phase 3 development was 100% effective at preventing the disease, according to the results of a small clinical trial in which volunteers were inoculated and then given a weakened dose of the most difficult dengue virus serotype to prevent 6 months later.

“The bottom line is the vaccine appears to be 100% effective at preventing a dengue [serotype] 2 infection,” Beth D. Kirkpatrick, MD, professor of medicine at the University of Vermont and investigator of a study about the vaccine, TV003, said during a teleconference with reporters.

Beth Kirkpatrick, MD

Beth D. Kirkpatrick

Human challenge model used

Kirkpatrick and colleagues used a human challenge model to test the efficacy of TV003, a live-attenuated tetravalent vaccine that was developed by the NIH’s National Institute of Allergy and Infectious Diseases and is currently undergoing a phase 3 trial in Brazil.

The study included 41 healthy participants — 21 who were given the vaccine and 20 assigned placebo. Each participant given the TV003 vaccine was protected from a weakened dose of dengue serotype 2 virus at 6 months, while all placebo group participants tested positive for the virus and developed mild symptoms such as rash and low white blood cell count, according to Kirkpatrick and colleagues.

The researchers said human challenge models may help identify promising vaccine candidates while weeding out poor ones before they reach much larger trials.

Their results were published in Science Translational Medicine.

“We believe the dengue human challenge infection model is an extremely useful tool, not only for the acceleration of vaccine development, but also [for] moving therapeutics through clinical trials and for better understanding the biological and immune response to dengue,” researcher Anna P. Durbin, MD, associate professor at Johns Hopkins University Bloomberg School of Public Health, said during the teleconference.

According to Kirkpatrick, human challenge models have been used in the past to study other infectious diseases, including malaria, norovirus, influenza, cholera, Campylobacter and Shigella.

The method can accelerate vaccine production and development if conducted properly, according to Kirkpatrick.

“It has to be used extremely carefully,” she said. “It can only be used in selective diseases in which when you’re going to be purposefully infecting someone, you have to know that it’s a completely controllable situation, that it’s a mild and completely controlled infection. So it’s only selectively used when the clinicians can 100% assure safety of the volunteers and would never be used in infections that you couldn’t.”

The need for a dengue vaccine

Dengue is the most common mosquito-borne virus in the world and is responsible for an estimated 400 million infections annually, according to Stephen S. Whitehead, PhD, of NIAID, another study investigator. Protecting against it, however, has been a challenge, particularly because an effective vaccine needs to prevent all four serotypes. A partially effective vaccine is dangerous, putting patients who were infected with one serotype at risk for more serious symptoms if they are infected with another.

Research on a dengue vaccine has been conducted for almost 100 years, according to Whitehead, and there are several candidates in different stages of development. In that climate, the human challenge model used to study TV003 gave researchers a way to safely demonstrate the vaccine’s efficacy on a small scale. The study was a “really remarkable success,” according to Whitehead.

“We really wanted to have an early clue that it was going to work,” he said.

A phase 3 trial of TV003 began on Feb. 22 and is being conducted by the Butantan Institute in Brazil, Durbin said. It will include a 5-year follow-up period.

“The results of our challenge study helped to inform Butantan which vaccine formulation to take into their phase 3 trial and was extremely helpful to regulators in Brazil who are doing the phase 3 trial,” she said.

The biggest difference between the human challenge model and the phase 3 trial for TV003 is the study size, according to Durbin. She said Brazilian researchers plan to enroll 17,000 adults, adolescents and children for their double blind, randomized phase 3 trial, with two-thirds of the volunteers getting TV003 and one-third receiving placebo.

“The other difference is that you’re following them over time to see when they might develop a clinical endpoint, which in this trial is dengue with any severity,” she said. “In addition, they will be following subjects for an additional 5 years looking for any potential [safety problems].”

A human challenge model for Zika virus?

Amid mounting evidence that Zika virus causes microcephaly and other grave outcomes in developing children, finding a vaccine for the rapidly emerging virus has become a priority for researchers.

Durbin said the experience of evaluating TV003 may lead to the development of a safe human challenge model for other flaviviruses like Zika, and will perhaps help researchers understand it better.

“There is an urgent need for a Zika vaccine,” Durbin said. “We are looking at strategies to really accelerate that timeline, and we think that a Zika human challenge model could be useful in that endeavor.” – by Gerard Gallagher

Disclosure: Whitehead reports being named as an inventor on three patents pertaining to this work. The other researchers report no relevant financial disclosures.

A dengue vaccine currently in phase 3 development was 100% effective at preventing the disease, according to the results of a small clinical trial in which volunteers were inoculated and then given a weakened dose of the most difficult dengue virus serotype to prevent 6 months later.

“The bottom line is the vaccine appears to be 100% effective at preventing a dengue [serotype] 2 infection,” Beth D. Kirkpatrick, MD, professor of medicine at the University of Vermont and investigator of a study about the vaccine, TV003, said during a teleconference with reporters.

Beth Kirkpatrick, MD

Beth D. Kirkpatrick

Human challenge model used

Kirkpatrick and colleagues used a human challenge model to test the efficacy of TV003, a live-attenuated tetravalent vaccine that was developed by the NIH’s National Institute of Allergy and Infectious Diseases and is currently undergoing a phase 3 trial in Brazil.

The study included 41 healthy participants — 21 who were given the vaccine and 20 assigned placebo. Each participant given the TV003 vaccine was protected from a weakened dose of dengue serotype 2 virus at 6 months, while all placebo group participants tested positive for the virus and developed mild symptoms such as rash and low white blood cell count, according to Kirkpatrick and colleagues.

The researchers said human challenge models may help identify promising vaccine candidates while weeding out poor ones before they reach much larger trials.

Their results were published in Science Translational Medicine.

“We believe the dengue human challenge infection model is an extremely useful tool, not only for the acceleration of vaccine development, but also [for] moving therapeutics through clinical trials and for better understanding the biological and immune response to dengue,” researcher Anna P. Durbin, MD, associate professor at Johns Hopkins University Bloomberg School of Public Health, said during the teleconference.

According to Kirkpatrick, human challenge models have been used in the past to study other infectious diseases, including malaria, norovirus, influenza, cholera, Campylobacter and Shigella.

The method can accelerate vaccine production and development if conducted properly, according to Kirkpatrick.

“It has to be used extremely carefully,” she said. “It can only be used in selective diseases in which when you’re going to be purposefully infecting someone, you have to know that it’s a completely controllable situation, that it’s a mild and completely controlled infection. So it’s only selectively used when the clinicians can 100% assure safety of the volunteers and would never be used in infections that you couldn’t.”

The need for a dengue vaccine

Dengue is the most common mosquito-borne virus in the world and is responsible for an estimated 400 million infections annually, according to Stephen S. Whitehead, PhD, of NIAID, another study investigator. Protecting against it, however, has been a challenge, particularly because an effective vaccine needs to prevent all four serotypes. A partially effective vaccine is dangerous, putting patients who were infected with one serotype at risk for more serious symptoms if they are infected with another.

Research on a dengue vaccine has been conducted for almost 100 years, according to Whitehead, and there are several candidates in different stages of development. In that climate, the human challenge model used to study TV003 gave researchers a way to safely demonstrate the vaccine’s efficacy on a small scale. The study was a “really remarkable success,” according to Whitehead.

“We really wanted to have an early clue that it was going to work,” he said.

A phase 3 trial of TV003 began on Feb. 22 and is being conducted by the Butantan Institute in Brazil, Durbin said. It will include a 5-year follow-up period.

“The results of our challenge study helped to inform Butantan which vaccine formulation to take into their phase 3 trial and was extremely helpful to regulators in Brazil who are doing the phase 3 trial,” she said.

The biggest difference between the human challenge model and the phase 3 trial for TV003 is the study size, according to Durbin. She said Brazilian researchers plan to enroll 17,000 adults, adolescents and children for their double blind, randomized phase 3 trial, with two-thirds of the volunteers getting TV003 and one-third receiving placebo.

“The other difference is that you’re following them over time to see when they might develop a clinical endpoint, which in this trial is dengue with any severity,” she said. “In addition, they will be following subjects for an additional 5 years looking for any potential [safety problems].”

A human challenge model for Zika virus?

Amid mounting evidence that Zika virus causes microcephaly and other grave outcomes in developing children, finding a vaccine for the rapidly emerging virus has become a priority for researchers.

Durbin said the experience of evaluating TV003 may lead to the development of a safe human challenge model for other flaviviruses like Zika, and will perhaps help researchers understand it better.

“There is an urgent need for a Zika vaccine,” Durbin said. “We are looking at strategies to really accelerate that timeline, and we think that a Zika human challenge model could be useful in that endeavor.” – by Gerard Gallagher

Disclosure: Whitehead reports being named as an inventor on three patents pertaining to this work. The other researchers report no relevant financial disclosures.