Vaccines in the Pipeline For Diseases Affecting Children Worldwide

VAIL, COLO. – Effective vaccines for two of the top causes of mortality and morbidity in children worldwide – malaria and dengue fever – are now in pivotal phase III clinical trials and could reach the market within 3 years.

In addition, promising vaccines for tuberculosis and group B streptococcus are in earlier-stage clinical trials, Dr. Edwin J. Asturias noted at a conference on pediatric infectious diseases, which was sponsored by the Children’s Hospital Colorado in Aurora.

Malaria

"The malaria vaccine is coming. It is close. It will be the most important vaccine for killer diseases in children. There is a lot of hope for that vaccine," according to Dr. Asturias of the center for global health at the University of Colorado, Denver.

Courtesy Jim Gathany/CDC

Malaria is endemic in 99 countries. An estimated 216 million new cases and 655,000 deaths resulting from the infection occurred in 2010. More than 90% of the world’s malaria deaths are in Africa, with most of them in children younger than age 5 years.

The malaria vaccine – now in the pivotal phase III MAL059 trial that’s expected to be completed by 2014 – has been in development by GlaxoSmithKline for 2 decades. The vaccine is known as RTS,S. It is designed for children living in endemic areas. The vaccine focuses on the pre-erythrocytic stage of infection, aiming to prevent the malaria parasite from multiplying in the liver and reentering the bloodstream.

In an interim report from the phase III trial, the three-dose series of RTS,S achieved a 56% reduction in clinical malaria among 5- to 17-month-olds (N. Engl. J. Med. 2008;359:2521-32).

"The question everybody has is, is 56% enough, or should we aim for higher efficacy in malaria?" the pediatric infectious disease specialist said.

For him, the answer is clear: "If we can reduce mortality from malaria by 50%, that would be a great success in terms of preventing this important killer around the world," Dr. Asturias said.

But the benefits will extend well beyond mortality reduction to include nationwide favorable impacts upon lost days of productivity and strain on health care systems. "In countries where malaria is endemic, every case of fever gets treated as malaria, and that’s a huge burden in terms of health resource utilization," he added.

It’s also hypothetically possible that herd immunity could amplify the clinical efficacy of RTS,S beyond that 56% figure. It all depends upon how good the vaccine is at quelling parasitemia, an issue that hasn’t been well studied as yet.

Frequent boosting may be necessary for several years after the three-dose series is given. In studies in African infants and children, the protective effect has been sustained for only about 18 months.

Much of the credit for the recent major advances in developing new vaccines for important childhood diseases worldwide belongs to an ongoing UNICEF/WHO initiative and to the Bill and Melinda Gates Foundation, which Dr. Asturias said "has been a game changer." During this decade, the foundation’s declared aim is to utilize existing vaccines and to support development of new ones in order to prevent the deaths of 7.6 million children younger than age 5 years.

Dengue Virus

Sanofi Pasteur’s chimeric flavivirus vaccine is in phase III studies totaling more than 30,000 participants in Latin America and Asia. These pivotal trials will be completed in 2014. The company is sufficiently confident that it has a winner that it has built a $440 million factory to produce the vaccine.

In a phase IIB clinical trial conducted in Thai children, the vaccine – which has received fast-track development status from the Food and Drug Administration – protected against three of the four dengue virus serotypes, which means it should decrease the incidence of dengue hemorrhagic fever, the most feared manifestation of the viral infection.

Other dengue vaccines using alternative immunization strategies are in earlier stages of development.

In countries where the mosquito-borne dengue virus is endemic and reporting is adequate, the incidence of infection is about 5% per year (Vaccine 2002;20:3043-6). Three-quarters of infections are asymptomatic or entail only a few days of mild flulike illness. Among the 25% of infections that are symptomatic, 98%-99% result in dengue fever, also known as "breakbone fever," whereas 1%-2% manifest as dengue hemorrhagic fever, which has a mortality rate of up to 5% depending upon the availability of supportive care. The infection is more severe in school-age youths and in individuals infected for the second time.

Tuberculosis

Twelve new candidate TB vaccines have entered clinical trials. Seven are subunit vaccines, two utilize immunotherapy as an adjunct to chemotherapy, and three are recombinant bacille Calmette-Guérin vaccines designed to replace the current BCG vaccine, which doesn’t protect adults from reactivation or reinfection decades after their first exposure to the pathogen. The two most advanced candidate vaccines are now in phase IIB trials; they are designed to enhance immunity in individuals who received BCG vaccine early in life. Phase II studies are likely to continue to 2020.

"We’re still far away from a good tuberculosis vaccine at this point," according to Dr. Asturias.

The most pressing need now is to define markers for TB infection and reactivation so that researchers can demonstrate vaccine efficacy without having to wait 30 years for pulmonary TB or other clinical disease to develop, he added.

Group B Streptococcus

The push to develop a group B strep vaccine stems from the fact that in developing countries, this infection is a leading cause of sepsis and meningitis in the first 3 months of life. And worldwide, the proportion of deaths in children younger than age 5 years that occur during the neonatal period hasn’t changed in 2 decades. A UNICEF/WHO estimate concluded that of 8.8 million deaths in children younger than age 5 years in 2008, 42% occurred in neonates. A maternal group B strep vaccine is key to reducing that disturbing figure, in Dr. Asturias’s view.

There are at least 10 group B strep serotypes, but most disease is caused by three of them. A Novartis trivalent vaccine showed "very promising" results in a phase I study; a phase III clinical trial for prevention of disease in pregnant women is scheduled to get underway late next year, he said.

Dr. Asturias reported having conducted vaccine research studies sponsored by Sanofi Pasteur and Crucell, serving on data safety monitoring boards for Inviragen, Sanofi Pasteur, and PATH, and acting as a consultant to the Bill and Melinda Gates Foundation.

VAIL, COLO. – Effective vaccines for two of the top causes of mortality and morbidity in children worldwide – malaria and dengue fever – are now in pivotal phase III clinical trials and could reach the market within 3 years.

In addition, promising vaccines for tuberculosis and group B streptococcus are in earlier-stage clinical trials, Dr. Edwin J. Asturias noted at a conference on pediatric infectious diseases, which was sponsored by the Children’s Hospital Colorado in Aurora.

Malaria

"The malaria vaccine is coming. It is close. It will be the most important vaccine for killer diseases in children. There is a lot of hope for that vaccine," according to Dr. Asturias of the center for global health at the University of Colorado, Denver.

Courtesy Jim Gathany/CDC

Malaria is endemic in 99 countries. An estimated 216 million new cases and 655,000 deaths resulting from the infection occurred in 2010. More than 90% of the world’s malaria deaths are in Africa, with most of them in children younger than age 5 years.

The malaria vaccine – now in the pivotal phase III MAL059 trial that’s expected to be completed by 2014 – has been in development by GlaxoSmithKline for 2 decades. The vaccine is known as RTS,S. It is designed for children living in endemic areas. The vaccine focuses on the pre-erythrocytic stage of infection, aiming to prevent the malaria parasite from multiplying in the liver and reentering the bloodstream.

In an interim report from the phase III trial, the three-dose series of RTS,S achieved a 56% reduction in clinical malaria among 5- to 17-month-olds (N. Engl. J. Med. 2008;359:2521-32).

"The question everybody has is, is 56% enough, or should we aim for higher efficacy in malaria?" the pediatric infectious disease specialist said.

For him, the answer is clear: "If we can reduce mortality from malaria by 50%, that would be a great success in terms of preventing this important killer around the world," Dr. Asturias said.

But the benefits will extend well beyond mortality reduction to include nationwide favorable impacts upon lost days of productivity and strain on health care systems. "In countries where malaria is endemic, every case of fever gets treated as malaria, and that’s a huge burden in terms of health resource utilization," he added.

It’s also hypothetically possible that herd immunity could amplify the clinical efficacy of RTS,S beyond that 56% figure. It all depends upon how good the vaccine is at quelling parasitemia, an issue that hasn’t been well studied as yet.

Frequent boosting may be necessary for several years after the three-dose series is given. In studies in African infants and children, the protective effect has been sustained for only about 18 months.

Much of the credit for the recent major advances in developing new vaccines for important childhood diseases worldwide belongs to an ongoing UNICEF/WHO initiative and to the Bill and Melinda Gates Foundation, which Dr. Asturias said "has been a game changer." During this decade, the foundation’s declared aim is to utilize existing vaccines and to support development of new ones in order to prevent the deaths of 7.6 million children younger than age 5 years.

Dengue Virus

Sanofi Pasteur’s chimeric flavivirus vaccine is in phase III studies totaling more than 30,000 participants in Latin America and Asia. These pivotal trials will be completed in 2014. The company is sufficiently confident that it has a winner that it has built a $440 million factory to produce the vaccine.

In a phase IIB clinical trial conducted in Thai children, the vaccine – which has received fast-track development status from the Food and Drug Administration – protected against three of the four dengue virus serotypes, which means it should decrease the incidence of dengue hemorrhagic fever, the most feared manifestation of the viral infection.

Other dengue vaccines using alternative immunization strategies are in earlier stages of development.

In countries where the mosquito-borne dengue virus is endemic and reporting is adequate, the incidence of infection is about 5% per year (Vaccine 2002;20:3043-6). Three-quarters of infections are asymptomatic or entail only a few days of mild flulike illness. Among the 25% of infections that are symptomatic, 98%-99% result in dengue fever, also known as "breakbone fever," whereas 1%-2% manifest as dengue hemorrhagic fever, which has a mortality rate of up to 5% depending upon the availability of supportive care. The infection is more severe in school-age youths and in individuals infected for the second time.

Tuberculosis

Twelve new candidate TB vaccines have entered clinical trials. Seven are subunit vaccines, two utilize immunotherapy as an adjunct to chemotherapy, and three are recombinant bacille Calmette-Guérin vaccines designed to replace the current BCG vaccine, which doesn’t protect adults from reactivation or reinfection decades after their first exposure to the pathogen. The two most advanced candidate vaccines are now in phase IIB trials; they are designed to enhance immunity in individuals who received BCG vaccine early in life. Phase II studies are likely to continue to 2020.

"We’re still far away from a good tuberculosis vaccine at this point," according to Dr. Asturias.

The most pressing need now is to define markers for TB infection and reactivation so that researchers can demonstrate vaccine efficacy without having to wait 30 years for pulmonary TB or other clinical disease to develop, he added.

Group B Streptococcus

The push to develop a group B strep vaccine stems from the fact that in developing countries, this infection is a leading cause of sepsis and meningitis in the first 3 months of life. And worldwide, the proportion of deaths in children younger than age 5 years that occur during the neonatal period hasn’t changed in 2 decades. A UNICEF/WHO estimate concluded that of 8.8 million deaths in children younger than age 5 years in 2008, 42% occurred in neonates. A maternal group B strep vaccine is key to reducing that disturbing figure, in Dr. Asturias’s view.

There are at least 10 group B strep serotypes, but most disease is caused by three of them. A Novartis trivalent vaccine showed "very promising" results in a phase I study; a phase III clinical trial for prevention of disease in pregnant women is scheduled to get underway late next year, he said.

Dr. Asturias reported having conducted vaccine research studies sponsored by Sanofi Pasteur and Crucell, serving on data safety monitoring boards for Inviragen, Sanofi Pasteur, and PATH, and acting as a consultant to the Bill and Melinda Gates Foundation.

VAIL, COLO. – Effective vaccines for two of the top causes of mortality and morbidity in children worldwide – malaria and dengue fever – are now in pivotal phase III clinical trials and could reach the market within 3 years.

In addition, promising vaccines for tuberculosis and group B streptococcus are in earlier-stage clinical trials, Dr. Edwin J. Asturias noted at a conference on pediatric infectious diseases, which was sponsored by the Children’s Hospital Colorado in Aurora.

Malaria

"The malaria vaccine is coming. It is close. It will be the most important vaccine for killer diseases in children. There is a lot of hope for that vaccine," according to Dr. Asturias of the center for global health at the University of Colorado, Denver.

Courtesy Jim Gathany/CDC

Malaria is endemic in 99 countries. An estimated 216 million new cases and 655,000 deaths resulting from the infection occurred in 2010. More than 90% of the world’s malaria deaths are in Africa, with most of them in children younger than age 5 years.

The malaria vaccine – now in the pivotal phase III MAL059 trial that’s expected to be completed by 2014 – has been in development by GlaxoSmithKline for 2 decades. The vaccine is known as RTS,S. It is designed for children living in endemic areas. The vaccine focuses on the pre-erythrocytic stage of infection, aiming to prevent the malaria parasite from multiplying in the liver and reentering the bloodstream.

In an interim report from the phase III trial, the three-dose series of RTS,S achieved a 56% reduction in clinical malaria among 5- to 17-month-olds (N. Engl. J. Med. 2008;359:2521-32).

"The question everybody has is, is 56% enough, or should we aim for higher efficacy in malaria?" the pediatric infectious disease specialist said.

For him, the answer is clear: "If we can reduce mortality from malaria by 50%, that would be a great success in terms of preventing this important killer around the world," Dr. Asturias said.

But the benefits will extend well beyond mortality reduction to include nationwide favorable impacts upon lost days of productivity and strain on health care systems. "In countries where malaria is endemic, every case of fever gets treated as malaria, and that’s a huge burden in terms of health resource utilization," he added.

It’s also hypothetically possible that herd immunity could amplify the clinical efficacy of RTS,S beyond that 56% figure. It all depends upon how good the vaccine is at quelling parasitemia, an issue that hasn’t been well studied as yet.

Frequent boosting may be necessary for several years after the three-dose series is given. In studies in African infants and children, the protective effect has been sustained for only about 18 months.

Much of the credit for the recent major advances in developing new vaccines for important childhood diseases worldwide belongs to an ongoing UNICEF/WHO initiative and to the Bill and Melinda Gates Foundation, which Dr. Asturias said "has been a game changer." During this decade, the foundation’s declared aim is to utilize existing vaccines and to support development of new ones in order to prevent the deaths of 7.6 million children younger than age 5 years.

Dengue Virus

Sanofi Pasteur’s chimeric flavivirus vaccine is in phase III studies totaling more than 30,000 participants in Latin America and Asia. These pivotal trials will be completed in 2014. The company is sufficiently confident that it has a winner that it has built a $440 million factory to produce the vaccine.

In a phase IIB clinical trial conducted in Thai children, the vaccine – which has received fast-track development status from the Food and Drug Administration – protected against three of the four dengue virus serotypes, which means it should decrease the incidence of dengue hemorrhagic fever, the most feared manifestation of the viral infection.

Other dengue vaccines using alternative immunization strategies are in earlier stages of development.

In countries where the mosquito-borne dengue virus is endemic and reporting is adequate, the incidence of infection is about 5% per year (Vaccine 2002;20:3043-6). Three-quarters of infections are asymptomatic or entail only a few days of mild flulike illness. Among the 25% of infections that are symptomatic, 98%-99% result in dengue fever, also known as "breakbone fever," whereas 1%-2% manifest as dengue hemorrhagic fever, which has a mortality rate of up to 5% depending upon the availability of supportive care. The infection is more severe in school-age youths and in individuals infected for the second time.

Tuberculosis

Twelve new candidate TB vaccines have entered clinical trials. Seven are subunit vaccines, two utilize immunotherapy as an adjunct to chemotherapy, and three are recombinant bacille Calmette-Guérin vaccines designed to replace the current BCG vaccine, which doesn’t protect adults from reactivation or reinfection decades after their first exposure to the pathogen. The two most advanced candidate vaccines are now in phase IIB trials; they are designed to enhance immunity in individuals who received BCG vaccine early in life. Phase II studies are likely to continue to 2020.

"We’re still far away from a good tuberculosis vaccine at this point," according to Dr. Asturias.

The most pressing need now is to define markers for TB infection and reactivation so that researchers can demonstrate vaccine efficacy without having to wait 30 years for pulmonary TB or other clinical disease to develop, he added.

Group B Streptococcus

The push to develop a group B strep vaccine stems from the fact that in developing countries, this infection is a leading cause of sepsis and meningitis in the first 3 months of life. And worldwide, the proportion of deaths in children younger than age 5 years that occur during the neonatal period hasn’t changed in 2 decades. A UNICEF/WHO estimate concluded that of 8.8 million deaths in children younger than age 5 years in 2008, 42% occurred in neonates. A maternal group B strep vaccine is key to reducing that disturbing figure, in Dr. Asturias’s view.

There are at least 10 group B strep serotypes, but most disease is caused by three of them. A Novartis trivalent vaccine showed "very promising" results in a phase I study; a phase III clinical trial for prevention of disease in pregnant women is scheduled to get underway late next year, he said.

Dr. Asturias reported having conducted vaccine research studies sponsored by Sanofi Pasteur and Crucell, serving on data safety monitoring boards for Inviragen, Sanofi Pasteur, and PATH, and acting as a consultant to the Bill and Melinda Gates Foundation.