SAGE backs recommendation to limit dengue vaccination

Upon further review of the dengue vaccine, Dengvaxia, WHO and the Strategic Advisory Group of Experts on Immunization reinforced a recommendation made in December to vaccinate people only in dengue-endemic regions if they are confirmed to have had a prior infection.

“We have clear information now that the vaccine needs to be dealt with in a much safer way by using it exclusively in people who have already been infected with dengue before,” SAGE Chair Alejandro Cravioto, MD, PhD, of the faculty of medicine at the Universidad Nacional Autónoma de México, said during a press conference. “We will continue to review the public health benefit of the vaccine if a country decides to use it under the new recommendation to test whether [patients] have been exposed to dengue or not.”

However, according to one expert, health officials missed signs that the vaccine was causing complications in children.

Dengvaxia concerns

Safety concerns about Dengvaxia (Sanofi Pasteur) arose late last year after the manufacturer announced the vaccine may cause severe disease in nonimmune patients who become infected after vaccination. In response, the Philippines Department of Health (DOH) suspended a dengue immunization program, during which more than 830,000 children received at least one dose of Dengvaxia. In February, health officials in the Philippines reported finding a “causal association” between three pediatric deaths and Dengvaxia vaccination. Two of these deaths may have been caused by vaccine failure, according to the DOH. Officials identified 11 other children who had died after vaccination. Three of these deaths were considered “coincidental,” and two had inadequate information. A temporal association was established in the remaining six children — all of whom died within 30 days of receiving the vaccine.

During the press conference, which was held to summarize the outcomes of the SAGE’s semiannual conference, Cravioto indicated that there was no evidence to suggest Dengvaxia was associated with such severe outcomes when SAGE first recommended its use in 2016.

Image of a child getting vaccinated.
A dengue vaccine that was administered to more than 830,000 children in the Philippines may cause severe disease in patients with no prior dengue virus infection.
Source: Shutterstock.com

“What we had to go over when the recommendations were initially made didn’t have any of this new information that could have only come after the vaccine had been used regularly,” he said. “It is impossible to decide [on] the use of a vaccine [based] on nonexistent evidence. Because the vaccine has been used and we have better information, now we can make an assessment of something we didn’t know then, which is how the vaccine actually behaves in someone who has not been exposed to the virus.”

SAGE established a conditional recommendation in July 2016 to administer Dengvaxia only to individuals aged 9 years or older in endemic regions. Cravioto said this recommendation was made because data from two phase 3 trials showed it was less effective and associated with an increased risk for hospitalization in younger children.

“Certainly, there was information in the clinical trials that children below 9 years of age were either not immunized properly or had adverse events,” he said.

Photo of Scott Halstead
Scott B. Halstead

However, Scott B. Halstead, MD, an adjunct professor in the department of preventive medicine and biometrics, Uniformed Services of the University of Health Sciences in Bethesda, Maryland, said there was evidence from the phase 3 trials to suggest the vaccine may have triggered antibody-dependent enhancement (ADE) in recipients with no prior infection. ADE, he said, occurs when a patient who has recovered from infection with one type of dengue virus develops antibodies that can react with other dengue viruses, making subsequent infections with dengue more severe and potentially fatal. ADE may have been overlooked because of how the clinical trials were designed, according to Halstead.

“I have published several papers using clinical trial data from the SAGE background papers that provide ample evidence that children of any age vaccinated as seronegatives were the ones being hospitalized for breakthrough dengue infections,” Halstead told Infectious Disease News. “WHO’s Dengue Vaccine Advisory Committee and SAGE consistently chose to ignore these published warnings. The retrospective serological data that Sanofi used to identify serostatus of hospitalized children when vaccinated (not yet published) are not new data but serve to confirm my earlier warnings. Data published in 2015 from the Sanofi clinical vaccine efficacy and safety trials reported a component with vaccine-enhanced disease. The incaution SAGE exhibited in dealing with this signal is an indictment of its organizational competence.” 

Because the newer recommendation requires prevaccination screening to determine whether patients are eligible for vaccination, Joachim Hombach, PhD, MPH, executive secretary of SAGE and WHO, said it will be important to have access to a rapid diagnostic test for dengue, which currently does not exist.

“There are tests available, but they are not point-of-care, so their implementation is cumbersome and requires that the person returns,” he said. “We see this as an obstacle in using the vaccine, but we are confident that this will spur the development of a rapid diagnostic test.”

Discussion on malaria, polio, measles and rubella

In addition to Dengvaxia, WHO and SAGE members reviewed information on the investigational RTS,S/AS01 malaria vaccine. Before making recommendations, Cravioto said the organizations need additional data to look into possible safety issues with the vaccine and whether the proposed four-dose schedule will be feasible to use in the real world. These questions will be assessed during a pilot implementation study that Cravioto said will launch soon in three sub-Saharan African countries.

“A lot has to been done in those countries to get them ready to conduct this study appropriately,” said Martin H. Friede, PhD, acting director of WHO’s department of immunization, vaccines and biologicals. “Very specifically, ensuring that they have adequate pharmacovigilance systems set up so that we can reliably monitor the safety of the vaccine and generate appropriate data.”

The pilot implementation study will last for about 3 or 4 years, Friede said.

The experts also discussed progress against other vaccine-preventable diseases, as well as the need to scale up immunization in regions that continue to experience outbreaks.

“It is clear that we have made advances in spite of not meeting all of the goals that were set up in this Global Vaccine Action Plan that started in 2010,” Cravioto said. “There is a critical need to establish a post-2020 strategy, which we will need to revise according to what has been achieved and the issues that are still pending.”

Although polio has largely been contained, Cravioto said the final stage of global eradication has been “constrained by the different groups that are looking into how to certify that there is no more wild virus circulation and, at the same time, that vaccine-derived viruses are controlled.” He also noted that several measles and rubella outbreaks are still reported in different parts of the world, particularly the Americas.

“We hope that by strengthening immunization in countries that are having cases, we will be able to better control these two diseases in the near future,” he said. – by Stephanie Viguers

References:

Halstead S. Hum Vaccin Immunother. 2018;doi:10.1080/21645515.2018.1445448.

Halstead SB. Vaccine. 2017;doi:10.1016/j.vaccine.2017.09.089.

Disclosures: Infectious Disease News was unable to confirm relevant financial disclosures at the time of publication.

Editor’s note: This article has been updated with comments from Halstead.

Upon further review of the dengue vaccine, Dengvaxia, WHO and the Strategic Advisory Group of Experts on Immunization reinforced a recommendation made in December to vaccinate people only in dengue-endemic regions if they are confirmed to have had a prior infection.

“We have clear information now that the vaccine needs to be dealt with in a much safer way by using it exclusively in people who have already been infected with dengue before,” SAGE Chair Alejandro Cravioto, MD, PhD, of the faculty of medicine at the Universidad Nacional Autónoma de México, said during a press conference. “We will continue to review the public health benefit of the vaccine if a country decides to use it under the new recommendation to test whether [patients] have been exposed to dengue or not.”

However, according to one expert, health officials missed signs that the vaccine was causing complications in children.

Dengvaxia concerns

Safety concerns about Dengvaxia (Sanofi Pasteur) arose late last year after the manufacturer announced the vaccine may cause severe disease in nonimmune patients who become infected after vaccination. In response, the Philippines Department of Health (DOH) suspended a dengue immunization program, during which more than 830,000 children received at least one dose of Dengvaxia. In February, health officials in the Philippines reported finding a “causal association” between three pediatric deaths and Dengvaxia vaccination. Two of these deaths may have been caused by vaccine failure, according to the DOH. Officials identified 11 other children who had died after vaccination. Three of these deaths were considered “coincidental,” and two had inadequate information. A temporal association was established in the remaining six children — all of whom died within 30 days of receiving the vaccine.

During the press conference, which was held to summarize the outcomes of the SAGE’s semiannual conference, Cravioto indicated that there was no evidence to suggest Dengvaxia was associated with such severe outcomes when SAGE first recommended its use in 2016.

Image of a child getting vaccinated.
A dengue vaccine that was administered to more than 830,000 children in the Philippines may cause severe disease in patients with no prior dengue virus infection.
Source: Shutterstock.com

“What we had to go over when the recommendations were initially made didn’t have any of this new information that could have only come after the vaccine had been used regularly,” he said. “It is impossible to decide [on] the use of a vaccine [based] on nonexistent evidence. Because the vaccine has been used and we have better information, now we can make an assessment of something we didn’t know then, which is how the vaccine actually behaves in someone who has not been exposed to the virus.”

SAGE established a conditional recommendation in July 2016 to administer Dengvaxia only to individuals aged 9 years or older in endemic regions. Cravioto said this recommendation was made because data from two phase 3 trials showed it was less effective and associated with an increased risk for hospitalization in younger children.

“Certainly, there was information in the clinical trials that children below 9 years of age were either not immunized properly or had adverse events,” he said.

Photo of Scott Halstead
Scott B. Halstead

However, Scott B. Halstead, MD, an adjunct professor in the department of preventive medicine and biometrics, Uniformed Services of the University of Health Sciences in Bethesda, Maryland, said there was evidence from the phase 3 trials to suggest the vaccine may have triggered antibody-dependent enhancement (ADE) in recipients with no prior infection. ADE, he said, occurs when a patient who has recovered from infection with one type of dengue virus develops antibodies that can react with other dengue viruses, making subsequent infections with dengue more severe and potentially fatal. ADE may have been overlooked because of how the clinical trials were designed, according to Halstead.

“I have published several papers using clinical trial data from the SAGE background papers that provide ample evidence that children of any age vaccinated as seronegatives were the ones being hospitalized for breakthrough dengue infections,” Halstead told Infectious Disease News. “WHO’s Dengue Vaccine Advisory Committee and SAGE consistently chose to ignore these published warnings. The retrospective serological data that Sanofi used to identify serostatus of hospitalized children when vaccinated (not yet published) are not new data but serve to confirm my earlier warnings. Data published in 2015 from the Sanofi clinical vaccine efficacy and safety trials reported a component with vaccine-enhanced disease. The incaution SAGE exhibited in dealing with this signal is an indictment of its organizational competence.” 

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Because the newer recommendation requires prevaccination screening to determine whether patients are eligible for vaccination, Joachim Hombach, PhD, MPH, executive secretary of SAGE and WHO, said it will be important to have access to a rapid diagnostic test for dengue, which currently does not exist.

“There are tests available, but they are not point-of-care, so their implementation is cumbersome and requires that the person returns,” he said. “We see this as an obstacle in using the vaccine, but we are confident that this will spur the development of a rapid diagnostic test.”

Discussion on malaria, polio, measles and rubella

In addition to Dengvaxia, WHO and SAGE members reviewed information on the investigational RTS,S/AS01 malaria vaccine. Before making recommendations, Cravioto said the organizations need additional data to look into possible safety issues with the vaccine and whether the proposed four-dose schedule will be feasible to use in the real world. These questions will be assessed during a pilot implementation study that Cravioto said will launch soon in three sub-Saharan African countries.

“A lot has to been done in those countries to get them ready to conduct this study appropriately,” said Martin H. Friede, PhD, acting director of WHO’s department of immunization, vaccines and biologicals. “Very specifically, ensuring that they have adequate pharmacovigilance systems set up so that we can reliably monitor the safety of the vaccine and generate appropriate data.”

The pilot implementation study will last for about 3 or 4 years, Friede said.

The experts also discussed progress against other vaccine-preventable diseases, as well as the need to scale up immunization in regions that continue to experience outbreaks.

“It is clear that we have made advances in spite of not meeting all of the goals that were set up in this Global Vaccine Action Plan that started in 2010,” Cravioto said. “There is a critical need to establish a post-2020 strategy, which we will need to revise according to what has been achieved and the issues that are still pending.”

Although polio has largely been contained, Cravioto said the final stage of global eradication has been “constrained by the different groups that are looking into how to certify that there is no more wild virus circulation and, at the same time, that vaccine-derived viruses are controlled.” He also noted that several measles and rubella outbreaks are still reported in different parts of the world, particularly the Americas.

“We hope that by strengthening immunization in countries that are having cases, we will be able to better control these two diseases in the near future,” he said. – by Stephanie Viguers

References:

Halstead S. Hum Vaccin Immunother. 2018;doi:10.1080/21645515.2018.1445448.

Halstead SB. Vaccine. 2017;doi:10.1016/j.vaccine.2017.09.089.

Disclosures: Infectious Disease News was unable to confirm relevant financial disclosures at the time of publication.

Editor’s note: This article has been updated with comments from Halstead.