Dengvaxia concern flagged nearly 2 years before Philippines pulls dengue vaccine

Photo of Scott Halstead
Scott B. Halstead

Sanofi Pasteur recently released long-term data on the company’s dengue vaccine Dengvaxia, which showed that the vaccine is effective in patients who had a prior dengue infection but may cause more severe disease in nonimmune patients who become infected after vaccination.

In light of these data, the Philippines Department of Health (DOH) suspended an immunization program that used the vaccine to prevent dengue virus infection, which is endemic in the country. During the immunization program, more than 700,000 individuals received at least one dose of Dengvaxia, according to the DOH. On Monday, the country’s Department of Justice granted the National Bureau of Investigation authority to look into “the alleged danger to public health” that the vaccine may have caused.

“The DOH assures the public that it is serious in carrying out its mandate to always guard the health and well-being of its constituents,” Health Secretary Francisco T. Duque III, MD, MSc, said in a statement. “Thus, it shall ensure that vaccines are always safe and effective to optimize its health benefits.”

Dengvaxia is a live, recombinant, tetravalent vaccine that is administered in three doses spaced 6 months apart. According to WHO, it is the first licensed dengue vaccine and has been approved by 19 regulatory authorities for use in endemic areas. Dengvaxia was introduced in vaccination programs targeting about 1 million people at risk for dengue in the Philippines and Brazil.

Pooled data from two phase 3 trials involving more than 30,000 participants aged 2 to 16 years showed the vaccine reduced severe dengue by 93% and hospitalizations by 81% within the first 25 months of vaccination, according to WHO. The trials, known as CYD14 and CYD15, further showed that vaccine efficacy was higher in participants aged 9 years and older. In contrast, younger participants aged 2 to 5 years had an increased risk for hospitalization. These participants were five times more likely to be hospitalized for dengue than participants enrolled in the placebo-controlled group, according to 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.

“That was a really significant warning sign,” Halstead told Infectious Disease News.

As a result, the Strategic Advisory Group of Experts and WHO made a conditional recommendation in July 2016 to administer the vaccine only to individuals aged 9 years or older in endemic regions.

In their own review published in March 2016 in Vaccine, Halstead and Philip K. Russell, MD, PhD, Professor Emeritus of the Johns Hopkins School of Hygiene and Public Health, found that hospitalization rates were higher not only in vaccinated children aged 2 to 5 years but in participants of any age who were not previously infected with dengue. In another research paper published last month, Halstead further highlighted evidence that antibody-dependent enhancement (ADE) triggered by the vaccine may be linked to hospitalizations among seronegative participants. ADE, he noted, 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. Dengvaxia, he added, may have been enhancing these antibodies in patients with no prior infection.

“This is something that is really unique in infectious disease and vaccinology where a vaccine can benefit certain people who had one prior dengue infection but increase the risk for severe disease in others who had never had dengue before,” Halstead said.

ADE may have been an overlooked source for hospitalizations because of how the clinical trials were designed, according to Halstead.

“You cannot conduct a normal vaccine efficacy study when there is a possibility that the vaccine is enhancing antibodies in some of the recipients,” he said. “Vaccine efficacy needs to be examined separately in two groups: those who are partially immune and those who are nonimmune. That did not happen. These studies were not designed correctly.”

After Sanofi conducted an additional review that included more information on serostatus at the time of vaccination and longer term data, the company similarly found that Dengvaxia may cause more severe disease in patients who were not infected with dengue before receiving the vaccine. In response, the company proposed that national regulatory agencies update the product label for Dengvaxia to reflect the new information. WHO announced that it will conduct a full review of the recent data. In the meantime, the world health agency recommends limiting use of the vaccine to patients who are known to have had a prior dengue infection.

“That is what WHO should have said 2 years ago,” Halstead said. “Hopefully, WHO will be more careful about its recommendations in the future. Once a patient develops antibodies to a dengue infection, that patient will carry those antibodies for the rest of their life. So, these patients who were seronegative at the time of vaccination will always be at risk for having vaccine-related severe disease. They are living in dengue endemic countries and are going to be infected sooner or later. It really is quite a serious problem.” – by Stephanie Viguers

References:

Hadinegoro SR, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1506223.

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

Halstead SB, Russell PK. Vaccine. 2016;doi:10.1016/j.vaccine.2016.02.004.

Sanofi Pasteur. 2017. Sanofi updates information on dengue vaccine. http://mediaroom.sanofi.com/sanofi-updates-information-on-dengue-vaccine/ Accessed: December 5, 2017.

WHO. 2017. Updated Questions and Answers related to information presented in the Sanofi Pasteur press release on 30 November 2017 with regards to the dengue vaccine Dengvaxia. http://www.who.int/immunization/diseases/dengue/q_and_a_dengue_vaccine_dengvaxia/en/ Accessed December 5, 2017.

Disclosures: Halstead reports no relevant financial disclosures. Infectious Disease News was unable to confirm relevant financial disclosures for Duque and Russell at the time of publication. 

Photo of Scott Halstead
Scott B. Halstead

Sanofi Pasteur recently released long-term data on the company’s dengue vaccine Dengvaxia, which showed that the vaccine is effective in patients who had a prior dengue infection but may cause more severe disease in nonimmune patients who become infected after vaccination.

In light of these data, the Philippines Department of Health (DOH) suspended an immunization program that used the vaccine to prevent dengue virus infection, which is endemic in the country. During the immunization program, more than 700,000 individuals received at least one dose of Dengvaxia, according to the DOH. On Monday, the country’s Department of Justice granted the National Bureau of Investigation authority to look into “the alleged danger to public health” that the vaccine may have caused.

“The DOH assures the public that it is serious in carrying out its mandate to always guard the health and well-being of its constituents,” Health Secretary Francisco T. Duque III, MD, MSc, said in a statement. “Thus, it shall ensure that vaccines are always safe and effective to optimize its health benefits.”

Dengvaxia is a live, recombinant, tetravalent vaccine that is administered in three doses spaced 6 months apart. According to WHO, it is the first licensed dengue vaccine and has been approved by 19 regulatory authorities for use in endemic areas. Dengvaxia was introduced in vaccination programs targeting about 1 million people at risk for dengue in the Philippines and Brazil.

Pooled data from two phase 3 trials involving more than 30,000 participants aged 2 to 16 years showed the vaccine reduced severe dengue by 93% and hospitalizations by 81% within the first 25 months of vaccination, according to WHO. The trials, known as CYD14 and CYD15, further showed that vaccine efficacy was higher in participants aged 9 years and older. In contrast, younger participants aged 2 to 5 years had an increased risk for hospitalization. These participants were five times more likely to be hospitalized for dengue than participants enrolled in the placebo-controlled group, according to 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.

“That was a really significant warning sign,” Halstead told Infectious Disease News.

As a result, the Strategic Advisory Group of Experts and WHO made a conditional recommendation in July 2016 to administer the vaccine only to individuals aged 9 years or older in endemic regions.

In their own review published in March 2016 in Vaccine, Halstead and Philip K. Russell, MD, PhD, Professor Emeritus of the Johns Hopkins School of Hygiene and Public Health, found that hospitalization rates were higher not only in vaccinated children aged 2 to 5 years but in participants of any age who were not previously infected with dengue. In another research paper published last month, Halstead further highlighted evidence that antibody-dependent enhancement (ADE) triggered by the vaccine may be linked to hospitalizations among seronegative participants. ADE, he noted, 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. Dengvaxia, he added, may have been enhancing these antibodies in patients with no prior infection.

“This is something that is really unique in infectious disease and vaccinology where a vaccine can benefit certain people who had one prior dengue infection but increase the risk for severe disease in others who had never had dengue before,” Halstead said.

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ADE may have been an overlooked source for hospitalizations because of how the clinical trials were designed, according to Halstead.

“You cannot conduct a normal vaccine efficacy study when there is a possibility that the vaccine is enhancing antibodies in some of the recipients,” he said. “Vaccine efficacy needs to be examined separately in two groups: those who are partially immune and those who are nonimmune. That did not happen. These studies were not designed correctly.”

After Sanofi conducted an additional review that included more information on serostatus at the time of vaccination and longer term data, the company similarly found that Dengvaxia may cause more severe disease in patients who were not infected with dengue before receiving the vaccine. In response, the company proposed that national regulatory agencies update the product label for Dengvaxia to reflect the new information. WHO announced that it will conduct a full review of the recent data. In the meantime, the world health agency recommends limiting use of the vaccine to patients who are known to have had a prior dengue infection.

“That is what WHO should have said 2 years ago,” Halstead said. “Hopefully, WHO will be more careful about its recommendations in the future. Once a patient develops antibodies to a dengue infection, that patient will carry those antibodies for the rest of their life. So, these patients who were seronegative at the time of vaccination will always be at risk for having vaccine-related severe disease. They are living in dengue endemic countries and are going to be infected sooner or later. It really is quite a serious problem.” – by Stephanie Viguers

References:

Hadinegoro SR, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1506223.

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

Halstead SB, Russell PK. Vaccine. 2016;doi:10.1016/j.vaccine.2016.02.004.

Sanofi Pasteur. 2017. Sanofi updates information on dengue vaccine. http://mediaroom.sanofi.com/sanofi-updates-information-on-dengue-vaccine/ Accessed: December 5, 2017.

WHO. 2017. Updated Questions and Answers related to information presented in the Sanofi Pasteur press release on 30 November 2017 with regards to the dengue vaccine Dengvaxia. http://www.who.int/immunization/diseases/dengue/q_and_a_dengue_vaccine_dengvaxia/en/ Accessed December 5, 2017.

Disclosures: Halstead reports no relevant financial disclosures. Infectious Disease News was unable to confirm relevant financial disclosures for Duque and Russell at the time of publication.