Study supports safety concerns of world’s only dengue vaccine

Findings published today in The New England Journal of Medicine affirm that receiving the world’s only licensed dengue vaccine increases the risk for severe disease and hospitalization in patients with no prior exposure to the disease.

A re-examination of trial data showed that Dengvaxia (Sanofi Pasteur) is protective in patients who have been previous exposed to dengue virus but potentially harmful in those who have not, researchers said.

The vaccine has been linked to pediatric deaths in the Philippines, and an expert panel has backed a recommendation to vaccinate people only in dengue-endemic regions if they are confirmed to have had a prior infection.

“Our findings indicate a major role for previous dengue exposure in modifying vaccine performance and provide some evidence of a possible age effect,” Saranya Sridhar, MD, PhD, director of clinical development at Sanofi Pasteur, and colleagues wrote.

The authors concluded that the reasons underlying the findings are unknown, but other experts say the complications associated with Dengvaxia are caused by a biological mechanism known as antibody-dependent enhancement (ADE).

Safety findings

Previously, results from two phase 3 trials involving more than 30,000 participants in Southeast Asia showed that Dengvaxia 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.

“Since younger children are less likely to have been exposed to dengue virus, it was hypothesized that older age in these studies may have been a surrogate for prior dengue infection,” Lisa Rosenbaum, MD, a cardiologist at Brigham and Women’s Hospital in Boston and an instructor at Harvard Medical School, wrote in an accompanying perspective in the journal. “It was thus thought that the vaccine could act like a primary infection in children not previously exposed to dengue, potentially contributing to a more severe illness when subsequent exposure to natural infection occurred.”

To further investigate the association, Sridhar and colleagues re-examined data from the phase 3 trials. The analysis included a subcohort of 3,578 patients and all articipants who had symptomatic virologically confirmed dengue (VCD; n = 1,258), who were hospitalized for VCD (n = 644) or who had severe VCD (n = 142).

An analysis of seronegative participants revealed a higher rate of hospitalization and severe VCD among those who were randomized to receive Dengvaxia vs. placebo. The risk for hospitalization (HR = 1.95; 95% CI, 1.19-3.19) and severe VCD (HR = 3.31; 95% CI, 0.87-12.54) was particularly high among younger children aged 2 to 8 years. Among seropositive participants, the risk for adverse events was lower in vaccine recipients vs. controls.

The role of ADE

Sridhar and colleagues said there were not enough data to confirm the exact cause for severe VCD or hospitalization among seronegative vaccine recipients. But Scott B. Halstead, MD, adjunct professor in the department of preventive medicine and biometrics, Uniformed Services of the University of Health Sciences in Bethesda, Maryland, and Philip K. Russell, MD, PhD, professor emeritus in the Johns Hopkins Bloomberg School Public Health, have said that ADE is causing the complications in children.

“The role of ADE has been a controversial subject for some time,” Russell told Infectious Disease News. “Sanofi has gone on record denying that antibodies were involved in the problem, but the underlying science of ADE has been, in my view, well established for many years.”

Sanjay Gurunathan, MD, head of clinical studies for Sanofi Pasteur, argued that the association between adverse events and vaccination is likely multifactorial. He said age, race/ethnicity and epidemiological setting are other factors that could increase the risk for severe VCD and hospitalization.

“ADE could be among the reasons why people get severe dengue, but it’s not the only reason,” Gurunathan told Infectious Disease News. “In this particular study, we confirmed the observation that if you are exposed to dengue and you get it for the second time, you are likely to get more severe outcomes. If you are vaccinated, the vaccine probably acts like a first infection, predisposing you to get more severe outcomes. However, we didn’t really look into what the underlying biology is. The study wasn’t designed to do that.”

Gurunathan said Sanofi Pasteur plans to work closely with the scientific community to further understand the underlying mechanisms associated with the increased risk for adverse events.

Death associated with vaccination

According to the researchers, no deaths during the study were linked to dengue or Dengvaxia. Earlier this year, however, Philippines health officials reported finding a “causal association” between three pediatric deaths and Dengvaxia. The children were vaccinated as part of a mass dengue immunization program, during which more than 830,000 children received at least one dose of the vaccine.

None of the deaths investigated by the Philippines were included in the current analysis. In contrast, Gurunathan said the Philippines government and ministry of health have yet to release the medical records to Sanofi Pasteur, which is the typical protocol when deaths are potentially linked to a vaccine.

“We have no access to those records and we really cannot comment on what the Philippine [health department] and government are actually saying about these deaths,” he said. “It is really important to have a rigorous process [to determine] whether these deaths can be ascribed to dengue and if the vaccine is contributing. WHO is overseeing this process. We will find out more.”

Gurunathan said Dengvaxia is still beneficial to patients with a prior dengue infection. The researchers estimated that, in a cohort of 1 million people aged 9 to 16 years with an 80% seropositivity rate, Dengvaxia could prevent approximately 11,000 hospitalizations and 2,500 severe cases of dengue over 5 years.

“We at Sanofi believe that this is an incredible public health tool to stem the tide of dengue,” he said. “There are millions of people around the world who can benefit from this vaccine. We are really excited to implement the vaccine and realize its full potential and public health benefit.” – by Stephanie Viguers

References:

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.

Republic of the Philippines Department of Health. Results of the Investigation of the Philippine General Hospital Dengue Investigative Task Force (PGH - DITF). http://www.doh.gov.ph/node/12849. Accessed June 13, 2018.

Rosenbaum L. N Engl J Med. 2018;doi:10.1056/NEJMp1804094.

Sridhar S, et al. N Engl J Med. 2018;doi:10.1056NEJMoa1800820.

Disclosures: Gurunathan and Sridhar report personal fees and other from Sanofi Pasteur outside the submitted work. Rosenbaum and Russell report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Findings published today in The New England Journal of Medicine affirm that receiving the world’s only licensed dengue vaccine increases the risk for severe disease and hospitalization in patients with no prior exposure to the disease.

A re-examination of trial data showed that Dengvaxia (Sanofi Pasteur) is protective in patients who have been previous exposed to dengue virus but potentially harmful in those who have not, researchers said.

The vaccine has been linked to pediatric deaths in the Philippines, and an expert panel has backed a recommendation to vaccinate people only in dengue-endemic regions if they are confirmed to have had a prior infection.

“Our findings indicate a major role for previous dengue exposure in modifying vaccine performance and provide some evidence of a possible age effect,” Saranya Sridhar, MD, PhD, director of clinical development at Sanofi Pasteur, and colleagues wrote.

The authors concluded that the reasons underlying the findings are unknown, but other experts say the complications associated with Dengvaxia are caused by a biological mechanism known as antibody-dependent enhancement (ADE).

Safety findings

Previously, results from two phase 3 trials involving more than 30,000 participants in Southeast Asia showed that Dengvaxia 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.

“Since younger children are less likely to have been exposed to dengue virus, it was hypothesized that older age in these studies may have been a surrogate for prior dengue infection,” Lisa Rosenbaum, MD, a cardiologist at Brigham and Women’s Hospital in Boston and an instructor at Harvard Medical School, wrote in an accompanying perspective in the journal. “It was thus thought that the vaccine could act like a primary infection in children not previously exposed to dengue, potentially contributing to a more severe illness when subsequent exposure to natural infection occurred.”

To further investigate the association, Sridhar and colleagues re-examined data from the phase 3 trials. The analysis included a subcohort of 3,578 patients and all articipants who had symptomatic virologically confirmed dengue (VCD; n = 1,258), who were hospitalized for VCD (n = 644) or who had severe VCD (n = 142).

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An analysis of seronegative participants revealed a higher rate of hospitalization and severe VCD among those who were randomized to receive Dengvaxia vs. placebo. The risk for hospitalization (HR = 1.95; 95% CI, 1.19-3.19) and severe VCD (HR = 3.31; 95% CI, 0.87-12.54) was particularly high among younger children aged 2 to 8 years. Among seropositive participants, the risk for adverse events was lower in vaccine recipients vs. controls.

The role of ADE

Sridhar and colleagues said there were not enough data to confirm the exact cause for severe VCD or hospitalization among seronegative vaccine recipients. But Scott B. Halstead, MD, adjunct professor in the department of preventive medicine and biometrics, Uniformed Services of the University of Health Sciences in Bethesda, Maryland, and Philip K. Russell, MD, PhD, professor emeritus in the Johns Hopkins Bloomberg School Public Health, have said that ADE is causing the complications in children.

“The role of ADE has been a controversial subject for some time,” Russell told Infectious Disease News. “Sanofi has gone on record denying that antibodies were involved in the problem, but the underlying science of ADE has been, in my view, well established for many years.”

Sanjay Gurunathan, MD, head of clinical studies for Sanofi Pasteur, argued that the association between adverse events and vaccination is likely multifactorial. He said age, race/ethnicity and epidemiological setting are other factors that could increase the risk for severe VCD and hospitalization.

“ADE could be among the reasons why people get severe dengue, but it’s not the only reason,” Gurunathan told Infectious Disease News. “In this particular study, we confirmed the observation that if you are exposed to dengue and you get it for the second time, you are likely to get more severe outcomes. If you are vaccinated, the vaccine probably acts like a first infection, predisposing you to get more severe outcomes. However, we didn’t really look into what the underlying biology is. The study wasn’t designed to do that.”

Gurunathan said Sanofi Pasteur plans to work closely with the scientific community to further understand the underlying mechanisms associated with the increased risk for adverse events.

Death associated with vaccination

According to the researchers, no deaths during the study were linked to dengue or Dengvaxia. Earlier this year, however, Philippines health officials reported finding a “causal association” between three pediatric deaths and Dengvaxia. The children were vaccinated as part of a mass dengue immunization program, during which more than 830,000 children received at least one dose of the vaccine.

PAGE BREAK

None of the deaths investigated by the Philippines were included in the current analysis. In contrast, Gurunathan said the Philippines government and ministry of health have yet to release the medical records to Sanofi Pasteur, which is the typical protocol when deaths are potentially linked to a vaccine.

“We have no access to those records and we really cannot comment on what the Philippine [health department] and government are actually saying about these deaths,” he said. “It is really important to have a rigorous process [to determine] whether these deaths can be ascribed to dengue and if the vaccine is contributing. WHO is overseeing this process. We will find out more.”

Gurunathan said Dengvaxia is still beneficial to patients with a prior dengue infection. The researchers estimated that, in a cohort of 1 million people aged 9 to 16 years with an 80% seropositivity rate, Dengvaxia could prevent approximately 11,000 hospitalizations and 2,500 severe cases of dengue over 5 years.

“We at Sanofi believe that this is an incredible public health tool to stem the tide of dengue,” he said. “There are millions of people around the world who can benefit from this vaccine. We are really excited to implement the vaccine and realize its full potential and public health benefit.” – by Stephanie Viguers

References:

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.

Republic of the Philippines Department of Health. Results of the Investigation of the Philippine General Hospital Dengue Investigative Task Force (PGH - DITF). http://www.doh.gov.ph/node/12849. Accessed June 13, 2018.

Rosenbaum L. N Engl J Med. 2018;doi:10.1056/NEJMp1804094.

Sridhar S, et al. N Engl J Med. 2018;doi:10.1056NEJMoa1800820.

Disclosures: Gurunathan and Sridhar report personal fees and other from Sanofi Pasteur outside the submitted work. Rosenbaum and Russell report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.