In the Journals

Researchers link Dengvaxia vaccination to false-positive dengue test results

Data from two phase 3 trials indicate that vaccination with Dengvaxia impacts the efficacy of immunoglobulin M- and immunoglobulin G-based assays for dengue virus infection.

Eric Plennevaux, PhD, head of the Global Strategic Program for Dengue at Sanofi Pasteur — the manufacturer of Dengvaxia — and colleagues reported in Clinical Infectious Diseases that their findings underscore the need for new dengue-specific diagnostics.

“The current immunological definitions of dengue infection based on IgM and IgG serology are inadequate in vaccinated individuals and need to be reevaluated urgently as the dengue vaccine is now available in several endemic countries,” they wrote. “Dengue vaccination history would now be needed to help interpret diagnosis and surveillance results based on serology alone.”

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. However, long-term data on the vaccine recently showed that it is effective in patients who had a prior dengue virus (DENV) 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 suspended a Dengvaxia immunization program, during which more than 700,000 individuals received at least one dose of the vaccine. In addition, WHO now recommends limiting its use to patients who are known to have had a prior dengue infection.

Plennevaux and colleagues previously found evidence that Dengvaxia-induced responses may impact the utility of assays that use IgM and IgG data to detect infection. To confirm their findings in a larger sample size, the researchers examined dengue testing results from more than 31,000 children aged 2 to 16 years in Asia and Latin America who were randomly assigned 2:1 to receive Dengvaxia or placebo during two phase 3 trials — CYD14 and CYD15.

“This large sample, with data for all four serotypes, allowed us to explore the impact of previous dengue exposure and other potential covariates on the serological diagnosis of dengue,” the researchers noted.

Overall, 1,284 virologically confirmed dengue (VCD) episodes, which were confirmed by reverse-transcriptase PCR (RT-PCR) or nonstructural protein 1 (NS1) antigen assays, and 17,673 other febrile episodes were identified. Vaccinated participants accounted for 575 VCD episodes and 11,668 other febrile episodes, whereas unvaccinated participants accounted for 709 VCD episodes and 6,005 other febrile episodes.

Compared with RT-PCR and NS1 antigen assays, IgM- and IgG-based assays identified probable dengue infection with 93.1% sensitivity and 77.2% specificity in febrile participants without VCD. The assays yielded a negative predictive value of 99.5% and a positive predictive value (PPV) of 22.9%, highlighting a much lower probability of correctly diagnosing dengue.

According to the researchers, IgM- and IgG-based assays led to a higher number of false-positive results among vaccinated participants. Vaccination-induced immunity was more evident in participants who were seronegative at baseline and presenting with febrile episodes. In these participants, false-positive results based on IgM assessments were identified in 33% of vaccinated participants vs. 14.7% of unvaccinated participants.

“In summary, new practical, dengue-specific diagnostic algorithms that include assays/tests (such as NS1 antigen and dengue PCR) that are not affected by vaccine-induced immunity are urgently needed for dengue case management and surveillance as vaccination can confound the interpretation of probable dengue diagnosis based solely on anti-dengue IgM and IgG,” the researchers concluded.

In a related editorial, Graham Simmons, PhD, and colleagues at the Blood Systems Research Institute and the University of California, San Francisco, warned that even NS1-based assays may need to be replaced if newer dengue vaccines that express the antigen are approved.

“Specific and sensitive anti-DENV NS1-based assays are a likely long-term solution to the issue of differentiating natural infection from vaccine-induced immunity described by Plennevaux and colleagues as the [Dengvaxia] vaccine lacks DENV NS1,” they wrote. “However, other vaccine candidates, such as TV003, are live-attenuated viruses and express DENV NS1. Thus, other solutions will be required for differential serology to avoid detection of vaccine-induced seroreactivity and diagnose vaccine breakthrough infections.” – by Stephanie Viguers

Disclosures: Plennevaux reports being an employee of Sanofi Pasteur. Simmons and colleagues report receiving financial support from Grifols and Roche Diagnostics and nonfinancial support from Abbott Diagnostics. Please see the study for all other authors’ relevant financial disclosures.

Data from two phase 3 trials indicate that vaccination with Dengvaxia impacts the efficacy of immunoglobulin M- and immunoglobulin G-based assays for dengue virus infection.

Eric Plennevaux, PhD, head of the Global Strategic Program for Dengue at Sanofi Pasteur — the manufacturer of Dengvaxia — and colleagues reported in Clinical Infectious Diseases that their findings underscore the need for new dengue-specific diagnostics.

“The current immunological definitions of dengue infection based on IgM and IgG serology are inadequate in vaccinated individuals and need to be reevaluated urgently as the dengue vaccine is now available in several endemic countries,” they wrote. “Dengue vaccination history would now be needed to help interpret diagnosis and surveillance results based on serology alone.”

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. However, long-term data on the vaccine recently showed that it is effective in patients who had a prior dengue virus (DENV) 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 suspended a Dengvaxia immunization program, during which more than 700,000 individuals received at least one dose of the vaccine. In addition, WHO now recommends limiting its use to patients who are known to have had a prior dengue infection.

Plennevaux and colleagues previously found evidence that Dengvaxia-induced responses may impact the utility of assays that use IgM and IgG data to detect infection. To confirm their findings in a larger sample size, the researchers examined dengue testing results from more than 31,000 children aged 2 to 16 years in Asia and Latin America who were randomly assigned 2:1 to receive Dengvaxia or placebo during two phase 3 trials — CYD14 and CYD15.

“This large sample, with data for all four serotypes, allowed us to explore the impact of previous dengue exposure and other potential covariates on the serological diagnosis of dengue,” the researchers noted.

Overall, 1,284 virologically confirmed dengue (VCD) episodes, which were confirmed by reverse-transcriptase PCR (RT-PCR) or nonstructural protein 1 (NS1) antigen assays, and 17,673 other febrile episodes were identified. Vaccinated participants accounted for 575 VCD episodes and 11,668 other febrile episodes, whereas unvaccinated participants accounted for 709 VCD episodes and 6,005 other febrile episodes.

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Compared with RT-PCR and NS1 antigen assays, IgM- and IgG-based assays identified probable dengue infection with 93.1% sensitivity and 77.2% specificity in febrile participants without VCD. The assays yielded a negative predictive value of 99.5% and a positive predictive value (PPV) of 22.9%, highlighting a much lower probability of correctly diagnosing dengue.

According to the researchers, IgM- and IgG-based assays led to a higher number of false-positive results among vaccinated participants. Vaccination-induced immunity was more evident in participants who were seronegative at baseline and presenting with febrile episodes. In these participants, false-positive results based on IgM assessments were identified in 33% of vaccinated participants vs. 14.7% of unvaccinated participants.

“In summary, new practical, dengue-specific diagnostic algorithms that include assays/tests (such as NS1 antigen and dengue PCR) that are not affected by vaccine-induced immunity are urgently needed for dengue case management and surveillance as vaccination can confound the interpretation of probable dengue diagnosis based solely on anti-dengue IgM and IgG,” the researchers concluded.

In a related editorial, Graham Simmons, PhD, and colleagues at the Blood Systems Research Institute and the University of California, San Francisco, warned that even NS1-based assays may need to be replaced if newer dengue vaccines that express the antigen are approved.

“Specific and sensitive anti-DENV NS1-based assays are a likely long-term solution to the issue of differentiating natural infection from vaccine-induced immunity described by Plennevaux and colleagues as the [Dengvaxia] vaccine lacks DENV NS1,” they wrote. “However, other vaccine candidates, such as TV003, are live-attenuated viruses and express DENV NS1. Thus, other solutions will be required for differential serology to avoid detection of vaccine-induced seroreactivity and diagnose vaccine breakthrough infections.” – by Stephanie Viguers

Disclosures: Plennevaux reports being an employee of Sanofi Pasteur. Simmons and colleagues report receiving financial support from Grifols and Roche Diagnostics and nonfinancial support from Abbott Diagnostics. Please see the study for all other authors’ relevant financial disclosures.