Communication Hurdles Remain For Sanofi’s Dengue Vaccine
Executive Summary
CDC drafting recommendation for Sanofi’s Dengvaxia, setting parameters for required pre-vaccination screening in the absence of tests approved by the US FDA.
Sanofi’s dengue vaccine Dengvaxia took another step toward a recommendation from the US Centers for Disease Control and Prevention, but concerns about the implementation of pre-vaccination screening testing still surround the first vaccine for the mosquito-borne illness.
Dengvaxia (dengue tetravalent vaccine, live) poses an unusual public health challenge: the vaccine is indicated only for people with laboratory confirmation of previous dengue infection. If vaccinated, people without an earlier infection are at increased risk for severe dengue disease if they are infected again.
However, as US labeling warns, “there is no FDA cleared test available to determine a previous dengue infection.” Additionally, “available non-FDA cleared tests may yield false positive results (e.g., due to cross-reactivity with other flaviviruses).”
The CDC’s Advisory Committee on Immunization Practices will not vote on Dengvaxia recommendations until the committee’s 23-24 June 2021 meeting, but the ACIP dengue vaccine workgroup updated the the committee on its deliberations during a 5 May session.
The workgroup’s draft recommendation for Dengvaxia is consistent with the indication approved by the Food and Drug Administration on 1 May 2019: a three-dose series administered to people 9 to 16 years of age with laboratory confirmation of previous dengue infection who live in endemic areas.
“I very much agree with the recommendation,” ACIP member Pablo Sanchez, Ohio State University-Nationwide Children’s Hospital, said, but “a lot of education is going to have to be done.”
Defining Test Parameters
FDA’s clinical review of the Dengvaxia biologics license application highlighted the [weaknesses] of the more than 60 dengue tests available internationally, reporting that the available evidence “indicates that the estimated sensitivity (30-99%) and specificity (60-99%) vary substantially depending on the test used.”
CDC medical epidemiologist Gabriela Paz-Bailey told ACIP that the dengue workgroup would set forth test performance guidance for pre-vaccination screening, calling for tests with a specificity of at least 98% and sensitivity of 75%.
The positive predictive value (PPV) should be at least 90%, she continued, with “a negative predictive value of ≥ 75% to minimize missing persons who would potentially benefit from the vaccine.”
“There are tests available with acceptable performance,” she said. Tests can be conducted by private laboratories under CLIA (Clinical Laboratories Improvement Amendments) regulations, but cost coverage by insurers and Medicaid is not assured.
However, implementation at the point of care in Puerto Rico – where 90% of US dengue exposure takes place – is “challenging,” Paz-Bailey said. At earlier ACIP meetings, she reported that two serotests are available in Puerto Rico through CLIA, both with a two-week turnaround time. (Also see "Sanofi's Dengvaxia: ACIP Decision On Use Will Hinge On Screening Test" - Pink Sheet, 27 Oct, 2019.)
More Granular Guidance Wanted
“Much depends on comfort levels with the assay,” Sanchez said, wondering if the ACIP recommendation could “say certain ones are preferred.”
“Naming test would be more helpful for physicians,” ACIP chair Jose Romero, director of the Arkansas Department of Health, said. “Physicians don't have time to check specificities with the reference lab.”
Paz-Bailey responded that the workgroup stayed away from recommending brands. “We propose a paragraph in MMWR [the CDC’s Morbidity and Mortality Weekly Report] stating specificity and sensitivity expectations.”
The American Academy of Pediatrics liaison to ACIP, Stanford University Division of Pediatric Infectious Diseases chief Yvonne Maldonado, stated that “much more prescriptive guidance would really be helpful.”
Maldonado expressed discomfort with “so many unknowns.” The recommendations on testing are “vague,” she said, while providers want “really explicit and granular guidance.”
Katherine Poehling, Wake Forest School of Medicine, observed that the “granularity of implementation” was a “source of many discussions at the workgroup.”
However, she pointed out, there is unmet need: the dengue outbreak in Puerto Rico has been ongoing since 2000, with no treatment available. And in Puerto Rico, physician offices are not allowed to do tests themselves but must send them to a reference lab, so there is “close health department control.”
While she called Dengvaxia “a great vaccine,” Maldonado said she was “not feeling ready to move on at this point” and expressed, “at least from pediatricians, concern if it is ready for prime time.”
ACIP wants to see “as detailed an implementation plan as possible” at the committee’s June meeting, Romero said.
Sanofi Is Working On A Diagnostic…
Sanofi has been working San Diego-based CTK Biotech to develop a rapid diagnostic test (RDT) to identify people with a past dengue infection. The CTK OnSite Dengue IgG RDT received its first licensure, in Thailand, as well as CE marking in September 2020.
“Regulatory submissions are currently ongoing in other countries, and a pilot program will be put in place to test the ‘screen and vaccinate’ approach,” Sanofi reported in its annual report filed with SEC in March 2021.
Sanofi had committed to develop a point-of-care test that could be used in a single visit. (Also see "Sanofi Gets A Helping Hand From US FDA At Dengvaxia Review" - Pink Sheet, 11 Mar, 2019.)
“Our goal is to ensure higher sensitivity than currently available tests (thereby improving the ability to detect those with a past infection), while maintaining high specificity (to avoid vaccinating truly seronegative people),” the Sanofi annual report states.
…But Takeda Vaccine Is On Horizon
While Sanofi waits for ACIP recommendations and ultimately an FDA-approved RDT, Takeda Pharmaceutical Co. Ltd.is moving forward with TAK-003, a quadrivalent dengue vaccine that the Japanese pharma says shows similar efficacy regardless of previous dengue exposure and lacks evidence of disease enhancement in seronegative individuals. (Also see "Takeda Looks To Ride 'Wave 1' To JPY5tn Target" - Scrip, 8 Dec, 2020.)
TAK-003 is set to be filed next year in “1st wave” endemic countries including the US, Brazil, Singapore, and the EU. The new dengue vaccine will be fast-tracked in the EU. (Also see "EU Fast-Track Review In Store For Takeda’s Dengue Vaccine" - Pink Sheet, 15 Sep, 2020.)
In addition to having no need for pre-vaccination screening for dengue exposure, TAK-003 could offer a convenience advantage over Dengvaxia. In the pivotal TIDES trial and large Phase II DEN-204 trial, TAK-003 is being studied as a two-dose regimen administered three months apart.
Dengvaxia, in contrast, requires three injections, with an initial dose and shots administered six and 12 months later.