4:20 PM
 | 
Dec 21, 2017
 |  BC Innovations  |  Product R&D

Dengvaxia’s warning

Sanofi’s dengue vaccine has the field asking hard questions

The fallout of Sanofi’s dengue vaccine debacle has researchers scrambling to rationalize whether competitor products will fall afoul of the same effects, and whether other, related fields should change course. The early upshot is that while NIH’s dengue candidate is likely on safer ground, and specific precautionary measures could avert problems, there’s concern the Zika field won’t learn the lessons.

On Nov. 29, Sanofi announced that long-term studies of its Dengvaxia vaccine confirmed the vaccine exacerbated dengue infection in some dengue-naïve or seronegative children instead of protecting them.

The company maintains that Dengvaxia still provides benefit in patients who have previously been infected with the virus, and in children over nine years old regardless of prior exposure. According to Sanofi spokesperson Ashleigh Koss, “Dengvaxia provides protection to 81.9% of people with prior dengue infection and there is short-term protection in seronegatives (52.3%) documented for up to 25 months.”

Sanofi has asked national regulatory agencies for a label change that warns doctors to make an independent assessment of the risk to benefit ratio before vaccinating any seronegative patients.

The problems aren’t a complete surprise given the known biology of dengue, in which a second infection is often more serious than the first. The prevailing theory is that this is due to a phenomenon dubbed antibody-dependent enhancement (ADE) in which antibodies from a first infection enhance the chances on a subsequent exposure that the virus will enter host cells and cause an infection (see “ADE Doesn’t Aid”).


Figure: ADE doesn’t aid

Phase III data reported by Sanofi (Euronext:SAN; NYSE:SNY) for its Dengvaxia dengue vaccine has put antibody-dependent enhancement (ADE) back in the spotlight. The theory was proposed 40 years ago by Scott Halstead to explain how the immune response to a first dengue infection could exacerbate a second infection by one of the four related dengue serotypes and cause severe disease. Halstead is an adjunct professor at the Uniformed Services University of the Health Sciences.

According to Halstead’s theory -- which is supported by experimental data from Halstead and others -- ADE occurs during a second dengue infection because the primary infection stimulates production of a dominant class of heterotypic or cross-reacting antibodies (green) that bind all dengue strains but aren’t neutralizing. Instead, the antibodies form immune complexes that facilitate binding to Fcγ receptor (FCGR) on monocytes, assisting viral entry and replication in monocytes, and boosting the viral titers and disease pathology.

Dengue is caused by an RNA flavivirus that exists in four strains, serotypes 1 through 4, that cause similar symptoms.

Stephen Whitehead, senior scientist at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), who led the development of NIH’s Phase III dengue vaccine candidate TV003, told BioCentury that ADE might partially explain Sanofi’s data. He said antibodies raised in response to a first strain bind a second infecting strain, but if they fail to neutralize it, the viral immune complexes will facilitate host infection and disrupt the protective immune response.

But he also thinks a...

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