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Paper of the Month April 2011

An Inactivated Cell-Culture Vaccine against Yellow Fever

New Engl J Med 2011; 364:1326-33


Monath TP, Fowler E, Johnson CT, Balser J, Merribeth J, Morin MJ, Sisti M, Trent DW


Yellow fever is a lethal, flavivirus disease carried by mosquitoes. The only currently available vaccine is a live attenuated virus (17D) developed in 1936 and widely used to protect travelers to and residents of endemic areas in tropical South America and Africa. Although remarkably immunogenic, the 17D vaccine may cause serious viscerotropic and neurotropic adverse events and anaphylaxis. Viscerotropic disease is a life-threatening active infection of the liver and visceral organs with 17D virus resembling naturally-acquired yellow fever. Neurotropic disease typically follows invasion of the brain by the live, replicating vaccine virus. Fortunately these adverse events are rare, but the lethality of viscerotropic adverse events (63%) is unprecedented for any vaccine. Recently Hayes drew attention to the need for a safer yellow fever vaccine (Vaccine 2010; 28:8073-6). In the current paper, the authors describe the first clinical trial of an inactivated yellow fever vaccine produced in cell cultures and adsorbed to alum adjuvant. Strong neutralizing antibody responses (the mediator of protection against yellow fever) were observed in all subjects who received two doses (21 days apart) of 4.8 micrograms of antigen, a dose similar to that contained in commercial vaccines against related viruses, such as Japanese encephalitis. Safety and tolerability of the vaccine appeared to be good. Although two inoculations of vaccine were required (compared to a single dose of the live vaccine), the new non-replicating vaccine may potentially have advantages in safety and could be used in persons with precautions and contraindications to 17D. The reported study is the first step in product development that will require additional clinical trials demonstrating safety and immunogenicity required for regulatory approval.