Immune correlates of protection against yellow fever determined by passive immunization and challenge in the hamster model

Abstract

Live, attenuated yellow fever (YF) 17D vaccine is highly efficacious but causes rare, serious adverse events resulting from active replication in the host and direct viral injury to vital organs. We recently reported development of a potentially safer β-propiolactone-inactivated whole virion YF vaccine (XRX-001) which was highly immunogenic in mice, hamsters, monkeys, and humans (Vaccine 2010; 28:3827–40; New Engl J Med 2011;364:1326–33). To characterize the protective efficacy of neutralizing antibodies stimulated by the inactivated vaccine, graded doses of serum from hamsters immunized with inactivated XRX-001 or live 17D vaccine were transferred to hamsters by the intraperitoneal (IP) route 24 hours prior to virulent, viscerotropic YF virus challenge. Neutralizing antibody (PRNT50) titers were determined in the sera of treated animals 4 hours before challenge and 4 and 21 days after challenge. Neutralizing antibodies were shown to mediate protection. Animals having 50% plaque reduction neutralization test (PRNT50) titers of ≥40 four hours before challenge were completely protected from disease as evidenced by viremia, liver enzyme elevation, and protection against illness (weight change) and death. Passive titers of 10–20 were partially protective. Immunization with the XRX-001 vaccine stimulated YF neutralizing antibodies that were equally effective (based on dose response) as antibodies stimulated by live 17D vaccine. The results will be useful in defining the level of seroprotection in clinical studies of new yellow fever vaccines.

Efficacy and Duration of Immunity after Yellow Fever Vaccination: Systematic Review on the Need for a Booster Every 10 Years

“…The 1:10 and 1:20 titers frequently used as cutoff titers have been estimated by extending the results of studies on passive immunization in hamsters, and available evidence on titers considered to be protective for other related viruses such as Japanese encephalitis virus. [20][21][22] Overall, there is agreement in the assumption that a titer 1:10 is associated with protective immunity, considering the paucity of YF cases in immunized persons. 10,11,23 Protective immunity after YF vaccination.…”

Mechanism and Significance of Cell Type-Dependent Neutralization of Flaviviruses

“…A vaccine-induced neutralizing antibody response predicts protection against several flaviviruses, including YFV, TBEV, and JEV (8)(9)(10). The selection of a cellular substrate is an important practical consideration in the design of assays to support vaccine development.…”

“…Vaccines against YFV, JEV, and tick-borne encephalitis viruses (TBEV) have been used extensively (5)(6)(7). In each instance, neutralizing antibodies have been established as a correlate of protection (8)(9)(10).…”

The yellow fever 17D virus as a platform for new live attenuated vaccines

“…Concordantly, the generation of neutralizing antibodies is a hallmark of protective antiviral immunity against the YF17D virus. 27,28 Neutralizing antibodies directed against structural protein E is believed to be the most critical in terms of protection. 29,30 These neutralizing antibodies may persist for 40 y post vaccination, which exhibits the ability of the virus to elicit an efficient immune response that will result in a long-lived humoral response.…”