Immunologic Interference from Sequential Administration of Live Attenuated Alphavirus Vaccines

Abstract

Two different human vaccine trials examined interference arising from sequential administration of vaccines against heterologous alphaviruses. The first trial indicated that persons previously vaccinated against Venezuelan equine encephalitis virus (VEEV) exhibited poor neutralizing antibody responses to a live attenuated chikungunya virus (CHIKV) vaccine (46% response rate). The second trial prospectively examined neutralizing antibody responses to live attenuated VEEV vaccine in persons previously inoculated with either CHIKV vaccine or placebo. Following seroconversion to CHIKV, CHIKV vaccine recipients' geometric mean titers (GMTs) to VEEV by 80% plaque-reduction neutralization titration never exceeded 10, compared with a peak GMT of 95 after VEEV vaccination for alphavirus-naive volunteers who initially received placebo (P < .003). ELISA antibody responses demonstrated cross-reactive IgG to VEEV after primary CHIKV immunization and then an anamnestic response upon subsequent VEEV vaccination. These data indicate that preexisting alphavirus immunity in humans interferes with subsequent neutralizing antibody response to a live attenuated, heterologous vaccine.

Host responses to live-attenuated Venezuelan equine encephalitis virus (TC-83)

“…7,8 Additionally, human vaccination studies have demonstrated immunological interference from other, related alphaviruses which impede the ability to induce neutralizing antibody production after VEEV vaccination. 7,9 A similar observation of altered ability to produce neutralizing antibody to VEEV has also been made in equines first vaccinated with eastern equine encephalitis virus (EEEV) vaccine or western equine encephalitis virus (WEEV) vaccine. 9 Exploratory attempts have been made to understand the host response mechanisms involved in VEEV immunity and infection.…”

“…7,9 A similar observation of altered ability to produce neutralizing antibody to VEEV has also been made in equines first vaccinated with eastern equine encephalitis virus (EEEV) vaccine or western equine encephalitis virus (WEEV) vaccine. 9 Exploratory attempts have been made to understand the host response mechanisms involved in VEEV immunity and infection. Knockout mouse studies for the IFNα/β receptor and for interferon regulatory factors, IRF1 and IRF2 have shown that these animals were susceptible to peripheral infection by virulent or attenuated strains of VEEV.…”

“…The procedures for both the alphavirus-specific ELISA and the PRNT-80 assay have been described previously. 9 The study design consisted of 10 volunteers per group, and that target was met in both the control and responder groups. The nonresponder group consisted of three volunteers.…”

Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218.

“…18 Reciprocal cross-protection after infection with other alphaviruses occurs in animal models, 19,20 although it is unclear if similar cross protection occurs in humans sequentially exposed to natural infection or live alphavirus vaccines. 21 An isolate from a patient in Thailand, CHIK strain 15561, was used to develop a small lot of vaccine first passaged in green monkey kidney (GMK) cells and then formalin-inactivated before administration to 16 volunteers. 22 The vaccine produced no untoward reactions and was highly immunogenic.…”

Status and challenges of filovirus vaccines

“…If high doses for multiple immunizations are required, manufacturing of sufficient VRP may be an issue although it should be noted that vaccines using VRP for other diseases are currently in clinical trials [84]. Finally, VEE is also considered a biodefense threat and armed forces and first responders may be vaccinated with VEE vaccine; as a result, pre-existing immunity to VEE may reduce the effectiveness of vaccination with VRPbased vaccines as has been seen with VEE vaccines given to personnel receiving vaccines for other alphaviruses [85].…”