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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.

We studied the persistence of antibody to Venezuelan equine encephalomyelitis (VEE) virus subtypes in sera of 20 volunteers inoculated seven or nine years previously with attenuated TC-83 VEE virus vaccine. Serological patterns were compared with those of 10 other persons from whom samples of serum were obtained 28 days after vaccination with TC-83 virus. Vaccines had no other known exposure to a group A arbovirus. Titers of neutralizing antibody of greater than or equal to 1:10 were measured against the homologous TC-83 strain of virus in all long- and short-term vaccinees. In both groups of vaccinees the percentage of antibody-positive persons and their geometric mean titers of antibody to the epizootic subtypes I-A, I-B, and I-C were higher than titers to the enzootic subtypes I-D, I-E, II, III, and IV. However, proportionally fewer long-term vaccinees than short-term vaccinees had detectable neutralizing antibody reactive with enzootic strains. These results reveal long-lasting circulation of neutralizing antibody to TC-83 virus and closely related epizootic variants in 95%-100% of vaccinees. The relatively lower rate of antibody conversion and the loss of antibody to more antigenically remote enzootic subtypes of VEE virus suggest that vaccinees may be less well protected against infection by these strains.

A new, formalin-inactivated vaccine for Venezuelan equine encephalitis (VEE) virus (C-84), prepared from an attenuated vaccine strain of virus (TC-83), was tested in humans. Only occasional, mild, local and systemic reactions were noted in 28 volunteers; no meaningful changes in clinical laboratory values occurred. The vaccine augmented preexisting titers of serum neutralizing antibody to VEE virus in seropositive recipients of TC-83 vaccine, and it induced high titers of neutralizing antibody in nonimmune subjects after one primary and two booster vaccinations. Circulating antibody persisted for at least 14 months in these persons. The neutralizing antibody produced after one dose of C-84 vaccine in immune subjects and after booster doses in nonimmune subjects had broad cross-reactivity within the VEE virus complex. The C-84 vaccine induced a VEE virus-specific lymphocyte transformation response. The vaccine was safe, and immunologic results showed it to be highly antigenic in healthy immune and nomimmune adults.

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