Immunologic Interference from Sequential Administration of Live Attenuated Alphavirus Vaccines

Division of Virology, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 04/1998; 177(3):634-41. DOI: 10.1086/514240
Source: PubMed


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.

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Available from: Cindy A Rossi, May 23, 2014
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    • "The recent outbreaks of chikungunya fever across several continents highlight the urgency of developing prevention and control methods for this agent [20]. Although many approaches for the development of chikungunya vaccine have been reported such as the use of live attenuated vaccine [21], [22], formalin-inactivated vaccine [23], a recombinant live attenuated vaccine [24], a chimeric alphavirus vaccine [25], DNA vaccines [26], [27] and VLP-based vaccines [15], [28], there is still no licensed vaccine available to prevent CHIKV infection. An attenuated virus vaccine was shown to elicit an immune response, but it was withdrawn during phase II clinical trials [29]. "
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    ABSTRACT: Chikungunya virus (CHIKV) is becoming a global concern due to the increasing number of outbreaks throughout the world and the absence of any CHIKV-specific vaccine or treatment. Virus-like particles (VLPs) are multistructured proteins that mimic the organization and conformation of native viruses but lack the viral genome. They are noninfectious and potentially safer vaccine candidates. Recent studies demonstrated that the yield of CHIKV VLPs varies depending on the strains, despite the 95% amino acid similarity of the strains. This might be due to the codon usage, since protein expression is differently controlled by different organisms. We optimized the region encoding CHIKV structural proteins, C-E3-E2-6k-E1, inserted it into a mammalian expression vector, and used the resulting construct to transfect 293 cells. We detected 50-kDa proteins corresponding to E1 and/or E2 in the cell lysate and the supernatant. Transmission electron microscopy revealed spherical particles with a 50- to 60-nm diameter in the supernatant that resembled the native CHIKV virions. The buoyant density of the VLPs was 1.23 g/mL, and the yield was 20 µg purified VLPs per 108 cells. The VLPs aggregated when mixed with convalescent sera from chikungunya patients, indicating that their antigenicity is similar to that of native CHIKV. Antibodies elicited with the VLPs were capable of detecting native CHIKV, demonstrating that the VLPs retain immunogenicity similar to that of the native virion. These results indicated that CHIKV VLPs are morphologically, antigenically, and immunologically similar to the native CHIKV, suggesting that they have potential for use in chikungunya vaccines.
    PLoS ONE 09/2014; 9(9):e108169. DOI:10.1371/journal.pone.0108169 · 3.23 Impact Factor
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    • "In 1973, Calisher et al. [11] demonstrated the phenomenon of vaccine interference in Texas horses receiving alphavirus vaccinations. McClain et al. [12] discovered immunologic suppression when live attenuated VEE and chikungunya (CHIK) virus vaccines were administered sequentially . In this report, we show that suppression of neutralizing antibody response to the live attenuated VEE vaccine can occur among volunteers who were previously vaccinated with eastern equine encephalitis and western equine encephalitis (EW) vaccines. "
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    ABSTRACT: We compared the effect of order of administration of investigational alphavirus vaccines on neutralizing antibody response. Volunteers who received the inactivated eastern and western equine encephalitis (EEE and WEE) vaccines before live attenuated Venezuelan (VEE) vaccine had significantly lower rates of antibody response than those receiving VEE vaccine before EEE and WEE vaccines (66.7% vs. 80.6%; p=0.026). The odds of having a VEE antibody non-response among those initially receiving EEE and WEE vaccines, adjusted for gender, were significant (odds ratio [OR]=2.20; 95% CI=1.2-4.1 [p=0.0145]) as were the odds of non-response among females adjusted for group (OR=1.81; 95% CI=1.2-2.7 [p=0.0037]). Antibody interference and gender effect have major implications for vaccine strategy among those receiving multiple alphavirus vaccines and those developing next generation vaccines for these threats.
    Vaccine 09/2009; 27(36):4879-82. DOI:10.1016/j.vaccine.2009.02.090 · 3.62 Impact Factor
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