Article

Edghill-Smith, Y. et al. Smallpox vaccine-induced antibodies are necessary and sufficient for protection against monkeypox virus. Nature Med. 11, 740-747

Animal Models & Retroviral Vaccines Section, National Cancer Institute, 41/D804, Bethesda, Maryland 20892, USA.
Nature Medicine (Impact Factor: 28.05). 08/2005; 11(7):740-7. DOI: 10.1038/nm1261
Source: PubMed

ABSTRACT Vaccination with live vaccinia virus affords long-lasting protection against variola virus, the agent of smallpox. Its mode of protection in humans, however, has not been clearly defined. Here we report that vaccinia-specific B-cell responses are essential for protection of macaques from monkeypox virus, a variola virus ortholog. Antibody-mediated depletion of B cells, but not CD4+ or CD8+ T cells, abrogated vaccine-induced protection from a lethal intravenous challenge with monkeypox virus. In addition, passive transfer of human vaccinia-neutralizing antibodies protected nonimmunized macaques from severe disease. Thus, vaccines able to induce long-lasting protective antibody responses may constitute realistic alternatives to the currently available smallpox vaccine (Dryvax).

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Available from: Chris Whitehouse, Sep 29, 2014
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    • "Antibodies are critical for protection against secondary orthopoxvirus infections [35] [36]. Thus, we are interested in enhancing our 4pox subunit vaccine such that it will elicit potent humoral responses after one or two vaccinations. "
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    ABSTRACT: The current live-orthopoxvirus vaccine is associated with minor to serious adverse affects, and is contraindicated for use in a significant portion of the population. As an alternative vaccine, we have previously shown that a DNA subunit vaccine (4pox) based on four orthopoxvirus immunogens (L1R, B5R, A27L and A33R) can produce protective immunity against lethal orthopoxvirus challenges in mice and nonhuman primates. Because antibodies are critical for protection against secondary orthopoxvirus infections, we are now interested in strategies that will enhance the humoral immune response against vaccine targets. Here, we tested the immunogenicity of an L1R construct to which a tissue plasminogen activator signal sequence was placed in frame with the full-length L1R gene. The tPA-L1R construct produced a more robust neutralizing antibody response in vaccinated mice when the DNA vaccine was administered by gene-gun as a prime/single boost. When the tPA-L1R construct was substituted for the unmodified L1R gene in the 4pox vaccine, given as a prime and single boost, animals were better protected from lethal challenge with vaccinia virus (VACV). These findings indicate that adding a tPA-leader sequence can enhance the immunogenicity of the L1R gene when given as a DNA vaccine. Furthermore, our results demonstrate that a DNA-based vaccine is capable of establishing protection from lethal orthopoxvirus challenges when administered as a prime and single boost without requiring adjuvant.
    Vaccine 07/2008; 26(27-28):3507-15. DOI:10.1016/j.vaccine.2008.04.017 · 3.49 Impact Factor
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    • "In humans, the smallpox vaccine induces robust, long-lasting humoral and cellular responses [22] [23]. Both have been demonstrated to be protective in animal models [24] [25]. So, while it is clear that vaccination in combination with ST-246 elicits comparable protective immunity to lethal challenge, the immune responses may not be the same. "
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    ABSTRACT: The re-emerging threat of smallpox and the emerging threat of monkeypox highlight the need for effective poxvirus countermeasures. Currently approved smallpox vaccines have unacceptable safety profiles and, consequently, the general populace is no longer vaccinated, leading to an increasingly susceptible population. ST-246, a small-molecule inhibitor of poxvirus dissemination, has been demonstrated in various animal models to be safe and effective in preventing poxviral disease. This suggests that it may also be used to improve the safety of the traditional smallpox vaccine provided that it does not inhibit vaccine-induced protective immunity. In this study, we compared the immune responses elicited by the smallpox vaccine alone or in combination with ST-246 in mice. Normal lesion formation following dermal scarification with the attenuated New York City Board of Health strain (Dryvax), commonly referred to as a vaccine "take", was not inhibited although severe lesions and systemic disease due to vaccination with the virulent Western Reserve (VV-WR) strain were prevented. The vaccine given with ST-246 did not affect cellular immune responses or neutralizing antibody titers although anti-vaccinia ELISA titers were slightly reduced. Vaccination in combination with ST-246 provided equivalent short- and long-term protection against lethal intranasal challenge with VV-WR when compared to vaccine alone. These results suggest that ST-246 does not compromise protective immunity elicited by the vaccine and provide the basis for future studies examining the efficacy of ST-246 in preventing or treating adverse events due to vaccination.
    Vaccine 03/2008; 26(7):933-46. DOI:10.1016/j.vaccine.2007.11.095 · 3.49 Impact Factor
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    • "The primary endpoint should be protection against a respiratory challenge. A number of animal models for smallpox infection have been established such as intranasal (i.n.) administration of VACV or cowpox virus (CPXV) Brighton strain to BALB/c mice [11] [12] [13], footpad infection with ectromelia virus (ECTV) [14], aerosolized or intratracheal [15] [16] or intravenous [17] monkeypox virus infection of Cynomolgus monkeys. However, only a few of these models satisfy EMEA recommendations. "
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    ABSTRACT: The intranasal infection of mice with cowpox virus (CPXV) has been evaluated as a model for smallpox infection in man. Administration of a lethal dose of CPXV allowed time for development of T-cell responses but antibodies could not be detected before death occurred. In contrast, infection with a sublethal dose was associated with an early T-cell response followed by neutralising antibodies which correlated with virus clearance. Comparison of two first generation smallpox vaccines revealed no significant differences in terms of immunogenicity, protection and post-challenge virus clearance. These studies show that the CPXV/mouse model is valuable for the initial assessment of smallpox vaccines.
    Vaccine 07/2007; 25(25):4809-17. DOI:10.1016/j.vaccine.2007.04.011 · 3.49 Impact Factor
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