Inactivated smallpox vaccine. A comparison of inactivation methods

Turner, G. S.; Squires, Edwina; Murray, H. G. S.

doi:10.1017/s0022172400028679

Cited by 31 publications

(17 citation statements)

References 43 publications

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“…UV radiation likely disrupted the critical disulfide bonds required for generating high-affinity neutralizing epitopes as it is well-known that UV light can break disulfide bonds, especially through the photo-excitation of aromatic residues (Neves-Petersen et al, 2006;Vanhooren et al, 2006). In the past, UV-killed poxvirus vaccines were tested for the capacity to protect (Turner et al, 1970). In retrospect, our data indicate that UV-inactivated poxvirus antigen lacks an important L1-neutralizing epitope.…”

Section: Discussionmentioning

confidence: 79%

Structural basis for the binding of the neutralizing antibody, 7D11, to the poxvirus L1 protein

Golden

Gittis

et al. 2007

Virology

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Medical countermeasures to prevent or treat smallpox are needed due to the potential use of poxviruses as biological weapons. Safety concerns with the currently available smallpox vaccine indicate a need for research on alternative poxvirus vaccine strategies. Molecular vaccines involving the use of proteins and/or genes and recombinant antibodies are among the strategies under current investigation. The poxvirus L1 protein, encoded by the L1R open reading frame, is the target of neutralizing antibodies and has been successfully used as a component of both protein subunit and DNA vaccines. L1-specific monoclonal antibodies (e.g., mouse monoclonal antibody mAb-7D11, mAb-10F5) with potent neutralizing activity bind L1 in a conformation-specific manner. This suggests that proper folding of the L1 protein used in molecular vaccines will affect the production of neutralizing antibodies and protection. Here, we co-crystallized the Fab fragment of mAb-7D11 with the L1 protein. The crystal structure of the complex between Fab-7D11 and L1 reveals the basis for the conformation-specific binding as recognition of a discontinuous epitope containing two loops that are held together by a disulfide bond. The structure of this important conformational epitope of L1 will contribute to the development of molecular poxvirus vaccines and also provides a novel target for anti-poxvirus drugs. In addition, the sequence and structure of Fab-7D11 will contribute to the development of L1-targeted immunotherapeutics.

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Section: Discussionmentioning

confidence: 79%

Structural basis for the binding of the neutralizing antibody, 7D11, to the poxvirus L1 protein

Golden

Gittis

et al. 2007

Virology

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“…Interferon seems to function as a mediator of cellular immunity (23,3,4) and has been detected at the dermal site of vaccination (24,25). Also, enhanced local interferon production by immunized mice has been observed after intracranial challenge with vaccinia (26). That such local interferon may play a very important role in recovery or resistance to reinfection has been documented by studies of Varicella zoster (another enveloped DNA virus affecting the skin) in patients with impaired cell-mediated immunity (27).…”

Section: Discussionmentioning

confidence: 99%

Selective Increase in Lymphocyte Interferon Response to Vaccinia Antigen after Revaccination

Epstein

Stevens

Merigan

1972

Proc. Natl. Acad. Sci. U.S.A.

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Viral antigen prepared by heat inactivation of vaccinia virus stimulated production of interferon in association with transformation of sensitized human lymphocytes in vitro. Involvement of a macrophage-lymphocyte interaction in production of interferon stimulated by viral antigen was found in which macrophages greatly augmented the amount of interferon produced by lymphocytes. Reimmunization with live vaccinia virus resulted in a selective increase in the ability of lymphocytes to produce interferon in the presence of viral antigen 4-7 weeks later without a corresponding increase in the degree of already significant lymphocyte transformation. There was no correlation between the extent of lymphocyte transformation and the amount of interferon produced. The augmented interferon response after reimmunization described in this study may be a significant component of the protective effect of immunization with vaccinia against disease occurring after exposure to smallpox.Epstein et al. demonstrated that a macrophage-lymphocyte interaction is involved in the mitogen-(1, 2) and antigen-(3, 4) stimulated production of interferon in cultures derived from human peripheral blood. Such interferon production occurred in association with the transformation of small lymphocytes to large blast-like cells observed in response to the nonspecific mitogen, phytohemagglutinin (PHA), and in the more specific immune reaction when sensitized lymphocytes transform in response to purified protein derivative (PPD). In both situations, lymphocytes were identified as the most likely cells responsible for the production of interferon, but the presence of macrophages greatly augmented the amount of interferon produced.Numerous authors have reported the transformation of sensitized human lymphocytes in response to smallpox vaccine (5-1 1). With one exception, the smallpox vaccine used contained live vaccinia virus, and the possibility that replication of vaccinia in leukocytes contributed to the response could not be ruled out. Many other studies have demonstrated interferon production in cultured leukocytes stimulated by vaccinia virus (12, 13) as well as by other viruses (14,15). Furthermore, cultures of leukocytes from animals immune to a given virus produced greater amounts of interferon when exposed to that virus than similar cultures from nonimmune animals (15). The present studies were therefore undertaken to answer the following questions:(a) Can human lymphocytes transform and produce interferon on an immune specific basis in response to a nonreplicating vaccinia virus antigen?Abbreviations: PHA, phytohemagglutinin; VH, heat-treated vaccinia antigen; PPD, purified protein derivative. 2632(b) Is involvement of a macrophage-lymphocyte interaction necessary in the production of interferon as has been observed with mitogen-and nonviral-antigen-stimulated interferon production?(c) Would reimmunization of donors with live vaccinia virus affect the degree of lymphocyte transformation and/or interferon production that occurred in vit...

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“…The tissue culture infective dose 50 (TCID 50 ) was determined in KOP cells using the formula after Spearman and Kärber . Chemical inactivation was performed using beta‐propiolactone (Merck) at a final concentration of 0.05% …”

Section: Methodsmentioning

confidence: 99%

Orf virus infection of human keratinocytes and dermal fibroblasts: Limited virus detection and interference with intercellular adhesion molecule‐1 up‐regulation

Schneider

Protschka

Müller

et al. 2019

Experimental Dermatology

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Orf virus (Parapoxvirus ovis, ORFV) is a dermatotropic virus causing pustular dermatitis in small ruminants and humans. We analysed isolated human primary keratinocytes (KC) and dermal fibroblasts (FB) for cell death and virus replication by infection with a patient‐derived ORFV isolate. ORFV infection was associated with rapid induction of cell death in KC allowing for considerable virus removal. Upon infection with ORFV, KC and FB harboured intracytoplasmic ORFV and showed viral protein presence; however, missing virus spread indicated an abortive infection. Upon ORFV exposure, KC but not FB secreted the pro‐inflammatory cytokine interleukin (IL)‐6. ORFV infection enhanced the frequency of KC expressing intercellular adhesion molecule (ICAM)‐1 which was independent of IL‐6. Interestingly, ORFV inhibited ICAM‐1 up‐regulation on infected but not on non‐infected KC. Even interferon‐γ, a potent inducer of ICAM‐1, up‐regulated ICAM‐1 only on non‐infected KC. Transfer of ORFV‐free supernatant from infected to non‐infected KC induced ICAM‐1 on non‐infected KC pointing to the involvement of soluble mediator(s). Similarly as in KC, in FB interference with ICAM‐1 up‐regulation by ORFV infection was also observed. In conclusion, we shed light on epidermal and dermal defense mechanisms to ORFV infection and point to a novel ICAM‐1‐related immune evasion mechanism of ORFV in human skin.

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Inactivated smallpox vaccine. A comparison of inactivation methods

Cited by 31 publications

References 43 publications

Structural basis for the binding of the neutralizing antibody, 7D11, to the poxvirus L1 protein

Structural basis for the binding of the neutralizing antibody, 7D11, to the poxvirus L1 protein

Selective Increase in Lymphocyte Interferon Response to Vaccinia Antigen after Revaccination

Orf virus infection of human keratinocytes and dermal fibroblasts: Limited virus detection and interference with intercellular adhesion molecule‐1 up‐regulation

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