Postexposure Prevention of Progressive Vaccinia in SCID Mice Treated with Vaccinia Immune Globulin

Fisher, Robert W.; Reed, Jennifer L.; Snoy, Philip; Mikolajczyk, Malgorzata G.; Bray, Mike; Scott, Dorothy E.; Kennedy, Michael

doi:10.1128/cvi.00280-10

Cited by 20 publications

(29 citation statements)

References 37 publications

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“…Furthermore, a number of studies have used animal models of OPV infection to demonstrate that passive transfer of vaccinia immune globulin (VIG) is protective in immunocompetent hosts, i.e., as long as T cells are also present (22,49). In humans, passive transfer of VIG to contacts of smallpox patients was shown to result in a reduction in smallpox incidence by nearly 70% (50,51).…”

Section: Discussionmentioning

confidence: 99%

“…It has long been recognized that individuals with T cell deficiencies given the smallpox vaccine can develop adverse reactions, including progressive vaccinia, which can be lethal without any intervention (reference 20; reviewed in references 21 and 24). Animal models of OPV infections have also been used to demonstrate essential roles for T cells in recovery from primary infection (17,19,22,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

“…Virus control and recovery from primary OPV infections (17)(18)(19) or VACV vaccination (20)(21)(22)(23)(24) require both CD4 T cell-dependent antibody responses and effector T cell function. However, while antibody is also critical for protection against secondary OPV infection following vaccination, the role of T cells has been unclear.…”

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confidence: 99%

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Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses

Chaudhri

Tahiliani

Eldi

et al. 2015

J Virol

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Antibody production by B cells in the absence of CD4 T cell help has been shown to be necessary and sufficient for protection against secondary orthopoxvirus (OPV) infections. This conclusion is based on short-term depletion of leukocyte subsets in vaccinated animals, in addition to passive transfer of immune serum to naive hosts that are subsequently protected from lethal orthopoxvirus infection. Here, we show that CD4 T cell help is necessary for neutralizing antibody production and virus control during a secondary ectromelia virus (ECTV) infection. A crucial role for CD4 T cells was revealed when depletion of this subset was extended beyond the acute phase of infection. Sustained depletion of CD4 T cells over several weeks in vaccinated animals during a secondary infection resulted in gradual diminution of B cell responses, including neutralizing antibody, contemporaneous with a corresponding increase in the viral load. Long-term elimination of CD8 T cells alone delayed virus clearance, but prolonged depletion of both CD4 and CD8 T cells resulted in death associated with uncontrolled virus replication. In the absence of CD4 T cells, perforin-and granzyme A-and B-dependent effector functions of CD8 T cells became critical. Our data therefore show that both CD4 T cell help for antibody production and CD8 T cell effector function are critical for protection against secondary OPV infection. These results are consistent with the notion that the effectiveness of the smallpox vaccine is related to its capacity to induce both B and T cell memory. IMPORTANCESmallpox eradication through vaccination is one of the most successful public health endeavors of modern medicine. The use of various orthopoxvirus (OPV) models to elucidate correlates of vaccine-induced protective immunity showed that antibody is critical for protection against secondary infection, whereas the role of T cells is unclear. Short-term leukocyte subset depletion in vaccinated animals or transfer of immune serum to naive, immunocompetent hosts indicates that antibody alone is necessary and sufficient for protection. We show here that long-term depletion of CD4 T cells over several weeks in vaccinated animals during secondary OPV challenge reveals an important role for CD4 T cell-dependent antibody responses in effective virus control. Prolonged elimination of CD8 T cells alone delayed virus clearance, but depletion of both T cell subsets resulted in death associated with uncontrolled virus replication. Thus, vaccinated individuals who subsequently acquire T cell deficiencies may not be protected against secondary OPV infection. T he vaccination campaign that culminated in eradication of smallpox is one of the most successful public health endeavors of modern medicine. The success of the smallpox vaccine is largely due to its being a live-virus vaccine that induces both cell-mediated and humoral immunity. Our understanding of immunity to smallpox in humans comes largely from prospective studies of the response to vaccinia virus (VACV) vaccinatio...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses

Chaudhri

Tahiliani

Eldi

et al. 2015

J Virol

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“…The combination treatments (antiviral drug plus VIG) were more effective than VIG alone in reducing cutaneous lesion severity and in delaying the time to death. Vaccinia infections in SCID mice are difficult to treat due to the profound immunosuppressive state of the mice, and a cure is not generally possible unless treatment is initiated very early postexposure (13). The delayed-treatment SCID mouse model may be a good representation of the treatment of vaccinia infections in immunocompromised humans, who require aggressive antiviral/ VIG therapy (3)(4)(5).…”

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confidence: 99%

“…Several studies in mice have reported VIG as a single treatment for severe vaccinia virus infections (9-12). Two reports addressed the use of CDV in combination with VIG to treat progressive vaccinia infections in severe combined immunodeficient (SCID) mice (13,14). These investigations were performed using vaccine strains of vaccinia virus to infect the animals at the base of the dorsal side of the tail.…”

mentioning

confidence: 99%

Enhanced Efficacy of Cidofovir Combined with Vaccinia Immune Globulin in Treating Progressive Cutaneous Vaccinia Virus Infections in Immunosuppressed Hairless Mice

Smee

Dagley

Downs

et al. 2015

Antimicrob Agents Chemother

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The treatment of progressive vaccinia in individuals has involved antiviral drugs, such as cidofovir (CDV), brincidofovir, and/or tecovirimat, combined with vaccinia immune globulin (VIG). VIG is costly, and its supply is limited, so sparing the use of VIG during treatment is an important objective. VIG sparing was modeled in immunosuppressed mice by maximizing the treatment benefits of CDV combined with VIG to determine the effective treatments that delayed the time to death, reduced cutaneous lesion severity, and/or decreased tissue viral titers. SKH-1 hairless mice immunosuppressed with cyclophosphamide and hairless SCID mice (SHO strain) were infected cutaneously with vaccinia virus. Monotherapy, dual combinations (CDV plus VIG), or triple therapy (topical CDV, parenteral CDV, and VIG) were initiated 2 days postinfection and were given every 3 to 4 days through day 11. The efficacy assessment included survival rate, cutaneous lesion severity, and viral titers. Delays in the time to death and the reduction in lesion severity occurred in the following order of efficacy: triple therapy had greater efficacy than double combinations (CDV plus VIG or topical plus parenteral CDV), which had greater efficacy than VIG alone. Parenteral administration of CDV or VIG was necessary to suppress virus titers in internal organs (liver, lung, and spleen). The skin viral titers were significantly reduced by triple therapy only. The greatest efficacy was achieved by triple therapy. In humans, this regimen should translate to a faster cure rate, thus sparing the amount of VIG used for treatment. Serious, life-threatening, progressive vaccinia infections have arisen in individuals after receipt of a smallpox vaccination, usually in military personnel or their household contacts, such as young children (1-3). A primary component of the treatment of such infections is vaccinia immune globulin (VIG) (4, 5). VIG is expensive and difficult to produce in large quantities. The U.S. government maintains a small stockpile of the material that can be severely depleted, even by just one treated individual. As an example, in 2012, the case of an immunosuppressed military vaccinee with a severe progressive vaccinia infection was reported. The individual was successfully treated, but treatment required 341 vials of VIG over the course of 75 days in addition to oral and topical treatments with tecovirimat (ST-246) and brincidofovir (CMX001, an orally active prodrug of cidofovir [CDV]) (4).Many animal models exist for studying the treatment of infections with vaccinia virus, including those using mice, prairie dogs, rabbits, and nonhuman primates (6-8). Mice are most often used because of their availability in large numbers and relatively low cost. Several studies in mice have reported VIG as a single treatment for severe vaccinia virus infections (9-12). Two reports addressed the use of CDV in combination with VIG to treat progressive vaccinia infections in severe combined immunodeficient (SCID) mice (13,14). These investigations were performe...

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Passive Immunization

Amanna¹

2018

Plotkin's Vaccines

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Postexposure Prevention of Progressive Vaccinia in SCID Mice Treated with Vaccinia Immune Globulin

Cited by 20 publications

References 37 publications

Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses

Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses

Enhanced Efficacy of Cidofovir Combined with Vaccinia Immune Globulin in Treating Progressive Cutaneous Vaccinia Virus Infections in Immunosuppressed Hairless Mice

Passive Immunization

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