Clinical Efficacy of Intramuscular Vaccinia Immune Globulin: A Literature Review

Hopkins, Robert J.; Lane, John

doi:10.1086/422999

Cited by 80 publications

(82 citation statements)

References 45 publications

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“…T he humoral immune response is a major correlate of protection for poxvirus infection (1)(2)(3)(4)(5)(6)(7)(8), as well as many infectious agents (reviewed in Ref. 9).…”

mentioning

confidence: 99%

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Pejoski¹,

Tchitchek²,

Pozo³

et al. 2016

The Journal of Immunology

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Broadening our understanding of the abundance and phenotype of B cell subsets that are induced or perturbed by exogenous Ags will improve the vaccine evaluation process. Mass cytometry (CyTOF) is being used to increase the number of markers that can be investigated in single cells, and therefore characterize cell phenotype at an unprecedented level. We designed a panel of CyTOF Abs to compare the B cell response in cynomolgus macaques at baseline, and 8 and 28 d after the second homologous immunization with modified vaccinia virus Ankara. The spanning-tree progression analysis of density-normalized events (SPADE) algorithm was used to identify clusters of CD20+ B cells. Our data revealed the phenotypic complexity and diversity of circulating B cells at steady-state and significant vaccine-induced changes in the proportions of some B cell clusters. All SPADE clusters, including those altered quantitatively by vaccination, were characterized phenotypically and compared using double hierarchical clustering. Vaccine-altered clusters composed of previously described subsets including CD27hiCD21lo activated memory and CD27+CD21+ resting memory B cells, and subphenotypes with novel patterns of marker coexpression. The expansion, followed by the contraction, of a single memory B cell SPADE cluster was positively correlated with serum anti-vaccine Ab titers. Similar results were generated by a different algorithm, automatic classification of cellular expression by nonlinear stochastic embedding. In conclusion, we present an in-depth characterization of B cell subphenotypes and proportions, before and after vaccination, using a two-step clustering analysis of CyTOF data, which is suitable for longitudinal studies and B cell subsets and biomarkers discovery.

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“…T he humoral immune response is a major correlate of protection for poxvirus infection (1)(2)(3)(4)(5)(6)(7)(8), as well as many infectious agents (reviewed in Ref. 9).…”

mentioning

confidence: 99%

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Pejoski¹,

Tchitchek²,

Pozo³

et al. 2016

The Journal of Immunology

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“…Neutralizing antibodies are of primary importance in the protection from smallpox provided by the smallpox vaccine in animal models (6,25,33,64) and humans (4). Vaccinia immune globulin (VIG) has been shown to be an effective treatment against smallpox (45) as it was able to reduce the number of smallpox cases by ϳ80% among exposed individuals in four case-controlled studies (42,45,50,51,66).Neutralizing antibodies confer protection mainly through the recognition of structures on the surface of virus particles, and therefore antiviral antibodies directed against the surface of virions are of primary interest. There are several interesting features and problems of the antibody response to variola and related poxviruses, including the large size of the viral particles and the abundance of distinct surface proteins (Ͼ25 total) (17,70,88).…”

mentioning

confidence: 99%

Vaccinia Virus Extracellular Enveloped Virion Neutralization In Vitro and Protection In Vivo Depend on Complement

Benhnia

McCausland

Moyron

et al. 2009

J Virol

171

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Antibody neutralization is an important component of protective immunity against vaccinia virus (VACV).Two distinct virion forms, mature virion and enveloped virion (MV and EV, respectively), possess separate functions and nonoverlapping immunological properties. In this study we examined the mechanics of EV neutralization, focusing on EV protein B5 (also called B5R). We show that neutralization of EV is predominantly complement dependent. From a panel of high-affinity anti-B5 monoclonal antibodies (MAbs), the only potent neutralizer in vitro (90% at 535 ng/ml) was an immunoglobulin G2a (IgG2a), and neutralization was complement mediated. This MAb was the most protective in vivo against lethal intranasal VACV challenge. Further studies demonstrated that in vivo depletion of complement caused a >50% loss of anti-B5 IgG2a protection, directly establishing the importance of complement for protection against the EV form. However, the mechanism of protection is not sterilizing immunity via elimination of the inoculum as the viral inoculum consisted of a purified MV form. The prevention of illness in vivo indicated rapid control of infection. We further demonstrate that antibody-mediated killing of VACV-infected cells expressing surface B5 is a second protective mechanism provided by complement-fixing anti-B5 IgG. Cell killing was very efficient, and this effector function was highly isotype specific. These results indicate that anti-B5 antibody-directed cell lysis via complement is a powerful mechanism for clearance of infected cells, keeping poxvirus-infected cells from being invisible to humoral immune responses. These findings highlight the importance of multiple mechanisms of antibody-mediated protection against VACV and point to key immunobiological differences between MVs and EVs that impact the outcome of infection.Vaccines are one of the most cost-effective medical treatments in modern civilization (80). A smallpox vaccine was the first human vaccine, and the modern smallpox vaccine, live vaccinia virus (VACV), is the most successful human vaccine, bringing about the worldwide eradication of smallpox disease due to a heroic World Health Organization campaign in the 1960s and 1970s (27). Elucidating the immunobiology underlying the protection provided by the smallpox vaccine will continue to reveal vaccinology principles that can be applied to future vaccine development against other infectious scourges (95). Neutralizing antibodies are of primary importance in the protection from smallpox provided by the smallpox vaccine in animal models (6,25,33,64) and humans (4). Vaccinia immune globulin (VIG) has been shown to be an effective treatment against smallpox (45) as it was able to reduce the number of smallpox cases by ϳ80% among exposed individuals in four case-controlled studies (42,45,50,51,66).Neutralizing antibodies confer protection mainly through the recognition of structures on the surface of virus particles, and therefore antiviral antibodies directed against the surface of virions are of primary inter...

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“…With animal models (6,15,18,36) and in human clinical studies (28,37,53,60), there are substantial data demonstrating the important role of antibodies in protecting against smallpox and related poxviruses (5). The most compelling animal model data came from a recent monkeypox study with macaques, demonstrating that smallpox vaccine-induced antibody responses are both necessary and sufficient for protection against lethal monkeypox infection while memory T cells were dispensable (15).…”

mentioning

confidence: 99%

“…Long-term antibody titers and T-cell memory for the smallpox vaccine do not correlate in humans (11,19), excluding the possibility that antibody titers were simply a biomarker for memory T cells. Vaccinia immune globulin (VIG) is an effective treatment against smallpox (28), since it was able to reduce the number of smallpox cases ϳ80% among exposed individuals in four case-controlled studies (25,28,32,33,38).…”

mentioning

confidence: 99%

Redundancy and Plasticity of Neutralizing Antibody Responses Are Cornerstone Attributes of the Human Immune Response to the Smallpox Vaccine

Benhnia

McCausland

et al. 2008

J Virol

100

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The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective humoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a "safety net" of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine.

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Clinical Efficacy of Intramuscular Vaccinia Immune Globulin: A Literature Review

Cited by 80 publications

References 45 publications

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Vaccinia Virus Extracellular Enveloped Virion Neutralization In Vitro and Protection In Vivo Depend on Complement

Redundancy and Plasticity of Neutralizing Antibody Responses Are Cornerstone Attributes of the Human Immune Response to the Smallpox Vaccine

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