Mouse neurotoxicity test for vaccinia-based smallpox vaccines

Li, Zhongqi; Rubin, Steven A.; Taffs, Rolf E.; Merchlinsky, Michael; Ye, Zhiping; Carbone, Kathryn M.

doi:10.1016/j.vaccine.2003.10.022

Cited by 25 publications

(23 citation statements)

References 23 publications

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Section: Resultsmentioning

confidence: 61%

“…2B). These experiments confirmed that newborn mice are highly susceptible to both VACV WR and to ECTV-MOS [3,10], that maternal antibodies protect infants efficiently against orthopoxvirus infection and that survived early infection can lead to long-lasting protection.Maternal antibodies are essential not only for infant protection but also have been correlated with failure of early infant vaccinations [11] because maternal antibodies may further attenuate live or inactivated vaccines unwontedly during the early phase of infancy.Of course, in nature, the concept of vaccination with attenuated strains does not exist. Here, maternal antibodies have been shown to attenuate an otherwise lethal infection to a level that they fulfilled the same role as ''artificial'' vaccinations.…”

mentioning

confidence: 61%

“…Newborn and infant mice are highly susceptible to WT of ectromelia (mousepox) virus (ECTV) and the empirically selected VACV [1][2][3]. Resistance to ECTV varies between mouse strains; C57BL/6 are one of the genetically more resistant strains.…”

Section: Introductionmentioning

confidence: 99%

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Long‐lasting immunity by early infection of maternal‐antibody‐protected infants

et al. 2009

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Newborn higher vertebrates are largely immuno-incompetent and generally survive infections -including poxviruses -by maternal antibody protection. Here, we show that mice survived epidemics as adults only if exposed to lethal orthopoxvirus infections during infancy under the umbrella of maternal protective antibodies. This implies that both the absence of exposure to infection during early infancy or of effective vaccination renders the population highly susceptible to new or old re-emerging pathogens.Key words: Ectromelia . Maternal antibody . Protection . Vaccination . Vaccinia IntroductionIn the last 50 years, several viral diseases have been largely confined or even eradicated, as in the case of smallpox (variola virus) for which routine vaccinations with vaccinia virus (VACV) have been subsequently stopped in the 1970s. Due to loss of regular exposure to immunizing viral antigens, herd immunity might wane and leave the population susceptible to pathogen reemergence. Therefore, the consequences of interruption of the natural re-exposure cycles in the absence of infectious antigen contact need to be better understood.For these studies, we used orthopoxvirus infections because in both humans and mice the species-specific pox virus has devastating consequences with mortalities reaching 50-80% in the 14th century in Europe or up to 100% for certain mouse colonies in research establishments. Newborn and infant mice are highly susceptible to WT of ectromelia (mousepox) virus (ECTV) and the empirically selected VACV [1][2][3]. Resistance to ECTV varies between mouse strains; C57BL/6 are one of the genetically more resistant strains. Orthopox viruses such as variola virus, VACV, and ECTV share the cross-reactive neutralizing protective epitope [4] in addition to many T-cell specificities. Accordingly, vaccination with VACV provides solid protection to smallpox or mousepox (named sometimes ''smallpox of mice'') [5,6]. In this paper, we describe that long-lasting immunological protection results after immuno-incompetent pups of immune mice encounter an otherwise lethal pox-virus infection. Results and discussionWe compared survival of Moscow strain of Ectromelia virus (ECTV-MOS) infection at the age of 12-42 wk when specific pathogen-free infant C57BL/6 (H-2 b ) mice from immune mothers had been exposed to a lethal orthopox virus infection within the first days of life or not. C57BL/6 dams were immunized with 2 Â 10 6 pfu of VACV WR (LD50$10 8 pfu). Four weeks later they were mated with normal male mice. The newborn pups were infected intranasally at day 1 of age with 3-10 LD 50 corresponding to about 10 3 pfu of VACV WR ( We do not define maternal antibodies as the sole effector mechanism in this study, although they are the only ones transferred from the mother to the offspring. The theoretical possibility that viral antigen persisting in the mother could have been transferred to immunize newborns is unlikely because first, mothers were vaccinated 4 wk before pregnancy and second, without challenge infection early a...

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Section: Resultsmentioning

confidence: 61%

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confidence: 61%

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Long‐lasting immunity by early infection of maternal‐antibody‐protected infants

et al. 2009

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“…Rodent models have also been used to assess the NV potential of other virus vaccine vectors and some licensed live virus vaccines and vaccine candidates, including smallpox vaccine (40), some yellow fever virus vaccine strains (6), attenuated Venezuelan equine encephalitis virus (41), the Jeryl Lynn strain of mumps virus vaccine (52) and a modified measles virus vaccine strain (17). Interestingly, some of the more highly attenuated rVSV vectors described here produced less morbidity and mortality following IC inoculation than some of the licensed live virus vaccines.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Attenuation of Vesicular Stomatitis Virus by Combination of Specific G Gene Truncations and N Gene Translocations

Clarke

Nasar

Lee

et al. 2007

J Virol

106

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A variety of rational approaches to attenuate growth and virulence of vesicular stomatitis virus (VSV) have been described previously. These include gene shuffling, truncation of the cytoplasmic tail of the G protein, and generation of noncytopathic M gene mutants. When separately introduced into recombinant VSV (rVSV), these mutations gave rise to viruses distinguished from their "wild-type" progenitor by diminished reproductive capacity in cell culture and/or reduced cytopathology and decreased pathogenicity in vivo. However, histopathology data from an exploratory nonhuman primate neurovirulence study indicated that some of these attenuated viruses could still cause significant levels of neurological injury. In this study, additional attenuated rVSV variants were generated by combination of the above-named three distinct classes of mutation. The resulting combination mutants were characterized by plaque size and growth kinetics in cell culture, and virulence was assessed by determination of the intracranial (IC) 50% lethal dose (LD 50 ) in mice. Compared to virus having only one type of attenuating mutation, all of the mutation combinations examined gave rise to virus with smaller plaque phenotypes, delayed growth kinetics, and 10-to 500-fold-lower peak titers in cell culture. A similar pattern of attenuation was also observed following IC inoculation of mice, where differences in LD 50 of many orders of magnitude between viruses containing one and two types of attenuating mutation were sometimes seen. The results show synergistic rather than cumulative increases in attenuation and demonstrate a new approach to the attenuation of VSV and possibly other viruses.Vesicular stomatitis virus (VSV) is a member of the Vesiculovirus genus of the family Rhabdoviridae. The negative-sense virus genome is 11,162 nucleotides long and contains five genes in the order 3Ј N-P-M-G-L 5Ј, encoding the five major viral proteins (1, 3). The bullet-shaped VSV particle (160 nm by 80 nm) contains a ribonucleoprotein core (nucleocapsid) composed of genomic RNA closely associated with N protein and a RNA polymerase composed of a complex of L and P proteins enveloped in a host cell-derived plasma membrane (4,18,19,44,53,56). Following uptake of the virus particle by susceptible cells, nucleocapsid and viral RNA polymerase are released into the cytoplasm and viral mRNA transcription ensues. A 3Ј-5Ј gradient of viral mRNA transcription leads to abundant N protein expression and successively decreasing levels of P, M, G, and L proteins (1,3,15,19,27,57). This gene expression gradient provides virus proteins in a suitable ratio for subsequent viral genome replication and assembly of mature virus particles. Virus replication in cell culture is rapid, and virus progeny are detectable 5 to 6 h postinfection.Since the initial recovery of infectious recombinant VSV (rVSV) from genomic cDNA (39, 61), effort has been directed towards the development of rVSV as a vaccine vector targeting a variety of different human pathogens, including human immu...

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“…The pathogenicity of NYCBHΔE3L was tested in the highly sensitive newborn CD1 mouse model and compared to NYVAC and MVA [14]. Increasing doses of each VACV strain were injected intracranially and the LD 50 was assessed.…”

Section: Resultsmentioning

confidence: 99%

The attenuated NYCBH vaccinia virus deleted for the immune evasion gene, E3L, completely protects mice against heterologous challenge with ectromelia virus

Denzler

Schriewer

Parker

et al. 2011

Vaccine

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The New York City Board of Health (NYCBH) vaccinia virus (VACV) vaccine strain was deleted for the immune evasion gene, E3L, and tested for its pathogenicity and ability to protect mice from heterologous challenge with ectromelia virus (ECTV). NYCBHΔE3L was found to be highly attenuated for pathogenicity in a newborn mouse model and showed a similar attenuated phenotype as the NYVAC strain of vaccinia virus. Scarification with one or two doses of the attenuated NYCBHΔE3L was able to protect mice equally as well as NYCBH from death, weight loss, and viral spread to visceral organs. A single dose of NYCBHΔE3L resulted in low poxvirus-specific antibodies, and a second dose increased levels of poxvirus-specific antibodies to a level similar to that seen in animals vaccinated with a single dose of NYCBH. However, similar neutralizing antibody titers were observed following one or two doses of NYCBHΔE3L or NYCBH. Thus, NYCBHΔE3L shows potential as a candidate for a safer human smallpox vaccine since it protects mice from challenge with a heterologous poxvirus.

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Mouse neurotoxicity test for vaccinia-based smallpox vaccines

Cited by 25 publications

References 23 publications

Long‐lasting immunity by early infection of maternal‐antibody‐protected infants

Long‐lasting immunity by early infection of maternal‐antibody‐protected infants

Synergistic Attenuation of Vesicular Stomatitis Virus by Combination of Specific G Gene Truncations and N Gene Translocations

The attenuated NYCBH vaccinia virus deleted for the immune evasion gene, E3L, completely protects mice against heterologous challenge with ectromelia virus

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