Smallpox DNA Vaccine Protects Nonhuman Primates against Lethal Monkeypox

Hooper, Jay W.; Thompson, E.; Wilhelmsen, Catherine L.; Zimmerman, Murray C.; Ichou, Mohamed; Steffen, S. E.; Schmaljohn, Connie S.; Schmaljohn, Alan L.; Jahrling, Peter B.

doi:10.1128/jvi.78.9.4433-4443.2004

Cited by 272 publications

(284 citation statements)

References 25 publications

(35 reference statements)

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“…Despite its relative paucity of whole progeny virions, EEV plays an important role in dissemination within the host (21). Because anti-B5R antibodies can neutralize EEV, expression of B5R has been proposed as an effective smallpox vaccine (14,(22)(23)(24)(25). In contrast, the results of the field trial in Japan showed that neutralizing (NT) antibody titers induced by m8 were similar to a conventional LO vaccine (5,6).…”

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confidence: 49%

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Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8

Kidokoro

Tashiro

Shida

2005

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

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A highly attenuated LC16m8 (m8) smallpox vaccine has been licensed in Japan because of its extremely low neurovirulence profile, which is comparable to that of replication incompetent strains of vaccinia virus. From 1973 to 1975, m8 was administrated to >100,000 infants where it induced levels of immunity similar to that of the originating Lister strain, without any serious side effects. Recently, we observed that m8 reverts spontaneously to large plaque forming clones that possess virulence equivalent to that of LC16mO, a parental virus strain of m8. Here, we report that the B5R gene is responsible for the reversion, and that we could construct a more genetically stable virus by deleting B5R from m8. The protective immunogenicity of the vaccine candidate proved to be equivalent to that of the U.S.-licensed product Dryvax, and much superior to modified vaccinia Ankara in a mouse model. Furthermore, the vaccine strain never elicited any symptoms in severe combined immunodeficiency disease mice, even at a dose 1,000-fold greater than that used in the immune protection experiments, which is in contrast to the lethal pathogenicity induced by Dryvax inoculation of severe combined immunodeficiency disease mice. Our results suggest that this vaccine strain is a good candidate as a suitable smallpox vaccine and a vector virus, and that B5R is not essential for protective immunity against smallpox.B5R gene ͉ reversion ͉ Lister strain ͉ extracellular enveloped virion

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confidence: 49%

“…B5R protein and a DNA vaccine expressing B5R have been reported to induce production of NT antibodies and achieve partial protection against the virus (22)(23)(24)(25). Therefore, we assessed the ability of B5R, which is expressed during viral replication in mice, to induce protective immunity.…”

Section: Discussionmentioning

confidence: 99%

Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8

Kidokoro

Tashiro

Shida

2005

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

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“…Disruption of the EEV exterior membrane, either by mechanical force or by host complement factors, can also release the IMV form (4). Vaccine development is targeting proteins from each form (5,6), although because of the fragile nature of the EEV outermost membrane, the IMV form of the virus is thought to play the major role in host-to-host transmission (7). L1 (also called L1R) is a myristoylated transmembrane protein of 250 residues that is expressed on the surface of the IMV form of the virus.…”

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confidence: 99%

The 1.51-Å structure of the poxvirus L1 protein, a target of potent neutralizing antibodies

Garman

Allison

et al. 2005

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

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Although eradicated from nature more than two decades ago, the threat of smallpox has reemerged because of concerns over its use as a biological weapon. We present the structure of the poxvirus L1 protein, a molecule that is conserved throughout the poxvirus family and is nearly identical in vaccinia virus and in variola virus, which causes smallpox. L1 is a myristoylated envelope protein that is a potent target for neutralizing antibodies and an important component of current experimental vaccines. The L1 structure reveals a hydrophobic cavity located adjacent to its N terminus. The cavity would be capable of shielding the myristate moiety, which is essential for virion assembly. The structure of L1 is a step in the elucidation of molecular mechanisms common to all poxviruses that may stimulate the design of safer vaccines and new antipoxvirus drugs.myristoylation ͉ virion protein ͉ x-ray structure P oxviruses are a family of large DNA viruses, the most infamous of which is variola virus, the cause of smallpox. After the worldwide eradication of smallpox more than two decades ago by immunization with the closely related vaccinia virus, routine immunization against smallpox ceased (1). With the threat of an intentional release of variola virus and the emergence of monkeypox virus that also infects humans, the development of antiviral drugs and safer vaccines has been urged (2). By better understanding mechanisms involved in poxvirus biology, therapeutics and vaccines can be designed to act against the whole family of poxviruses (3).Poxviruses have Ϸ200 genes and a complex life cycle. After entry into the host cell, the virus reproduces in the cytoplasm, encoding its own replication machinery and transcription factors. Maturing vaccinia virions undergo a transformation from spherical immature particles to the brick-shaped intracellular mature virions (IMVs) that have lipid membranes and are the first infectious form of the virus. Most IMVs are released directly by lysis of the host cell. Some IMVs acquire additional membranes and are then transported out through the host cell membrane. They can either remain attached to the outside of the cell or detach from the cell as an extracellular enveloped virus (EEV). Disruption of the EEV exterior membrane, either by mechanical force or by host complement factors, can also release the IMV form (4). Vaccine development is targeting proteins from each form (5, 6), although because of the fragile nature of the EEV outermost membrane, the IMV form of the virus is thought to play the major role in host-to-host transmission (7).L1 (also called L1R) is a myristoylated transmembrane protein of 250 residues that is expressed on the surface of the IMV form of the virus. It is an essential protein because vaccinia viruses with the L1 gene deleted are not capable of maturation (8). Although L1 has a C-terminal hydrophobic segment embedded in the viral membrane, the 185-residue, disulfide-bonded ectodomain is located in the cytoplasm before lysis of the host cell. In the otherwise re...

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“…While the current licensed live vaccinia virus-based vaccine is extremely effective [3] and results in remarkably long-lived immune responses (e.g., [4]), it has an unacceptable safety profile [5,6] for wide use when considered in today's setting of global eradication of active smallpox disease. Approaches to develop safer smallpox vaccines have ranged from the study of more attenuated live vaccinia viruses (such as MVA [7][8][9] or LC16m8 [10,11]) to subunit vaccines that rely on specific viral targets delivered either as DNA plasmids [12][13][14][15] or purified proteins [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Some key targets on the EV envelope that are important for protection are encoded by the A33R [29] and B5R [30,31] genes. Because the viral proteins present on MV and EV envelopes differ, there is rationale and evidence [12][13][14]17] to include proteins from both virion forms to confer maximal protection. Theoretically, antibody responses to MV proteins could neutralize some of the initial infecting inoculum, while antibodies to EV targets would then limit spread of the progeny virus within the infected host.…”

Section: Introductionmentioning

confidence: 99%

A protein-based smallpox vaccine protects mice from vaccinia and ectromelia virus challenges when given as a prime and single boost

Xiao

Aldaz-Carroll

Ortiz

et al. 2007

Vaccine

104

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The heightened concern about the intentional release of variola virus has led to the need to develop safer smallpox vaccines. While subunit vaccine strategies are safer than live virus vaccines, subunit vaccines have been hampered by the need for multiple boosts to confer optimal protection. Here we developed a protein-based subunit vaccine strategy that provides rapid protection in mouse models of orthopoxvirus infections after a prime and single boost. Mice vaccinated with vaccinia virus envelope proteins from the mature virus (MV) and extracellular virus (EV) adjuvanted with CpG-ODN and alum were protected from lethal intranasal challenge with vaccinia virus and the mousespecific ectromelia virus. Organs from mice vaccinated with three proteins (A33, B5 and L1) and then sacrificed after challenge contained significantly lower titers of virus when compared to control groups of mice that were not vaccinated or that received sub-optimal formulations of the vaccine. Sera from groups of mice obtained prior to challenge had neutralizing activity against the MV and also inhibited comet formation indicating anti-EV activity. Long-term partial protection was also seen in mice challenged with vaccinia virus 6 months after initial vaccinations. Thus, this work represents a step toward the development of a practical subunit smallpox vaccine.

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Smallpox DNA Vaccine Protects Nonhuman Primates against Lethal Monkeypox

Cited by 272 publications

References 25 publications

Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8

Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8

The 1.51-Å structure of the poxvirus L1 protein, a target of potent neutralizing antibodies

A protein-based smallpox vaccine protects mice from vaccinia and ectromelia virus challenges when given as a prime and single boost

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