Clinical Responses to Undiluted and Diluted Smallpox Vaccine

Division of General Medicine, University of Rochester, Rochester, New York, United States
New England Journal of Medicine (Impact Factor: 55.87). 05/2002; 346(17):1265-74. DOI: 10.1056/NEJMoa020534
Source: PubMed


To evaluate the potential to increase the supply of smallpox vaccine (vaccinia virus), we compared the response to vaccination with 10(8.1), 10(7.2), and 10(7.0) plaque-forming units (pfu) of vaccinia virus per milliliter.
In this randomized, single-blind, prospective study, 680 adults who had not been previously immunized were inoculated intradermally with undiluted vaccine (mean titer, 10(8.1) pfu per milliliter), a 1:5 dilution, or a 1:10 dilution of vaccinia virus with use of a bifurcated needle, and the site was covered with a semipermeable dressing. Subjects were monitored for vesicle formation (an indicator of the success of vaccination) and adverse events for 56 days after immunization.
Success rates did not differ significantly among the groups and ranged from 97.1 to 99.1 percent after the first vaccination. Both the undiluted and diluted vaccines were reactogenic. In addition to the formation of pustules, common adverse events included the formation of satellite lesions, regional lymphadenopathy, fever, headache, nausea, muscle aches, fatigue, and chills consistent with the presence of an acute viral illness. Generalized and localized rashes, including two cases of erythema multiforme, were also observed.
When given by a bifurcated needle, vaccinia virus vaccine can be diluted to a titer as low as 10(7.0) pfu per milliliter (approximately 10,000 pfu per dose) and induce local viral replication and vesicle formation in more than 97 percent of persons.

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Available from: Mark Wolff, Jan 17, 2014
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    • "This is important because while VSV is a highly promising vaccine vector and oncolytic agent, its clinical development has lagged behind that of other live viruses because of concerns about vector-associated pathology. Fever, myalgia, and the “sickness response” are induced by many live viral or bacterial vaccines [32], [33], [34], [35], [36], and these vaccine-induced side effects are among the leading reasons why some individuals elect not to receive protective vaccines [37], [38], [39]. Consistent with our results obtained in the mouse model and presented here, several recent studies have correlated increased levels of IL-1 or other pro-inflammatory cytokines with the induction of high fevers or other adverse events in response to live virus vaccination in humans [36], [40], or have identified genetic polymorphisms in the IL-1 gene which predispose individuals to severe adverse events after receiving live virus vaccines [41]. "
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    ABSTRACT: Vaccines based on live viruses are attractive because they are immunogenic, cost-effective, and can be delivered by multiple routes. However, live virus vaccines also cause reactogenic side effects such as fever, myalgia, and injection site pain that have reduced their acceptance in the clinic. Several recent studies have linked vaccine-induced reactogenic side effects to production of the pro-inflammatory cytokine interleukin-1β (IL-1β) in humans. Our objective was therefore to determine whether IL-1β contributed to pathology after immunization with recombinant vesicular stomatitis virus (rVSV) vaccine vectors, and if so, to identify strategies by which IL-1β mediated pathology might be reduced without compromising immunogenicity. We found that an rVSV vaccine induced local and systemic production of IL-1β in vivo, and that accumulation of IL-1β correlated with acute pathology after rVSV immunization. rVSV-induced pathology was reduced in mice deficient in the IL-1 receptor Type I, but the IL-1R-/- mice were fully protected from lethal rechallenge with a high dose of VSV. This result demonstrated that IL-1 contributed to reactogenicity of the rVSV, but was dispensable for induction of protective immunity. The amount of IL-1β detected in mice deficient in either caspase-1 or the inflammasome adaptor molecule ASC after rVSV immunization was not significantly different than that produced by wild type animals, and caspase-1-/- and ASC-/- mice were only partially protected from rVSV-induced pathology. Those data support the idea that some of the IL-1β expressed in vivo in response to VSV may be activated by a caspase-1 and ASC-independent mechanism. Together these results suggest that rVSV vectors engineered to suppress the induction of IL-1β, or signaling through the IL-1R would be less reactogenic in vivo, but would retain their immunogenicity and protective capacity. Such rVSV would be highly desirable as either vaccine vectors or oncolytic therapies, and would likely be better tolerated in human vaccinees.
    PLoS ONE 10/2012; 7(10):e46516. DOI:10.1371/journal.pone.0046516 · 3.23 Impact Factor
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    • "are compiled data from all 6 recombinant purified antigens used in ELISA to assay sera from individual human volunteers before and after smallpox vaccination. Fig. 5A shows vaccinia-naïve individuals from protocol #3 ([62] also shown in Supplemental Data, Fig. 1), before and after Dryvax inoculation. Under the conditions used, WR148 and WR113/D8L gave the strongest OD 450nm signals overall and were also the most commonly recognized antigens, giving 95.7% and 97.9% coverage of the Dryvax vaccinees, respectively. "
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    ABSTRACT: Modified Vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus that is being considered as a safer alternative to replicating vaccinia vaccine strains such as Dryvax(®) and ACAM2000. Its excellent safety profile and large genome also make it an attractive vector for the delivery of heterologous genes from other pathogens. MVA was attenuated by prolonged passage through chick embryonic fibroblasts in vitro. In human and most mammalian cells, production of infectious progeny is aborted in the late stage of infection. Despite this, MVA provides high-level gene expression and is immunogenic in humans and other animals. A key issue for vaccine developers is the ability to be able to monitor an immune response to MVA in both vaccinia naïve and previously vaccinated individuals. To this end we have used antibody profiling by proteome microarray to compare profiles before and after MVA and Dryvax vaccination to identify candidate serodiagnostic antigens. Six antigens with diagnostic utility, comprising three membrane and three non-membrane proteins from the intracellular mature virion, were purified and evaluated in ELISAs. The membrane protein WR113/D8L provided the best sensitivity and specificity of the six antigens tested for monitoring both MVA and Dryvax vaccination, whereas the A-type inclusion protein homolog, WR148, provided the best discrimination. The ratio of responses to membrane protein WR132/A13L and core protein WR070/I1L also provided good discrimination between primary and secondary responses to Dryvax, whereas membrane protein WR101/H3L and virion assembly protein WR118/D13L together provided the best sensitivity for detecting antibody in previously vaccinated individuals. These data will aid the development novel MVA-based vaccines.
    Vaccine 11/2011; 30(3):614-25. DOI:10.1016/j.vaccine.2011.11.021 · 3.62 Impact Factor
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    • "Therefore, vaccination with 6.8 × 107 pfu/mL of ACAM2000™ is as effective as a 1.6 × 108 pfu/mL dose of Dryvax® in vaccinia-naïve subjects. However, in contrast with Dryvax®, which causes a cutaneous reaction in over 97% of vaccinees even when diluted up to 10-fold (approximately 1 × 107 pfu/mL), a fivefold dilution (1.4 × 107 pfu/mL) of ACAM2000™ failed to offer the requisite 90% take-rate in the vaccinia-naïve group.25 The Phase II clinical trial in vaccinia-experienced subjects showed that the group receiving the highest dose of ACAM2000™ (6.8 × 107 pfu/mL) had an 88% take-rate, compared with 100% in the Dryvax® group (1.6 × 108 pfu/mL). "
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    ABSTRACT: Smallpox was eradicated more than 30 years ago, but heightened concerns over bioterrorism have brought smallpox and smallpox vaccination back to the forefront. The previously licensed smallpox vaccine in the United States, Dryvax (Wyeth Laboratories, Inc.), was highly effective, but the supply was insufficient to vaccinate the entire current US population. Additionally, Dryvax had a questionable safety profile since it consisted of a pool of vaccinia virus strains with varying degrees of virulence, and was grown on the skin of calves, an outdated technique that poses an unnecessary risk of contamination. The US government has therefore recently supported development of an improved live vaccinia virus smallpox vaccine. This initiative has resulted in the development of ACAM2000 (Acambis, Inc.), a single plaque-purified vaccinia virus derivative of Dryvax, aseptically propagated in cell culture. Preclinical and clinical trials reported in 2008 demonstrated that ACAM2000 has comparable immunogenicity to that of Dryvax, and causes a similar frequency of adverse events. Furthermore, like Dryvax, ACAM2000 vaccination has been shown by careful cardiac screening to result in an unexpectedly high rate of myocarditis and pericarditis. ACAM2000 received US Food and Drug Administration (FDA) approval in August 2007, and replaced Dryvax for all smallpox vaccinations in February 2008. Currently, over 200 million doses of ACAM2000 have been produced for the US Strategic National Stockpile. This review of ACAM2000 addresses the production, characterization, clinical trials, and adverse events associated with this new smallpox vaccine.
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