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This chapter demonstrates a problem—in rule (or content) individuation—for the defeasible rule model of precedent and suggests an alternative. The defeasible rule model was designed to account for distinguishing. However, a defeasible rule model cannot be combined with a satisfactory account of rule (or content) individuation and be explanatorily adequate—that is, fit precedential practice in legal systems. Precedential practice, including distinguishing, is better explained by an alternative based on the idea that partial groupings of sameness with a source case are contextually salient. There will be such salient partial groupings, even in the absence of a determined (though defeasible) rule set down by the source court.

Older statutes sometimes alter the legal content of newer statutes in a way not apparent from the text of the newer statutes. The puzzle is how, even if a new statute is the choice of the current p...

Dworkin's theoretical disagreement argument, developed in Law's Empire, is presented in that work as the motivator for his interpretive account of law. Like Dworkin's earlier arguments critical of legal positivism, the argument from theoretical disagreement has generated a lively exchange with legal positivists. It has motivated three of them to develop innovative positivist positions. In its original guise, the argument from theoretical disagreement is presented as ‘the semantic sting argument’. However, the argument from theoretical disagreement has more than one version. This article briefly discusses two versions and the leading replies to them, then focuses on the most influential (recast) version, directed at Hartian positivism. The article surveys the leading positivist rejoinders to the recast version, indicating key Dworkinian replies or assessing the strength of these rejoinders, and concludes with a rejoinder of its own, making a new case that the argument from theoretical disagreement isn't fatal for Hartian legal positivism.

This review covers comprehensive data accumulated during the long history of using monkeys in the determination of neurovirulence activity and safety of live poliomyelitis, flaviviral, smallpox and mumps vaccines, as well as newly developed transgenic mouse and molecular-biological tests. The review also analyzes processes caused by some of these viruses in infant rodents (mice, rats) and evaluates the role of these processes in vaccine safety control. Recommendations resulting from this analysis are presented.

This essay presents a new theory of statutory application that is superior to two competitors. One of the competitors claims that statutory directives apply to act-tokens fitting the legislature's intention. The other holds that statutes apply to act-tokens that are of the genuine kinds named by the classifying words. These theories solve certain problems badly or not at all, respectively: (1) accounting for the capacity of statutes for epistemic guidance; and (2) avoiding literalism. Both do a limited job of accounting for the rationality of statutory promulgation. The theory developed here, social salience theory, does better on all counts. According to social salience theory, the default position is that statutes apply to act-tokens that are socially salient, given the linguistic and social contexts. The departure from that position is also social, produced by conventions to defer to experts on the statute's applications to particular cases.

Current requirements for control of live viral vaccines, including yellow fever 17D, produced from potentially neurotropic wild-type viruses include tests for neurovirulence in nonhuman primates. We have used yellow fever 17D virus as a live vector for novel flavivirus vaccines (designated ChimeriVax) against dengue, Japanese encephalitis (JE), and West Nile (WN) viruses. For control of these vaccines, it would be preferable to substitute a test in mice for the test in a higher species (monkeys). In this study, we compare the neurovirulence of ChimeriVax vaccine candidates in suckling mice inoculated by the intracerebral (IC) route with graded doses of the test article or yellow fever 17D vaccine as a reference control. Mortality ratio and survival distribution are the outcome measures. The monkey safety test is performed as described for control of yellow fever vaccines. In both mice and monkeys, all chimeric vaccines were significantly less neurovirulent than yellow fever 17D vaccine. The test in suckling mice discriminated between strains of two different vaccines (ChimeriVax-JE and ChimeriVax-DEN1) differing by a single amino acid change, and was more sensitive for detecting virulence differences than the test in monkeys. The results indicate that the suckling mouse test is simple to perform, highly sensitive and, with appropriate validation, could complement or possibly even replace the neurovirulence component of the monkey safety test. The test in infant mice is particularly useful as a means of demonstrating biological consistency across seed virus and vaccine lots.

A chimeric yellow fever-dengue 1 (ChimeriVax-DEN1) virus was produced by the transfection of Vero cells with chimeric in vitro RNA transcripts. The cell culture supernatant was subjected to plaque purification for the identification of a vaccine candidate without mutations. Of 10 plaque-purified clones, 1 containing no mutation (clone J) was selected for production of the vaccine virus. During subsequent cell culture passaging of this clone for vaccine production, a single amino acid substitution (K to R) occurred in the envelope (E) protein at residue 204 (E204) (F. Guirakhoo, K. Pugachev, Z. Zhang, G. Myers, I. Levenbook, K. Draper, J. Lang, S. Ocran, F. Mitchell, M. Parsons, N. Brown, S. Brandler, C. Fournier, B. Barrere, F. Rizvi, A. Travassos, R. Nichols, D. Trent, and T. Monath, J. Virol. 78: 4761-4775, 2004). The same mutation was observed in another clone (clone E). This mutation attenuated the virus in 4-day-old suckling mice inoculated by the intracerebral (i.c.) route and led to reduced viremia in monkeys inoculated by the subcutaneous or i.c. route. The histopathology scores of lesions in the brain tissue of monkeys inoculated with either the E204K or E204R virus were reduced compared to those for monkeys inoculated with the reference virus, a commercial yellow fever 17D vaccine (YF-VAX). Both viruses grew to significantly lower titers than YF-VAX in HepG2, a human hepatoma cell line. After intrathoracic inoculation into mosquitoes, both viruses grew to a similar level as YF-VAX, which was significantly lower than that of their wild-type DEN1 parent virus. A comparison of the E-protein structures of nonmutant and mutant viruses suggested the appearance of new intramolecular bonds between residues 204R, 261H, and 257E in the mutant virus. These changes may be responsible for virus attenuation through a change in the pH threshold for virus envelope fusion with the host cell membrane.

A familiar jurisprudential view is that a judicial decision functions as a legal precedent by laying down a rule and that the content of this rule is set by officials. Precedents can be followed only by acting in accordance with this rule. This view is mistaken on all counts. A judicial decision functions as a precedent by being an example. At its best, it is an example both for officials and for a target population. Even precedents outside of law function as examples when they have conduct-guiding significance. Examples may be rule-like in their scope, but need not be. Their import is independent of their justification; this point has implications for coherence theories of precedent meaning. The content and scope of a legal decision’s extension is not set exclusively by officials. It is socially set and depends upon social salience.

Yellow fever 17D virus, a safe and effective live, attenuated vaccine, was used as a vector for genes encoding the protective antigenic determinants of a heterologous member of the genus Flavivirus , Japanese encephalitis (JE) virus, the leading cause of acute viral central nervous system infection and death throughout Asia. The viral envelope (prM and E) genes of a full-length cDNA clone of YF 17D virus were replaced with the corresponding genes of JE SA14-14-2, a strain licensed as a live, attenuated vaccine in China. Full-length RNA transcripts of the YF/JE chimaera were used to transfect Vero cells. The progeny virus (named `ChimeriVax™-JE'), was used to define safety after intracerebral (IC) inoculation of rhesus monkeys. Monkeys ( N =3) inoculated with a high dose (6.6 log 10 pfu) developed a brief viremia, showed no signs of illness, developed high titers of anti-JE neutralizing antibody, and had minimal brain and spinal cord lesion scores according to criteria specified in the WHO monkey neurovirulence test. A control group of 3 monkeys that received a lower dose (4.2 log 10 pfu) of commercial YF 17D vaccine had slightly higher lesion scores. To develop a lethal monkey model of JE for vaccine protection tests, we inoculated groups of monkeys IC or intranasally (IN) with a JE virus strain found to be highly neurovirulent and neuroinvasive for mice. Monkeys inoculated IC, but not IN, developed severe encephalitis after an incubation period of 8–13 days. The ChimeriVax™-JE virus was passed in a cell line acceptable for human use (diploid fetal rhesus lung) and 4.3 or 5.3 log 10 pfu were inoculated into groups of 3 monkeys by the subcutaneous route. All 6 animals developed brief viremias (peak titer 10 pfu/ml) and subsequently had anti-JE but no yellow fever neutralizing antibodies. On day 64, the monkeys were challenged IC with 5.5 log 10 pfu of virulent JE virus. The immunized animals had no detectable viremia post-challenge, whereas 4 unimmunized controls became viremic. Only 1 of 6 (17%) vaccinated monkeys but 4 of 4 (100%) unvaccinated controls developed encephalitis. Histopathological examination 30 days after challenge confirmed that the protected, immunized animals had no or minimal evidence of encephalitis. These data demonstrated the ability of the ChimeriVax™-JE to induce a rapid humoral immune response and to protect against a very severe, direct intracerebral virus challenge. Target areas of neuronal damage and inflammation in monkeys infected IC with wild-type JE, the chimaeric virus and YF 17D were similar, indicating that the histopathological scoring system used for the WHO yellow fever monkey neurovirulence test will be applicable to control testing of chimaeric seed viruses and vaccines.

Transgenic mice susceptible to poliovirus (TgPVR mice) have been used to study poliovirus neurovirulence and attenuation. It was shown recently that mouse line TgPVR21 may be a suitable model to evaluate neurovirulence safety of oral poliovirus vaccine. It was important to determine whether TgPVR21 mice are sensitive enough to discriminate between type-3 reference and ‘marginal’ vaccines, i.e. those that failed the monkey test while containing only slightly increased amounts of neurovirulent revertants at position 472 of the viral genome as measured by a molecular assay MAPREC. Data presented here demonstrate that TgPVR21 mice are not less sensitive than monkeys in the detection of marginal vaccines. In contrast to the monkey neurovirulence test, which is based on histological examination of the CNS, the TgPVR21 mouse neurovirulence test revealed marginal vaccines by simple analysis of clinical signs without requiring a laborious histological examination.