New Findings about Rhabdoviruses from
Human Rabies Virus-neutralizing Antibodies
Development of human rabies virus-specific monoclonal antibodies
may provide a safer replacement for human rabies immune globulin (HRIG).
Using B cells of volunteers who had received a rabies vaccine (HDCV),
Champion et al. prepared mouse-human heterohybrid myeloma cells that
produced rabies virus-specific human monocolonal antibodies. These
antibodies provide a number of advantages over HRIG, which is currently
used in post-exposure treatment for rabies. First of all antibodies will
eliminate the possibility of anaphylaxis and will not be affected by
reduced bioavailability or supply limitations. Human monoclonal
antibodies will also reduce the likelihood of infectious contaminants. In
addition, antibody specificities may be selected to target epitopes
important in recognition of rabies virus strains, and also to ensure that
passive antibody administration will not interfere with active
(Champion, et al., 2000)
Chromatographically Purified Rabies Vaccine
A two-stage clinical trial carried out in the Philippines suggests
that chromatographically purified rabies vaccine (CPRV) is an effective
and improved immunization for patients with severe confirmed exposure.
The chromatographic procedure purifies the current rabies vaccine prepared
from Vero-cell culture (PVRV). The clinical trial provided post-exposure
treatment that included five injections of vaccine together with a dose of
rabies immunoglobulin. In stage 1, 231 subjects treated with CPRV and
PVRV displayed equivalent immunogenicity. Of the 132 subjects included in
stage 2, 62 were followed for a year. There were no reports of severe
local or systemic reactions in either stage, and no treatment-related
adverse events occurred.
(Quiambao, et al., 2000)
Spread of Rabies Virus Across Europe
An analysis of the nucleotide sequences of 245 isolates of rabies
virus nucleoprotein and glycoprotein genes suggests a possible path by
which the virus evolved and spread across Europe during this century.
Through the use of gene sequence data, Bourhy et al. determined distinct
phylogenetic groups associated with geographical areas. The pattern
indicated a spread westwards and southwards across Europe over the last
100 years. Physical barriers enabled localized evolution, most likely due
to restricted movement of infected hosts. In addition, there were two
changes of host species involving dogs and foxes.
(Bourhy et al., 1999)
Folding of Rabies Virus Glycoprotein Ectodomain
The ectodomain of the rabies virus glycoprotein was investigated
in order to determine the specifics of its folding. The trimeric
transmembrane glycoprotein mediates recognition of the virus receptor and
membrane fusion. pH plays an important role in the equilibrium of the
three structurally different states. The native (N) state is detected at
the virus surface and is responsible for receptor binding. The activated
hydrophobic (A) state interacts with the target membrane as fusion begins.
The fusion-inactive (I) state is the predominant conformation at low pH.
When glycoprotein is synthesized to exclude transmembrane and
intracytoplasmic domains, it will be secreted in an I-like state. In
addition, membrane anchorage by this domain is sufficient to fold the
ectodomain into the N state. These results suggest that the G
transmembrane domain may be important in ectodomain folding, and could
assist in determining how to attack the virus at points of receptor
recognition and fusion.
(Gaudin et al., 1999)
Role of p75NTR as a Rabies Virus Receptor
Previously it was hypothesized that the low-affinity neurotrophin
(NT) receptor, p75NTR was a rabies virus receptor in cultured BSR cells.
A study by Jackson and Park investigated rabies infection in
p75NTR-deficient mice. The mice developed a fatal encephalitis similar to
that of wild-type mice. This suggests that p75NTR is not an important
receptor for animals infected with rabies, because otherwise it would have
been expected that the knockout mice would have diminished neuropathologic
disease features. Jackson and Park concluded that either p75NTR is not an
important receptor or there are other receptors in brain neurons that
recognize rabies virus.
(Jackson and Park, 1999)
Dynamics of rabies virus quasispecies
A study of the quasispecies structure of the nucleoprotein and
glycoprotein genes of rabies virus explored how the rabies virus may adapt
and infect new hosts through mutations and genetic rearrangements.
'Quasispecies' is a term used when a virus exhibits heterogenous
population structure within a single individual. Kissi et al. obtained
gene sequences from the brain and salivary glands of a European fox, and
then from mice, dogs, cats, and cell culture after allowing for serial
infection. At the quasispecies level, two mechanisms of evolution were
found: accumulation of limited mutations with no replacement, and rapid
elective overgrowth of certain favored variants. This selective process
allows rabies to adapt to new host species. This investigation also
supported previous findings that when large virus populations are used in
passages, subtle replicative differences only affect long-term dominance
of virus subpopulations.
(Kissi et al., 1999)
Structural model of rhabdovirus glycoproteins
Walker and Kongsuwan aligned the G protein sequences of fourteen
rhabdoviruses. Their analysis indicates that the structural features of
the G protein have been highly preserved. Some of the preserved features
include cysteine residues, antigenic sites, and elements of secondary
structures. The pattern of cysteine residue preservation was used to
suggest a model for the G protein structure. This predicted structure
accounts for preservation of conformational antigenic sites and supports
(Walker and Kongsuwan, 1999)
Postexposure booster injections
In this study, Jaijaroensup et al. administered
purified chick embryo rabies vaccinations to 138 veterinary students. One
group received intradermal vaccinations, and the other group received
intramuscular vaccinations. After one year, the students received booster
injections. The students who had received intradermal vaccinations had
lower postexposure booster antibody responses than the students who had
received intramuscular vaccinations. In addition, while all the students
had antibody titers above the recommended level of 0.5 IU/mL at the time
of the booster, residual neutralizing antibodies were significantly higher
in the intramuscular group. The authors concluded that subjects receiving
intradermal vaccinations may not be fully protected during the first five
days after exposure.
(Jaijaroensup et al., 1999)
Apoptotic cell death in brain neurons of bax-deficient mice
Jackson reports on the occurrence of apoptosis in brain neurons associated
with rabies infection in mice missing the Bax protein in the hippocampus
and cerebral cortex. Bax-deficient mice were inoculated with challenge
virus standard (CVS) or the RV194-2 (avirulent) variant of rabies virus.
While the clinical disease was similar, CVS produced apoptosis that was
more marked in neurons of the dentate gyrus and cortical neurons in the
cerebral cortex, hippocampus, and cerebellum of the bax-deficient mice
compared to the wild-type mice. Since apoptosis occurred in all cases,
this suggests that Bax protein plays an important role in rabies-induced
apoptosis, but additional modulators are likely to be important.
ELISA for detection of rabies virus antibodies following vaccination
ELISA was used to examine sera from humans vaccinated with
cell-culture vaccine or suckling-mouse-brain vaccine. Results were
compared to resutls from the virus neutralization test. Sensitivity,
specificity, and agreement values were 87.5%, 92.4%, and 88.5%,
respectively. There were no significant differences in these values
between the two vaccinated groups. The authors suggest that these results
indicate that this ELISA method may be used as a screening test in rabies
laboratories, regardless of the kind of vaccine used in immunization.
(Piza et al., 1999)