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The Pathogenesis of West Nile Virus—Toward The Development of Effective Therapies and Vaccines
infection and resulted in decreased WNV viral loads and mortality.
33,34
reducing morbidity and mortality in patients with known or suspected WNV
Treatment with IFN-α reduced complications in human St Louis infection was recently completed (www.clinicaltrials.gov/NCT00068055),
encephalitis virus cases and has been used successfully—albeit in although the results have not been announced. Additional phase I/II trials
an uncontrolled manner—to treat small numbers of human cases of with human or humanized mAbs against WNV are in progress or planned.
WNV encephalitis.
35–37
Nonetheless, in Vietnam a double-blinded,
randomized, placebo-controlled clinical trial was performed on Development of West Nile Virus Vaccines
children with suspected or documented Japanese encephalitis virus Induction of neutralizing antibodies is a critical determinant for the efficacy
infection; treatment with IFN α
2a
failed to improve outcome.
38
of WNV vaccines. Several immunization strategies have been utilized to
Although no consensus has emerged, a randomized, non-blinded clinical promote neutralizing antibody responses against WNV in multiple animal
trial of IFN α
2b
has been initiated for WNV infection (see models. One major challenge to WNV vaccination may be to induce
http://nyhq.org/posting/rahal.html). protective humoral immunity in the populations most at risk for severe
clinical disease: the elderly and immunosuppressed.
Antibody Therapy
Although antibodies have been utilized as a therapeutic against several viral Live-attenuated and Chimeric West Nile Virus Strains
infections, with the exception of its prophylactic use against tick-borne Live-attenuated WNV vaccine strains are inherently less pathogenic, yet can
encephalitis virus
39
it has not been used extensively against flavivirus replicate and elicit both humoral and cellular immune responses in a
infections in humans. Although antibodies could have a potential manner akin to infection with virulent WNV strains. The WNV-25 strain was
therapeutic role, there are at least theoretical concerns that treatment could developed in Israel by serial passage in mosquito cells until mutations
exacerbate WNV infection. Sub-neutralizing concentrations of antibody accumulated that reduced neuroinvasiveness by more than than 106-fold.
50
enhance flavivirus replication in myeloid cells in vitro,
40
and thus could Mice infected with WNV-25 seroconvert, and immunization protected geese
complicate the therapeutic administration of antibodies. This phenomenon against lethal challenge with a virulent WNV isolate.
51
Analogously,
of antibody-dependent enhancement of infection (ADE) may contribute to
a pathological cytokine cascade during secondary dengue virus infection
and causes a severe hemorrhagic syndrome.
41
Despite its extensive One major challenge to West Nile virus
characterization in vitro, the significance of ADE in vivo with WNV or other
vaccination may be to induce protective
flaviviruses remains uncertain.
humoral immunity in the populations
Recent animal studies suggest that passive administration of anti-WNV
most at risk for severe clinical disease:
antibodies is both protective and therapeutic and does not cause adverse
effects related to immune enhancement. Passive administration of immune the elderly and immunosuppressed.
serum or antiserum that recognized WNV E protein protected hamsters and
mice against lethal WNV infection. Humanized or human monoclonal
antibodies or antibody fragments with therapeutic activity against WNV mutation of a single amino acid residue in the NS2A gene converted an
infection
42–44
have recently been developed. These reagents have higher inherently less virulent Australian subtype of WNV—Kunjin virus (KUNV)—
neutralizing activity in vitro and provide equivalent or superior protection in to a highly attenuated strain.
52
Infection with A30P-KUN elicited antibody
vivo in mice. In therapeutic trials in mice, several groups have demonstrated responses similar to the parent virus and significantly protected mice from
that immune human γ-globulin or humanized mAbs protected rodents both peripheral and CNS challenge with a virulent WNV strain. However,
against WNV-induced mortality.
42–47
Therapeutic intervention even five days the introduction of additional attenuating mutations may be necessary to
after infection reduced mortality; this time-point is significant because reduce the risk of parental virus reversion.
virological data indicate that between days four and five WNV had spread
to the brain and spinal cord. Thus, passive transfer of immune antibody Live-attenuated WNV vaccine strains have also been generated by
improved clinical outcome even after WNV had disseminated into the CNS. chimerization, which may further reduce the likelihood of viral reversion.
Nonetheless, although the mice had virological evidence of CNS infection Transplantation of the prM and E structural genes of WNV into the
at day five after infection, frank neurological symptoms did not develop infectious clone backbone of the attenuated yellow fever or dengue virus
until day six or seven after infection. vaccine strains has produced candidate chimeric WNV vaccine strains that
induce specific neutralizing antibody responses.
53,54
Generation of these
Small numbers of human patients have received antibody therapy against chimeric vaccine strains on virus backgrounds that are already attenuated
WNV infection. Immunoprophylaxis and immunotherapy with neutralizing limits the neuroinvasiveness and neurovirulence of these strains.
55,56
anti-WNV antibodies may be a possible intervention in the elderly and Additionally, the process of chimerization itself independently attenuates
immunocompromised. Case reports
48,49
have documented clinical flavivirus virulence. Immunization with a single dose of chimeric WNV-YFV
improvement in humans with neurological WNV infection after receiving virus induced neutralizing antibodies in rodents and non-human primates
immune γ-globulin from Israeli donors. Given the endemic nature of WNV and completely protected animals from a lethal challenge of virulent
in the Middle East, pooled human immunoglobulin from Israeli donors WNV.
55–57
In clinical trials in humans, administration of WNV-YFV chimeric
(OmriGam™) were shown to contain significant neutralizing titers of virus to healthy volunteers resulted in transient viremia and a low incidence
antibodies against WNV. A phase I/II clinical trial in the US to assess the of flu-like symptoms. All subjects developed neutralizing antibodies and
pharmacokinetics and safety of OmriGam and to estimate its efficacy in most developed antiviral T-cell responses to WNV.
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US INFECTIOUS DISEASE 2007 47