VAIL, COLO. — An intensive drug development effort targeting severe West Nile virus infections may be approaching a payoff.
Options in the developmental pipeline include a number of monoclonal antibodies directed as passive immunotherapy against West Nile virus (WNV) proteins, as well as a promising Israeli human intravenous immunoglobulin (IVIG) product containing high titers of viral antibodies. In addition, a whole series of vaccines are in various stages of clinical trials, according to Dr. Kenneth L. Tyler, professor of neurology, medicine, and microbiology at the University of Colorado, Denver.
West Nile virus has continued to spread in the United States since the first U.S. cases were documented in New York City a decade ago. The overall frequency of West Nile encephalitis also has steadily risen and now approaches that of herpes simplex encephalitis, which accounts for four cases per 1 million population per year.
Given that most West Nile cases occur in the summer and in certain geographic areas—and that herpes simplex infection occurs year-round and without any geographic predilection—the comparative incidence of West Nile encephalitis is “actually quite large,” Dr. Tyler said at a conference on pediatric infectious diseases sponsored by the Children's Hospital, Denver. In the central states where WNV infections are primarily found, the rate of West Nile encephalitis is at least 25-fold the rate of herpes simplex encephalitis.
Infection with WNV adheres to the typical arbovirus pyramid: Roughly 80% of human infections are entirely asymptomatic, 20% result in West Nile fever, and about 1 in 150 infections lead to severe CNS disease.
“Neurologic West Nile disease is relatively unheard of in infants, children, and young adults,” observed Dr. Tyler. In the 2002 Chicago-area outbreak, the incidence of WNV encephalitis was less than 5 cases per 100,000 among 45- to 59-year-olds, triple that in 60- to 74-year-olds, and more than the 30 per 100,000 among individuals aged 75 years and older.
With no treatment proven to be effective, there are anecdotal reports from the Middle East and the United States of therapeutic benefit using Israeli IVIG, called Omr-IgG-am. Israeli IVIG contains high titers of antibodies against WNV, which has circulated in that part of the world for a long time. In contrast, U.S. IVIG contains almost no WNV antibodies because the virus reached the Western Hemisphere just 10 years ago.
Dr. Tyler said he has tried Omr-IgG-am with some success in his patients. A major U.S. multicenter trial was recently completed of patients with neurologic West Nile disease and acutely infected individuals at high risk for bad outcomes due to advanced age or immunodeficiency. Study subjects were randomized to the Israeli IVIG, U.S. IVIG, or saline. The data are now being analyzed, according to Dr. Tyler.
Panels of monoclonal antibodies directed against various viral proteins also have been developed and tested successfully in cell culture and animal studies. Dr. Tyler has been involved in the development of one such monoclonal antibody directed against the WNV envelope.
A phase I clinical trial of this humanized monoclonal antibody, called MGAWN1, proved successful. A phase II double-blind trial is underway in which 60 adults with suspected acute severe West Nile disease are being given a single dose of the investigational agent or a placebo.
Dr. Tyler disclosed serving as a consultant to MacroGenics Inc., which is developing MGAWN1.
A veterinary IVIG used to treat horses infected with WNV is licensed in the United States. So are three equine vaccines.
“On a theoretical basis, we know from the Japanese encephalitis experience and we know from yellow fever we can develop vaccines that are reasonably safe and efficacious, so this should be possible for West Nile as well,” according to Dr. Tyler. Indeed, one candidate human vaccine is in phase II clinical testing. Two others are in phase I trials.
Interferon alpha-n3 (Alferon), a human leukocyte–derived product already licensed by the Food and Drug Administration for other indications, is being used off-label to treat patients with severe neurologic infections. The protocol was developed by Dr. James J. Rahal, director of the infectious disease section at New York Hospital Queens, Flushing, and professor of medicine at Weill Medical College of Cornell University, New York. The regimen involves a total of eight doses at 3 million U each: one dose given intravenously on day 1 followed 12 hours later by a subcutaneous dose, then a single daily subcutaneous dose on days 2-7.
“There are no data; it's just kind of being done. But there is some logic behind it,” Dr. Tyler said.
A study conducted in patients with St. Louis encephalitis suggested interferon-alpha was of benefit. However, a better-quality study in patients with Japanese encephalitis showed no benefit, he noted.
Neurologic disease caused by WNV takes three forms: encephalitis, accounting for 55%-60% of cases; meningitis, accounting for 25%-40%; and the often-devastating acute flaccid paralysis, comprising 5%-10%.
Patients with meningitis or encephalitis typically develop fever, headache, nausea and vomiting, and myalgia. Rash, diarrhea, and arthralgia are also common.
In herpes simplex encephalitis, well over 90% of patients with biopsy-proven disease display intracranial neuroimaging abnormalities. In WNV encephalitis, only about half of patients have such abnormalities and some can only be discerned with flare or fast-spin MRI techniques.
In most CNS viral infections, the classic finding in the cerebrospinal fluid is lymphocytic pleocytosis. In a study of 250 patients with West Nile meningitis or encephalitis, however, Dr. Tyler found that 37% of the encephalitis patients and 45% of the meningitis patients had polymorphonuclear leukocytes as the predominant cell type in their CSF, which often persisted for a week or more (Neurology 2006;66:361-5).
Further, neurologic deficits can persist even in patients whose disease does not progress beyond West Nile fever, he said. In a not-yet-published study of 108 patients in Texas, 60% of patients reported persistent symptoms of weakness, fatigue, memory deficits, personality change, new-onset depression, or walking difficulties after 1 year; 42% still had neurologic complaints after 5 years.
Nearly 90% of patients who develop acute flaccid paralysis reach their maximum involvement in less than 24 hours. Respiratory failure occurs in 40% of patients with acute flaccid paralysis; the mortality rate is 50% in these patients.
Genetic Studies Highlight WNV Risks
The first genetic risk factor to be identified for symptomatic West Nile virus infection was a deletion mutation in the cell surface protein called chemokine receptor 5 (CCR5). In a meta-analysis involving 619 seropositive individuals, investigators at the National Institute of Allergy and Infectious Diseases demonstrated that homozygotes for the CCR5 delta 32 mutation had a fourfold increased risk of symptomatic disease (J. Infect. Dis. 2008;197:262-5).
Studies in mouse models of West Nile virus infection clearly demonstrate that the CCR5 delta 32 mutation is associated with a reduction in brain tissue lymphocytes, reflecting inhibition of the cell-mediated host immune response to the viral pathogen.
Interestingly, AIDS researchers discovered more than a decade ago that CCR5 is the primary coreceptor used by HIV to infect cells. Homozygosity for CCR5 delta 32 was shown to confer powerful protection against HIV infection in exposed individuals. So the same mutation that protects an individual against acquiring HIV pre-disposes to neuroinvasive West Nile virus (WNV) infection, Dr. Tyler said at the conference.
CCR5 antagonists, both monoclonal antibodies and small molecules, are a promising new class of investigational HIV drugs in active development.
Investigators at the Human Genome Sequencing Center at Baylor College of Medicine, Houston, found that a particular single nucleotide polymorphism in the gene encoding for oligoadenylate synthetase—part of the innate viral resistance defense system—was present in 84% of a group of patients with severe neurologic WNV disease and in 48% of seropositive individuals without severe disease (J. Infect. Dis. 2005;192:1741-8).
Most recently, investigators at Washington University, St. Louis, have shown that Toll-like receptor 3 (TLR3), a viral sensor that's part of the innate immune system, protects against WNV infection in mice (J. Virol. 2008;82:10349-58).
TLR3, when functioning normally, generates high levels of inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6. But TLR3 expression is often reduced in the elderly, which may account for their increased propensity for severe infections. The TLR3 findings provide a therapeutic rationale for studies of interferon alpha-n3 (Alferon) in the treatment of neurologic West Nile disease, Dr. Tyler noted.
Chikungunya Fever: Could an Outbreak Occur?
Chikungunya fever is a tropical disease few American physicians are familiar with—but that could change quite suddenly, Dr. Tyler said at the conference.
He presented Chikungunya fever as an example of an emerging CNS viral infection moving into new geographic regions as a result of expanded vector competence.
Until an outbreak of 254 cases—one fatal—struck out of the blue in August 2007 in the Ravenna province of northeastern Italy, it had occurred in only sub-Saharan Africa and Asia.
The mosquito-borne disease is a dengue feverlike illness characterized by 2-5 days of sudden-onset high fever and chills and a petechial or maculopapular rash, mainly on the trunk. This is followed by arthralgic disease that can last weeks or months.
The neurologic manifestations in children include encephalitis, meningitis, and febrile seizures. In adults, meningitis and encephalitis can occur early, during the acute febrile stage of the disease, with acute neuropathy and myelitis occurring later.
The traditional vector of Chikungunya virus is the Aedes aegypti mosquito. But when the virus underwent a mutation in a gene coding for a viral envelope protein, the mutant strain became at least 100-fold more infective for the A. albopictus mosquito.
A. albopictus was responsible for a 2005-2006 outbreak of 500,000 cases of Chikungunya fever in the Reunion Islands off the eastern coast of Africa. The outbreak then spread to India and Sri Lanka, causing 1.3 million cases, Dr. Tyler explained.
The disease was imported to northern Italy by a traveler from India who arrived June 21, 2007, got sick 2 days later, and somewhere along the line was bitten by the A. albopictus mosquitos endemic in that area of Italy. The virus quickly established itself in the regional A. albopictus population.
Could something similar occur in the United States? As it happens, A. albopictus is endemic in the United States. The mosquito is thought to have arrived in 1985 via the port of Galveston, Tex., in a shipment of tires from Southeast Asia and has since gradually spread through much of the south. And 37 U.S. cases of Chikungunya fever imported from the Indian Ocean outbreak have been documented, including 5 viremic patients. Two of those five returned to Louisiana and South Carolina, states where A. albopictus is endemic. So perhaps a U.S. outbreak was a near-miss.
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