Problems

The influenza viruses are highly infectious respiratory pathogens that have
plagued the human race since ancient times. Influenza is characterized by
recurrent annual epidemics and periodic, major worldwide pandemics.
Because of high disease-related morbidity and mortality, the direct and
indirect social and economic impacts of influenza are enormous. Every year,
influenza remains the most common cause of medically attended acute
respiratory illness in the U.S. On average, up to 20% of the population in the
United States becomes infected with an influenza virus annually, resulting in
approximately 300,000 hospitalizations and 36,000 deaths per year.
According to the Centers for Disease Control and Prevention (CDC) and the
American Lung Association, influenza causes 70 million lost workdays and
38 million lost school days per year (Adams, P.F, 1996. National Center for
Health Statistics. Vital Health Sta. 10:200).

In the past century there have been three influenza pandemics - 1918, 1957,
and 1968. Together, they resulted in at least 50 million deaths. It has now
been over 30 years since the last pandemic, and a new pandemic is
projected as imminent and inevitable. Both the World Health Organization
(WHO) and the CDC have said that an avian influenza (H5N1) pandemic is
the single greatest threat to world health at present. Pandemics typically
result from an avian influenza virus acquiring the ability to infect and spread
among humans. Over the last several years, continuing and more widely-
distributed infection of humans by the highly virulent avian influenza virus
H5N1 has set off the alarm for a potential global pandemic. Based the WHO
analysis, in such a pandemic, up to 25% of the world’s population may be
infected within a matter of months, and the death rate may reach 30% or
higher (Enserink, M., 2003. Science 300:718). In human cases of H5N1
infection to date (Azerbaijan, Cambodia, China, Egypt, Indonesia, Iraq,
Thailand, Turkey, Viet Nam), the death rate has been over 50%. In February
of 2006, the Australia-based Lowy Institute Think Tank Study Report predicted
that an avian influenza pandemic could take 142 million lives and $4.4 trillion
in a worst-case scenario. Other fatality estimates have ranged from 50
million to 300 million lives.

Inactivated or attenuated live human influenza vaccines are now in
worldwide use, especially in high-risk groups. However, these vaccines
must be modified yearly to maintain efficacy. Furthermore, the US vaccine
supply for the influenza season of 2004-2005 was abruptly cut in half due to
manufacturing problems, highlighting both the limits of vaccine technology
and the serious issues around reliability of supply. At present, no vaccine
against the potential pandemic strain H5N1 is available. Each year it usually
takes up to 8 months before the updated or modified influenza vaccine is
ready for use against annual epidemic influenza. Past pandemics have
spread to most continents within 6 months; however, the future pandemics
are expected to spread even faster due to increased international travel.
Compounding the problem, it is nearly impossible to predict the exact
immune signatures of a pandemic virus strain in advance. Consistent with
this is the recent discovery that genetically and antigenically distinct
sublineages of the H5N1 virus have become established in poultry in
different geographical regions of Southeast Asia (Chen, et. al., 2006, PNAS
101:10452). Ominously, H5N1 has also already jumped to non-avian
species, having now become established in swine and cats. The fact is
that, inevitably, vaccines will be either unavailable or in extremely short
supply during the first waves of future pandemics.

Antiviral chemical compounds have become the mainstay of therapy for
treating inter-pandemic influenza diseases. Currently they are also the only
option for controlling pandemics during the initial period, since vaccines will
not be available. Two classes of antiviral compounds are currently in the
market: the M2 inhibitors, such as amantadine and rimantadine, and the NA
inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza). In January 2006,
the CDC advised physicians to stop prescribing rimantadine and
amantadine for annual influenza infections, since over 91% of the viruses
involved have become resistant to these drugs. Viruses resistant to Tamiflu
have also been reported in children at a high frequency (18%) (Kiso, 2004,
The Lancet 364:759). In addition, a mutant H5N1 viral strain highly resistant
to Tamiflu has been isolated from two patients in Vietnam who had been
treated with the drug, and both patients died from the infection (de Jong,
2005, N Eng J Med 353:2667). It has been repeatedly observed that some of
the Tamiflu-resistant H5N1 viral strains also exhibit cross-resistance
against similar neuraminidase (NA) inhibitors. Consequently, additional NA
inhibitors which may be introduced to the market may not prove successful
against Tamiflu-resistant strains. Clearly, new therapeutics with a novel
mechanism of action are urgently needed for both general influenza
treatment and especially against H5N1.