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Despite recent studies reporting its efficacy in
preventing flu, particularly in children, the latest live virus candidate
vaccine against influenza (FluMist, Aviron, Mountain View, Calif), faces
an uphill road on its way to licensure.
Several live virus influenza vaccines have been
developed in the past 25 years or so; the agent of current interest was
devised in the late 1980s by Hunein F. Maassab, PhD, a professor in the
University of Michigan School of Public Health. In this vaccine, three
of the six nonstructural viral genes are mutated so the virus is unable
to replicate in the warmer temperatures of the lower respiratory tract.
However, it proliferates in the cooler upper airways, where it stimulates
mucosal antibodies and T-cell responses more effectively than does inactivated
vaccine.
The live virus vaccine contains three temperature-sensitive
mutant strains that are expected to circulate in the community during
the next flu season. Two antigens on the influenza virus, hemagglutinin
and neuraminidase, change over time, sometimes abruptly, allowing the
virus to circumvent any immunity an individual may have acquired from
earlier exposure to flu. Thus, the antigens in the live virus vaccine,
like those in the killed virus vaccine, must be reformulated annually
to meet the antigenic changes occurring in the wild-type virus.
Because to elicit an immune response the vaccine
must cause infection, it is particularly effective in children, since
they are immunologically naive compared with adults, whose immune response
may be reduced by preexisting antibody. Immunization with the current
inactivated influenza vaccine is recommended only for children aged 6
months and older with conditions that put them at high risk of serious
complications from the disease, such as chronic pulmonary, cardiovascular,
or metabolic disorders like asthma, diabetes, or renal dysfunction.
In June 1998, Aviron submitted a license application
to the US Food and Drug Administration (FDA) and was confidently predicting
that the vaccine would be available to physicians for the 2000-2001 flu
season. Two months later, the agency rejected the application, and the
company has not yet resubmitted it. Aviron has said the FDA needed additional
technical information, especially about the manufacturing processes and
the facilities where the vaccine will be made. The company plans to make
the vaccine in bulk in England and ship it to the United States for packaging..
One major concern has dogged live virus flu vaccine
development from the beginning: the possibility that the attenuated vaccine
virus could reassert with virulent wild-type virus and produce a new agent
to which the population is susceptible. The result, some scientists hold,
could well be an influenza pandemic paralleling that of 1918-1919.
It is difficult if not impossible to assess the
probability for such adverse reassortment in nature. Human infection with
the H5N1 chicken virus in Hong Kong has renewed the concern (JAMA.1998;279:259-260
and 643-644). Still, the report noted, live virus flu vaccines have been
widely used for many years in Central and Eastern Europe and in the former
Soviet Union, and there has been no evidence suggesting increased prevalence
or severity of disease through reassortment of the vaccine virus with
wild-type virus.
Researchers expressed concern that the virus that
goes into people, is not the virus that may come out of people or may
recombine in the field, where intergenetic interactions may occur that
cannot be predicted. The phenotype of the vaccine virus may be stable,
but researchers have to be concerned about the possibility of interactions
in the field. If you vaccinate using a trivalent vaccine with two different
live influenza A strains, and then look at the viruses that come out of
the recipient, there is a recombination rate of 50%. This indicates that
there is great possibility for generating something novel. This issue
hasn't been addressed very well.
JAMA Vol.
283 No. 14, April 12, 2000
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