H1N1 COUNTERMEASURES STRATEGY AND ... - PHE Home

NBSB Pandemic Influenza Working Group
Detailed Report
prompted NIAID to develop a SARS plasmapheresis study. Dr. Beigel said it took about
18 months to establish a SARS IVIG protocol, but the study eventually collected about
30 liters of convalescent plasma (much less than expected). By the time this was
collected and manufactured into a IVIG product (lab scale), the end product lacked hightiter
antibodies. The timeline from concept to product (GLP IVIG) was 4.5 years.
The threat of H5N1 also required a quick treatment, and there were concerns about
resistance. Dr. Beigel said getting convalescent plasma from areas affected by H5N1
may be even harder than getting it from Hong Kong, so he and his colleagues developed
a hyperimmunization plasmapheresis program for H5N1. The concept of plasma
treatment for influenza was supported by a paper looking at eight studies during the 1918
influenza pandemic. The paper described the use of convalescent plasma for sick people
and noted they had a lower mortality rate than others. Again, the study would not meet
modern standards, but it offered some insight.
Early studies of hyperimmunized horse serum showed some protection in mice.
Prompted by these studies and the H5N1 vaccine studies, Dr. Beigel designed a multiplecohort
study in which each cohort received higher doses than previously studied (90, 120,
or 180 mcg), for four doses, in an effort to increase antibody titers. Both hemaglutination
inhibition (HI) and microneutralization (MN) did not increase with higher doses of
vaccine but did increase with subsequent vaccinations. However, serial vaccination did
not increase the number of subjects who got to high-titer antibodies of HI (above 1:160).
The subjects chose their vaccine sites, with early data suggesting those receiving vaccine
in the arm had higher HAI titers; so the study added a fourth cohort that received two
doses of the vaccine in the deltoid or the buttock. Overall, the study had 126 subjects, 10
of which met the criteria for plasmapheresis. From those 10, investigators got about 30
liters of plasma. Nine units were manufactured into IVIG. Dr. Beigel said the titer of the
output was higher than the input, but much lower than expected. Studies evaluating this
are ongoing. The process for the IVIG effort took 2.5 years from concept to product. If
preclinical and phase-1 trials were needed, the process would take even longer. Dr.
Beigel broke down the timeline into the component parts and discussed each one’s issues.
For example, manufacturing IVIG instead of using source plasma adds several months
from the last unit of plasma collected (although in an urgent setting, it’s possible the
manufacturing process could be faster). Plasma is less expensive to manufacture. From a
scientific standpoint, IVIG is preferred because antibody titers can be standardized and
there are no confounding factors such as different drug volumes.
Plasma collection and development of IVIG are not as rapid as people think. Some steps
could be optimized. The use of source plasma as the therapeutic could improve the
timeline by 6–12 months, but you sacrifice some scientific benefits.
Dr. Beigel then compared polyclonal and monoclonal antibody-based treatment for
emerging infectious diseases:
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