A vCJD Risk-Assessment Case Study by srq97410


									A vCJD Risk-Assessment Case Study
A Preliminary Quantitative Assessment of Canadian Vaccines
Incorporating Bovine Biological Materials in Their Manufacture
Susie ElSaadany and Antonio Giulivi

Reprinted with permission from BioProcess International 3(3): pp 62-68 (March 2005)

   In 1986, bovine spongiform                         Kingdom, the manufacturer of an oral      vaccine manufacture (Tables 2 and 3).
encephalopathy (BSE), a new                           polio vaccine recalled and removed it     One general assumption is that the
transmissible spongiform                              from the market after discovering that    infectivity of bovine-derived material
encephalopathy (TSE), was                             the virus stocks or master/working cell   is equal to the infectivity of ovine-
recognized in the United Kingdom                      banks used for the vaccine’s              derived material (7). Because BSE is a
(UK) (1). In 1996, the Creutzfeldt-                   manufacture had incorporated fetal        neural disease with its greatest
Jakob Disease (CJD) Surveillance                      calf serum (FCS) sourced locally (5).     infectivity found in neural tissue (7),
Unit in Edinburgh identified a new                       The following preliminary              bovine brain is assumed to be 100
variant of the disease (vCJD) in                      quantitative risk-assessment modeling     million times more infective than
humans that exhibited characteristics                 exercise was undertaken to help           bovine muscle. If bovine brain
linking it to BSE-infected animals (1).               inform decision makers about the          contains 10 million infective doses (8,
Discussion in the UK BSE Inquiry                      potential risk to the Canadian public     9), then it can be assumed that bovine
allowed for consideration that vaccines               of vCJD from vaccines administered        muscle is 100 million times less
might transmit the BSE agent to                       from 1975 to 2001.                        infective and contains 0.1 infective
humans (1, 2). If vaccines routinely                                                            doses per gram. Another assumption
administered in childhood could                       Methods                                   is that all people are susceptible to
transmit BSE, and if vCJD was first                   A non-vaccine-specific overview of        vCJD (with no specific genetic
detected in 1996, and with the average                animal-derived components in the          susceptibility of patients with
age at onset of vCJD at 28 years of                   vaccine manufacturing process was         methionine-methionine variation at
age (3), then BSE might have                          conducted to model worst-case             codon 129 in the PrP gene), and no
originated sometime in the early 1970s                historical and current risk to            reduction factor has been assigned. It
and not in the early 1980s, as was                    Canadians from vCJD through the           is assumed that there is no species
originally thought.                                   use of bacterial and viral vaccines       barrier for BSE from bovines to
   As more became known about                         (Table 1). The exercise assumes,          humans. All data used in the
vCJD in the early 2000s, and as BSE                   though it is unlikely, that the           calculations are assumed to be
was detected in other parts of Europe                 manufacture of those vaccines             applicable during the peak of the BSE
(from which, subsequently, bovine                     included BBM sourced from BSE-            epidemic in the United Kingdom and
biological material could no longer be                reporting countries. We considered        Europe (1980–1992). We also assumed
sourced due to regulatory                             vaccines incorporating BBM (beef          that the risk outputs (concentrations)
requirements), efforts increased to                   broth and fetal calf serum) that were     are equal for the master seed and
qualify and quantify the risk of BSE                  potentially manufactured before           working seed in viral vaccine
from vaccines. When the BSE Inquiry                   institution of safety measures banning    manufacture, and equal for the master
proposed the presence of BSE in the                   the sourcing of BBM from countries        seed, working seed, and fermentor for
1970s (4), it acknowledged the                        with BSE, and which might still have      bacterial vaccine manufacture. Table 2
possibility that master/working cell                  been included in existing stocks and      shows the estimated infectivity of
banks or seed stocks for vaccines                     administered between 1975 and 2001.       bovine tissue by category (10).
developed at that time using bovine                      Our risk-assessment equations              Calculating the risk from viral
biological material (BBM) may have                    incorporate many assumptions              vaccines manufactured with fetal calf
been contaminated. In the United                      regarding raw materials used in           serum requires the following

62   BioProcess International           M arch 2005
assumptions. Sera from approximately
1500 calves are pooled for the
manufacture of fetal calf serum (7).
The assessment, therefore, created
scenarios to accommodate a range of
1000–2000 calves. The incidence of
BSE in adult cattle is assumed to have
been about 1/200 during the mid-
1980s, the time at which the FCS was
used to establish master and working
cell lots (7). Maternal-fetal
transmission rate may have ranged
from 10% (11) up to as high as 20%.
Scenarios were created to
accommodate a range from less than
10% to a maximum of 20%. We
assumed that the serum of an infected
calf could contain up to one infectious
unit per mL (7–12). The number of
infectious BSE units that potentially
entered the vaccine production process
would be equal to the number of
infectious units that remain in the
vaccine at the end. (The vCJD risk is
the input number of infectious units
divided by the number of doses of
vaccine in the batch). We assumed an
absence of effective purification steps    pooling of animal material for beef          and the effect of that processing on
to eliminate infectivity during vaccine    broth and that material from only one        the survival and inactivation or
processing and that the BSE agent          animal was used (7). An additional           physical presence of BSE in the final
does not replicate during the              scenario was created where material          product. Vaccines of these types have
manufacturing process. Our                 from five to 10 cattle was pooled in         been administered to all Canadian
assessment considered that the entire      the broth used for the manufacture of        children who received routine
birth cohort of Canada, some 400,000       bacterial vaccine. The nutrient              vaccinations from infancy to 16 years
children for any given year, was           medium used to grow bacteria for the         of age from between 1975 and 2001.
vaccinated with those products. In the     vaccine contained approximately 750             Statistical analysis was conducted
risk estimate, a factor of 200 is          grams of skeletal muscle and 200             using decision-making techniques that
allowed for reduced transmission by        grams of pancreatic extract (7). This        used scenario analysis (estimating
the intramuscular (parenteral) route. It   creates two scenarios: one assuming          possible outcomes) followed by Monte
is assumed that every child receives       that the media component of skeletal         Carlo simulation (100,000 runs).
eight doese of viral vaccine and that      muscle (Category IV) is free of              Monte Carlo simulation was used to
each dose carries the same risk (12). In   nervous tissue contamination and the         predict critical outcomes based on the
the absence of information at the time     other assuming that Category IV              impact and sensitivity of theoretical
of this assessment, we assumed that        components are 0.01% contaminated            factors. The analysis used available
inactivated polio vaccine also may         with Category 1 material (neural             information to estimate the theoretical
have been manufactured with risky          tissue) (13). The incidence of BSE in        risks. Tables 4 and 5 show input
material during the time period            European cattle is one in 10,000. The        variables for viral and bacterial vaccine
studied.                                   average BSE rate in Europe is                risk equations.
    For calculating risk from bacterial    multiplied by a factor of 10 to account
vaccines manufactured with beef            for uncertainty (10). A reduction            Results
broth, we assumed that the broth was       factor of 20 is assigned to the              The risk of vCJD to the Canadian
not sourced from the United                autoclaving (wet high temperature            population for viral vaccines
Kingdom, but from other European           treatment) of the broth (7). It is           manufactured with fetal calf serum
countries. Table 3 details the Risk        assumed that every child receives 11         was estimated as follows (Table 6):
Categories for Bovine Media                doses of bacterial vaccine and that
Components Used in Manufacture of          each carried the same risk (12).                  T
                                                                                            • heprobabilityofinfectionper
Bacterial Vaccine (2,13). Our                  Information gaps include the                   treatment for each child is
calculations assumed that there was no     method of raw materials processing                 estimated at 8 × 10−9, with a

                                                                                     M arch 2005      BioProcess International   63
     lower limit of certainty of 1 ×         manufactured with beef broth was               children, with a lower limit of
     10−9 and an upper limit of              estimated to be as follows (Table 7):          certainty of 0.001 and an upper
     certainty of 1 × 10−7                                                                  limit of certainty of 0.663.
   • heestimatedtotalnumberof              T
                                                • heprobabilityofinfectionper
     children infected in the birth               treatment per child is estimated at
     cohort is estimated at 0.0003                6 × 10−9, with a lower limit of       discussion
     children, with a lower limit of              certainty of 5 × 10−8 and an          Every risk factor and model parameter
     certainty of 0.00009 and an upper            upper limit of certainty of 1 ×       carries its own uncertainty, expressed
     limit of certainty of 0.006                  10−5.                                 through the confidence limits
                                                • heestimatedtotalnumberof       surrounding the estimates. Extracts or
  The risk of vCJD to the Canadian                children infected in the birth        infusions of bovine tissues are
population for bacterial vaccines                 cohort is estimated at 0.002          considered to carry the highest risk for

64 BioProcess International    M arch 2005
fermentation broths and are used for    which bovine material was sourced.          accommodated into our model as the
this worst-case scenario analysis.      All materials of concern (e.g.,             information becomes available.
Monte Carlo simulation was the          mixtures) may not be known. No                 Purification Processes: A
method of choice to accommodate the     distinction or accommodation has            worthwhile goal for future refinement
uncertainty caused by lack of           been made for cattle reaching               of risk estimates may be to study
information. The model may become       sufficient age to exhibit BSE               whether purification processes during
more robust, and a more sophisticated   symptoms. The incubation time of            vaccine production eliminate BSE.
approach may be used to                 vCJD in humans is not taken into            The current model makes no
accommodate new or additional data.     account. For the master seed/reference      assumptions in that regard.
The years during which the vaccines     and working seed, the amount and            Conversely, an assumption is made
were distributed to the Canadian        type of bovine material used for            that the vaccine production process
population have not been concretely     dilution throughout the                     does not replicate prions that may
identified, nor are the years during    manufacturing process will be               have been present in seed stocks or

                                                                                 M arch 2005    BioProcess International   65
                                                                                                      12 National Advisory Committee on
BBM, nor result in their concentration         manuscript drafting and revision of               Immunization. Recommended Childhood
                                                                                                 Vaccination Schedule. Division of
in the final product. The question             content, the authors acknowledge Ms.
                                                                                                 Immunization, Health Canada; External Web
then is whether changes in BSE                 Natalie Hanna, communication                      site .
“spiked” material should be                    officer, and Dr. Mohammad Afzal,                       13 Vann W. Bacterial Vaccines: Overview
experimentally quantified through the          senior biostatistician of the Statistics          of Manufacturing and Risk Assessment.
vaccine production process, as has             and Risk Assessment Section, Blood                Presented at the Joint Meeting of the
been done for prions in human plasma           Safety Surveillance and Health Care               Transmissible Spongiform Encephalopathies
                                                                                                 Advisory Committee and Vaccines Related
fractionation. That would validate             Acquired Infections Division, Centre
                                                                                                 Biological Products Advisory Committee. 27
certain “dilution” steps that have been        for Infectious Disease Prevention and             July 2000; External Web site .
assumed to occur. Additionally, the            Control, Public Health Agency of
assessment has not considered the              Canada.
possibility of risk material being in                                                            Corresponding author Susie ElSaadany is
fillers and stabilizers of the final           RefeRences:                                       chief of the Statistics and Risk Assessment
vaccine product. It would be valuable               1 Government of the United Kingdom,          Section, Blood Safety Surveillance and
to have detailed information regarding         House of Commons. The BSE Inquiry,                Health Care Acquired Infections Division,
                                               Volume 1: Findings and Conclusions.               Centre for Infectious Disease Prevention
changes over time in vaccine                   Executive Summary of the Report of the            and Control, Public Health Agency of
manufacture that would reduce the              Inquiry, Section 8 of the executive summary,      Canada, A.L. 0601E2/Health Canada
risk vCJD contamination.                       Medicines. London: The Stationery Office,         Building No.6, Tunney’s Pasture, Ottawa,
    As a worst-case analysis, this             2000: xxix–xxvi; External Web site .
                                                                                                 Ontario K1A 0L2; 1-613-952-6925; fax: 1-613-
assessment may overestimate                         2 Government of the United Kingdom -         952-6668; susie_elsaadany@hc-sc.gc.ca.
Canadian risk, assuming as it does             House of Commons. The BSE Inquiry.
                                                                                                 Antonio Giulivi (MD, FRCP(C)) is director of
                                               Volume 7 of the inquiry report, Medicines and
that all beef broth was sourced from           Cosmetics. London: The Stationery Office,
                                                                                                 the Blood Safety Surveillance and Health
Europe. The risk assessment addresses          2000: 1, 37–39, 56–91, 100–101, 126–130,          Care Acquired Infections Division, Centre for
only those vaccines recommended for            223.                                              Infectious Disease Prevention and Control,
routine administration by Health                    3 US Food and Drug Administration.           Public Health Agency of Canada.
Canada’s National Advisory                     Questions and Answers on Variant CJD. 2001,
Committee on Immunization                      External Web site
(NACI). It does not necessarily                     4 Government of the United Kingdom -
                                               House of Commons. The BSE Inquiry,
include other vaccines that may be             Volume 1:. Findings and Conclusions.
routinely administered to children,            Executive Summary of the Report of the
such as varicella vaccine and flu shots,       Inquiry Volume 8, Medicines. London: The
as well as those approved for use in           Stationery Office, 2000. xvii-xxxi, 14–19, 121,
                                               166, 177, 192, 220, 261.
children but not part of a routine
                                                    5 Department of Health, United Kingdom.
immunization schedule. Additional
                                               Recall of Medeva Oral Polio Vaccine. 20
data on the quantity of risky material         October 2000, External Web site .
used throughout the manufacturing                   6 National Advisory Committee on
process for the vaccines in question is        Immunization, Health Canada. Recommended
required for a more sophisticated              Immunization for Infants, Children and
assessment. Determining such data              Adults. Canadian Immunization Guide, Fifth
                                               Edition, Part 2: 45–47, 1998; External Web
requires collaboration with laboratory
                                               site .
specialists from vaccine
                                                    7 U.S. Food and Drug Administration,
manufacturers, regulators, and                 Center for Biologics Evaluation and Research.
investigators. Despite these                   Estimating Risks for vCJD in Vaccines Using
limitations, we expect that our                Bovine-Derived Materials; External Web site .
assessment adequately captures                      8 Taylor DM, et al. Decontamination
Canadian risk because sensitivity              Studies with the Agents of Bovine Spongiform
                                               Encephalopathy and Scrapie. Arch. Virol. 139,
analysis using a Monte Carlo
                                               1997: 313–326.
simulation accommodated uncertainty
                                                    9 Bradley R. BSE Transmission Studies
and yielded likely values from a               with Particular Reference to Blood. Dev. Biol.
minimum to maximum range. Despite              Stand. 99, 1999: 35–40.
the modeling exercise’s worst-case                  10 Bader F, et al. Assessment of Risk of
scenario approach, risk to Canadians           Bovine Spongiform Encephalopathy in
of vCJD from vaccines is estimated to          Pharmaceutical Products. BioPharm 11(1)
                                               1998: 20–31.
be quite low.
                                                    11 Wilesmith JW, et al. A Cohort Study
                                               To Examine Maternally-Associated Risk
AcknowledgMents                                Factors for Bovine Spongiform
For contributions to acquisition of            Encephalopathy. The Vet Record 141, 1997:
data and editorial work including              23–243.

66 BioProcess International      M arch 2005

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