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Volume 29 Number 3, 2005 ISSN: 1080–0549
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Clinical Reviews in Allergy and Immunology
Virus Safety of IVIg © Copyright 2005 by Humana Pre3ss3 In3c.
All rights of any nature whatsoever reserved.
1080-0549/05/333–344/$30.00
Virus Safety of Intravenous Immunoglobulin
Future Challenges
Nicola Boschetti,1* Martin Stucki,1 Peter J. Späth,1
and Christoph Kempf1,2
1ZLB Behring AG, Bern, Switzerland; 2Department of Chemistry and Biochemistry, University of Bern,
Bern, Switzerland
Patients with immunodeficiencies or some types of autoimmune diseases are dependent
on safe therapy with intravenous immunoglobulins. State-of-the-art manufacturing processes
provide a high safety standard by incorporating virus elimination procedures into the manu-
facturing process. Based on their mechanism, these procedures are grouped into three classes:
partitioning, inactivation, and removal based on size.
Because of current socioeconomic and ecological changes, emerging pathogens continue
to be expected. Such pathogens may spread very quickly because of increased interconti-
t
c nental traffic. Severe acute respiratory syndrome-coronavirus and the West Nile virus are
a
r recent examples. Currently, it is not possible to predict the impact such a pathogen will have
t
s on blood safety because the capacity for a globally coordinated reaction to such a threat is also
b
A evolving.
The worst-case scenario would be the emergence of a transmissible, small, nonenveloped
virus in the blood donor population. Examples of small nonenveloped viruses, which change
host and tissue tropism, are discussed, with focus on parvoviridae.
Although today’s immunoglobulins are safer than ever, in preparation for future chal-
lenges it is a high priority for the plasma industry to proactively investigate such viruses on a
molecular and cellular level to identify their vulnerabilities.
Index Entries
IVIg; virus; safety; emerging.
*Author to whom all correspondence and reprint requests should be addressed. E-mail: nicola.boschetti@
zlbbehring.com.
Clinical Reviews in Allergy & Immunology 333 Volume 29, 2005
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334 Boschetti et al.
Introduction In 1948, Gellis and coworkers reported that
hepatitis transmission by albumin was elimi-
One of the most important clinical applica-
nated by heating for 10 h at 60°C (8). This
tions of intravenous immunoglobulin (IVIg) is
procedure was possible because of the discovery
to supply a broad spectrum of antibodies to
that 40 mM acetyltryptophan and 20 mM sodium
patients who are antibody-deficient. Through-
caprylate increased the heat resistance of albu-
out their lives, patients with inherited (pri-
min. Unfortunately, other plasma proteins in
mary) antibody deficiencies are treated with
solution are inactivated by heat and early
relatively high doses of IVIg. Patients who
attempts to inactivate viruses in high-risk
develop secondary antibody deficiencies because
products were unsuccessful. Immunoglobu-
of disease or disease-related therapy may also
lins produced by cold ethanol fractionation
receive high-dose IVIg for prolonged periods
of time. With the observation of platelet count were found to have low risk of virus transmis-
rise in the circulation after treatment of immune sion, similar to heated albumin solution (9).
thrombocytopenic purpura (ITP) with high- The reason for this was unknown. This per-
dose IVIg in the early 1980s (1), the door was ception changed in 1983, when Lane reported
opened to explore the potential of high-dose that an IVIg produced by cold ethanol fraction-
IVIgs in several other nonimmunodefi-ciency ation transmitted non-A, non-B hepatitis (10).
diseases. Single or multiple courses of high- At this time, human immunodeficiency virus
dose IVIg were successfully used to treat a (HIV) was isolated and proven as transmissible
wide variety of other autoimmune disorders by blood and blood products (11,12), although
(for review, see refs. 2 and 3). The mechanisms there was no confirmed HIV transmission by
of action of IVIg in such a wide variety of dis- IVIg. The emergence of HIV and reports of
eases were recently reviewed (4–7). Because non-A, non-B hepatitis transmission by some
regular exposure to large quantities of a human IVIg products (13,14) but not others caused
plasma protein carries the risk of infection with manufacturers and regulatory agencies to exam-
bloodborne pathogens, increasing the patho- ine existing IVIg manufacturing processes for
gen safety of IVIg, without diminishing its their capacity to eliminate viruses (15–24).
clinical efficacy, is a high priority. Development of dedicated virus inactivation
Transmission of “homologous serum hepa- procedures for IVIg production was also initi-
titis” through whole blood, plasma, and serum ated (25,26).
was a great concern during development of It was discovered that the relatively low
plasma fractionation procedures to produce risk of virus transmission by immunoglobulins
human serum albumin during World War II. was caused by the removal of viruses during
Yellow fever vaccines stabilized with human the manufacturing of most products by two
serum produced 23,000 cases of hepatitis in mechanisms: partitioning and inactivation.
American military personnel. Most epidemio- Over the years, procedures based on these
logical investigations strongly suggested that mechanisms were developed and refined. With
pooled human plasma presented a higher risk virus filtration, a third, gentle mechanism was
of hepatitis transmission than whole blood. added: removal of viruses based on size.
This was attributed to the increased probabil-
ity that pooled plasma would be contaminated
Virus Elimination Procedures
by one or several donors. Because plasma pools
from 250 to 2000 blood donations were being As outlined in Table 1, virus elimination
used to produce albumin, efforts were initiated procedures (“elimination” means “removal”
to inactivate hepatitis viruses in human serum and “inactivation”) may be grouped into three
albumin solutions (8). principal mechanisms (partitioning, inactiva-
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Virus Safety of IVIg 335
Table 1
Virus Elimination Mechanisms
Mechanism of elimination Method Effective against
Partitioning Precipitation Viruses depending on their surface properties
(charge/hydrophobicity, etc.)
Inactivation Chromatography
S/D Enveloped viruses
Caprylate
Low pH Enveloped virusesa
Pasteurization Enveloped and many nonenveloped viruses
Dry heat Enveloped and many nonenveloped viruses
UVC Many viruses with different effectiveness
γ-Irradiation
Chemical modifications
Elimination based on size Virus filtration All viruses; dependent on size
aAlso effective against B19 virus.
S/D, solvent–detergent; UVC, ultraviolet C.
tion, and elimination based on size) according
to their mode of action. A procedure is selected
for a biologic based on its effectiveness. Limi-
tations must be considered carefully to achieve
the highest possible net safety (pathogen safety,
as well as protein integrity) and product yield.
Some commonly used procedures, and some
experimental elimination procedures, are intro-
duced under the following subheadings.
Virus Removal by Partitioning
Precipitation
During classical plasma fractionation, classes
of proteins are precipitated and separated from
proteins that remain in solution either by cen-
trifuging or by filtration. Viruses—should they
be present—are frequently precipitated along
Fig. 1. Virus elimination by partitioning. Partition-
with the proteins (Fig. 1); hence, they may end ing is achieved whenever a biological mixture is
up in a “waste fraction.” The most effective separated by retention of a fraction due to certain
virus-removal step during immunoglobulin physicochemical properties.
(Ig)G production occurs during fractional pre-
cipitation of Fraction II+III. As demonstrated a precipitation step depends on the surface
by experimental validation studies almost all properties of the viruses as well as of the solu-
the virus in Cohn Fraction II+III is removed tion composition (filter aids, salts, pH, etc.). A
during precipitation of Fraction III (Kistler- particular role is assigned to filter aids, which
Nitschmann Precipitate B), a waste fraction are needed to allow filtration of protein pre-
that contains IgA, IgM, plasminogen, and other cipitates and which can adsorb viruses effi-
proteins (Fig. 2). The virus-removal capacity of ciently.
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336 Boschetti et al.
Fig. 2. Kistler-Nitschmann fractionation scheme for the manufacturing of intravenous immunoglobulin.
The corresponding Cohn-Oncley fractions are indicated in brackets.
Chromatography Virus Inactivation
Chromatography may be a potent virus-
Virus inactivation capacity is usually de-
removal step. Some newer manufacturing
scribed with log reduction factors (LRF) and
processes for plasma derivatives also use chro-
inactivation kinetics. Rapid inactivation kinet-
matography as a virus-removal step (27–29). The
ics are considered an indication of a robust pro-
virus-removal capacity of a chromatography
cess (Fig. 3).
step depends on the surface properties of the
Pasteurization
viruses, the chromatography resin, and the
solution composition (pH, salts, etc.). When The challenge in developing virus inactiva-
chromatography is used for virus removal, it is tion procedures for protein solutions is to inac-
crucial to show reproducibility over the lifespan tivate viruses without harming the therapeutic
of the resin and that the column can be properly protein. The noncovalent bonds involved in
sanitized between production cycles. virus assembly are the same as those that main-
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Virus Safety of IVIg 337
B19 virus (B19V) by dry-heat-treated coagula-
tion factors was also reported (39,40).
Low pH Virus Inactivation
Many reports showed inactivation of envel-
oped viruses at low pH (e.g., pH 4.0) in pres-
ence or absence of limited amounts of pepsin
(21–23). The nonenveloped B19V was recently
found susceptible to such conditions. The ani-
mal parvovirus mice minute virus (MMV) was
resistant to such a treatment (41).
Virus inactivation at low pH is based on
conformational changes in viral structural pro-
Fig. 3. Commonly used virus inactivation methods.
teins, mainly membrane-associated glycopro-
teins of enveloped viruses or capsid proteins
of nonenveloped viruses.
tain proteins in their native, biologically active,
Solvent and/or Detergent Virus Inactivation
three-dimensional structures (conformation).
The presence of lipid envelopes on blood-
Consequently, processes that inactivate viruses
borne viruses makes them uniquely suscep-
may also denature proteins. Some proteins can
tible to inactivation by chemicals that dissolve
withstand small changes in conformation with-
or dissociate lipids, such as solvents and deter-
out losing their biological activity or may
gents. Although proteins can also be denatured
renature spontaneously. Other proteins lose
by solvents and detergents, they can be exposed
biological activity from minor changes in con-
to low levels for limited periods of time without
formation. The denaturation temperature of a
significant irreversible effects on structure or
protein is sharply defined and is different for
function. This observation was exploited by
each protein (30). Heating for a definite time to
Horowitz and coworkers, who developed a
a temperature just below the denaturing tem-
virus inactivation process that involves addi-
perature of a particular protein is used in some
tion of both a solvent and a detergent (42). Sol-
protein purification procedures to inactivate
vent–detergent virus inactivation was soon
viruses. In the presence of substrate, enzymes
applied to a wide variety of plasma proteins
can be heated to temperatures 10°C higher than
considered at risk of transmitting viruses. After
in the absence of substrate (30). Pasteurization
hepatitis C transmission by IVIg was reported
is used to inactivate predominantly enveloped
(13,14), solvent–detergent virus inactivation
viruses in a wide variety of plasma derivatives
was incorporated into several IVIg manufac-
(31–33). However, it is also effective against
turing processes (24,25).
some nonenveloped viruses (e.g., B19 virus;
By disrupting the viral lipid envelope, the
refs. 34 and 35).
action of caprylate is similar to solvent–detergent
Dry-Heat Treatment treatment. Nonionized caprylate was shown to
inactivate several enveloped viruses (43). This
Dry-heat treatment is broadly applied to
mechanism has also been applied in a recently
coagulation factors in the final container.
established IVIg manufacturing process (44).
Inactivation of enveloped and nonenveloped
viruses have been reported (36,37). The low Ultraviolet C
susceptibility of bovine parvovirus (BPV) and The energy of ultraviolet C (UVC) light
canine parvovirus (CPV) was observed under (100–290 nm, corresponding to 12.4–4.3 eV) is
some circumstances (38) and transmission of strong enough to break atomic bonds (C-C
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338 Boschetti et al.
bond dissociation energy env. 3.6 eV). UVC
inactivates pathogens by disrupting/modify-
ing nucleic acid and protein molecules. It is an
unspecific inactivation procedure, which may
also harm the therapeutic proteins. Loss in pro-
tein yield or protein activity and generation of
neoantigenicity must be carefully investigated.
Inactivation by UVC may be of interest for the
manufacture of some fragile or large proteins.
Inactivation of enveloped and nonenveloped
viruses was also achieved (45–49). The design
of state-of-the-art UVC devices was recently
described (50,51).
γ-Irradiation
Fig. 4. Virus removal based on size: the principle
γ-Irradiation has been proposed as a broadly of virus filtration.
effective virus inactivation method for biologics
(52). Although much higher doses must be
Virus Filtration
applied for virus inactivation in biologics
Filtration has long been used to remove
(45–50 kGy) than for the sterilization of medi-
blood-borne pathogens from plasma products.
cal devices (20–25 kGy), functional properties
Sterile or germ filtration through 0.22-µm fil-
of an experimental IVIg were shown to be
ters removes bacteria and fungi. This process
maintained (53). Like UVC, γ-irradiation is effec-
has been so effective that the development of
tive against a broad range of viruses (54). The
filters with pore sizes small enough to remove
loss in protein yield or protein activity and gen-
viruses was a logical consequence. Develop-
eration of neoantigenicity owing to γ-irradia-
ment of virus-removal filters for therapeutic
tion must be carefully investigated.
protein solutions was handicapped by the need
Inactivation by Chemical Modifications
to process large volumes at reasonable flow
The viral genome is the ideal target for inac- rates. Initial problems were resolved in the
tivating viruses without damaging therapeutic early 1990s, and the viral safety of plasma
proteins. This approach was chosen with inter- products was improved by implementing virus
calating (e.g., psoralens; ref. 55) and electro- filtration at the process scale. Virus filtration is
philic (ethyleneimines; ref. 56) chemicals that, a simple, robust, nondestructive process that
when activated, should covalently modify pre- adds size exclusion, a new mechanism, to con-
dominantly nucleic acids. Such treatments are ventional virus inactivation and partitioning.
never exclusively selective for nucleic acids; Because it does not discriminate between envel-
therefore the risk for generating neoantigens oped and nonenveloped viruses, virus filtration
through chemical modifications of proteins has the potential to remove the broadest range
must be carefully investigated (57). The same of pathogens (60–64) (Fig. 4).
is true for chemicals that inactivate viruses by The term “virus filtration” has become the
modification of proteins (β-propiolactone; ref. accepted nomenclature for what was previ-
58) or by unspecific chemical modification ously called “nanofiltration” (65). Virus filtra-
through singlet oxygen using sensitizers, such tion has become a generally accepted, efficient,
as methylene blue (59). and very robust method for the removal of
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Virus Safety of IVIg 339
viruses larger than the pore size of the filter.
However, differences were observed in removal
studies with viruses of about the same size, or
smaller than, the pore size of the virus filter. In
addition to pore size, other factors, such as the
composition of the immunoglobulin (Ig)G
solution and the model virus used, may play
a role. Ig solution may contain antibodies inter-
acting with the virus; this leads to the retention
of viruses that are smaller than the pore size Fig. 5. The relationships among microbes, hosts,
(66). The elimination capacity for small viruses and environment are submitted to constant changes.
Therefore the intersections among the three players
has been studied by several authors (62,64).
are variable.
Emerging Viruses
Emerging and reemerging viruses may be new and resurging pathogens in the future.
defined as “viruses that have newly appeared However, countermeasures, such as treatments,
in a population or have existed previously but prophylaxis, and surveillance, and the capabil-
are rapidly increasing in incidence or geo- ity to rapidly investigate and react to new
graphic range” (67). Over the past century, the threats on a global scale have also evolved over
developed world believed that diseases, includ- the past 50 yr. Therefore, it is not possible to
ing emerging diseases, would regress in the make predictions about the severity of future
future. Vaccination programs have eradicated outbreaks of emerging pathogens.
smallpox and almost eliminated polio, reliev- The most prominent recent example of an
ing the burden of childhood diseases. With the emerging virus was severe acute respiratory
introduction of antibiotics, many bacterial dis- syndrome (SARS)-coronavirus. In November
eases have been vanquished. Improved sani- 2002, the first known case of atypical pneumo-
tary conditions and medical care have also nia occurred in Foshan City (Guangdong Prov-
contributed to the decrease in devastating infec- ince, China). Until March 2003, the “severe
tious diseases. atypical pneumonia” spread over three conti-
The world changes continuously, and we nents (13 countries). Then, the World Health
are now living in a phase called globalization. Organization (WHO) set up global networks
The socioeconomic impact of globalization on to expedite detection of the causative agent;
humankind has both direct and indirect impacts develop a robust and reliable diagnostic test;
on the emergence of pathogens. Three factors pool clinical knowledge on symptoms, diagno-
are important for emerging pathogens to occur sis, and management; and study SARS epide-
(Fig. 5): Microbe–host interactions, adapta- miology. Schools were closed, thousands of
tion of the microbe to the environment, and people were put under quarantine in affected
colonialization of the environment by a poten- areas, travel recommendations were issued,
tial host. Globalization increases long-distance and airlines started screening their passengers
trade and travel, urbanization (often in dense, for symptoms. Exactly 1 mo after its establish-
impoverished settlements), pressure on land ment, the WHO laboratory network announced
reserves, and migration into these lands. Cli- conclusive identification of the SARS causative
mate change also influences the environment, agent: an entirely new coronavirus, unlike any
the host, and the microbes. Therefore, we expect other human or animal member of the family
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340 Boschetti et al.
Coronaviridae. In July 2003, the last known strictly dependent on dividing erythroid pro-
chain of transmission was interrupted in Tai- genitor cells. Therefore, B19V infection of indi-
wan. The coordinated control measures rec- viduals with underlying hematological disorders
ommended by WHO, which included early may show transient aplastic crisis. Immuno-
identification and isolation of patients, vigor- compromised persons may be persistently
ous contact tracing, management of close con- infected with the manifestation of pure red cell
tacts, and public information and education to aplasia and chronic anemia. Other nonhemato-
encourage prompt reporting of symptoms— logical disorders, such as rheumatic (68) and
certainly together with a portion of luck—were neurological (69) manifestations have been
effective to overcome the SARS epidemic. reported. Pregnant women are at special risk,
An example of a reemerging virus is West because B19V infection may lead to hydrops
Nile virus (WNV) in the United States. Within fetalis. Until now no human disease has been
4 yr WNV spread from the East Coast to the definitively linked to circoviruses. Although
West Coast. Birds are the primary amplifying the search for associated diseases goes on,
hosts, and the virus is maintained in a bird– these have already been described as submerg-
mosquito–bird cycle. Infection of mammals is ing viral threats (70).
a dead-end infection. The reason for the rapid Because of the highly sensitive techniques
dynamics of the WNV epidemics in North available today we have reversed the situation;
America is that the virus found a favorable envi- we may identify a pathogen without knowing
ronment with the appropriate vectors and naïve the disease instead of knowing the disease and
hosts. not the pathogen. It is now possible to prospec-
These two examples show how changes of tively investigate potential threats from emerg-
the host, environment, and microbe relation- ing pathogens. However, it is of eminent
ships may contribute to the emergence and importance to keep in mind that commensal
reemergence of viruses (Fig. 5). and nonpathogenic microbes prevail over the
After having learned the lessons of HIV number of human pathogens.
and hepatitis C transmission, the plasma pro- Here, we focus on small, nonenveloped
cessing industry of today copes very well with viruses with the potential for emergence owing
enveloped and large viruses. The viruses of to their history and circulation. To date, we are
future concern are the small nonenveloped not aware that emergent human pathogens
ones. Such viruses are difficult to inactivate with these characteristics have been described.
using physicochemical treatments. Currently, However, these have occurred in animals. A
the most promising measure is probably virus classical example of an emerging virus of this
filtration. type is canine parvovirus (CPV) type 2, a mem-
Representatives of this class of viruses are ber of the family of Parvoviridae. Parvoviruses
already present in the human population: infect different vertebrate hosts and tissues
Picornaviridae (e.g., hepatitis A virus), Parvoviridae with the constriction that cells must be in a
(e.g., B19V), and Circoviridae (e.g., TT virus, SEN dividing state to allow virus replication. A
virus) circulate ubiquitously. Hepatitis A is shift in species tropism of feline panleukopenia
known as a causative agent for hepatitis and virus (FPV) was recently observed (for review
B19V may cause a variety of illnesses, the see ref. 71). This resulted in the emergence of
manifestations of which depend on the immu- CPV as a new pathogen in dogs in mid-1978
nological and hematological state of the host. with a subsequent rapid global spread (72). The
In healthy immunocompetent individuals, B19V event occurred through a limited number of
infections are mostly asymptomatic or cause amino-acid changes involving the transferrin
erythema infectiosum. B19V replication is receptor (TfR) binding surrounding the three-
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Virus Safety of IVIg 341
fold spike (73). The virus evolved over the fol- and the nonpathogenic NADL-2 strain of por-
lowing years from CPV-2, which does not rep- cine parvovirus (82).
licate in cats, to CPV-2a and b, which replicate There may be several reasons for these high
efficiently in cats and cause an infection as mutation frequencies. First, although parvovirus
FPV. The substitution rate in the capsid pro- DNA replication is strictly dependent on host
tein was calculated to be 2 × 10–4 nucleotides/ replication factors in the S-phase of the cell
year, just about 10 times less than for RNA cycle, the mechanism for the unidirectional
viruses (74). leading strand DNA synthesis differs from cel-
Another parvovirus where a high mutation lular semiconservative DNA replication with
frequency was reported is MMV. Lopez-Bueno leading and lagging strands. It was also observed
et al. (75) reported a mutation frequency of 2.8 that parvovirus DNA replication uses distinct
× 10–5 substitutions per nucleotide and round replication bodies not identical with nuclear
of replication when in vivo and in vitro repli- DNA replication bodies (83). This may be the
cation in presence of a neutralizing monoclonal reason why parvovirus DNA replication is less
antibody was studied. This mutation frequency accurate than cellular DNA replication. Sec-
is very close to the one reported for retroviruses ond, this highly antigenic structure (threefold
(76). In the presence of the monoclonal anti- spike) must be under a high selective pressure
body, which bound to the highly antigenic, from the host defense. Third, the low pressure
threefold spike, viruses that escaped antibody from negative selection may be an additional
neutralization were selected and enriched to reason for the observed mutation frequency.
100% within three passages. In in vivo experi- Apparently parvoviral capsids may tolerate
ments in severe combined immunodeficient certain variability without negative impact on
mice treated with the same antibody from day infectivity or capsid stability. Figure 6 shows
25 postinfection, such escape mutants were the high degree of variability for amino acids
also selected. Virus stocks used in these experi- in two stretches (301–313, 389–406) making up
ments were cultivated from single MMV clones. the threefold spike of the erythrovirus capsids.
The presence of viruses resistant to the neutral- The mentioned sequences have all been depos-
izing antibody already in stock preparations ited in the Uniprot database and were retrieved
shows the considerable diversity in clonal by a low stringency WU-BLAST search (search
populations of parvoviruses. This phenom- matrix: PAM10). This quasispecies behavior of
enon is generally called “viral quasispecies”
parvoviruses provides a pool of genetic vari-
and is well-known in the retrovirus field (77).
ance, which can rapidly adapt to selective pres-
A high genomic variability was also described
sures.
for B19V in isolates of persistently infected
There may also be parvoviruses lurking in
patients (78). Protein-sequence deviations of
the animal kingdom that may jump to humans
up to 8.2% (from the reference isolate Au) in
without mutating their genomes. This was
some regions were described.
described by Brown et al. (84) for simian
The threefold spike of parvoviruses is highly
parvovirus (SPV), an erythrovirus of macaques.
antigenic and involved in many interactions
SPV belongs to the genus of erythroviruses
with different host-cell receptors. It has the
and causes a very similar disease pattern in
capacity to control the host tropism for cats
macaques as B19V does in humans. The authors
and dogs for FPV and CPV via the interaction
report that handlers with SPV-positive macaque
with TfR (79), the tissue tropism in MMV for
colonies carried antibodies against SPV. SPV-
i
leukocytes and of MMV for fibroblasts (80,81),
p specific but also B19V-crossreactive antibodies
and the tissue tropism of the pathogenic Kresse were detected in individuals. Interestingly, 6 of
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