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>>>>> Help ME Circle <<<<
>>>> 5 August 2011 <<<<
Editorship : j.van.roijen@chello.nl
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Quote:
Xenotropic murine leukemia virus-related virus (XMRV) is
a recently discovered human retrovirus that has been
found in both chronic fatigue syndrome and prostate
cancer patients.
Although these findings need further confirmation, there
is a potential safety concern regarding XMRV in cell
substrates used in vaccines and in transmission by blood
transfusion and blood products.
~jvr
````
U.S. Department of Health and Drug Administration
FDA u.s. Food and Drug Administration
Vaccines, Blood & Biologics
Investigating Viruses in Cells Used to Make Vaccines;
and Evaluating the Potential Threat Posed by
Transmission of Viruses to Humans
Principal Investigator: Arifa S. Khan, PhD
Office / Division / Lab: OVRR / DVP / LR
General Overview
The emergence of pathogenic virus infections like
influenza and HIV have created an urgent need for new
vaccines.
Virus-based vaccines are made in living cells (cell
substrates). Some manufacturers are investigating the
use of new cell lines to make vaccines. The continual
growth of cell lines ensures that there is a consistent
supply of the same cells that can yield high quantities of
the vaccine.
In some cases the cell lines that are used might be
tumorigenic, that is, they form tumors when injected into
rodents. Some of these tumor-forming cell lines may
contain cancer-causing viruses that are not actively
reproducing.
Such viruses are hard to detect using standard methods.
These latent, or *quiet,* viruses pose a potential threat,
since they might become active under vaccine
manufacturing conditions.
Therefore, to ensure the safety of vaccines, our
laboratory is investigating ways to activate latent viruses
in cell lines and to detect the activated viruses, as well
as other unknown viruses, using new technologies.
We will then adapt our findings to detect viruses in the
same types of cell substrates that are used to produce
vaccines. We are also trying to identify specific biological
processes that reflect virus activity.
These methods will enable FDA scientists to help
manufacturers to determine whether their specific cell
substrate is safe to use for vaccine production.
The methods our laboratory are developing and testing will
help to ensure the production of safe and effective
vaccines in two ways:
1) FDA will be able to develop testing guidelines for
manufacturers who use new cell substrates for producing
vaccines; and
2) FDA will publish the new methods it develops in
peer-reviewed scientific journals, thus making them
readily accessible to all manufacturers.
We are also evaluating the risk of retrovirus infections in
humans. (Retroviruses are RNA viruses that use an
enzyme called reverse transcriptase (RT) to replicate;
RNA is the de-coded form of DNA).
Simian foamy virus (SFV) can be transmitted from
nonhuman primates (e.g., monkeys) to humans. Although
there is no evidence that SFV causes disease, the virus
can remain in a lifelong quiet state in the DNA after
infection.
Moreover, two individuals in Africa were recently found to
be infected with both HIV-1 and SFV. Therefore, it is
important to determine if SFV poses a threat to human
health and to understand how the virus spreads in order
to create strategies for controlling human infections.
Such work will also help FDA to develop a new policy
regarding blood donation by individuals working with
nonhuman primates and implementing formal safety
guidelines for people working with SFV-infected animals.
We are also investigating the consequences of dual SFV
and HIV-1 infection in the monkey model.
Similarly, we are investigating the transmission and
infection processes of a new human retrovirus,
xenotropic murine leukemia virus-related virus (XMRV).
We are pursuing this work both in vitro (*test tube*
studies) as well as in the monkey model, in order to
address potential safety concerns in vaccine cell
substrates and in blood products.
Scientific Overview
Detection of latent viruses in cell substrates for vaccine
safety. The urgent demand for vaccines against emerging
diseases has necessitated the use of novel cell
substrates. These include tumorigenic cells such as MDCK
and CHO cells (for influenza virus vaccines), 293 and
PER.C6 cells (for adenovirus-vectored HIV-1 and other
vaccines), and tumor-derived cells such as HeLa cells
(for HIV-1 vaccines).
The use of tumorigenic and tumor-derived cells is a major
safety concern due to the potential presence of viruses
such as retroviruses and oncogenic DNA viruses that
could be associated with tumorigencity.
Therefore, detection of persistent, latent DNA viruses,
and endogenous retroviruses in vaccine cell substrates is
important for vaccine safety, particularly in the
development of live viral vaccines, where there are no or
minimal virus inactivation and removal steps during
vaccine manufacturing.
Chemical induction is a rigorous method for evaluating the
presence of endogenous retroviruses as well as some
latent DNA viruses that have the potential to become
active and produce infectious virus.
This approach has been extensively used for mouse cells.
We have optimized virus induction conditions in mouse
cells using a standardized, highly sensitive, single-tube
fluorescent PCR enhanced reverse transcriptase
(STF-PERT) assay.
We have further determined optimum conditions for
activating latent DNA virus from a human cell line. We
have extended the assay to develop a stepwise approach
to induce and detect endogenous retroviruses and latent
DNA viruses during evaluation of cell substrates for
vaccine safety.
The chemical induction algorithm developed using these
positive control cell lines can be used to evaluate the
safety of novel vaccine cell substrates for new vaccines.
We are now investigating emerging technologies for broad
virus detection to identify novel, induced and other
unknown viruses. Additionally, we are investigating
potential biomarkers for virus induction
In vitro and in vivo investigations to address retrovirus
concerns in biologics.
Simian foamy viruses (SFVs) are highly prevalent in all
nonhuman primates (NHPs) and can infect humans by
cross-species transmission.
Although there is no evidence yet of disease with SFV,
infectious virus persists in the host DNA.
Therefore, we are trying to understand SFV latency and
activation and factors involved in virus transmission,
which will be important for managing SFV infections in
humans.
We are also invesgtigating potential interactions of SFV
and SIV in the monkey model to predict the outcome of
SFV and HIV-1 dual-infections in human cases, reported
in Africa.
Furthermore, our blood transfusion studies in monkeys
regarding the risk of SFV transmission from infected blood
donors to recipients will contribute to blood donation
policy-making decisions.
Xenotropic murine leukemia virus-related virus (XMRV) is a
recently discovered human retrovirus that has been
found in both chronic fatigue syndrome and prostate
cancer patients.
Although these findings need further confirmation, there is
a potential safety concern regarding XMRV in cell
substrates used in vaccines and in transmission by blood
transfusion and blood products.
We are developing sensitive detection assays for XMRV to
evaluate cell substrates and investigate virus
transmission by blood transfusion in a monkey model.
Publications
J Virol 2011 Jul;85(13):6579-88
Chemical induction of endogenous retrovirus
particles from the vero cell line of african green
monkeys.
Ma H, Ma Y, Ma W, Williams DK, Galvin TA, Khan AS
Biologicals 2011 May;39(3):158-66
Optimization of chemical induction conditions for
human herpesvirus 8 (HHV-8) reactivation with
12-O-tetradecanoyl-phorbol-13-acetate (TPA) from
latently-infected BC-3 cells.
Ma W, Galvin TA, Ma H, Ma Y, Muller J, Khan AS
PDA J Pharm Sci Technol 2010 Sep-Oct;64(5):426-31
Testing considerations for novel cell substrates: a
regulatory perspective.
Khan AS
PDA J Pharm Sci Technol 2010 Sep-Oct;64(5):451-7
Regulatory considerations for raw materials used in
biological products.
Khan AS
Transfusion 2010 Jan;50(1):200-7
Role of neutralizing antibodies in controlling simian
foamy virus transmission and infection.
Williams DK, Khan AS
Biologicals 2009 Jun;37(3):196-201
Proposed algorithm to investigate latent and occult
viruses in vaccine cell substrates by chemical
induction.
Khan AS, Ma W, Ma Y, Kumar A, Williams DK, Muller J, Ma
H, Galvin TA
Expert Rev Anti Infect Ther 2009 Jun;7(5):569-80
Simian foamy virus infection in humans: prevalence
and management.
Khan AS
J Virol Methods 2009 May;157(2):133-40
Evaluation of different RT enzyme standards for
quantitation of retroviruses using the single-tube
fluorescent product-enhanced reverse transcriptase
assay.
Ma YK, Khan AS
Transfusion 2006 Aug;46(8):1352-9
Simian foamy virus infection by whole-blood transfer
in rhesus macaques: potential for transfusion
transmission in humans.
Khan AS, Kumar D
Contact Us Consumer Affairs Branch (CBER)
(800) 835-4709 (301) 827-1800 ocod@fda.hhs.gov
Division of Communication and Consumer Affairs
Office of Communication, Outreach and Development
Food and Drug Administration
1401 Rockville Pike
Suite 200N/HFM-47
Rockville, MD 20852-1448
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