The case for reconsidering the FDA restriction on the use of cells, tissues and tissue products
from individuals having resided in Europe for 5 or more years

 

In May 2004 the FDA finalized its Guidance on Human Cells, Tissues and Tissue Products in relation to the risk of contracting variant Creutzfeldt-Jakob disease (vCJD).  The WHO subsequently held a Consultation in September 2005 and issued a document in July 2006 entitled ‘WHO Guidelines on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies’.

 

vCJD tissue risk is a function of: 1) geographic location of donor; 2) tissue infectivity level;
3) tissue processing; 4) route of administration; and 5) total amount of administered tissue.  However, the FDA Guidance essentially addresses only the issue of geographic location,
as a measure of the risk of exposure to BSE, and recommended exclusion of all tissues from individuals with a residence of 3 or more months in the UK, and 5 or more years in all countries of continental Europe.  As a consequence, these criteria exclude the use of tissues and tissue products from the entire European population.

 

One example of an excluded tissue is sperm from European donors, including sperm collected by Nordisk Cryobank, located in Denmark.  Taking the above-mentioned risk factors in order, we make the following observations:

 

1) Geographic source.  Denmark has had a systematic active surveillance of BSE for 7 years and of CJD for 10 years.  During this time, a total of 14 cases of BSE have been identified, with decreasing numbers each year (and none in 2006), and among 54 cases of CJD, none have had the variant form of disease.  In fact, there are only 5 non-French cases of vCJD in all of continental Europe, and to consider France and other European countries as a single group is illogical.  It is also worth noting that Canada during this same period (and with far less systematic surveillance) has identified 9 cases of BSE, including one in 2006, and as in Denmark, no cases of vCJD, yet the FDA has not thought it necessary to restrict tissue donations from the Canadian population.

 

2) Tissue infecivity level.  The WHO expert panel constructed a table of infectivity and prion protein distribution summarizing the current state of knowledge for human TSEs, BSE, and scrapie, from which the section on reproductive tissues is attached.  All experimental attempts to transmit disease from reproductive tissues, including semen, in cattle with BSE and sheep with scrapie have failed, as have limited attempts to transmit disease in humans wtih TSE; and disease-associated prion protein has been undetected in both animal and human forms of disease.  Epidemiological observations provide further impressive support for the absence of infectivity in sperm, as several decades of searching have failed to reveal a single incident of vertical transmission of TSE in either humans or animals.  Interestingly, the USDA permits the importation of bovine sperm, even from the UK, if several criteria are met that minimize the possibility of an infected donor: these do not include travel histories. 

 

3) Tissue processing.  In blood, leukocytes have been consistently shown to contain the highest concentration of infectivity, and there is some experimental evidence (Rohwer, 2006) that simple washing significantly reduces the infectivity associated with leukocytes.  The protocol for extracting sperm from semen includes a density gradient step that reduces the white cell population from 1-2 million/ml to undetectable levels (under 10,000/ml).  The collected fraction
is then subjected to a wash in culture medium.

 

4) Route of administration.  Venereal transmission of disease has not been adequately studied experimentally, but epidemiological evidence indicates that it does not occur.

 

5) Total amount of administered tissue.  Infectious tissue can be administered by a peripheral route in a single dose that is too small (or too diluted) to transmit disease, although repeated sub-transmissible doses have been shown to overcome this failure.  A typical insemination uses one sixth (0.5 ml) of the semen processed from a single donation.

 

A consideration of all of the above information leads to the conclusion that sperm donated from healthy young individuals living in Denmark does not pose a risk of vCJD transmission, and that its exclusion from use in the US is unwarranted, and should be reconsidered by the FDA.

 

 

 

 

 

 

 

 

Table 1C.  Tissues with no detected infectivity

 

 

 

Tissues	Human TSEs				Cattle		Sheep & goats
	vCJD		Other TSEs		BSE		Scrapie
	Infectivity	PrPTSE	Infectivity	PrPTSE	Infectivity	PrPTSE	Infectivity	PrPTSE
Reproductive tissues
Testis	NT	-	(-)	-	-	NT	-	NT
Prostate/            Epididymis/ Seminal vesicle	NT	-	(-)	-	-	NT	-	NT
Semen	NT	-	(-)	-	-	NT	-	NT
Ovary	NT	-	NT	-	-	NT	-	NT
Uterus (Non-gravid)	NT	-	NT	-	-	NT	-	NT
Placenta fluids	NT	NT	(-)	NT	-	NT	NT	NT
Fetus14	NT	NT	NT	NT	-	NT	-	-
Embryos14	NT	NT	NT	NT	-	NT	?	NT

 

 

NT = Not Tested; parentheses indicate limited data