Donor Screening Recommendations to 
Reduce the Risk of Transmission of 
Zika Virus by Human Cells, Tissues, 
and Cellular and Tissue-Based 
Products
 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, 
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or 
from the Internet at 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/default.htm. 
 
For questions on the content of this guidance, contact OCOD at the phone numbers or email 
address listed above. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
March 2016 
Updated May 2018  Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  ZIKV Epidemiology and Public Health Impact ................................................. 2 
B.  Potential for Transmission of ZIKV by Blood Products and Solid Organs .... 3 
C.  Potential for Transmission of ZIKV by HCT/Ps ............................................... 3 
III.  DISCUSSION .................................................................................................................... 4 
IV.  RECOMMENDATIONS .................................................................................................. 5 
A.  Recommendations for Living Donors of HCT/Ps .............................................. 5 
B.  Recommendations for Non-Heart-Beating (Cadaveric) Donors of HCT/Ps ... 6 
V.  IMPLEMENTATION ...................................................................................................... 6 
VI.  REFERENCES .................................................................................................................. 7 
i  Contains Nonbinding Recommendations 
 
Donor Screening Recommendations to Reduce the Risk of 
Transmission of Zika Virus by Human Cells, Tissues, and Cellular 
and Tissue-Based Products 
 
 
Guidance for Industry 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page. 
 
 
I.  INTRODUCTION 
 
This guidance provides you, establishments that make donor eligibility (DE) determinations for 
donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps), with 
recommendations for screening donors for evidence of, and risk factors for, infection with Zika 
virus (ZIKV).  This guidance updates and supersedes the guidance of the same title dated March 
2016 which identified ZIKV as a relevant communicable disease agent or disease (RCDAD) as 
defined in 21 CFR Part 1271.  This guidance also supplements the recommendations contained 
in the guidance titled Eligibility Determination for Donors of Human Cells, Tissues, and 
Cellular and Tissue-Based Products (HCT/Ps) dated August 2007. 
 
This guidance updates information in the March 2016 guidance by:  1) providing findings from 
more recent epidemiological studies including impact on public health; 2) reporting new data 
that informs the potential for transmission of ZIKV; 3) discussing the current status of 
availability of ZIKV tests; 4) updating sexual contact risk factors; 5) updating when an area is 
considered to have an increased risk for ZIKV transmission; and, 6) providing additional 
scientific references.  This update supports the continuation of recommendations to screen living 
donors of HCT/Ps for risks of infection with ZIKV based on geographic areas with risk. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. 
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
 
   
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
A.  ZIKV Epidemiology and Public Health Impact 
 
ZIKV is an RNA arbovirus from the Flaviviridae family, genus Flavivirus.  It is 
transmitted to humans primarily by the Aedes aegypti mosquito, but it may also be 
transmitted by other mosquitoes such as Aedes albopictus (Ref. 1).  Past studies indicate 
that the vast majority of infected individuals are asymptomatic (Ref. 2).  Even for those 
who experience symptoms, the symptoms are usually mild.  In individuals with clinical 
manifestations, current estimates suggest symptoms may occur between 3-14 days after 
mosquito bite and most commonly include low-grade fever, arthralgia, myalgia, 
headache, retro-ocular headaches, non-purulent conjunctivitis, and cutaneous 
maculopapular rash (Refs. 3, 4).   
 
Infection with ZIKV is also associated with neurologic manifestations, including 
Guillain-Barre syndrome, for which an increased incidence has been reported in areas 
experiencing a ZIKV outbreak (Refs. 5-9).  Although rare, deaths have been reported in 
ZIKV-infected persons; however, the contribution of other comorbidities remains 
uncertain (Refs. 10-12). 
 
ZIKV infection can also be vertically transmitted to a fetus during pregnancy, including 
from asymptomatic mothers (Refs. 13, 14).  Symptoms of congenital infections include 
microcephaly, ophthalmologic abnormalities, and other neurologic abnormalities (Ref. 
15).  Nascent ZIKV infection during the first few weeks of pregnancy also can result in a 
miscarriage (Refs. 16, 17). 
 
The virus was first isolated in 1947 from a rhesus monkey in the Zika Forest of Uganda, 
and isolated from a human in 1968 in Nigeria (Ref. 18).  Epidemiological studies showed 
that the virus has circulated in humans between 1951 and 1981 in African and Asian 
countries (Ref. 8).  In 2007, ZIKV illness was first detected outside of Africa and Asia 
causing an outbreak on Yap Island, Micronesia (Ref. 19).  The next large outbreak of 
ZIKV was reported in French Polynesia from October 2013 to February 2014, possibly 
sickening up to 11% of the population (Ref. 20).  Autochthonous (local) transmission was 
reported in Brazil in early 2015 (Ref. 21).  In February 2016, the World Health 
Organization (WHO) declared a Public Health Emergency of International Concern in 
response to the clusters of microcephaly and other neurological disorders and their 
possible association with ZIKV.  The disease became a nationally notifiable condition in 
the United States (U.S.) in January 2016, and the first case of local, mosquito-borne 
transmission of ZIKV was reported in July 2016 (Refs. 22, 23). 
 
In general, an area is considered to have an increased risk for ZIKV transmission when 
locally transmitted, mosquito-borne ZIKV has been reported or the potential is suspected 
based on epidemiological evidence.  For the purposes of this guidance, areas with 
increased risk for ZIKV infection are provided on the Centers for Disease Control and 
Prevention (CDC) website for Blood and Tissue Safety:  
https://www.cdc.gov/zika/areasatrisk.html. 
2  Contains Nonbinding Recommendations 
 
 
 
B.  Potential for Transmission of ZIKV by Blood Products and Solid Organs 
 
ZIKV can be transmitted through transfusion of blood and blood products.  During the 
2013-2014 outbreak in French Polynesia, 2.8% of specimens collected from 
asymptomatic blood donors were found to contain detectable ZIKV RNA (Refs. 20, 24). 
In 2016, screening of asymptomatic blood donors in Puerto Rico identified that 
approximately 1% of donor specimens were ZIKV RNA positive (Ref. 25).  Likely ZIKV 
transmission by transfused blood products has also been reported in Brazil (Refs. 26, 27). 
 
ZIKV RNA has been detected in brain, liver, kidney, lung, and other organs of persons 
with ZIKV-associated deaths (Refs. 10, 28, 29).  Studies in rhesus macaques also indicate 
presence of ZIKV in these and other organs and tissues, although the impact of 
inoculation methods on tissue tropism is unclear (Refs. 30, 31). 
 
C.  Potential for Transmission of ZIKV by HCT/Ps  
 
There is a theoretical risk for transmission of ZIKV by HCT/Ps.  In particular, HCT/Ps 
typically recovered from living donors, such as amnion/chorion, hematopoietic 
stem/progenitor cells (HPCs) from cord blood and peripheral blood, and reproductive 
tissues such as semen and oocytes, appear to have the highest potential for harboring 
ZIKV.  For example, infectious virus has been isolated from semen up to 69 days after 
onset of symptoms, and sexual transmission of ZIKV from male partners has been 
confirmed for both symptomatic and asymptomatic persons (Refs. 32-34).  Although the 
upper limit of duration of infectious ZIKV in semen is unclear, ZIKV RNA has been 
detected in semen months after initial infection, including a few reports of ZIKV RNA 
detected at approximately 6 and 12 months after onset of symptoms; however, the studies 
did not indicate the virus was infectious (Refs. 34-43).  Furthermore, ZIKV may directly 
infect spermatozoa thereby rendering preventive measures commonly used in assisted 
reproductive technology (ART) procedures, such as sperm washing, ineffective for 
preventing transmission of ZIKV (Refs. 44-46).  A single case of female-to-male sexual 
transmission of ZIKV has also been reported, and ZIKV has been detected in genital and 
endocervical swabs from infected females (Refs. 47-50). 
 
In addition to detection of ZIKV in reproductive cells and tissues, ZIKV has been 
identified in HPCs derived from peripheral blood and umbilical cord blood indicating 
potential risk for transmission of ZIKV through HPCs (Refs. 45, 51, 52).  Transmission 
through HPCs is presumably similar to that of blood transfusion given the similarities in 
product composition and donor characteristics (e.g., recovered from similar populations 
composed of healthy, living donors).  Moreover, typical recipients of HPCs are severely 
immunocompromised which may affect outcomes of infection.  ZIKV infection and some 
deaths have been reported in persons with suppressed immune systems and autoimmune 
disorders.  However, the contribution of a compromised immune system on ZIKV disease 
presentation remains unclear (Refs. 10, 53-55). 
 
3  Contains Nonbinding Recommendations 
 
There is also the potential for transmission of ZIKV by HCT/Ps derived from gestational 
tissues such as HCT/Ps derived from amniotic membrane and umbilical cord.  ZIKV is 
readily identified in gestational tissues from both symptomatic and asymptomatic 
mothers when infection occurred early or late in pregnancy (Refs. 16, 51, 56, 57).  In 
some cases, ZIKV RNA and antigens have been detected in third trimester placentas 
when maternal infection occurred during the first trimester and in placentas from 
apparently healthy infants (Refs. 56, 57).  In laboratory settings, ZIKV has been shown to 
infect and replicate in primary human placental macrophages (also known as Hofbauer 
cells), cytotrophoblasts, and umbilical cord mesenchymal stromal cells (Refs. 58-62). 
 
Based on current information, as summarized above, the types of HCT/Ps with the 
highest potential for transmission of ZIKV appear to be those recovered from living 
donors.  Less evidence exists regarding the potential for transmission of ZIKV by 
HCT/Ps typically recovered from non-heart-beating (cadaveric) donors.  As more 
information regarding the pathogenesis of ZIKV becomes available, the understanding of 
risks to recipients of HCT/Ps, including HCT/Ps recovered from non-heart-beating 
donors, may evolve. 
 
 
III.  DISCUSSION 
 
FDA has identified ZIKV as a relevant communicable disease agent or disease (RCDAD) under 
21 CFR 1271.3(r)(2).  This determination was based on the risk of transmission, severity of 
effect, and availability of appropriate screening measures.  Since ZIKV is an RCDAD and 
appropriate screening measures exist, you must screen donors of HCT/Ps for risk factors for, and 
clinical evidence of, infection with ZIKV (21 CFR 1271.75(a)).  Appropriate testing measures to 
prevent the transmission of ZIKV through HCT/Ps are not available at this time. 
 
Risk of Transmission:  There is a potential risk of transmission of ZIKV by HCT/Ps.  This is 
supported by evidence that ZIKV has been detected in tissues such as semen, placenta and others 
described above.  Although it is not possible to predict the incidence or severity of future ZIKV 
epidemics, the rapid geographic spread of the disease, together with the widespread presence of 
mosquito vectors in parts of the U.S., suggests that ZIKV will be a persistent threat to the 
potential HCT/P donor population.  Local mosquito-borne transmissions of ZIKV are actively 
occurring or have recently been reported in three U.S. territories (Puerto Rico, U.S. Virgin 
Islands, and American Samoa) and specific counties in the continental U.S.  Furthermore, travel-
associated cases, as well as cases in their sexual partners, have occurred throughout the 
continental U.S. (Refs. 4, 63).  
 
Severity of Effect:  ZIKV disease is associated with a risk for development of neurologic 
complications including Guillain-Barre syndrome.  Deaths have also been reported in association 
with the infection.  The disease also causes microcephaly and other abnormalities in infants born 
to mothers with ZIKV infection during pregnancy.  Therefore, infection with ZIKV could be 
fatal or life-threatening, could result in permanent impairment of a body function or permanent 
damage to body structure, or could necessitate medical or surgical intervention to preclude 
permanent impairment of body function or permanent damage to a body structure. 
4  Contains Nonbinding Recommendations 
 
 
Availability of Appropriate Screening and/or Testing Measures:  Appropriate screening measures 
have been developed for ZIKV, such as review of medical and travel history (discussed in 
section IV. of this document).  Appropriate testing measures to prevent the transmission of ZIKV 
through HCT/Ps are not currently available.  
 
Although nucleic acid tests (NATs) for donor screening are available, they are not considered 
appropriate for preventing transmission of ZIKV through HCT/Ps.  The currently available 
NATs are designed to detect ZIKV RNA in plasma isolated from a donor blood specimen. ZIKV 
is readily detected in HCT/Ps, such as semen and umbilical cord blood or other gestational 
tissues, after viral RNA is no longer detectable in plasma; therefore, blood plasma NAT alone is 
not sufficient to determine whether a donors HCT/Ps may be infected with ZIKV (Refs. 35, 43, 
49, 50, 62-65).  NAT screening tests using donor specimens other than blood plasma and ZIKV 
antibody screening tests are not currently available, therefore the potential utility of current tests 
for preventing transmission of ZIKV through HCT/Ps remains unclear at this time.  If 
appropriate tests become available, we will consider recommending their use for donor testing 
within the context of the current knowledge of ZIKV, the performance characteristics of the test, 
and any additional screening methods in place at the time appropriate tests become available.  
 
 
IV.  RECOMMENDATIONS 
 
As noted in section I. of this document, FDA identified in March 2016 that ZIKV is an RCDAD 
as defined in 21 CFR 1271.3(r)(2).  Therefore, review of relevant medical records, as defined in 
21 CFR 1271.3(s) and required under 21 CFR 1271.75, must indicate that a donor of an HCT/P 
is free from risk factors for, or clinical evidence of, ZIKV infection for purposes of determining 
donor eligibility.  The following recommendations are intended to reduce the risk of transmission 
of ZIKV by HCT/Ps. 
 
A.  Recommendations for Living Donors of HCT/Ps1 
 
Living donors of HCT/Ps should be considered ineligible if they have any of the 
following risk factors: 
 
1.  Medical diagnosis of ZIKV in the past 6 months. 
2.  Residence in, or travel to, an area with an increased risk for ZIKV 
transmission within the past 6 months. 
3.  Sex within the past 6 months with a person who has either of the risk 
factors listed in items 1 or 2, above. 
                                                 
1 In some instances, donor screening for certain living donors of HCT/Ps may be performed within the few weeks 
prior to recovery of the HCT/Ps.  Establishments performing a DE determination for such donors may wish to screen 
the donor again at the time of recovery.  This additional screening on the day of recovery is not required for 
determining donor eligibility, but may be useful for making informed decisions about the use of an HCT/P.  
Similarly, establishments performing a DE determination for donors of cord blood may wish to request post-
donation donor health information. 
5  Contains Nonbinding Recommendations 
 
 
Additionally, donors of umbilical cord blood, placenta, or other gestational tissues should 
be considered ineligible if the birth mother who seeks to donate gestational tissues has 
any of the following risk factors: 
 
4.  Medical diagnosis of ZIKV infection at any point during that pregnancy. 
5.  Residence in, or travel to, an area with an increased risk for ZIKV 
transmission at any point during that pregnancy. 
6.  Sex at any point during that pregnancy with a person who has either of the 
risk factors listed in items 1 or 2, above. 
 
Note:  Limited instances for which use of HCT/Ps recovered from an ineligible donor is 
not prohibited, or in which a DE determination is not required, are described in 
21 CFR 1271.65(b) and 21 CFR 1271.90, respectively. 
 
B.  Recommendations for Non-Heart-Beating (Cadaveric) Donors of HCT/Ps 
 
The following non-heart-beating (cadaveric) donors should be considered ineligible: 
 
Persons with a medical diagnosis of ZIKV infection in the past 6 months. 
 
 
V.  IMPLEMENTATION 
 
FDA recommends that you implement the recommendations in this guidance as soon as feasible, 
but not later than 4 weeks after the guidance issue date. 
 
6  Contains Nonbinding Recommendations 
 
VI.  REFERENCES 
 
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Countries.  N Engl J Med, 2016. 375(16):1598-1601. 
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7  Contains Nonbinding Recommendations 
 
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2017.  23(5):296-305. 
34. Garcia-Bujalance, S, et al, Persistence and infectivity of Zika virus in semen after returning 
from endemic areas:  Report of 5 cases.  J Clin Virol, 2017.  96:110-115. 
35. Gaskell, KM, et al, Persistent Zika Virus Detection in Semen in a Traveler Returning to the 
United Kingdom from Brazil, 2016.  Emerg Infect Dis, 2017.  23(1). 
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Lancet Infect Dis, 2016.  16(8):894-895. 
37. Barzon, L, et al, Virus and Antibody Dynamics in Travelers With Acute Zika Virus 
Infection.  Clin Infect Dis, 2017.  2018.66(8):  1173-1180. 
38. Huits, R, et al, Zika virus in semen: a prospective cohort study of symptomatic travellers 
returning to Belgium.  Bull World Health Organ, 2017.  95(12):802-809. 
8  Contains Nonbinding Recommendations 
 
39. Barzon, L, et al, Infection dynamics in a traveller with persistent shedding of Zika virus RNA 
in semen for six months after returning from Haiti to Italy, January 2016.  Euro Surveill, 
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40. Nicastri, E, et al, Persistent detection of Zika virus RNA in semen for six months after 
symptom onset in a traveller returning from Haiti to Italy, February 2016.  Euro Surveill, 
2016.  21(32). 
41. Barry, A, et al, Detection of Zika Virus in Semen. Emerg Infect Dis, 2016.  22(5).  
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16(10):1106-1107. 
45. Joguet, G, et al, Effect of acute Zika virus infection on sperm and virus clearance in body 
fluids:  a prospective observational study. Lancet Infect Dis, 2017. 
46. Bagasra, O, et al, Cellular Targets and Receptor of Sexual Transmission of Zika Virus. Appl 
Immunohistochem Mol Morphol, 2017.  25(10):  679-686. 
47. Prisant, N, Zika virus in the female genital tract.  Lancet Infect Dis, 2016.  16(9):1000-1001. 
48. Centers for Disease Control and Prevention.  Suspected Female-to-Male Sexual 
Transmission of Zika Virus - New York City, 2016.  MMWR, 2016.  65(28):716-717. 
49. Nicastri, E, et al, Zika Virus Infection in the Central Nervous System and Female Genital 
Tract.  Emerg Infect Dis, 2016.  22(12):2228-2230. 
50. Sanchez-Montalva, A, et al, Zika virus dynamics in body fluids and risk of sexual 
transmission in a non-endemic area.  Trop Med Int Health, 2018.  23(1):92-100. 
51. Benjamin, I, et al, Zika virus detected in amniotic fluid and umbilical cord blood in an in 
vitro fertilization-conceived pregnancy in Venezuela.  Fertil Steril, 2017.  107(6):1319-1322. 
52. Murray, KO, et al, Prolonged Detection of Zika Virus in Vaginal Secretions and Whole 
Blood.  Emerg Infect Dis, 2017.  23(1):99-101. 
53. Nogueira, ML, et al, Zika Virus Infection and Solid Organ Transplantation:  A New 
Challenge.  Am J Transplant, 2017.  17(3):791-795. 
54. Schwartzmann, PV, et al, Zika Virus Meningoencephalitis in an Immunocompromised 
Patient.  Mayo Clin Proc, 2017.  92(3):460-466. 
55. Raboni, SM, et al, Flavivirus cross-reactivity in serological tests and Guillain-Barre 
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57. Bhatnagar, J, et al, Zika Virus RNA Replication and Persistence in Brain and Placental 
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58. Jurado, KA, et al, Zika virus productively infects primary human placenta-specific 
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59. Rosenberg, AZ, et al, Placental Pathology of Zika Virus:  Viral Infection of the Placenta 
Induces Villous Stromal Macrophage (Hofbauer Cell) Proliferation and Hyperplasia. Arch 
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60. Quicke, KM, et al, Zika Virus Infects Human Placental Macrophages.  Cell Host Microbe, 
2016.  20(1):83-90. 
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61. Tabata, T, et al, Zika Virus Targets Different Primary Human Placental Cells, Suggesting 
Two Routes for Vertical Transmission.  Cell Host Microbe, 2016.  20(2):155-166. 
62. El Costa, H, et al, ZIKA virus reveals broad tissue and cell tropism during the first trimester 
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63. Hills, SL, et al, Epidemiology of Zika Virus Infection.  J Infect Dis, 2017.  
216(suppl_10):S868-S874. 
64. Schaub, B, et al, Analysis of blood from Zika virus-infected fetuses:  a prospective case 
series.  Lancet Infect Dis, 2017.  17(5):520-527. 
65. Lustig, Y, et al, Detection of Zika virus RNA in whole blood of imported Zika virus disease 
cases up to 2 months after symptom onset, Israel, December 2015 to April 2016. Euro 
Surveill, 2016.  21(26). 
66. Centers for Disease Control and Prevention.  Evaluation of Placental and Fetal Tissue 
Specimens for Zika Virus Infection - 50 States and District of Columbia, January-December, 
2016.  MMWR 2017.  66(24):636-643. 
67. Paz-Bailey, G, et al, Persistence of Zika Virus in Body Fluids - Preliminary Report.  N Engl J 
Med, 2017. 
 
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