Zika virus in the blood supply

In this issue of Blood, Gallian et al describe Zika virus (ZIKV) viremia in 1.8% of asymptomatic blood donors during an explosive 2016 outbreak on Martinique Island when ∼42.2% of donors seroconverted, highlighting the risk to the US blood supply.¹ 

Major outbreaks of ZIKV and chikungunya virus (CHIKV) have occurred recently in naive populations in French Polynesia, South America, and more recently, the Caribbean, where dengue virus (DENV) is endemic.²  The US blood supply is threatened by donations from travelers returning from affected areas and during local outbreaks. All 3 viruses are transmitted by Aedes sp mosquitoes, although ZIKV may also be spread by sexual, maternal-fetal, and laboratory routes. In Tahiti, 2.8% of healthy blood donors were viremic during the ZIKV epidemic peak and cases of transfusion-transmission were documented in Brazil.^2,3  In this way, ZIKV is similar to other transfusion-transmitted arboviruses, that is, West Nile virus, DENV, yellow fever virus, and perhaps CHIKV. Unlike DENV and CHIKV,⁴  most ZIKV infections were asymptomatic, increasing the likelihood of blood donation by an infected donor.²  With the first indication of a ZIKV outbreak on Martinique, the French Blood Service instituted multiple interventions to safeguard the blood supply. Similar to prior outbreaks of CHIKV on Martinique in 2014,⁴  and on La Réunion in 2006,⁵  red blood cells (RBC) and plasma were imported from France and/or local whole blood (WB) collections were screened in France using research nucleic acid tests (NATs).⁴  Given the time delay in shipping samples, platelets were treated with a pathogen reduction (PR) system that is effective at inactivating a wide range of pathogens, including arboviruses (Intercept Blood System; Cerus Corporation, Concord, CA).

In this issue, Gallian et al document a peak ZIKV viremia detection of ∼3.0% in healthy blood donors, with an average of ∼1.8% over 6 months. They estimate that, although ∼80% to 85% of infected individuals never sought medical care, the majority (54.7%) of blood donors displayed signs and symptoms 1 to 6 days after donation. Although no control group was reported, this is a surprisingly high proportion compared with prior reports that indicated that only 20% of infections are symptomatic,²  especially because healthy donors were actively selected for blood donation.

It is interesting to contrast the French response to that of the United States, including Puerto Rico (home to ∼3.5 million US citizens). DENV is endemic, and 0.07% to 0.19% of blood donors were viremic during seasonal epidemics in 2005 and 2007.⁶  Similarly, 2.1% were viremic during the peak months of a CHIKV epidemic in 2014.⁷  During each outbreak, most local blood collections continued without DENV or CHIKV NAT screening, as no testing was required by the US Food and Drug Administration (FDA). For CHIKV, enhanced donor symptomatology screening was implemented by the local department of health, with donations released based on a negative postdonation health history, although the efficacy of this approach was limited. The FDA took a more aggressive approach to ZIKV, noting that the mosquitoes that carry all 3 infections are widely spread in the southern United States and Hawaii and are the source of prior outbreaks of DENV in Florida, Texas, and Hawaii.²  In February 2016, all WB collections were halted on Puerto Rico, and blood components were imported from the United States. The largest blood collector in Puerto Rico rapidly implemented PR for apheresis platelets and continued local collections. A month later, an investigational NAT for ZIKV (Roche Molecular Systems, Inc, Pleasanton, CA) was implemented, and WB collections resumed on the island. Repeatedly reactive screening tests were found on the first day.⁸  Peak incidence was lower than in Martinique and occurred later, in June to August 2016 (see figure).

With the discovery of an outbreak in Miami-Dade County in Florida and the availability of a second investigational ZIKV NAT (Hologic, Bedford, MA), the FDA issued final guidance requiring all voluntary collections in the United States be screened with ZIKV NAT or to be treated with FDA-approved PR systems. At a recent FDA BPAC (Silver Spring, MD; 18 November 2016), industry representatives reported initial ZIKV NAT reactivity in 335 of 44 947 donors in Puerto Rico and 57 of 1 069 311 donors in the continental United States. The large majority of the ∼25 confirmed mainland cases had a history of travel to endemic areas. During the same period, the Centers for Disease Control and Prevention reported 139 locally acquired cases in Florida and 4035 travel-related cases in the continental United States, including 1057 pregnant women.

Plasma viremia in blood donors is generally short lived (1-2 weeks). Of concern is that high levels of infectious ZIKV may persist in saliva and urine for ∼3 months and in semen for ∼6 months. The propensity of ZIKV to reenter the blood from these reservoirs is unknown. Low levels of ZIKV RNA also persist for up to 3 months in WB⁹  and are associated with RBC (M. Busch, personal communication, presented at FDA BPAC, 18 November 2016). The infectivity of ZIKV RNA-positive RBCs is unknown, but likely to be low in the presence of high concentrations of ZIKV neutralizing antibodies. Nonetheless, these data call into question the effectiveness of donor screening using NATs performed on plasma samples: in Martinique and Puerto Rico, several-fold more donors are likely to have had ZIKV RNA detectable by testing their RBCs than were detected using plasma-based NATs. The risk to the recipients of the donated blood that is positive for ZIKV RNA based on WB or RBC testing but negative by plasma testing is being investigated at this time.

The data of Gallian et al once more emphasize the susceptibility of blood donor populations to emerging pathogens and the current reliance on rapidly deployed investigational tests to protect patients. Recognizing these risks, the US Department of Health and Human Services Biological Advanced Research and Development Authority is funding the development of PR systems for RBC components to complement the existing approved systems for platelets and plasma as part of a national program for pandemic preparedness. However, as pointed out by Snyder et al,¹⁰  these systems are unlikely to be universally implemented unless mandated by the FDA.