Transfusion-Related Transmission of Yellow Fever Vaccine Virus --- California, 2009

In the United States, yellow fever (YF) vaccination is recommended for travelers and active duty military members visiting endemic areas of sub-Saharan Africa and Central/South America (1,2). The American Red Cross recommends that recipients of YF vaccine defer blood product donation for 2 weeks because of the theoretical risk for transmission from a viremic donor (3). On April 10, 2009, a hospital blood bank supervisor learned that, on March 27, blood products had been collected from 89 U.S. active duty trainees who had received YF vaccine 4 days before donation. This report summarizes the subsequent investigation by the hospital and CDC to identify lapses in donor deferral and to determine whether transfusion-related transmission of YF vaccine virus occurred. The investigation found that a recent change in the timing of trainee vaccination had occurred and that vaccinees had not reported recent YF vaccination status at time of donation. Despite a prompt recall, six units of blood products were transfused into five patients. No clinical evidence or laboratory abnormalities consistent with a serious adverse reaction were identified in four recipients within the first month after transfusion; the fifth patient, who had prostate cancer and end-stage, transfusion-dependent, B-cell lymphoma, died while in hospice care. Three of the four surviving patients had evidence of serologic response to YF vaccine virus. This report provides evidence that transfusion-related transmission of YF vaccine virus can occur and underscores the need for careful screening and deferral of recently vaccinated blood donors.

On April 10, 2009, during a routine record review in connection with a subsequent blood drive, the blood bank supervisor learned of a breach in the deferral protocol for blood products collected from trainees. Further investigation revealed that the blood obtained in the previous drive was from trainees who had been vaccinated with YF vaccine 4 days before the drive. All of those blood products already had been processed and incorporated into the inventory at the hospital's blood bank. The blood bank supervisor reviewed blood bank records and identified 87 whole blood units and three apheresis platelet units obtained from the recently vaccinated trainees. Blood products that had been released for transfusion were tracked forward to identify the patients who had received the implicated blood products. Remaining unused blood products were identified and destroyed.

During April 20--30, investigators reviewed inpatient and outpatient records of patients who received the potentially infected blood products. A data collection tool was developed to capture demographic information, underlying medical conditions, blood product received, and information on previous YF vaccine doses. Because YF vaccine has been recognized to cause serious adverse events in persons who are immunocompromised or aged >60 years (1), information was collected on potential adverse events (e.g., fever, meningismus, mental status changes, elevated transaminases, or multisystem organ failure) that might have occurred during the 1 month after receipt of the blood products. All blood product recipients were notified in writing of the potential exposure to YF vaccine virus, and serum samples from the recipients were tested by enzyme-linked immunosorbent assay for immunoglobulin M (IgM) antibodies against YF virus (YFV). Samples testing positive for YFV-specific IgM antibodies were evaluated using the plaque reduction neutralization test, with a 90% cutoff value for neutralizing antibody titers against YFV (the standard evaluation at CDC for determining serologic response to YF vaccine virus). Additional testing for West Nile virus and St. Louis encephalitis virus IgM and IgG antibodies was performed using enzyme immunoassays to evaluate for possible cross-reactive flaviviral antibodies.

Blood Product Recipients

During March 31--April 9, five patients had received six blood products (three platelets, two fresh frozen plasmas, and one packed red cell unit) from six of the trainees. These six trainees had no previous history of vaccination or travel history consistent with exposure to wild-type YFV. In the month after the transfusion, one blood product recipient had died. The decedent was a man aged 82 years who was in hospice care for terminal prostate cancer and end-stage, transfusion-dependent, B-cell lymphoma. He died 20 days after receiving one of the implicated platelet units. No autopsy was performed, and no pre-mortem blood specimens were available for testing. The other four recipients of blood products had no documented laboratory abnormalities or symptoms attributable to YF vaccine (Table).

Residual blood products from the six transfusions had been discarded. Testing for pretransfusion serologic status of the blood product recipients could not be performed because banked sera were not available. However, serum samples drawn 26--37 days posttransfusion indicated that three of the four recipients had YFV-IgM antibodies confirmed by plaque reduction neutralization test. Testing for cross-reactive flaviviral infection by IgM and IgG antibodies was negative for all four recipients. Testing by reverse transcription--polymerase chain reaction or culture for the presence of YF vaccine virus in the surviving recipients was not performed because samples were obtained when viremia would no longer be expected if transfusion-related transmission had occurred. The patient without YFV-specific antibodies was a premature infant who received multiple aliquots of red blood cells from one donor. Of the three recipients demonstrating YFV-IgM antibodies, two had been previously vaccinated with YF vaccine at least 20 years earlier. A booster response was identified in these two previously vaccinated donor recipients by the presence of YFV-IgM antibodies and high neutralizing antibody titers (160 and 40,960, respectively).

Public Health Response

A review of records associated with the blood product donations confirmed that, in accordance with standard blood bank screening procedures, each trainee had been questioned regarding recent vaccinations on the day of donation. However, none reported having received YF vaccine 4 days earlier. To prevent a similar event in the future, personnel at the military training center now provides the blood bank with immunization records of all trainees at least 1 week before the blood drive, and just before donation, staff members ask each donor individually about his or her vaccination history.

Reported by

E Lederman, MD, T Warkentien, MD, M Bavaro, MD, J Arnold, MD, D DeRienzo, MD, US Navy. JE Staples, MD, M Fischer, MD, JJ Laven, OL Kosoy, RS Lanciotti, PhD, Div of Vector-Borne Infectious Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC.

Editorial Note

This investigation documents, for the first time, serologic evidence for transmission of YF vaccine virus through infected blood products. Before this report, the risk for transmitting YF vaccine virus through blood products was only theoretical. From this investigation, various blood products, including irradiated platelets, appear capable of transmitting the YF vaccine virus. Although irradiation can minimize transfusion-associated graft-versus-host disease, the dose is inadequate to kill YF vaccine virus (A. Barrett, University of Texas Medical Branch, personal communication, 2009).

Of the four surviving blood product recipients, three had YFV-IgM and neutralizing antibodies. The one surviving recipient who did not have serologic evidence of exposures was a preterm infant. Two potential reasons for the lack of detectable levels of YFV-IgM antibodies in the preterm infant are the infant's immune system was not mature enough to mount an adequate immune response and lower levels of YF vaccine virus were present in red blood cells compared with other serum-containing products. Despite evidence of transmission of YF vaccine virus, no adverse events attributable to the transfused virus were identified in the blood recipients. In addition, these blood recipients were not ideal candidates for YF vaccination because of age or compromised immune status.

Persons receiving their first dose of YF vaccine often will develop a low-level viremia within 3--7 days after vaccination that persists for 1--3 days (4). As neutralizing antibody develops, viremia resolves. Neutralizing antibody develops in 90% of recipients within 10 days of vaccination and in 99% of recipients within 30 days (5). Immunity lasts for at least 10 years (1). Persons receiving subsequent doses typically do not develop viremia but might have an elevation in IgM antibodies if several years have passed since their last vaccination (6). YFV-IgM antibodies detected in the recipients might represent passive immunization (i.e., transfer of antibodies formed in the donor) rather than transmission of vaccine virus via blood product. However, this explanation is unlikely because all the donors were primary vaccine recipients, and they would be expected to have viremia with low or nonexistent levels of IgM antibodies at 4 days post-vaccination, when the blood donation occurred (7,8). Detection of YF vaccine virus in the original blood products or acute sera from recipients could have confirmed vaccine virus transmission, but samples were unavailable to perform such testing. Two of the three recipients with positive YFV-IgM antibody titers had been vaccinated previously with YF vaccine more than 20 years earlier likely had an anamnestic response to the vaccine virus in the blood products. This immunologic response is consistent with reports that YFV-IgM antibodies can reform after a booster dose of the vaccine, particularly with longer time between vaccinations (6,8).

Transfusion-related transmission of attenuated YF vaccine virus is preventable. Health-care providers should inform persons receiving live vaccines about the temporary deferral for blood donation. Providing additional checks and balances is especially important when blood product donors receive several vaccinations within a short period (e.g., in the case of active duty military personnel or travelers). If feasible, occupational health personnel at military training facilities should collaborate with the organizers of blood drives targeting military trainees to coordinate a minimum 2-week interval separating receipt of live vaccines and collection of blood products. All potential blood donors should be individually screened for a recent history of receipt of vaccines containing live virus during the month before donation, and temporary deferment should be based upon the expected post-vaccination period of viremia. Most temporary deferments due to receipt of live vaccines are 2 weeks; however, recipients of measles, mumps, and rubella vaccines and varicella vaccines should be deferred for 4 weeks because of the theoretical risk for prolonged viremia.

References

1. CDC. Yellow fever. In: CDC health information for international travel 2010. Atlanta, GA: US Department of Health and Human Services, Public Health Service; 2009. Available at http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/yellow-fever.aspx. Accessed January 14, 2010.
2. Grabenstein JD, Pittman PR, Greenwood JT, Engler RJM. Immunization to protect the US armed forces: heritage, current practice, and prospects. Epidemiol Rec 2006;28:3--26.
3. American Red Cross. Donating blood: eligibility requirements. Available at http://www.redcrossblood.org/donating-blood/eligibility-requirements/eligibility-criteria-alphabetical-listing. Accessed January 14, 2010.
4. Monath TP, McCarthy K, Bedford P, et al. Clinical proof of principle for ChimeriVax(tm): recombinant live, attenuated vaccines against flavivirus infections. Vaccine 2002;20:1004--18.
5. Barnett ED. Yellow fever: epidemiology and prevention. Clin Infect Dis 2007;44:850--6.
6. Reinhardt B, Jaspert R, Niedrig M, Kostner C, L'age-Stehr J. Development of viremia and humoral and cellular parameters of immune activation after vaccination with yellow fever virus strain 17D: a model of human flavivirus infection. J Med Virol 1998;56:159--67.
7. Monath TP. Neutralizing antibody responses in the major immunoglobulin classes to yellow fever 17D vaccination of humans. Am J Epidemiol 1971;93:122--9.
8. Bennevie-Nielsen V, Heron I, Monath TP, Calisher. Lymphocytic 2', 5' oligoadenylate synthetase activity increases prior to the appearance of neutralizing antibodies and immunoglobulin M and immunoglobulin G antibodies after primary and secondary immunization with yellow fever vaccine. Clin Diagn Lab Immunol 1995;2:302--6.

All MMWR HTML versions of articles are electronic conversions from typeset documents. This conversion might result in character translation or format errors in the HTML version. Users are referred to the electronic PDF version (http://www.cdc.gov/mmwr) and/or the original MMWR paper copy for printable versions of official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

**Questions or messages regarding errors in formatting should be addressed to mmwrq@cdc.gov.