Adventitious viral genomes in vaccines but not in vaccinees.

It is a pleasant change to write about viruses that might have emerged but haven't. In this issue, Hussain and colleagues at the Centers for Disease Control and Prevention, the U.S. Department of Agriculture, and Harvard University report that recipients of measles, mumps, and rubella (MMR) vaccine show no evidence of infection by endogenous avian retroviruses, even though viral genomes and reverse transcriptase activity have been detected in vaccine preparations. Influenza, yellow fever, and MMR vaccines are usually prepared in embryonated eggs or in cultures of chick embryo fibroblasts (CEF). These fibro-blasts contain and express endogenous retroviral genomes (1). In any vaccine, adventi-tious agents in the cellular substrate may contaminate the biological product. In live, attenuated vaccines, such contaminants are not inactivated, and endogenous retroviruses by their very nature as Mendelian transmitted genomes are particularly difficult to eliminate. Endogenous retrovirus release also has ramifications for pharmaceutical proteins made in cell substrates (e.g., monoclonal antibodies) and for xenotransplantation (2,3). Some 45 years ago, it was found that apparently healthy hens could transmit avian leukosis virus (ALV) vertically in eggs (4); later it was demonstrated that live virus vaccines made in CEF were contaminated with infectious ALV (5). However, no increased risk for cancer was found in yellow fever vaccinees with the longest presumed exposure to ALV (6). Nevertheless, vaccine manufacturers were soon required to use eggs or CEF from leukosis-free flocks. To screen for ALV infection, a complement fixation for ALV (COFAL) antigen test was devised, and through pioneering work in the 1960s, the existence of endogenous retroviruses came to light because many ALV-free birds were COFAL positive (7-9). As a graduate student at the time, I observed that CEF of COFAL-positive embryos complemented envelope-defective Rous sarcoma virus, yielding pseudotype viruses with xenotro-pic properties. The endogenous virus was genetically transmitted in chickens but was infectious for other hosts such as quail and pheasant. Many copies of partial or complete ALV genomes were located in chicken DNA (1). We showed that ALV had colonized the host germ line of red jungle fowl before domestica-tion to become chickens but after divergence of the genus Gallus into distinct species. Even so, it proved possible in the 1970s to breed white leghorns free of endogenous ALV genomes; such chickens are now being introduced by Merck as preferred substrates for vaccine production. A second class of endogenous avian retroviral genome (EAV), discovered in 1985 (10), is …