Presence of High‐Titer Neutralizing Antibodies against Enterovirus 71 in Intravenous Immunoglobulin Manufactured from Chinese Donors

To the Editor—Enterovirus 71 (EV71) has been widely recognized as the major pathogen that causes hand, foot, and mouth disease (HFMD). In recent years, severe forms of HFMD—including fatal encephalitis, aseptic meningitis, and poliomyelitis-like paralysis—have been associated with EV71 infections [1]. Especially in China, EV71 outbreaks have raised public and media concerns in light of the millions of infections that have occurred, which have caused hundreds of deaths in young children [2]. No vaccine or antiviral drugs are currently available; several candidates are in development. There is an extensive body of literature supporting the value of intravenous immunoglobulin for viral infections. One report has shown that intravenous immunoglobulin at a neutralization titer of 1:32 should decrease the severity of enterovirus infection [3]. The potential of intravenous immunoglobulin therapy for severe EV71 infections is not well understood. Thus, we sought to determine the level of EV71 neutralizing antibody in commercial intravenous immunoglobulin manufactured from Chinese plasma donors. Nine liquid intravenous immunoglobulin preparations from the 7 major Chinese manufacturers were 2-fold serially diluted for microneutralization tests. EV71 antibody titers were measured by standard protocols on human rhabdomyosarcoma cells, using 3 Chinese isolates and the prototype BrCr strain. The results showed that high-titer EV71 neutralizing antibodies (>1:128) were present in all 9 Chinese intravenous immunoglobulin preparations. In contrast, undetectable levels (<1:8) of EV71 antibodies were present in an intravenous immunoglobulin preparation of Canadian origin (Privigen; CSL Behring Canada). Although EV71 infections in adults rarely result in clinical symptoms, the infection rate among adults might be high. A recent report demonstrated that ∼75% of German adults have EV71 antibodies [4]; thus, we further determined the seroprevalence of EV71 antibodies in Chinese plasma donors. A total of 1012 samples from Chinese donors were collected, and microneutralization tests were performed as described above. The results showed that 89 of the samples (8.8%) contained high-titer EV71 neutralizing antibodies (>1:128). Given the intravenous immunoglobulin manufacturing procedure, these data explain the source of EV71 antibodies in Chinese intravenous immunoglobulin. The presence of high-titer EV71 neutralizing antibodies in Chinese intravenous immunoglobulin supports the value of intravenous immunoglobulin interventions, especially considering the current lack of treatment for fatal EV71 infections. Intravenous immunoglobulin therapy has been used in recent outbreaks in Taiwan, and a better survival rate was achieved [5]. Furthermore, EV71-specific intravenous immunoglobulin containing high-titer EV71 antibodies could be developed from selected donors in areas in which EV71 is endemic—for example, China. High-titer West Nile virus-specific intra-venous immunoglobulin produced from selected Israeli donors recently proved to be useful [6, 7]. In any case, well-designed and well-powered controlled clinical trials and laboratory research are clearly needed to evaluated the potential of intravenous immunoglobulin therapy for EV71 infection. Potential conflicts of interest. All authors: no conflicts.