In conclusion, our data confirms earlier findings of dysregulated host response in severe infections with H5N1 [12] and 1918 influenza viruses [25, 26, 27] . However, the mechanisms leading to similar end results seem to vary with the type of viral infection. Indepth studies to understand the role of virus/viral proteins in modulating host response need to be undertaken on priority. Identification of specific pathways might provide clues to include immunomodulators for the treatment of severe cases, albeit in conjunction with potent antivirals.  Generation of Human Antigen-Specific Monoclonal IgM Antibodies Using Vaccinated “Human Immune System” Mice BACKGROUND: Passive transfer of antibodies not only provides immediate short-term protection against disease, but also can be exploited as a therapeutic tool. However, the ‘humanization’ of murine monoclonal antibodies (mAbs) is a time-consuming and expensive process that has the inherent drawback of potentially altering antigenic specificity and/or affinity. The immortalization of human B cells represents an alternative for obtaining human mAbs, but relies on the availability of biological samples from vaccinated individuals or convalescent patients. In this work we describe a novel approach to generate fully human mAbs by combining a humanized mouse model with a new B cell immortalization technique. METHODOLOGY/PRINCIPAL FINDINGS: After transplantation with CD34(+)CD38(−) human hematopoietic progenitor cells, BALB/c Rag2(−/−)IL-2Rγc(−/−) mice acquire a human immune system and harbor B cells with a diverse IgM repertoire. “Human Immune System” mice were then immunized with two commercial vaccine antigens, tetanus toxoid and hepatitis B surface antigen. Sorted human CD19(+)CD27(+) B cells were retrovirally transduced with the human B cell lymphoma (BCL)-6 and BCL-XL genes, and subsequently cultured in the presence of CD40-ligand and IL-21. This procedure allows generating stable B cell receptor-positive B cells that secrete immunoglobulins. We recovered stable B cell clones that produced IgM specific for tetanus toxoid and the hepatitis B surface antigen, respectively. CONCLUSION/SIGNIFICANCE: This work provides the proof-of-concept for the usefulness of this novel method based on the immunization of humanized mice for the rapid generation of human mAbs against a wide range of antigens. Hyper-immune sera containing polyclonal immunoglobulins (Igs) have been widely used in both therapeutic and prophylactic clinical settings [1] . However, the use of polyclonal sera was associated with several problems, such as the stimulation of allergic reactions, low reproducibility between clinical batches and high off-label use, which finally caused a decline in their use [2] . The advent of technologies to make monoclonal antibodies (mAbs) derived from animals, especially mice, has overcome many of the problems associated with the use of polyclonal sera. The technology to make monoclonal cell lines of antibody-producing cells by fusing antibody producing plasma cells with myeloma cells was described for the first time in 1975 by Milstein and Kohler [3] . The therapeutic potential of mAbs was immediately recognized and in 1980 the first mAb, OKT3, was approved for therapeutic applications. This antibody inactivates T cells, thereby preventing rejections of organ transplants [4] . However, because of the animal origin of the first generation of mAbs that were used in clinical trials, human subjects treated with these antibodies developed vigorous immune reactions against the animal proteins, which were thereby eliminated preventing their therapeutic actions [5] . To overcome these problems technologies were developed to diminish the immunogenicity of mouse antibodies by replacing part or the complete mouse antibody backbone by its human equivalent, first generating chimeric, and subsequently fully humanized antibodies [6] . In a parallel approach transgenic mice bearing the human Ig region were created to obtain fully human antibodies following immunization. The use of these mice obviates the elaborate molecular engineering of antibodies that is needed to humanize antibodies generated in wild-type mice, however, the maturation process of the mouse B cells expressing human Igs is different from that of fully human B cells [7] .