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September 15, 2009 (Vol. 29, No. 16)

Parvovirus B19 VLP Vaccine Manufacturing

Meridian Developed Production Process for Technology Licensed from NHLBI

  • Click Image To Enlarge +
    Figure 1. This bone marrow aspirate from an infected patient lacks mature erythroid precursors and has giant pronormoblasts that result from the cytopathic effect of the virus. (Photo courtesy of Dr. O. Caul)

    A clinical-grade recombinant virus-like particle (VLP) vaccine has been developed to prevent human parvovirus B19 (HPVB19) infection, which can have severe and potentially fatal complications in susceptible populations. The vaccine consists of two viral proteins (VP1 and VP2) in separate baculovirus vectors that are co-infected at the correct multiplicity of infections (MOIs) into Spodoptera frugiperda (Sf9) cells and that, upon expression, self-assemble into immunogenic virus-like particles.

    HPVB19 replicates principally in human erythrocyte precursors resulting in suppression of erythropoesis and anemia Figure 1. The incubation period is 4 to 20 days with viremia at 6 to 8 days. The healthy host is asymptomatic during viremia with a characteristic rash appearing at approximately 16 days. The virus is shed from the nasopharynx and is spread by respiratory droplets.

    In the healthy host, HPVB19 causes fifth disease (erythema infectiosum) and an arthralgia syndrome in adults. In individuals with underlying hemolysis, infections result in transient aplastic crisis (TAC), a temporary cessation of red blood cell production with severe and occasionally fatal anemia.

    Immunosuppressed and immune-compromised individuals may experience persistent and severe anemia and pure red cell aplasia. Infection during the first and second trimesters of pregnancy can result in hydrops fetalis and fetal loss (miscarriage).

    HPVB19 infection has been reported worldwide and occurs year round, although infections in temperate climates are more common in late winter and spring. Current treatment modalities include red blood cell transfusions for patients with TAC, transfusions and immune globulin administration for infected immunocompromised patients, and intrauterine exchange transfusions for hydrops fetalis. 

    Immunization is a promising strategy to prevent serious parvovirus infection in high-risk groups, as well as in the general population. Studies in the hematology branch of the National Heart, Lung, and Blood Institute (NHLBI) have resulted in the production of recombinant parvovirus capsids, which lack infectious DNA, but retain the immunogenicity of native virions. These empty viral capsids have been utilized in human volunteer studies to elicit neutralizing antibody responses.

    HPVB19 has a small linear, single-stranded DNA genome, which encodes two capsid proteins and a single nonstructural protein (NS-1). The major capsid protein, VP2, constitutes about 95% of the capsid structure, the minor capsid protein, VP1, is identical except for an additional 226 amino acids at the amino terminus. Investigators at the NHLBI further showed that neutralizing linear epitopes cluster in the VP1-unique and VP1-VP2 junction regions.

    Technology to express VP1 and VP2, derived from a copy of the parvovirus B-19 genome (strain Au) obtained from a child with sickle cell disease and TAC, was developed at the NHLBI. Individual viral proteins were expressed in a baculovirus system and, when recombinant vectors are cotransfected into insect cells, VP1 and VP2 spontaneously assemble into empty parvovirus VLP’s. 

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