MedImmune, Inc. (Gaithersburg, MD) has started a Phase I clinical trial with a recombinant baculovirus-expressed B19 parvovirus virus-like particle (VLP) vaccine, MEDI-491. This is the first parvovirus vaccine to enter human testing. The vaccine and related diagnostics have been exclusively licensed from and are being developed through a Collaborative Research and Development Agreement (CRADA) with the National Heart, Lung and Blood Inst. (NHLBI, NIH; Bethesda, MD). The clinical trial is being sponsored by MedImmune and conducted by NHLBI. Twenty healthy adult volunteers with no evidence of B19 parvovirus infection will be divided into five groups, each receiving different doses of vaccine and a booster at eight weeks. MedImmune is also using similar recombinant empty parvovirus capsid VLP technology to develop human papillomavirus (HPV) vaccines.

MEDI-491 uses parvovirus VLP technology described in U.S. patent application 07/612,672, exclusively licensed by NIH to MedImmune, and further described in "Candidate Recombinant Vaccine for Human B19 Parvovirus, Journal of Infectious Diseases, vol. 167, May 1993, p. 1034-44. This patent application covers the use of empty, noninfectious, recombinant parvovirus capsid proteins and self-assembling parvovirus capsids for vaccines, diagnostics and as vectors for packaging genes for gene therapy uses. Large amounts of recombinant parvovirus capsid proteins, which are usually toxic to host cells in most culture systems, can be produced using baculovirus expression systems. B19 parvovirus capsids naturally contain about 5% VP1 protein and 95% VP2 protein. When these are co-expressed in the same culture system, these two proteins self-assemble with the VP1 protein assuming an external position on the viral capsid, presenting VP1-specific epitopes recognized by virus neutralizing antibodies. MedImmune and NHLBI researchers found that only empty capsid VLPs composed of at least 25% VP1 were highly immunogenic and demonstrated prophylactic efficacy in mice, guinea pigs and rabbits. MEDI-491 is composed of B19 VP1 and VP2 co-expressed in insect cell (Spodofera frugiperda) culture using two baculovirus vectors. VP1 and VP2 self-assemble and form virus-like particles or empty viruses that closely resemble B19 parvovirus. Besides substantially increasing the efficacy of candidate B19 parvovirus vaccines, VP1 protein may also be useful for its cytotoxic, vaccine carrier and adjuvant properties (e.g., VP1 protein may be used directly or conjugated with other antigens to produce polyvalent vaccines). Recombinant empty parvovirus capsids can also be used to package foreign gene sequences to form VLP gene therapy vectors.

There are currently no approved diagnostics or treatments for B19 parvovirus infection. Development of parvovirus vaccines and diagnostics has been hampered by the limited host range of the virus, the lethal effects of viral protein products in culture and on transfected host cells, and related difficulties in obtaining quantities of virus. Viral samples from infected persons are difficult to obtain since symptoms do not usually appear until after viremia has been suppressed by the immune system. There are no convenient methods for culture of large quantities of native B19 parvovirus that normally replicates in human bone marrow.

B19 parvovirus was discovered in 1975 and has been linked to a number of conditions including certain types of miscarriages in pregnant women, sudden reductions in the red blood cell counts in persons with sickle cell or other anemias, including chronic anemia in AIDS and chemotherapy patients, and persistent arthritis in some adults. The virus infects and kills hematopoietic blood cells in the bone marrow that produce erythrocytes (red blood cells), usually only causing a temporary disruption of red blood cell production. B19 parvovirus is common worldwide--infection usually occurs during childhood, and over 60% of the U.S. population has evidence of having been infected with B19 parvovirus.

In most persons, B19 parvovirus infection causes only a brief illness with mild fever, rash and joint aching. However in women, joint pain and arthritis may persist for months. B19 parvovirus infection may be fatal, causing life-threatening transient aplastic crisis (abrupt loss of red blood cells) in sickle cell anemia and immune suppressed (including AIDS) patients who cannot handle further loss of red blood cells. Treatment of severe disease involves multiple transfusions of red blood cells and immune globulin. In pregnant women, B19 parvovirus is an established cause of hydrops fetalis or fetal death due to congestive heart failure associated with severe anemia. In children, the virus causes erythema infectosium or fifth disease, characterized by a "slapped cheek"-like rash on the face and benign flu-like symptoms. The primary markets for a B19 parvovirus vaccine are persons with sickle cell anemia, immune suppression and pregnant women, particularly those with no evidence of previous infection.