Stem Cells, Vol. 14, No. 2, 151-163,
March 1996
© 1996 AlphaMed Press
Parvoviruses and Bone Marrow Failure
Kevin E. Brown,
Neal S. Young
Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
Key Words. Parvovirus B19 infection • Bone marrow diseases • Red cell aplasia • Hematopoiesis • Diagnosis • Treatment
Dr. Kevin E. Brown, Building 10/Room 7C218, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1652, USA.
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Abstract
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Parvovirus B19, the only known human pathogenic parvovirus, is highly tropic to human bone marrow and replicates only in erythroid progenitor cells. The basis of this erythroid tropism is the tissue distribution of the B19 cellular receptor, globoside (blood group P antigen). In individuals with underlying hemolytic disorders, infection with parvovirus B19 is the primary cause of transient aplastic crisis. In immunocompromised patients, persistent B19 infection may develop that manifests as pure red cell aplasia and chronic anemia. B19 infection in utero can result in fetal death, hydrops fetalis or congenital anemia. Diagnosis is based on examination of the bone marrow and B19 virological studies. Treatment of persistent infection with immunoglobulin leads to a rapid, marked resolution of the anemia.
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Introduction
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The human parvovirus B19 (B19), the only known human pathogenic parvovirus, was discovered in 1975. The disease manifestations of infection with parvovirus B19 vary widely with the immunological and hematological status of the host (Table 1
). In normal, immunocompetent individuals, B19 causes erythema infectiosum or fifth disease. "Slapped cheek" disease is an innocuous rash illness of childhood, but parvovirus infection in adults may also be associated with an acute symmetrical polyarthropathy. The main target of B19 infection is the erythroid progenitor cell of the bone marrow. In individuals with underlying hemolytic disorders, B19 causes transient aplastic crisis (TAC). In immunocompromised patients, persistent B19 viremia manifests as chronic pure red cell aplasia (PRCA). Erythroid tropism is based on the tissue distribution of the B19 cellular receptor, globoside (blood group P antigen). Many reviews have been written on the molecular biology and general clinical manifestations of B19 infection [1]. Here we consider the effect of B19 infection on hematopoiesis and bone marrow failure.
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Biological Characteristics of Parvovirus B19
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Parvoviruses (from the Latin parvum = small) are among the smallest known DNA-containing viruses to infect mammalian cells. Parvovirus B19 is a nonenveloped, 22 to 26 nm icosahedral virus (Fig. 1), containing a single strand of DNA of approximately 5,500 nucleotides. As with other parvoviruses, B19 employs overlapping reading frames to encode nonstructural proteins and two capsid proteins.
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Fig. 1. Electron micrograph of parvovirus B19 particles (reproduced by courtesy of Dr. Anne Field, Virus Reference Division, London).
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The B19 virion is an icosahedron consisting of 60 copies of the capsid proteins. Most of the capsid consists of VP2, the major structural protein (molecular weight 58 kDa), with 5% or less of the larger VP1 protein, the minor protein (83 kDa). Using genetic engineering techniques, the capsid proteins have been expressed in a variety of both mammalian and insect cell lines, where they self-assemble in the absence of DNA and form recombinant empty capsids [2]. VP1 is not required for capsid formation.
As a consequence of their lack of a membrane envelope and limited DNA content, parvoviruses are extremely stable to physical inactivation. Parvoviruses remain infectious after treatment at 56°C for > 60 min (and at high viral concentration, at 80°C for 72 h) or in lipid solvents, but they can be inactivated by formalin, ß-propiolactone, 
-irradiation and oxidizing agents.
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Epidemiology
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Parvovirus B19 is a common infection in humans worldwide. By age 15, approximately 50% of children have detectable IgG. Infection also occurs throughout adult life, so that more than 90% of the elderly are seropositive [3]. Infections in temperate climates are more common in late winter, spring and early summer months, and rates of infection may also increase every three to four years; women of child-bearing age show an average annual seroconversion rate of 1.5% [4]. No antigenic strain variation has been detected, even between isolates from different countries.
B19 DNA has been found in the respiratory secretions of patients during viremia, suggesting that infection is transmitted by the respiratory route. Nosocomial transmission in hospital situations has been well documented [5, 6], and patients with aplastic crisis or persistent infection should be considered infectious. The rash or arthropathy stage of fifth disease is not concurrent with viremia, and therefore clinically apparent fifth disease is not infectious.
Virus can be found in serum and although viremia is rare, infection can be transmitted by blood and blood products. Among blood donors, approximately 1:20,000–1:40,000 units of blood during epidemic seasons will contain high titers of B19. Screening of pooled samples from blood donors showed that 1:3,000 units contained detectable B19 DNA by the more sensitive polymerase chain reaction (PCR) technique. As described above, the physical properties of parvovirus make them resistant to conventional thermal and solvent treatments to destroy infectious agents. B19 infection has been transmitted by steam- or dry-heated factor VIII or IX preparations and by detergent-treated factor VIII, although in one study, hemophiliacs who received heat-treated factor VIII alone had lower prevalence of B19 antibody and lower rates of seroconversion compared to those receiving nonheat-treated factor [7].
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Pathogenesis
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Parvovirus B19 Cellular Receptor and the P Blood Group System
The cellular receptor for parvovirus B19 has recently been identified as globoside, a neutral glycosphingolipid found predominantly on erythroid cells and their progenitors, where it is known as the blood group P antigen [8]. The P blood group was discovered in 1927 by Landsteiner and Levine as part of their studies to identify new human erythrocyte antigens by immunizing rabbits with human red blood cells [9]. The P blood group system contains two common antigens, P1 and P, and the rarer antigen, Pk. Red cells of individuals with blood group P1 phenotype have P1 and P antigens; individuals with P1k phenotype have P1 and Pk antigens; individuals with P2 phenotype have P antigen alone; and individuals with the rare p phenotype (previously known as Tja–) lack all three antigens. The P1 and P2 phenotypes are both very common and account for virtually 100% of individuals in all ethnic groups studied. The Pk phenotypes and p phenotype are very rare, with estimates of the prevalence of the p phenotype in the general population being 1:200,000, but these phenotypes occur somewhat more commonly in Japan, Sweden and among the Amish in the USA [10]. Bone marrow from persons who lack P on their erythrocytes (p phenotype) cannot be infected with parvovirus B19 in vitro, and in seroprevalence studies, p phenotype individuals have had no evidence of previous infection with parvovirus B19 [11].
Transcription
While the viral receptor is probably the major determinant of host cell specificity, an intracellular block also exists in nonpermissive cells. When the viral genome is transfected into cells that do not ordinarily support replication, the entire genome is not transcribed, with a functional block between the left (nonstructural protein gene transcripts) and right side (capsid protein genes) [12]. Incomplete transcription of the viral genome in cells that are not permissive for viral replication may produce cell death, as for example in megakaryocyte progenitors in vitro [13].
Bone Marrow Infection
Parvovirus B19, like all autonomous parvoviruses, depends on mitotically active cells for its own replication. B19 also has a very narrow target cell range and can only be propagated in human erythroid cells from marrow [14, 15], blood [16], fetal liver [17, 18] and in a few leukemic cell lines [19–21], tropism now explicable by the nature of the cellular receptor. In human clonal progenitor studies, there is marked inhibition of erythroid colony from colony forming unit-erythroid and burst forming unit-erythroid, with no effect on myeloid colony formation from colony forming unit-granulocyte-macrophage [22]. Susceptibility to parvovirus B19 in the erythroid lineage increases with differentiation and the pluripotent stem cell appears to be spared [22]. Infected cultures are characterized by the presence of giant pronormoblasts or "lantern cells"—early erythroid cells, 25–32 µm in diameter, with cytoplasmic vacuolization, immature chromatin and large eosinophilic nuclear inclusion bodies (Fig. 2). The light microscopic findings are also seen in the bone marrow of infected patients [23].
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Fig. 2. Light micrograph of a giant pronormoblast: an early erythroid cell, 25–32 µm in diameter, with cytoplasmic vacuolization, immature chromatin and large eosinophilic nuclear inclusion body.
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Cytotoxicity
The virus is directly toxic to human erythroid progenitor cells, producing a cytopathic effect with characteristic light and electron microscopic changes [24, 25]. Electron microscopy of infected bone marrow reveals the typical features of cells undergoing apoptosis [26]. Cell death is secondary to expression of the viral nonstructural protein, not to the capsid genes [27]. Nonstructural proteins of parvoviruses are not homologous to other human or viral proteins and their mechanism of action on the cell is unknown. However, nonstructural proteins have helicase and other enzymatic activities as well as nucleotide triphosphate binding sites [28, 29]; the latter are required for their killing action on host cells [30, 31].
In Vivo Infection
Viral inoculation of normal volunteers produces an acute but self-limited (four-to-eight days) cessation of red cell production and a corresponding decline in hemoglobin level [32] (Fig. 3). In patients with normal red blood cell turnover, this short interruption of erythropoiesis does not lead to anemia, but in patients with hemolysis, blood loss or "erythropoietic stress" can precipitate severe anemia. The aplastic crisis resolves with disappearance of viremia during the development of a specific humoral immune response. In patients with compromised immunity, infection can persist and produce chronic PRCA. The infected fetus may suffer severe effects because both red blood cell turnover is high and the immune response is deficient, particularly during the second trimester.
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Fig. 3. Virological, immunological and clinical course after acute B19 infection in a normal individual (adapted from [32]).
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Immune Response to B19 Infection
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In immunocompetent individuals, virus-specific IgM and IgG antibodies are made following experimental and natural B19 parvovirus infection (Fig. 3
). After purposeful intranasal inoculation, virus can first be detected at days 5 –6 and peaks at days 8–9. IgM antibody to B19 appears about 10–14 days after infection and may be found in serum samples for several months after exposure [33]. IgG antibody also appears about two weeks after infection; the IgG response persists for life, and levels rise with re-exposure. Early in convalescence the antibody response is to the major capsid protein VP2, but as the immune response matures, reactivity to the minor capsid protein VP1 dominates. The immune response to VP1 may be critical for protective immunity, as neutralizing linear epitopes cluster in the VP1 unique region [34]. Patients with persistent B19 infection typically lack antibody to virus, or they may have virus-specific IgM and not IgG or IgG antibody to VP2 but not to VP1 [35].
The humoral arm dominates the immune response to B19: recovery from infection correlates with the appearance of circulating specific antivirus antibody, and administration of commercial Ig can cure or ameliorate persistent parvovirus infection in immunodeficient patients (see below). Attempts to detect a cellular response to B19 in lymphocyte proliferative assays have been unsuccessful and the precise role of T lymphocytes in controlling infection remains uncertain.
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Acute Hematologic Syndromes
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Transient Aplastic Crisis
The term "aplastic crisis" was coined by Owren [36] to describe the abrupt onset of severe anemia with absent reticulocytes in patients with hereditary spherocytosis in contrast to hemolytic crises which are associated with increased bone marrow turnover and reticulocyte production. Aplastic crisis occurred as a single episode in the patient's life. In TAC cases there was often a history of a preceding prodromal illness, and the occurrence of epidemics in large kindreds of hereditary spherocytosis suggested an infectious etiology.
TAC was the first clinical illness associated with B19 infection. When stored sera from (600) children admitted to a London hospital were examined for B19 antigen by counter immune electrophoresis, a precipitin line was found in a child with sickle-cell disease suffering a hypoplastic crisis. Five other patients presenting with similar symptoms were also investigated and all had evidence of recent infection with B19 (either antigenemia or seroconversion). All were Jamaican immigrants with sickle-cell disease presenting with aplastic crisis. There was a reduced hematocrit and evidence of aplastic crises on their bone marrow [37]. Retrospective studies of sera from Jamaican sickle-cell patients showed that 86% of TAC were associated with recent parvovirus infection [38].
TAC, due to B19, has been described in a wide range of patients with underlying hemolytic disorders, including hereditary spherocytosis [39], thalassemia [40], hereditary pyropoikilocytosis [41], red cell enzymopathies such as pyruvate kinase deficiency [42, 43] and autoimmune hemolytic anemia [44]. TAC had been observed under conditions of erythroid "stress", such as hemorrhage [45], iron deficiency anemia [46] and following kidney [47] or bone marrow transplantation [48]. Acute anemia has been described in normal persons infected [49, 50], and a drop in red cell count (and reticulocytes) was seen in inoculated healthy volunteers [32], but usually the normal hematopoietic reserve prevents parvovirus-induced erythropoietic failure from becoming clinically apparent.
Although suffering from an ultimately self-limiting disease, patients with aplastic crisis can be severely ill. Symptoms include not only the dyspnea and lassitude of worsening anemia but at times confusion, congestive heart failure and severe bone marrow necrosis [51, 52], and the illness can be fatal [53]. Aplastic crisis can be the first presentation of an underlying hemolytic disease in a well-compensated patient with chronic hemolysis [54, 55].
Community acquired aplastic crisis is almost always due to parvovirus B19 [56] and should be the presumptive diagnosis in any patient with anemia due to abrupt cessation of erythropoiesis as documented by reduced reticulocytes and bone marrow appearance. In contrast to patients with erythema infectiosum, TAC patients are often viremic at the time of presentation with concentrations of virus as high as 1014 genome copies/ml. The diagnosis is readily made by detection of B19 DNA in the serum. As B19 DNA is cleared from the serum, B19-specific IgM becomes detectable.
Typical TAC is readily treated by blood transfusion. It is a unique event in the patient's life, and following the acute infection immunity is lifelong.
Transient erythroblastopenia of childhood (TEC), the temporary failure of red cell production in hematologically normal children, does not appear to be associated with B19 infection [57, 58]. Sporadic cases of TEC have been described with evidence of recent B19 infection [59–61], but in the virus-associated cases TEC was unusually associated with thrombocytopenia (in classical TEC, platelet counts are high).
Thrombocytopenia and Neutropenia
TAC and B19 infection in hematologically normal patients are often associated with changes in other blood lineages. There may be varying degrees of neutropenia [62, 63] and thrombocytopenia [61, 64]. Some cases of idiopathic thrombocytopenic purpura (ITP) [65] and Henoch-Schoenlein purpura [66] have reportedly followed parvovirus B19 infection. In a French study, 5% (3/61) of patients with "typical" idiopathic thrombocytopenia had evidence of recent B19 infection [67], but there was no control group and "typical" ITP was not defined. Transient pancytopenia after parvovirus infection is less common [45, 62, 68]. Some cases of chronic neutropenia of childhood have also been ascribed to parvovirus B19 infection [69], but in a recent study of serum from children and adults with chronic neutropenia, we were unable to confirm the association [70]. A case of recurrent agranulocytosis ascribed to persistent parvovirus B19 has also been reported [71].
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Chronic Bone Marrow Failure
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Persistent infection follows from failure of the immune system to mount an effective response to parvovirus B19. Persistent parvoviremia can occur when immunodeficiency is congenital, iatrogenic or due to concurrent human immunodeficiency virus infection. The dominant clinical manifestation of chronic parvovirus infection is PRCA.
Congenital Immunodeficiency Syndromes
Persistent B19 infection producing PRCA has been reported in several patients with proven or suspected congenital immunodeficiency syndromes. The first report was of a 27-month-old boy suffering from Nezelof's syndrome, a combined T and B cell defect in which serum Ig is present but at low levels. This child presented with abrupt onset anemia and reticulocytopenia, as well as neutropenia [72]. High concentrations of B19 parvovirus (~108 genome copies/ml) were found in the serum coincident with the onset of anemia and persisted for five months (Fig. 4). Giant pronormoblasts were present on marrow smears, and B19 virus was detectable by molecular methods in bone marrow cells. The patient was treated with red cell transfusions and commercial Ig preparations. Remission of the anemia was associated with absence of virus in the serum and remission with its reappearance. Similar cases have been described in a 21-month-old boy with common variable immunodeficiency (predominantly CD4 lymphopenia, with normal Ig levels) [73] and a 12-month-old girl with severe combined immunodeficiency [74]. The most dramatic example of chronic marrow failure due to parvovirus infection occurred in a 24-year-old male, who presented with a 10-year history of PRCA [75]. B19 DNA was found in serum and bone marrow cells at presentation and also in frozen spleen surgically removed three years earlier. His sibling, remarkably. had developed PRCA simultaneously but died later of complications secondary to transfusion hemosiderosis. That the brother also suffered from chronic B19 infection was demonstrated by post-mortem detection of B19 DNA in his fixed spleen tissue. On treatment with commercial Ig, virus disappeared from the patient's bone marrow and serum, and the hemoglobin rose; once virus was no longer detectable in the blood, periodic Ig injections were discontinued and blood counts have remained normal for several years. Although there was no clinical history of increased susceptibility to infections, underlying immunodeficiency was suggested by skin test anergy, poor in vitro lymphocyte responses to mitogens, a very high helper/suppressor T cell ration, low natural killer cell numbers and depressed serum Ig levels.
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Fig. 4. Clinical course and serum studies of a child with congenital immunodeficiency and persistent parvovirus B19 infection (first published in [72]).
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AIDS
AIDS also predisposes to persistent parvovirus infection [76]. Typically, patients present with apparent PRCA and antibody to HIV-1 is detected in the blood. Giant pronormoblasts in bone marrow suggest the diagnosis, and B19 genome can be detected in the sera intermittently over several months. In one study, all patients lacked IgG antibody to B19 before treatment. Anemia improves with Ig therapy with a concomitant decrease in viral titers. Patients may develop fifth disease symptoms after antibody treatment, consistent with their immune complex-mediated origin. B19 may remain detectable in serum by PCR, with subsequent relapse of anemia heralded by increasing viral DNA levels.
The prevalence of B19-induced anemia in HIV seropositive patients is probably higher than recognized at present. In one study of 50 patients with AIDS, no patients with B19 viremia were identified [77]. In a larger cohort study, DNA was found in only 1 of 191 (0.5%) HIV-seropositive homosexuals. However, B19 DNA was found in 4 of 24 (17%) transfusion-dependent HIV-seropositive homosexuals, and when a hematocrit of <22 was used as a criterion, 4/17 (24%) were positive [78]. In contrast to the earlier studies, the marrow morphology was not always suggestive of PRCA nor were giant pronormoblasts apparent.
Immunocompromised Patients
Lymphoproliferative Disorders
Chronic parvovirus B19 has been described in iatrogenically immunocompromised patients, mostly children with acute lymphoblastic leukemia [79]. As with the AIDS cases, these patients present with persistent anemia and do not have immune-mediated symptoms of rash or arthropathy. Other blood lineages may also be affected, even to pancytopenia. Patients have absent or low levels of B19-specific antibody and persistent or recurrent parvoviremia. Bone marrow examination generally reveals the presence of giant pronormoblasts. Administration of Ig can be beneficial but is not always curative. Temporary cessation of maintenance chemotherapy has also led to resolution of the anemia [80, 81].
Transplant Patients
Although B19 infection has been documented following renal transplantation, there is no evidence of persistent infection. Chronic infection has been described after organ transplants which require stronger immunosuppression, including cardiac and liver transplant recipients.
Chronic B19 infection has also been described following allogenic bone marrow transplant [48, 82]. In the first case, the patient developed pancytopenia nine months after transplant for acute myeloid leukemia. The bone marrow was hypocellular marrow with giant pronormoblasts. In retrospective B19, viremia was documented for at least 42 days. The source of the infection was unknown; the patient was B19 seropositive prior to transplant, but B19 antibodies were not detectable in his serum immediately prior to the pancytopenia; the donor was seronegative. In a second case the patient developed PRCA one month following transplant for acute promyelocytic leukemia [48]. B19 DNA was detected in sera 12 days apart and the virus was shown to be infectious by tissue culture assay. This patient made a spontaneous recovery. Serum was B19 seronegative prior to transplantation and the donor was seropositive. One possible source of virus was platelet transfusion.
Immunosuppressed Patients
Prolonged anemia following B19 infection has also been noted in less severely immunosuppressed patients, as for example in systemic lupus erythematosus treated with corticosteroids. Atypical manifestations of B19 disease may predominate (prolonged rash/IgM antibody response). However in these patients there was a spontaneous, if perhaps delayed, development of antibodies and viremia resolved without therapy.
Hemophagocytic Syndrome
Virus-associated hemophagocytic syndrome (VAHS) is characterized by histiocytic hyperplasia, marked hemophagocytosis and cytopenia in association with a systemic viral illness [83]. In contrast to malignant histiocytosis, VAHS was often a benign self-limiting illness with reversible histiocytic proliferation. Subsequent reports indicated that VAHS is not uncommon and occurs in the setting of a wide range of viral, bacterial, rickettsial, fungal and parasitic infections [84]. However, in many patients there is underlying immunosuppression, so the role of the incriminated pathogen as etiological agent or coincidental opportunistic infection remains unclear. In two reported cases of VAHS, PRCA was concurrent [84, 85].
Parvovirus B19 has now been associated with 15 cases of hemophagocytosis syndrome in both children and adults [86–92]. The majority of patients was previously healthy, but four patients were immunosuppressed. In all but one case there was a favorable outcome (one immunosuppressed patient died of fulminant aspergillosis [92]). Further studies are required to determine not only if parvovirus B19 is the major cause of VAHS, but also the incidence of VAHS in otherwise uncomplicated parvovirus B19 infection.
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Congenital Bone Marrow Failure
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Recently, we reported three infants born with chronic anemia following a history of maternal B19 exposure and intrauterine hydrops [93]. Bone marrows have shown PRCA or dyserythropoiesis with multinuclear erythroid cells. In all the virus load was low, and B19 virus could be detected in bone marrow samples by PCR but not in concurrent serum samples. The first case died at nine months, and B19 DNA was detected in a variety of tissues, including heart, liver and spleen. The other two cases were treated with Ig therapy, and although B19 DNA could no longer be detected in bone marrow (by PCR), the children remained severely anemic.
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Diagnosis of Bone Marrow Failure Due to Parvovirus B19 Infection
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Parvovirus B19 should be considered as part of the differential diagnosis in any patient with persistent anemia and low or absent reticulocytes, especially in patients who have underlying immunodeficiency or who are medically immunosuppressed. Immune dysfunction may be clinically subtle and only recognized retrospectively [75].
Bone marrow should be examined if feasible. In persistent B19 infection there is generally a decrease or absence of erythroid precursors, with sparing of other bone marrow lineages. Giant pronormoblasts are frequently (but not always) present and are virtually (but not absolutely) pathognomonic of B19 infection [78].
Confirmation of the diagnosis is based on detection of B19 DNA by nucleic acid hybridization assays. Most patients with persistent infection have >105 B19 virions/ml of serum, and the diagnosis can be easily made by simple dot blot hybridization assays [94]. In acute B19 infection, B19 DNA is only detectable for two to four days—B19 DNA in two serum samples or more than two days after the onset of anemia suggests chronic infection. The sensitivity level of detection of B19 is greatly increased by the use of the PCR but at the risk of possible contamination and false positive results. Even in immunocompetent persons, B19 DNA may be detectable in serum by PCR for more than four months following acute infection [94]. In most symptomatic chronic B19 infections PCR testing is unnecessary. However, a sensitive PCR-based assay may be required in patients who have been treated with Ig and for the diagnosis of congenital B19 infection [93]. PCR can also be useful in monitoring the response to treatment and predicting relapses [76].
B19 DNA can also be detected in the bone marrow of patients with persistent anemia, by dot blot hybridization, in situ hybridization, and in situ PCR, and so used to confirm serology. However, in patients with chronic bone marrow failure, serological studies for B19 antibodies are not helpful, the results often being equivocal or negative. High titers of B19 IgG (in the absence of Ig treatment) make a diagnosis of persistent B19 infection unlikely.
Investigation of B19 fetal or congenital infection should be accompanied by serological studies of maternal serum. At the time of fetal infection, the mother should have evidence of recent B19 infection with detectable IgG and possibly IgM. If the IgM titer is low or absent, recent infection can be documented using IgG avidity studies. Fetal infection can be confirmed by amniotic fluid sampling, fetal blood sampling or from post-mortem tissue.
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Treatment
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Temporary cessation of immunosuppression may be sufficient to allow the host to mount an immune response and resolve the B19 infection with no additional treatment being required [80]. When discontinuation of therapy is impractical or ineffective, administration of Ig can be beneficial (Fig. 5) [76, 79]. We recommend treatment with IgG at a dose of 0.4 g/kg by the intravenous route for five days. Patients often respond with a marked reduction in the level of B19 viremia, reticulocytosis and resolution of the anemia within one to two weeks of treatment. However, patients should be monitored for evidence of relapse, by observation of the reticulocyte counts and assays for B19 viremia if indicated. If relapse occurs less than six months after the initial treatment, especially in HIV-positive patients, an empiric maintenance treatment with a single-day infusion of 0.4 g/kg IgG every four weeks may control the B19 viremia.
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Fig. 5. Response to immunoglobulin treatment of a patient with pure red cell aplasia due to persistent B19 infection (first published in [75]).
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Future Prospects
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Vaccine Development
Baculovirus-produced B19 parvovirus capsids induce neutralizing antibodies in experimental animals, even without adjuvant. In addition, baculovirus antigens are noninfectious and can be prepared in large volumes. Thus, the prospects for a B19 parvovirus vaccine are good, and one preparation of recombinant B19 capsid vaccine entered phase I trials in early 1995.
Animal Model for Bone Marrow Failure Due to Parvovirus B19 Infection
Parvovirus B19 cannot be grown in standard tissue culture and has only been propagated in human erythroid progenitor cells. Recently we have been able to show that B19 can also replicate in vitro in cynomolgus bone marrow [95], suggesting that it may be possible to infect some monkey species and develop an animal model for B19 pathogenesis. An animal model would allow further investigation of the role of in utero B19 infection inducing constitutional bone marrow failure syndromes.
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accepted for publication August 9, 1995.
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Abstract
Introduction
