Elsevier

Vaccine

Volume 29, Issue 43, 6 October 2011, Pages 7357-7363
Vaccine

Safety and immunogenicity of a candidate parvovirus B19 vaccine

https://doi.org/10.1016/j.vaccine.2011.07.080Get rights and content

Abstract

Parvovirus B19 is an important human pathogen causing erythema infectiosum, transient aplastic crisis in individuals with underlying hemolytic disorders and hydropsfetalis. We therefore evaluated a parvovirus B19 virus like particle (VLP) vaccine. The safety and immunogenicity of a 25 μg dose of parvovirus B19 recombinant capsid; 2.5 and 25 μg doses of the recombinant capsid given with MF59; and saline placebo were assessed in healthy adults. Because of 3 unexplained cutaneous events the study was halted after enrollment of 43 subjects and before any subject received their third scheduled dose. The rashes developed 5–9 days after the first or second injection and were seen in one placebo recipient (without an injection site lesion) and two vaccine recipients (with injection site reactions). No clear cause was established. Other safety evaluations revealed mostly injection site reactions that were mild to moderate with an increase in pain in subjects receiving vaccine and MF59. After dose 2 the majority of vaccine recipients developed ELISA and neutralizing antibody to parvovirus B19. Given the possible severe consequences of parvovirus B19 infection, further development of a safe and effective vaccine continues to be important.

Introduction

Parvoviruses are small DNA viruses that infect rapidly dividing cells and cause a diversity of diseases in animal species [1]. Parvovirus B19 and the newly discovered Bocavirus are the only members of the Parvoviridae family known to cause disease in humans. In healthy individuals, parvovirus B19 causes erythema infectiosum, more commonly known as fifth disease, a rash illness in children that can manifest as an arthralgia syndrome in adults. Its role in myocarditis may also have been underestimated [2], [3]. In individuals with underlying hemolytic disorders, parvovirus B19 infection results in transient aplastic crisis (TAC), a temporary cessation of red blood cell production with severe worsening of anemia, which is occasionally fatal [1], [4]. Similarly, parvovirus B19 infections play a significant role in the etiology of severe anemia in areas where malarial is endemic and contributes to the morbidity and mortality associated with severe anemia in such regions [5], [6]. In immunosuppressed individuals, parvovirus B19 can persist and cause severe anemia and pure red cell aplasia. In patients with organ transplantation, parvovirus B19 may account for considerable mortality [7].

Importantly, infection of a pregnant woman in mid-trimester can result in hydrops fetalis and fetal loss. Up to 40% of all pregnant women are seronegative and susceptible to parvovirus B19. Transplacental transmission rates have been reported to vary from 24% to 33%. In addition to hydrops fetalis, fetal parvovirus B19 infection is associated with fetal anemia, spontaneous abortion, and stillbirth. Fetal infection rates are estimated to range from 1% to 9% [8]. Detection and treatment is complicated due to the fact that in many cases, pregnant women may be asymptomatic, requiring detection of IgM in maternal serum or via visualization of hydrops by ultrasound. In a seroepidemiologic maternal risk study in five European countries Mossong et al. showed that that the annual fetal loss was close to 900 and when considering Europe as a whole, the number could be several thousand [9]. There are no known effective antiviral drugs for the treatment of parvovirus B19 infections.

The major capsid protein of parvovirus B19, VP2, constitutes about 95% of the capsid structure. The minor capsid protein, VP1, is identical except for an additional 227 amino acids at the amino terminus. Studies in the Hematology Branch of the NHLBI have demonstrated that the individual capsid proteins can be expressed in a baculovirus system and, when recombinant vectors are cotransfected, VP1 and VP2 spontaneously assemble into empty parvovirus capsids [10]. The capsids were shown to be immunogenic in a variety of animals and in humans, eliciting neutralizing antibody responses [11], [12]. Enrichment of empty capsids by manipulation of the multiplicity of infection of the recombinant insect virus can produce capsids containing approximately 20–40% VP1. These capsids are particularly effective in promoting a neutralizing antibody response.

A previous evaluation of a capsid preparation that was approximately 25% VP1 and about 75% VP2 (Medi-491) was conducted as an open-label, dose-escalation study in healthy adults using doses of 1, 3, 10, 30, and 100 μg. The vaccine was poorly immunogenic when given with the adjuvant alum (Balsley unpublished results). In a subsequent trial of this vaccine, all parvovirus B19 seronegative subjects (n = 24) immunized with 2.5 μg or 25 μg of vaccine formulated with the adjuvant MF-59 (an oil in water emulsion) seroconverted after receiving at least 2 doses of vaccine [11]. Antibody titers were significantly higher in the 25 μg dose group.

In the study presented here, we compared the safety and immunogenicity of a baculovirus expressed parvovirus B19 recombinant capsid vaccine at a dose of 25 μg to 2.5 and 25 μg doses of the vaccine given with MF59. Baculovirus derived vaccines present an alternative to cell culture based vaccines especially in the development of new influenza vaccines [13]. MF 59 is currently licensed as an adjuvant for influenza vaccines in several countries and is licensed in the USA for seasonal influenza vaccines in the elderly. Its mechanism of action is not fully understood, but enhancement of the interaction between the antigen and the dendritic cell appears to be involved [14].

Section snippets

Vaccine and adjuvant

The vaccine is a recombinant parvovirus B19 vaccine composed of the VP1 and VP2 proteins of the virus [11]. VP1 and VP2 were expressed in a baculovirus system in which the 2 capsid proteins self-assemble into virus like particles (VLP), as previously described [10]. The capsid preparation was approximately 22.6% VP1 and about 77.4% VP2, meeting pre-specified specifications. Vaccine was supplied by Meridian Life Science, Inc. (fdba Viral Antigens, Inc., Memphis, TN, USA) and has a designation of

Results

Because of the unexplained reactions described below the study was halted after enrollment of 43 subjects. A first dose of vaccine was received by 12–14 subjects in each vaccine group, while 5 received placebo. A second dose of vaccine was given to 8–10 subjects in each of the vaccine groups while 4 of the 5 subjects in the placebo group received the second dose. None of the subjects received the third dose of vaccine. Demographic characteristics of the enrolled subjects are shown in Table 1.

Discussion

This is the third evaluation of VLP vaccines for prevention of parvovirus B19 infections. In the first trial the vaccine was poorly immunogenic when given with the adjuvant alum, (Balsley unpublished results). However, in a subsequent trial, the addition of the adjuvant MF-59 improved immunogenicity, so that all vaccines developed neutralizing antibody after the second dose with the highest titers in the group receiving 25 μg compared to the 2.5 μg dose. In the trial presented here, there was

Conclusion

Parvovirus B19 is a global infection that can cause serious and life threatening complications in susceptible patient groups. Given the possible severe consequences, fatal anemia and the loss of an unborn child, further development of a safe and effective vaccine continues to be important.

Acknowledgements

This work was supported by the National Institute of Health Contracts; No.: AI 45248 to Cincinnati Children's Hospital Medical Center and AI 25465 to Baylor College of Medicine, Houston, TX, United States.

David Bernstein, Hana El Sahly, Wendy Keitel, Gina Simone, Walla Dempsey, Susan Wong, had no conflicts. Neal Young is a co-discoverer on multiple patents related to recombinant B19 parvoviruses as potential vaccine candidates. Daniel Shelly is an employee of Meridian Biosciences which licensed

References (19)

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