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Biomedical subjects

Malcolm A Lawson

Publications and source records attributed to Malcolm A Lawson.

7 recordsLinked to original sources
PubMed2006

Viral vectored immunocontraception: screening of multiple fertility antigens using murine cytomegalovirus as a vaccine vector.

Mouse cytomegalovirus (MCMV) has previously been used as a vaccine vector for viral vectored immunocontraception (VVIC). MCMV expressing murine zona pellucida 3 (mZP3) induces long term infertility in up to 100% of female BALB/c mice following a single inoculation. Whilst a large number of antigens have been investigated as potential immunocontraceptive vaccines, it has been difficult to compare these antigens as few studies have used identical approaches or even animal species. Here a range of protein and polyepitope antigens, all expressed by MCMV, were tested for the ability to sterilise female mice. The antigens tested were bone morphogenic protein 15 (BMP15), oviduct glycoprotein (OGP) and ubiquitin-tagged mZP3. In addition, four polyepitope constructs that contain rodent or mouse specific epitopes were tested. This study found that when expressed by an MCMV vector, only full-length mZP3 or ubiquitin-tagged mZP3 induced infertility in female mice. BMP15 and OGP had no effect. Of the four polyepitopes tested, one had a partial effect on fertility. These data indicate that while MCMV is an effective vector for VVIC, the antigen used needs to be tested empirically. The partial infertility seen in mice infected with one of the polyepitope vaccines is a promising finding suggesting that it may be possible to combine a species specific virus with a species specific antigen for use as a disseminating mouse control agent.

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PubMed2006

Innate antiviral resistance influences the efficacy of a recombinant murine cytomegalovirus immunocontraceptive vaccine.

Recombinant betaherpesviruses are attractive vaccine candidates because of their persistence in the host. A recombinant murine cytomegalovirus expressing the mouse ovarian glycoprotein zona pellucida 3 induces long lasting sterility in female BALB/c mice. Using inbred mouse strains selected for their innate resistance or susceptibility to MCMV, we show that genetically determined innate resistance to MCMV can reduce immunocontraceptive success. The Cmv1 locus that controls natural killer cell mediated responses to MCMV was implicated in determining vaccine efficacy. However, the role of the H-2 haplotype was less clear. Interestingly, Mus domesticus from an outbred colony of wild-derived mice were readily sterilised by vaccination, consistent with observations that strong innate immunity to MCMV is not common in Australian wild mice.

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PubMed2006

Mixed infection with multiple strains of murine cytomegalovirus occurs following simultaneous or sequential infection of immunocompetent mice.

As with human cytomegalovirus (HCMV) infection of humans, murine CMV (MCMV) infection is widespread in its natural host, the house mouse Mus domesticus, and may consist of mixed infection with different CMV isolates. The incidence and mechanisms by which mixed infection occurs in free-living mice are unknown. This study used two approaches to determine whether mixed infection with MCMV could be established in laboratory mice. The first utilized two naturally occurring MCMV strains, N1 and G4, into which the lacZ gene was inserted by homologous recombination. The lacZ gene was used to track recombinant and parental viruses in simultaneously coinfected mice. In the second approach, a real-time quantitative PCR (qPCR) assay was used to detect viral immediate-early 1 (ie1) gene sequences in mice successively coinfected with G4 and then with the K181 MCMV strain. In both systems, mixed infection was detected in the salivary glands and lungs of experimentally infected mice. MCMV-specific antibody in sera and G4 IE1-specific cytotoxic lymphocyte responses in the spleens of twice-infected mice did not prevent reinfection. Finally, the prevalence of mixed infection in free-living mice trapped in four Australian locations was investigated using real-time qPCR to detect ie1 DNA sequences of N1, G4 and K181. Mixed infection with MCMVs containing the G4 and K181 ie1 sequences was detected in the salivary glands of 34.2 % of trapped mice. The observations that mixed infections are common in free-living M. domesticus and are acquired by immunocompetent mice through simultaneous or successive infections are important for vaccine development.

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PubMed2005

Use of a murine cytomegalovirus K181-derived bacterial artificial chromosome as a vaccine vector for immunocontraception.

Cytomegaloviruses (CMVs) are members of the Betaherpesvirinae subfamily of the Herpesviridae, and their properties of latency, large DNA size, gene redundancy, and ability to be cloned as bacterial artificial chromosomes (BACs) suggest their utility as vaccine vectors. While the K181 strain of murine CMV (MCMV) is widely used to study MCMV biology, a BAC clone of this virus had not previously been produced. We report here the construction of a BAC clone of the K181(Perth) strain of MCMV. The in vivo and in vitro growth characteristics of virus derived from the K181 BAC were similar to those of wild-type K181. The utility of the K181 BAC as a method for the rapid production of vaccine vectors was assessed. A vaccine strain of BAC virus, expressing the self-fertility antigen, murine zona pellucida 3, was produced rapidly using standard bacterial genetics techniques and rendered female BALB/c mice infertile with a single intraperitoneal inoculation. In addition, attenuated vaccine strains lacking the open reading frames m07 to m12 exhibited no reduction in efficacy compared to the full-length vaccine strain. In conclusion, we describe the production of a K181-based BAC virus which behaved essentially as wild-type K181 and allowed the rapid production of effective viral vaccine vectors.

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PubMed2004

Assessment of contraceptive vaccines based on recombinant mouse sperm protein PH20.

Mouse PH20 (mPH20), the mouse homologue to guinea pig hyaluronidase protein PH20 (gpPH20), was used to produce contraceptive vaccines that target both sexes of mice. Previously, immunization with a female gamete antigen (the zona pellucida subunit 3 protein) delivered in a recombinant murine cytomegalovirus (MCMV), or as a purified recombinant protein, has been shown to induce infertility in female mice. There is evidence, however, that sperm protein antigens could provide broader contraceptive coverage by affecting both males and females, and the most promising has been gpPH20 when tested in a guinea pig model. Mice were therefore either inoculated with a recombinant MCMV expressing mPH20 or immunized directly with purified recombinant mPH20 protein fused to maltose-binding protein. Mice treated with either vaccine formulation developed serum antibodies that cross-reacted to a protein band of 55 kDa corresponding to mPH20 in Western blots of mouse sperm. However, there was no significant reduction in the fertility of males or females compared with control animals with either formulation. We conclude from our data that recombinant mPH20 is not a useful antigen for inclusion in immunocontraceptive vaccines that target mice.

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PubMed2003

Immunocontraception is induced in BALB/c mice inoculated with murine cytomegalovirus expressing mouse zona pellucida 3.

Immunocontraception, the prevention of oocyte fertilization through immunological means, could potentially be used to control plaguing mouse populations in Australia. This paper describes the construction of a mouse-specific betaherpesvirus, murine cytomegalovirus, which has been engineered to express the murine zona pellucida 3 (ZP3) gene. A single inoculation of this recombinant virus resulted in almost complete infertility, persistent anti-ZP3 antibody production, and profound changes to ovarian morphology in BALB/c mice in the absence of significant virus replication during the acute phase of infection. Murine cytomegalovirus may prove to be useful as a vector for the delivery of a mouse-specific immunocontraceptive agent to target populations of wild mice in the field.

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