Biomedical subjects
Publications and source records attributed to M Tollis.
Inactivation of Newcastle Disease Virus (NDV) by binary ethylenimine (BEI) is reported. The activity of an oil vaccine prepared with BEI-inactivated NDV was compared to a vaccine prepared with formalin-inactivated NDV. The BEI inactivated vaccine had almost twice the efficacy.
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Incubation of radiolabeled rabies virus with neutralizing monoclonal antibodies (MAbs) resulted in complete neutralization of the virus but only partial inhibition of virus binding to, and internalization by, BHK cells. Several of the neutralizing MAbs were capable of preventing infection after virus adsorption to cells; up to 30% of the bound virus was released when cells containing adsorbed virus were incubated with these MAbs at 4 degrees, indicating that the release of bound virus accounts only in part for the neutralization of adsorbed virus. To study the mechanism of neutralization of cell-bound virus, temperature shift experiments were carried out to follow the fate of neutralized cell-adsorbed virus at 37 degrees. Treatment of infected cells with each of the tested neutralizing MAbs had no effect on virus uptake at 37 degrees and the MAbs were endocytosed together with the virus; however, the ability of some of the MAbs to neutralize cell-adsorbed rabies virus correlated with the fusion inhibition activity of these MAbs. We hypothesize from these data that these MAbs neutralize rabies virus by inhibiting the intraendosomal acid-catalyzed fusion step that leads to virus uncoating.
We have studied the ability of rabies virus ribonucleoprotein (RNP) to induce a protective immune response in animals against lethal challenge with rabies and rabies-related lyssa viruses. Liposomes containing either RNP or the glycoprotein (G protein) of a variant virus with multiple alterations in the G antigenic structure conferred no or poor protection, respectively, against lethal intracerebral challenge with rabies virus. By contrast, liposomes containing RNP and the variant G protein induced a good protective response, comparable to that achieved with inactivated virus vaccine against intracerebral challenge. Moreover, mice or raccoons immunized with RNP alone resisted lethal peripheral challenge with homologous or heterologous virus strains. These results indicate that the RNP of rabies virus plays a crucial role in induction of protective immunity.
Immunization experiments with vaccines prepared from the PM and ERA strains of rabies virus demonstrated that in mice, only ERA vaccine primes for an anamnestic response to the rabies-related strain Duvenhage (DUV6); in rabbits, both ERA and PM vaccines induced immunologic memory to DUV6 virus. In mice, ERA vaccine, but not an equal concentration of PM vaccine, conferred protection against a lethal challenge infection with DUV6 virus. This result indicated that the protective activity correlated with the vaccine's ability to induce immunologic memory. A vaccine prepared from a sequentially selected, neutralization-resistant, multiple-variant virus conferred protection against challenge with the parental strain, a result indicating that antigenic variation of the glycoprotein may not be the sole factor in determining the relative efficacy of rabies prophylaxis. We found no correlation between titers of neutralizing antibody and mortality rates in mice immunized with purified glycoprotein from these viruses.
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Rabies virus-specific monoclonal antibodies (MAbs) have served to describe operationally the topography of the antigenic structure of the glycoprotein and nucleocapsid proteins of rabies virus. With the use of nucleocapsid protein-specific MAbs and cleavage fragments of the nucleoprotein and phosphoprotein, it has been possible to identify the chemical structure of two antigenic sites of the nucleoprotein and one antigenic site of the phosphoprotein. Antisera produced to synthetic peptides that make up the structure of these antigenic sites exhibited reactivities similar to those of MAbs. Analysis of a large number of isolates of rabies virus from different animal species and from different geographic locations revealed that rabies viruses differ considerably in their antigenic structure and can be identified according to their characteristic reactivity patterns with MAbs. Analysis of field virus isolates has also revealed that strains of rabies virus generally are associated with only one or a few major mammalian hosts within any given geographic area. Protection experiments in mice have not demonstrated correlations between protective activity and degree of antigenic difference between the vaccine strain and the challenge virus. Therefore, changes in antigenic structure, as determined by analysis with rabies virus-specific MAbs, cannot predict whether a given rabies vaccine will protect against a particular field virus.
The complete coding regions of the surface glycoproteins, nucleoprotein (NP), polymerase 2 (PB2), and matrix (M) of A/turkey/214845/02 and A/turkey/220158/99 (H7N3) low pathogenicity avian influenza (LPAI) viruses isolated in October 2002 in Italy were amplified and sequenced to determine the epidemiologic relationships with an A/turkey/Italy/4603/99 (H7N1/4603/99) LPAI virus isolated during the 1999-2001 epizootic in Italy. The hemagglutinin (HA) of H7N3 viruses showed 97.8% nucleotide similarity with A/turkey/Italy/4603/99 (H7N1), and NP, M, and PB2 gene similarities were 93.6%, 98.2%, and 96.2%, respectively. Phylogenetic analyses of HA, PB2, and M genes showed that H7N3 and H7N1 viruses were closely related. Sequence analysis revealed a 23 amino acid deletion in the stalk of the neuraminidase of H7N3 viruses and a unique deletion of amino acid glycine in position 17 in the NP gene of H7N1 virus.