Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2002-12-16
2003-12-16
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S005000, C424S184100, C424S199100, C536S023720
Reexamination Certificate
active
06664066
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to isolated, recombinantly-generated, negative-sense, single-stranded RNA viruses of the genus Morbillivirus having one or more mutations and/or deletions which reduce the repression normally caused by the V protein.
BACKGROUND OF THE INVENTION
Enveloped, negative-sense, single-stranded RNA viruses are uniquely organized and expressed. The genomic RNA of negative-sense, single-stranded viruses serves two template functions in the context of a nucleocapsid: as a template for the synthesis of messenger RNAs (mRNAs) and as a template for the synthesis of the antigenome (+) strand. Viral replication occurs after synthesis of the mRNAs and requires the continuous synthesis of viral proteins. The newly synthesized antigenome (+) strand serves as the template for generating further copies of the (−) strand genomic RNA.
The RNA-dependent RNA polymerase complex actuates and achieves transcription and replication by engaging the cis-acting signals at the 3′ end of the genome, in particular, the promoter region. Viral genes are then transcribed from the genome template unidirectionally from its 3′ to its 5′ end.
Based on the revised reclassification in 1993 by the International Committee on the Taxonomy of Viruses, an Order, designated Mononegavirales, has been established. This Order contains three families of enveloped viruses with single-stranded, nonsegmented RNA genomes of minus polarity (negative-sense). These families are the Paramyxoviridae, Rhabdoviridae and Filoviridae. The family Paramyxoviridae has been further divided into two subfamilies, Paramyxovirinae and Pneumovirinae. The subfamily Paramyxovirinae contains three genera, Respirovirus (formerly Paramyxovirus), Rubulavirus and Morbillivirus. The subfamily Pneumovirinae contains the genus Pneumovirus. The new classification is based upon morphological criteria, the organization of the viral genome, biological activities and the sequence relatedness of the genes and gene products. The current taxonomical classification of the Morbilliviruses is as follows:
Order Mononegavirales
Family Paramyxoviridae
Subfamily Paramyxovirinae
Genus Morbillivirus
Measles virus
Dolphin morbillivirus
Canine distemper virus
Peste-des-petits-ruminants virus
Phocine distemper virus
Rinderpest virus
For many of these viruses, no vaccines of any kind are available. Thus, there is a need to develop vaccines against such human and animal pathogens. Such vaccines would have to elicit a protective immune response in the recipient. The qualitative and quantitative features of such a favorable response are extrapolated from those seen in survivors of natural virus infection, who, in general, are protected from reinfection by the same or highly related viruses for some significant duration thereafter.
A variety of approaches can be considered in seeking to develop such vaccines, including the use of: (1) purified individual viral protein vaccines (subunit vaccines); (2) inactivated whole virus preparations; and (3) live, attenuated viruses.
Subunit vaccines have the desirable feature of being pure, definable and relatively easily produced in abundance by various means, including recombinant DNA expression methods. To date, with the notable exception of hepatitis B surface antigen, viral subunit vaccines have generally only elicited short-lived and/or inadequate immunity, particularly in naive recipients.
Formalin inactivated whole virus preparations of polio (IPV) and hepatitis A have proven safe and efficacious. In contrast, immunization with similarly inactivated whole viruses such as respiratory syncytial virus and measles virus vaccines elicited unfavorable immune responses and/or response profiles which predisposed vaccinees to exaggerated or aberrant disease when subsequently confronted with the natural or “wild-type” virus.
Appropriately attenuated live derivatives of wild-type viruses offer a distinct advantage as vaccine candidates. As live, replicating agents, they initiate infection in recipients during which viral gene products are expressed, processed and presented in the context of the vaccinee's specific MHC class I and II molecules, eliciting humoral and cell-mediated immune responses, as well as the coordinate cytokine and chemokine patterns, which parallel the protective immune profile of survivors of natural infection.
This favorable immune response pattern is contrasted with the delimited responses elicited by inactivated or subunit vaccines, which typically are largely restricted to the humoral immune surveillance arm. Further, the immune response profile elicited by some formalin inactivated whole virus vaccines, e.g., measles and respiratory syncytial virus vaccines developed in the 1960's, have not only failed to provide sustained protection, but in fact have led to a predisposition to aberrant, exaggerated, and even fatal illness, when the vaccine recipient later confronted the wild-type virus.
While live, attenuated viruses have highly desirable characteristics as vaccine candidates, they have proven to be difficult to develop. The crux of the difficulty lies in the need to isolate a derivative of the wild-type virus which has lost its disease-producing potential (i.e., virulence), while retaining sufficient replication competence to infect the recipient and elicit the desired immune response profile in adequate abundance.
Historically, this delicate balance between virulence and attenuation has been achieved by serial passage of a wild-type viral isolate through different host tissues or cells under varying growth conditions (such as temperature). This process presumably favors the growth of viral variants (mutants), some of which have the favorable characteristic of attenuation. Occasionally, further attenuation is achieved through chemical mutagenesis as well.
This propagation/passage scheme typically leads to the emergence of virus derivatives which are temperature sensitive, cold-adapted and/or altered in their host range—one or all of which are changes from the wild-type, disease-causing viruses—i.e., changes that may be associated with attenuation.
Several live virus vaccines, including those for the prevention of measles and mumps (which are paramyxoviruses), and for protection against polio and rubella (which are positive strand RNA viruses), have been generated by this approach and provide the mainstay of current childhood immunization regimens throughout the world.
Nevertheless, this means for generating attenuated live virus vaccine candidates is lengthy and, at best, unpredictable, relying largely on the selective outgrowth of those randomly occurring genomic mutants with desirable attenuation characteristics. The resulting viruses may have the desired phenotype in vitro, and even appear to be attenuated in animal models. However, all too often they remain either under- or overattenuated in the human or animal host for whom they are intended as vaccine candidates.
Even as to current vaccines in use, there is still a need for more efficacious vaccines. For example, the current measles vaccines provide reasonably good protection. However, recent measles epidemics suggest deficiencies in the efficacy of current vaccines. Despite maternal immunization, high rates of acute measles infection have occurred in children under age one, reflecting the vaccines, inability to induce anti-measles antibody levels comparable to those developed following wild-type measles infection (Bibliography entries 1,2,3). As a result, vaccine-immunized mothers are less able to provide their infants with sufficient transplacentally-derived passive antibodies to protect the newborns beyond the first few months of life.
Acute measles infections in previously immunized adolescents and young adults point to an additional problem. These secondary vaccine failures indicate limitations in the current vaccines' ability to induce and maintain antiviral protection that is both abundant and long-lived (4,5,6). Recently, yet another potential problem was revealed
Gordon Alan M.
Park Hankyel T.
Rozek Carol E.
Wyeth Holdings Corporation
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