Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant or stably-transformed bacterium encoding one or...
Reexamination Certificate
1999-10-08
2002-02-26
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant or stably-transformed bacterium encoding one or...
C424S255100, C424S093400, C424S201100, C424S203100, C424S234100, C424S184100, C424S235100, C424S827000
Reexamination Certificate
active
06350454
ABSTRACT:
TECHNICAL FIELD
This invention pertains to fish vaccines, particularly to certain live-attenuated bacterial vaccines against fish pathogens.
BACKGROUND ART
Immune responses to live vaccines are generally of greater magnitude and of longer duration than those produced by killed or subunit vaccines. A single dose of a live-attenuated vaccine can provide better protection against later infection by the wild-type organism, because the attenuated organism persists and metabolizes within the host, and in some cases may replicate in the host for a time. See, e.g., M. Roberts et al., “Salmonella as Carriers of Heterologous Antigens,” pp. 27-58 in O'Hagan (ed.),
Novel Delivery Systems for Oral Vaccines
(1994). Live vaccines better elicit cell-mediated immune responses, which can have a crucial role in controlling infections by intracellular pathogens. Injectable vaccines are impractical in most commercial fish culture due to extensive pond or cage production techniques, large numbers of individual animals, and low value per individual animal. Prior immersion or oral delivery of killed vaccines to fish has yielded inconsistent results. The invasion, persistence, and replication of live-attenuated vaccines has the potential to provide effective, inexpensive vaccines. R. Thune et al., “Studies on Vaccination of Channel Catfish,
Ictalurus punctatus
, against
Edwardsiella ictaluri
” pp. 11-23 in D. Tave et al. (ed.),
Recent Developments in Catfish Aquaculture
(1994).
An auxotrophic bacterium is a nutritional mutant requiring one or more growth factors to survive and replicate. Certain nutrients have limited availability in vertebrate tissues. A bacterium from an otherwise pathogenic species will be attenuated if it is made auxotrophic for such a limited nutrient. These auxotrophic mutants are potentially useful as live-attenuated vaccines.
Roberts et al. (1994) reviews the use of live-attenuated, transformed Salmonella as potential vectors for vaccinating humans and other mammals orally with heterologous antigens derived from other pathogens. Attenuated strains have been produced by a variety of routes, including strains with aroA or purA mutations. (The aroA gene encodes an enzyme needed in the biosynthesis of aromatic amino acids; and the purA gene encodes an enzyme needed in the biosynthesis of adenine.) See also C. Hornaeche, “Live Attenuated Salmonella Vaccines and Their Potential as Oral Combined Vaccines Carrying Heterologous Antigens,”
J. Immunol. Meth
., vol. 142, pp. 113-120 (1991); D. Sigwart et al., “Effect of a purA Mutation on a Efficacy of Salmonella Live-Vaccine Vectors,”
Infection and Immunity
, vol. 57, pp. 1858-1861 (1989); and S. Hoiseth et al., “Aromatic-Dependent
Salmonella Typhimurium
are Non-Virulent and Effective as Live Vaccines,” Nature, vol. 291, pp. 238-239 (1981). In mammalian hosts, however, adenine auxotrophic Salmonella purA mutants are less effective as vaccines than aroA mutants, possibly because purA mutants are overly attenuated due to the extremely low availability of adenine in mammalian tissues.
The channel catfish (
Ictalurus punctatus
) is the most important aquaculture species in the United States. R. Thune, “Bacterial Diseases of Catfish,” Chapter 57 (pp. 511-520) in Stoskopf, M. K. (ed.),
Fish Medicine
(1993) reviews the major bacterial diseases encountered in commercial catfish aquaculture, the most serious of which is enteric septicemia of catfish (ESC).
Edwardsiella ictaluri
, the bacterium that causes ESC, was first described in 1979 after isolation from catfish farms in Georgia and Alabama. Since then it has been reported in every state that produces channel catfish commercially.
Edwardsiella ictaluri
was isolated from 46.2% of the channel catfish cases submitted to aquatic animal diagnostic laboratories in Alabama, Louisiana, and Mississippi during 1987-89.
The various
Edwardsiella ictaluri
strains that have been examined to date have been serologically and biochemically homogenous. As a result, killed bacterins have been evaluated as vaccines against ESC. A protective response has been inconsistent in field trials using killed preparations, and it has been suggested that prior, sub-clinical exposure of vaccinated fish to
E. ictaluri
during periods in which temperatures were not conducive to disease may have been an important factor in establishing this response; and that a similar response might not be seen in naive fish without a similar sub-clinical exposure. Thune et al. (1994). A variety of preparations were found to stimulate antibody production in these studies, but a positive antibody response did not always correlate to protective immunity unless very high titers of antibody were achieved. Protection of laboratory-reared
E. ictaluri
-free fish has not been demonstrated and no commercial vaccines for ESC are currently available.
A strong cell-mediated immune response could provide a more effective vaccination against ESC—both for the above reasons, and because
E. ictaluri
is a facultative intracellular pathogen.
Injection of a killed preparation with an adjuvant is one way to stimulate cell-mediated immunity (CMI), but because of the large numbers, small size, and low economic value of individual fish, this route of vaccination is not practical in commercial catfish production. Live-attenuated strains of pathogenic bacteria could potentially generate a strong CMI. In addition, attenuated strains of invasive pathogens may be delivered via oral and immersion routes, making their administration more economical. However, no previous vaccines have been reported to stimulate cell-mediated immunity against
E. ictaluri.
Commercial farming of hybrid striped bass (
Morone saxatilis
x
Morone chrysops
) is a rapidly expanding aquaculture industry in the United States, the Mediterranean region, and southeast Asia, including Taiwan. In the United States, hybrid striped bass production increased from 3750 tons in 1994 to 7000 tons in 1996 (Hybrid Striped Bass Growers Association, personal communication). This fish is adapted for culture in both fresh and brackish water, resulting in the development of significant production of this hybrid species in coastal areas worldwide. In the United States, coastal hybrid striped bass farms are located in Louisiana, Texas, and Florida. In addition, United States producers ship millions of fry and fingerlings annually to marine and brackish water mariculture farms in Taiwan and in the Mediterranean region.
Along with the growth of this industry in coastal areas has come the emergence of the bacterial disease agent
Pasteurella piscicida
, which has seriously restricted the expansion of commercial aquaculture in warm water coastal areas. (
Pasteurella piscicida
has recently been renamed
Photobacterium damsela
subspecies piscicida. The historical nomenclature
Pasteurella piscicida
is used here.) Pasteurellosis was relatively unknown outside of Japan prior to 1990. In Japan pasteurellosis has caused losses in excess of $20 million annually in cultured yellowtail. The recent growth of coastal aquaculture in the United States and in the Mediterranean region has created ideal conditions for this highly pathogenic, halophilic organism. In Louisiana alone, 32 cases of heavy mortality in coastal hybrid striped bass farms have been reported in the last five years (Louisiana Aquatic Animal Diagnostic Lab case records), with two farms closing as a result of
P. piscicida
losses.
The gilthead seabream
Sparus aurata
, and seabass
Dicentrarchus labrax
, species that are farmed in Israel, Europe, and the Mediterranean, are also highly susceptible to
P. piscicida
. Production of hybrid striped bass, seabream, and seabass throughout the Mediterranean region is estimated to be tens of thousands of tons annually.
P. piscicida
has become a serious problem throughout the region.
Pasteurellosis is an acute, rapidly developing disease. Antibiotic treatments have often been impractical or ineffective. In addition,
P. piscicida
has quickly developed resistance to certain antibiotics. An effe
Board of Supervisors of Louisiana State University and Agricultu
Davis Bonnie J.
Devi S.
Runnels John H.
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