Pasteurella haemolytica vaccine

Details Pasteurella haemolytica vaccine Pasteurella haemolytica vaccine

1999-04-22

2001-01-30

Graser, Jennifer (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C424S234100, C424S236100, C424S235100, C424S200100, C435S069100, C435S173300, C435S252300, C536S023700, C536S024100

Reexamination Certificate

active

06180112

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to compositions and methods for the prevention of disease due to
P. haemolytica
. In particular, the present invention provides
P. haemolytica
strains that produce inactive leukotoxin.
BACKGROUND OF THE INVENTION
Bovine respiratory disease (BRD) encompasses a variety of syndromes that cause serious economic losses. Included within this group of syndromes are diseases associated with Pasteurella species, most commonly
P. haemolytica
, the major etiologic agent bovine pneumonic pasteurellosis (“shipping fever”)(See e.g., Yates Can. J. Comp. Med., 46:225-263 [1982]; Confer et al., J. Amer. Vet. Med. Assoc., 193:1308-1316 [1988]; and Martin et al., Can. J. Comp. Med., 44:1-10 [1980], for reviews of BRD and pneumonic pasteurellosis). Shipping fever is the greatest source of economic loss in feedlot cattle due to the significant mortality rate, as well as the unthriftiness and decreased rate of gain of animals that survive the disease (See e.g., Haynes,
Keeping Livestock Healthy
, Garden Way Publishing, Charlotte, Va. [1978], pp.145-148).
Shipping fever is common in North America, the United Kingdom, and continental Europe. Although cattle of all ages and breeds are susceptible, those most commonly affected are young beef cattle that have been recently (i.e., within 3 weeks) introduced into feedlots. However, it can be equally disastrous in dairy herds. Risk factors for disease include mixing of calves from different origins or ages (clustering of cases often occurs among particular truckloads and/or pens of cattle), stresses associated with transportation, feed shortages, water deprivation, and vaccination upon arrival at feedlots. Other risk factors include communal summer grazing, drafty, humid indoor housing, and close housing of cattle in communal sales and rail yards. The major cause of loss is by death, with the case fatality rate of 5-10%, and a herd morbidity rate of up to 35% (See, Blood,
Pocket Companion to Veterinary Medicine
, Bailli{grave over (e)}re Tindall, London [1994], pp. 309-310). Peak losses occur in cattle 6 months to 2 years of age. Other losses include the lengthened stay in fattening units required by affected cattle that survive the disease. Pasteurellosis represents losses to the American cattle industry of more than 500 million dollars annually (McMillan, in
Bovine Respiratory Disease: A Symposium
, R. W. Loan (ed.), [1984],. p. 64).
Transmission of pasteurellosis is usually accomplished via contact with or aerosolization of nasal and ocular discharges from clinical cases, although carrier animals may also contribute to spread of disease, as healthy animals often carry the organisms in their upper respiratory tracts. In addition, the organisms appear to increase in virulence as the disease becomes active in animals under stress, and increases to the point where animals not under stress also succumb to the disease.
Clinical findings include rapid onset, depression, rapid, shallow breathing, increased loudness of breath sounds that increase in area over time, progression to crackles and wheezing, dyspnea, fever, cough, anorexia, gaunt abdomen, mucopurulent nasal discharge, crusty nose, and ocular discharge. In addition, pleuritic friction sounds are present early in disease, grunting with each expiration of breath is observed later in disease. As the disease progresses, fluid, cellular debris, and pus accumulate in the small air passages. Consolidation of lung tissue may become sufficiently severe that cyanosis results. Sequelae include chronic bronchopneumonia, pleural adhesions, lung abscess, chronic pleurisy, pericarditis, and congestive heart failure. At necropsy, marked consolidation of anteroventral parts of the lung with serofibrinous exudate accumulation in the interlobular spaces is observed, as well as catarrhal bronchitis, bronchiolitis, serofibrinous pleurisy with accumulation of large quantities of pleural fluid, and fibrinous pericarditis.
Shipping fever is associated with various organisms, including
P. haemolytica, P. multocida
, bovine herpes virus 1, parainfluenza-3, bovine respiratory syncytial virus, and Mycoplasma. Exposure to stress, in combination with infection by various viruses appears to facilitate the development of pneumonic pasteurellosis, with
P. haemolytica
infection resulting in the development of fibrinous pneumonia. Although it appears to have a multi-factorial etiology, methods for prevention and treatment of shipping fever has focused on
P. haemolytica. P. multocida
is also sometimes associated with shipping fever, although it is associated with bronchopneumonia with little fibrinous exudate.
P. haemolytica
and
P. multocida
are responsible for numerous diseases of veterinary and medical importance. For example, in addition to shipping fever,
P. haemolytica
is also associated with other economically important diseases, including ovine and caprine pasteurellosis, horse, donkey and mule meningoencephalitis.
P. multocida
is associated with calf and yearling meningoencephalitis, lamb lymphadenitis, horse and donkey septicemia, bovine septicemic pasteurellosis (hemorrhagic septicemia, barbone), swine pasteurellosis, porcine septicemic pasteurellosis, and fowl cholera. Human disease with these organisms usually occurs in infected bite wounds, as many animals carry Pasteurella as normal flora in their oral cavities. Thus, these organisms are of importance in the feedlot, as well as other settings.
Treatment of shipping fever involves administration of oxytetracycline, trimethoprim-sulfadoxine, penicillin or tilmicosin, although the response in animals with complicated etiologies or late disease is poor. Complete failure to respond sometimes occurs in animals with lung abscesses, bronchiectasis, pleurisy, and other, non-bacterial causes. Chemoprophylaxis is sometimes practiced by mass medication of all animals on arrival at the feedlot. However, mass medication (e.g., in the feed), while potentially reducing mortality, has little effect on morbidity, and the number of cases may actually increase due to relaxed disease surveillance. Routine prophylactic feeding of broad-spectrum antimicrobials to all cattle housed in feedlots has resulted in the development of resistance to many antimicrobials, making the disease difficult to treat. Furthermore, this use of broad-spectrum antimicrobials may result in the development of resistance in organisms of veterinary and/or medical importance, other than
P. haemolytica.
Vaccination is commonly used in an attempt to prevent disease. However, the results have been marginal. Indeed, vaccination on arrival of animals to the feedlot with modified live vaccine often increases the mortality rate (See e.g., Blood, supra; and Martin et al., Can. J. Comp. Med., 44:1-10 [1980]). These observations have led to numerous investigations into development of vaccines to prevent disease due to
P. haemolytica
. Previous vaccines utilized live or heat-killed whole cell preparations of mixed serotypes (See e.g., U.S. Pat. Nos. 4,328,210, 4,171,354, 3,328,352, 4,167,560, and 4,346,074). Other vaccine preparations have included crude supernatant extracts from
P. haemolytica
cultures, as well as capsular extracts, and saline extracted antigens (See e.g., Shewen and Wilkie, Can. J. Vet Res., 52:30-36 [1988]; Donachie et al., J. Gen. Microbiol., 130:1209-1216 [1984]; Lessley et al., Vet. Immunol, Immunopathol., 10:279-296 [1985]; and U.S. Pat. No. 4,346,074). However, the results obtained with these preparations have been variable.
While other potential factors are involved in the pathogenesis of shipping fever (e.g., lipopolysaccharide, polysaccharide capsule, fimbriae, glycoprotease, neuraminidase, a serotype-specific antigen, and outer membrane proteins), leukotoxin is considered to be the primary virulence factor of
P. haemolytica
(See, Petras et al., Infect. Immun., 63:1033-1039 [1995]; Shewen and Wilkie, Infect. Immun.

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