Combination vaccine for enhancing immunity against brucellosis

Details Combination vaccine for enhancing immunity against brucellosis Combination vaccine for enhancing immunity against brucellosis

2000-12-14

2003-06-24

Navarro, Mark (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

C424S193100, C424S197110, C424S203100, C424S234100, C424S252100

Reexamination Certificate

active

06582699

ABSTRACT:

FIELD OF INVENTION
The present invention relates to a vaccine, comprising a combination of bacterial components derived either from different species of Brucellae, or one strain expressing different components, that enhances immunity against brucellosis. The vaccine formulations are applicable for one or more cross-reactive bacteria thereof.
BACKGROUND OF THE INVENTION
Brucellosis is a debilitating disease that can cause abortions and weight loss in animals as well as undulating fevers, night sweats, incapacitation and arthritis in humans. It is very hardy to environmental factors, easily aerosolized and infectious through skin abrasions, ingestion and the pulmonary route. It is difficult to treat with antibiotics and often persists as a life-long infection. Brucellosis is a disease endemic to most countries, especially under-developed nations where Brucella species infect 0.1 to 10% of the livestock such as cattle, swine, sheep, goats, and camels. A zoonotic disease, these also infect other domestic animals such as dogs and poultry, wildlife such as bison, caribou and wolves and marine mammals such as whales and dolphins. People are especially vulnerable to infection either through handling infected products or ingesting contaminated foods.
Up-to-date, effective treatment against brucellosis for animals, including humans, has been limited. For humans, administering high doses of combination antibiotics, for example doxycycline with rifampin over long periods, has been found to be effective to clear the disease, but non-compliance and relapses are common. For animals, the cost and limited effectiveness of antibiotic treatments often lead to the decision of either no treatment or elimination of the infected animal and its associated herd.
The most preferred type of disease management is to avoid infection and to reduce the incidence and spread of the disease by vaccination. For livestock, namely cattle, at present vaccination consists of using an attenuated (weakened) vaccine strain such as
Brucella abortus
strain 19. Although it is one of the best vaccines for cattle, it does have limitations in that the vaccine does not give absolute protection and there is about a 20% failure rate, results from serological tests can be confusing for a positive serology may be caused by vaccination, infection, or vaccination with subsequent infection, the vaccine although tolerated by cattle is pathogenic for humans, and on occasion the vaccine does revert to a “wild” or virulent form.
For humans, there existed a French vaccine that consisted of a phenol insoluble residue. However, this vaccine has been discontinued as it was found that the residue caused a high rate of reactogenicity (in one study, a large percentage of the vaccine recipients developed swollen lymph glands and granuloma at the site of injection) and hyper-sensitivity (vaccinates that touched killed Brucella preparations presented symptoms of anaphylactic shock).
Recently, the Applicant has discovered a new vaccine that protected animals (e.g. mice, guinea pigs and swine) from brucellosis and which may upon further development be suitable for protecting humans. The vaccine is as described in U.S. Pat. No. 5,951,987 which is herein incorporated by reference. The vaccine consists of an outer-polysaccharide (OPS) isolated from Brucella such as Brucella abortus. The vaccine protected animals from different strains and species of Brucella tested (e.g.
B. abortus
30,
B. abortus
2308 and
B. suis
biovar 1) as well as infections from
Francisella tularensis
live vaccine strain (LVS) which causes tularemia in mice. This gave evidence that the vaccine would likely offer effective protection against infections from a broad spectrum of Brucella species and cross-reactive bacteria. However, it has subsequently been found otherwise. Although the
B. abortus
OPS vaccine was effective in offering animals protection from brucellosis, it did so only against species and strains that resembled
B. abortus
in serology (i.e. had “A” OPS antigens). It did not appear to be effective against species and strains that resembled
B. melitensis
in serology (i.e. had the “M” or “A&M” OPS antigens). Hence, there still remains a need for a vaccine which is effective against infections from a wide spectrum of Brucella species.
SUMMARY OF THE INVENTION
In accordance with one aspect of the present invention, there is provided a vaccine comprising a combination of Brucella “A” and “M” outer-polysaccharides and “R” protein antigens. The outer-polysaccharides may be obtained from the same or different species of Brucellae. The most preferred source of OPS is derived from Brucella but a logical extension of this finding is to use bacterial species cross-reactive thereof.
The combination may be obtained from combining “A” outer-polysaccharides extracted from Brucella species selected from the group consisting of
B. abortus
biovar 1,
B. abortus
biovar 2,
B. abortus
biovar 3,
B. abortus
biovar 6,
B. melitensis
biovar 2,
B. suis
biovar 1,
B. suis
biovar 2,
B. suis
biovar 3,
B. neotomae
and
B. maris;
“M” outer-polysaccharide extracted from Brucella species selected from the group consisting of
B. abortus
biovar 4,
B. abortus
biovar 5,
B. abortus
biovar 9,
B. melitensis
biovar 1,
B. suis
biovar 5; and “R” core polysaccharide and proteins extracted from Brucella species selected from the group consisting of
B. ovis
and
B. canis.
Alternatively, the combination may be obtained by combining “AM” outer-polysaccharides extracted from Brucella species selected from the group consisting of
B. abortus
biovar 7,
B. melitensis
biovar 3 and
B. suis
biovar 4 (note:
B. suis
145 biovar 4 is used in the present patent submission), and “R” core polysaccharide and protein extracted from Brucella species selected from the group consisting of
B. ovis
and
B. canis.
In accordance with another aspect of the present invention, there is provided a vaccine comprising a combination of Brucella outer-polysaccharides containing the “A” and “M” antigens and a Brucella outer-polysaccharide-protein complex.
In this case, the combination may be obtained by combining “A” outer-polysaccharide purified from Brucella species selected from the group consisting of
B. abortus
biovar 1,
B. abortus
biovar 2,
B. abortus
biovar 3,
B. abortus
biovar 6,
B. melitensis
biovar 2,
B. suis
biovar 1,
B. suis
biovar 2,
B. suis
biovar 3,
B. neotomae
and
B. maris;
“M” outer-polysaccharide purified from Brucella species selected from the group consisting of
B. abortus
biovar 4,
B. abortus
biovar 5,
B. abortus
biovar 9,
B. melitensis
biovar 1,
B. suis
biovar 5; and an outer-polysaccharide-protein complex selected from the group consisting of outer-polysaccharide and Brucella membrane proteins, outer-polysaccharide and Brucella surface proteins, outer-polysaccharide and Brucella surface enzymes and outer-polysaccharide and Brucella cytoplasmic proteins.
Alternatively, the vaccine may be obtained by combining “AM” outer-polysaccharides extracted from Brucella species selected from the group consisting of
B. abortus
biovar 7,
B. melitensis
biovar 3 and
B. suis
biovar 4, and an outer-polysaccharide having a protein selected from the group consisting of Brucella membrane proteins, Brucella surface proteins, Brucella surface enzymes and Brucella cytoplasmic proteins.
The vaccine may consist of 1 ng to 10 ug, preferably 1 ug, of each of the OPS forming the combination for vaccination of mice weighing about 20 grams.
The vaccine is effective as a prophylactic treatment from infection against a wide range of Brucella species namely
B. abortus, B. melitensis
and
B. suis.
By logical extension the vaccine is likely to be effective for the prevention of brucellosis from
B. ovis, B. canis, B. neotomae
and
B. maris.
Animal studies support its use as a vaccine for livestock, and with further development possibly as a vaccine for humans. It is most effective by intra-peritoneal, sub-cutaneous and intramuscular administration. It is least effe

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