NZ616804B2 - Vaccine delivery method - Google Patents
Vaccine delivery method Download PDFInfo
- Publication number
- NZ616804B2 NZ616804B2 NZ616804A NZ61680412A NZ616804B2 NZ 616804 B2 NZ616804 B2 NZ 616804B2 NZ 616804 A NZ616804 A NZ 616804A NZ 61680412 A NZ61680412 A NZ 61680412A NZ 616804 B2 NZ616804 B2 NZ 616804B2
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- antigen
- vaccine
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Abstract
Disclosed is a composition comprising: -a self assembling peptide that forms a stable hydrogel at physiological salt concentrations; -an adjuvant, wherein the adjuvant comprises a Toll-Like Receptor (TLR) agonist; and -one or more antigens. Also disclosed is the use of the above-described composition in the manufacture of a medicament for immunising a subject. osition in the manufacture of a medicament for immunising a subject.
Description
VACCINE DELIVERY METHOD
CONTINUING APPLICATION DATA
This application claims the benefit ofUS. Provisional Application Serial No.
61/476,431, filed April 18, 2011, which is incorporated by reference herein.
GOVERNMENT FUNDING
This invention was made with government support under Grant Nos. AIO7l883 and
A1036657, awarded by that National utes of Health. The Government has certain rights in
the invention.
BACKGROUND
Vaccines remain the single greatest public health asset for combating infectious es.
The goal of vaccine delivery is to present vaccine antigens in a manner that enhances antigen
presenting cell tion, uptake of antigen and processing. An additional goal is to reduce the
number of vaccinations required to induce an ive, vaccine-specific response, especially if a
single effective dose of a vaccine is ble. Current, conventional vaccine delivery s
use alum. um salts, such as alum, were first licensed for use as adjuvants in human
vaccines in the 1920's. There is a need for improved delivery modes and adjuvants that are safe
for use in vaccine formulations.
SUMMARY OF THE INVENTION
The present invention includes a ition including as one component a slurry matrix
that is a liquid at room temperature and a gel at physiological salt concentrations and/or
physiological temperatures and as another component one or more antigens. In some aspects of
the composition, the slurry matrix is a peptide hydrogel. In some aspects, the peptide hydrogel
includes PURAMATRIX, or a derivative thereof. In some aspects, the peptide hydrogel includes
the peptide scaffold RADARADARADARADA, or a derivative f. In some aspects of the
composition, the slurry matrix es MATRIGEL, or a derivative thereof
In some aspects of the composition, the composition further includes one of more
nts. In some aspects, an adjuvant includes a Toll-Like Receptor (TLR) agonist and/or a
cytokine. In some s, a TLR agonist includes a TLR4 agonist. In some aspects, a TLR
agonist includes a TLR9 agonist. In some aspects, a TLR9 agonist includes a CpG
oligodeoxynucleotide (ODN).
In some aspects of the composition, the composition further includes a Toll-Like
Receptor (TLR) agonist and/or a cytokine. In some aspects, a TLR agonist includes a TLR4
agonist. In some aspects, a TLR agonist includes a TLR9 agonist. In some aspects, a TLR9
t includes a CpG oligodeoxynucleotide (ODN).
In some aspects of the composition, the antigen includes a hepatitis antigen, an influenza
antigen, a schistosomiasis antigen, and/or a burkolderia antigen, or an nic fragment thereof
The present invention includes a method of producing an immune response in a subject,
the method including administering a composition as described herein to the subject.
The present invention includes a method of immunizing a subject, the method including
administering a composition as described herein to the subject.
The present invention includes a method of delivering one or more immunogenic
antigens to a subject, the method including administering a composition as described herein to
the subject.
The present invention includes a method of delivering one or more therapeutic antigens
to a t, the method including administering a composition as described herein to the t.
In some aspects of the methods of the present invention, the subject is a domestic
livestock or a companion animal. In some aspects of the methods of the present invention, the
subject is y. In some aspects of the methods of the present invention, the t is human.
In some aspects of the methods of the present invention, stration of the
composition es subcutaneous (sc) injection or intramuscular (im) injection.
In some aspects of the methods of the present ion, administration of the
ition es administration as a primary and/or booster vaccination.
In some aspects of the methods of the t invention, administration of the
composition includes administration as a booster vaccination after a primary vaccination with a
polypeptide vaccine or a plasmid DNA vaccine.
The t invention includes a method of producing an anti-schistosome immune
response in a bovoid, the method including stering a composition including as one
component a slurry matrix that is a liquid at room temperature and is a gel at physiological
conditions and as another component one or more schistosome antigens to the bovoid.
The present invention includes a method of producing an anti-schistosome immune
response in a bovoid, the method including administering a composition as described herein to
the bovoid, wherein one or more antigen includes a schistosome antigen.
The present invention includes a method of schistosomiasis vaccination in a bovoid, the
method including stering a composition including as one component a slurry matrix that is
a liquid at room temperature and is a gel at physiological ions and as another component
one or more schistosome antigens.
The present invention includes a method of schistosomiasis vaccination in a bovoid, the
method including administering a composition as described herein to the bovoid, wherein one or
more antigen includes a schistosome antigen.
In some aspects of the methods, the composition fiarther es one or more nts.
In some aspects, an adjuvant includes a Toll-Like Receptor (TLR) agonist and/or a cytokine. In
some aspects, a TLR agonist includes a TLR4 and/or a TLR9 t. In some aspects, a TLR9
agonist includes a CpG oligodeoxynucleotide (ODN). In some aspects, a CpG ODN includes
bovine CpG. In some aspects, the nt includes the cytokine IL-12.
In some aspects of the methods, the composition further includes a Toll-Like Receptor
(TLR) agonist and/or a cytokine. In some s, a TLR agonist includes a TLR4 and/or a
TLR9 agonist. In some aspects, a TLR9 agonist includes a CpG oligodeoxynucleotide (ODN).
In some aspects of the s, a CpG ODN includes bovine CpG.
In some aspects of the methods, the osome n es a Schistosoma
japonz'cum antigen, or an antigenic fragment thereof.
In some aspects of the s, the schistosome antigen includes is a SjCTPI
polypeptide, a SjCTPI-Hsp70 polypeptide, a SjC23 polypeptide, and/or a SjC23-Hsp70
polypeptide, or an antigenic fragment thereof.
In some s of the methods, administration of the composition includes
administration as a primary and/or a booster vaccination.
In some aspects of the methods, administration of the composition includes
administration as booster ation after a primary vaccination with a SjCTPI-Hsp70 plasmid
DNA vaccine.
In some aspects of the s, the method r includes administration of one or
more anti-schistosome chemotherapeutic agents.
In some aspects of the methods, the method trates at least 45% efficacy in the
prevention of infection with a schistosome parasite.
The present invention includes methods of making the composition described herein.
The term "and/or" means one or all of the listed elements or a combination of any two or
more of the listed elements.
The words "preferred" and "preferably" refer to ments of the invention that may
afford certain benefits, under certain circumstances. However, other embodiments may also be
preferred, under the same or other circumstances. rmore, the recitation of one or more
preferred embodiments does not imply that other embodiments are not , and is not intended
to exclude other embodiments from the scope of the invention.
The terms "comprises" and variations f do not have a limiting meaning where these
terms appear in the description and claims.
Unless otherwise specified, "a, an," "the," and "at least one" are used interchangeably
and mean one or more than one.
Also herein, the recitations of numerical ranges by endpoints include all numbers
subsumed within that range (e.g., l to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
Where a range of values is ed, it is understood that each intervening value, to the
tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the
upper and lower limit of that range and any other stated or intervening value in that stated range,
is encompassed within the invention. The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges, and are also encompassed within the invention,
subject to any specifically excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those included limits are also
included in the invention.
For any method disclosed herein that includes discrete steps, the steps may be conducted
in any feasible order. And, as appropriate, any combination of two or more steps may be
conducted simultaneously.
The above summary of the present invention is not ed to describe each disclosed
embodiment or every implementation of the present invention. The description that follows
more particularly ifies illustrative embodiments. In several places hout the
application, guidance is ed through lists of examples, which examples can be used in
various combinations. In each instance, the recited list serves only as a representative group and
should not be interpreted as an exclusive list.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the kinetics of IgA anti-HBsAg antibody titers. Data shown is pooled
from two independent experiments for total n=l 0.
Figure 2 shows the kinetics of IgM anti-HBsAg antibody titers. Data shown is pooled
from two independent experiments for total n=l 0.
Figure 3 shows the cs of IgG BsAg antibody titers. Data shown is pooled
from two independent ments for total n=l 0.
Figure 4 shows the kinetics of IgG1 anti-HBsAg antibody . Data shown is pooled
from two independent experiments for total n=l 0.
Figure 5 shows the kinetics of Inga anti-HBsAg antibody titers. Data shown is pooled
from two independent experiments for total n=l 0.
Figure 6 shows higher anti-HBsAg antibody titers after single vaccination (21 days).
Data shown is pooled from two independent experiments for total n=lO; *p<0.05, **p<0.0l,
**p<0.00l, ****p<0.0001 compared to antigen alone using two-way ANOVA with Bonferroni
post-test.
Figure 7 shows higher anti-HBsAg antibody titers after single vaccination (35 days).
Data shown is pooled from two independent ments for total n=lO; *p<0.05 compared to
n alone using two-way ANOVA with Bonferroni post-test.
Figure 8 shows cytokine profile twenty-four hours after HBsAg mulation of
splenocytes. Data shown is representative of one experiment, n=5; *p<0.05, ****p<0.0001
compared to antigen alone using two-way ANOVA with Bonferroni post-test.
Figure 9 shows cytokine profile forty-eight hours after HBsAg re-stimulation of
splenocytes. Data shown is pooled from two independent experiments for total n=10 (n=5 for
adjuvants only); no statistical differences seen (p<0.05) ed to antigen alone using two-
way ANOVA with Bonferroni post-test.
Figure 10 shows cytokine profile seventy-two hours after HBsAg re-stimulation of
splenocytes. Data shown is pooled from two independent experiments for total n=10 (n=5 for
nts only); **p<0.01 compared to antigen alone using two-way ANOVA with Bonferroni
post-test.
Figure ll shows increased HBsAg-specific cell-mediated immunity by ELISpot in
HbsAg-specific T cell responses. Data shown is pooled from two independent experiments for
total n=lO; *p<0.05 compared to antigen alone using two-way ANOVA with Bonferroni post-
test.
Figure 12 shows increased specific T cell-mediated ty by flow try.
Data shown is pooled from two independent experiments for total n=lO; 01 compared to
antigen alone using two-way ANOVA with Bonferroni post-test.
Figure 13 is a radar graph representing the prevalence of ex vivo cytokine balance in a
range of cell subsets from immunized mice (n=lO/group) 24 hours post-primary inoculation.
The values of the axis can be joined to form the central polygon area which represents the
general cytokine balance. The analysis of the radar chart axes highlights the contribution of
leukocyte for the overall cytokine balance.
Figures 14A and 14B are radar graphs representing the prevalence of ex vivo ne
balance in a range of cell subsets from immunized mice group) 48 hours post-primary
ation. Fig. 14A presents TNF and IFN gamma. Fig. 14B presents IL-5 and IlL-4. Each
axis displays the proportion of each cytokine balance category. The values of each axis can be
joined to form the central polygon area which represents the general cytokine balance.
sing or decreasing central polygon areas reflect higher or lower contribution of
inflammatory or regulatory cytokine balance in each group.
Figure 15 is a radar graph representing the prevalence of ex vivo cytokine balance in a
range of cell subsets from immunized mice group) 72 hours rimary inoculation.
The values of the axis can be joined to form the central polygon area which represents the
general cytokine balance. The analysis of the radar chart axes highlights the contribution of
leukocyte for the overall cytokine balance.
s 16A to 16D are comparisons of rHepBag-specific antibodies induced in
immunized mice (n=10/group) between 14 and 35 days rime inoculation. The boost was
performed 28 days after prime immunization and g-specific antibodies levels were
determined by ELISA assay. Fig. 16A presents data from 14 days, Fig. 16B ts data from
21 days, Fig. 16C presents data from 28 days, and Fig. 16D presents data from 35 days.
Statistical significance at P S 0.05 are represented by superscript letters 'a', 'b' and 'c' for
comparisons with rHepBag, rHepBag in Alhydrogel ® and rHepBag in Freund, respectively.
Figures 17A to 17D show IgGl :IgG2a ratio after immunization of mice (n=10/group)
with rHepBag plus adjuvants between 14 and 35 days. The boost was performed 28 days after
prime immunization and rHepBag-specific antibodies levels were determined by ELISA assay.
Fig. 17A presents data from 14 days, Fig. 17B presents data from 21 days, Fig. 17C ts data
from 28 days, and Fig. 17D ts data from 35 days.
Figures 18A and 18B show increased anti-NP IgG titers in two strains of mice vaccinated
with rNP. Fig. 18A shows titers in C57BL/6 mice. Fig. 18B shows titers in Balb/c mice. Sera
were collected four weeks post-last vaccination (4wplv).
Figures 19A and 19B show increased anti-influenza IgG titers in in C57Bl/6 mice
vaccinated with PR8 WIV. Fig. 19A and Fig. 19B represent results from two independent
experiments. Sera were collected four weeks post-last vaccination (4wplv).
Figures 20A and 20B show increased tion from lethal challenge in 6 mice
vaccinated with PR8 WIV. Fig. 20A shows results from an independent experiment with lethal
challenge at 30 LD50. Fig. 20B shows results from an independent experiment with lethal
challenge at 1000 LD50.
Figures 2lA-2lC show increased urkholderia IgG titers in mice zed with a
cocktail of three recombinant burkholderia protein antigens with three different adjuvants (alum,
CFA, or PURAMTRIX gel). Fig. 21A shows anti-burkholderia protein 4-9 IgG titers in
zed mice. Fig. 21B shows anti-burkholderia protein 22-ll IgG titers in immunized mice.
Fig. 21C shows anti-burkholderia protein 42 IgG titers in immunized mice.
Figures 22A and 22B show IgG anti-schistosome CCA protein antibody titers in mice
immunized with CCA in complete Freund’s adjuvant (Fig. 22A) and CCA in MATRIGEL plus
CpG (Fig. 22B).
DETAILED DESCRIPTION OF RATIVE EMBODIMENTS
OF THE PRESENT INVENTION
The present invention provides compositions and methods that provide for improved
vaccine ry, providing for the improved focal and sustained delivery of antigen at the site of
vaccine administration; enhancing antigen presenting cell activation and antigen uptake and
processing. With the t invention, one or more immunogenic agents is administered in a
composition ing a slurry matrix component that is a liquid at room temperature and/or low
salt concentrations and a gel at physiological salt concentrations and/or physiological
temperatures. Gelling may be induced by the physiological body ature of a vertebrate,
such as a mammal or bird. Such a temperature may be, for example, at least about 25° Celsius
(C), at least about 30° Celsius, at least about 32° Celsius, at least about 35° Celsius, at least about
37°Celsius, at least about 39° Celsius, or at least about 40°. Gelling may be induced by the
physiological salt concentrations. In some embodiments, gelling may in the presence of
millimolar concentrations of salt, for e by a salt concentration of r than about 0.05
molar (M).
Thus, the vaccine composition gels or rizes after administration to a subject,
localizing the vaccine antigens to a single site where innate n presenting cells can home
and begin taking up vaccine antigens. Ideally, the slurry matrix is a biocompatible material will
not induce rable reactions in the body as a result of contact with bodily fluids or tissue,
such as tissue death, tumor formation, allergic reaction, foreign body reaction (rejection),
atory reaction, antibody se, or blood ng, for example. A slurry matrix may
also be referred to herein as a “biomedical polymer hydrogel,” a “biomedical hydrogel,”
“biomedical polymer,” a “polymer hydrogel,” a “biocompatible polymer hydrogel,” a
“biocompatible hydrogel,” a mpatible polymer,” or a “hydrogel.” As used herein, a
“hydrogel” is a 3-dimensional network of cross-linked, hydrophilic macromolecules capable of
being swelled and incorporating about 20 percent to about 95 percent water by weight. A
hydrogel is a gel in which the liquid constituent is water. As used herein, a gel is a solid, j elly-
like material that can have properties ranging from soft and weak to hard and tough. A gel is a
ntially dilute cross-linked system, which exhibits no flow when in the steady-state. By
weight, gels are mostly liquid, yet they behave like solids due to a three-dimensional cross-linked
network within the liquid. It is the crosslinks within the fluid that give a gel its structure
(hardness). In this way gels are a dispersion of molecules of a liquid within a solid in which the
solid is the continuous phase and the liquid is the discontinuous phase. Hydrogel is a network of
polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the
dispersion medium. Hydrogels are highly absorbent (they can contain over 99.9% water) natural
or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural
tissue, due to their cant water content.
Any of a wide variety of biomedical polymer els available for use in medical
technologies may be used with the methods and itions described herein.
In some ments, the slurry matrix is lly occurring, such as for example,
fibrin, collagen, n, agarose, methylcellulose, hyaluronan, and other lly derived
polymers. In some embodiments, the slurry matrix is MATRIGEL, or a derivative thereof.
EL is a basal membrane extract from mouse cells and includes laminin, collagen IV,
entactin, nidogen, and proteoglycans. The invasion of tumor cells into MATRIGEL has been
used to study the involvement of extracellular matrix receptors and matrix degrading enzymes in
tumor progression and invasion and MATRIGEL has been used also as an in vitro and in vivo
angiogenesis model (MATRIGEL plug assay) to study the activity of enic and anti-
angiogenic cytokines and other substances. MATRIGEL is commercially available as BD
MatrigelTM Matrix. See the world wide web at bdbiosciences.com/cellculture/ecm/
ecmtypes/index.j sp.
In some embodiments, a slurry matrix is synthetic, such as for example, a synthetic
e el or a self-assembling peptide (sapeptide) scaffold. The sapeptide scaffolds are
formed h the neous assembly of ionic self-complementary beta-sheet oligopeptides
under physiological conditions, producing a hydrogel material. These short peptides (typically
about 8, about 12, about 16, about 24, or about 32 amino acid residues with intemally-repeating
sequences) self-assemble in aqueous salt solution into three-dimensional matrices. The peptides
are characterized as being amphiphilic, having alternating hydrophobic and hydrophilic amino
acid residues; greater than 12 amino acids, and preferably at least 16 amino acids;
complementary and structurally compatible. Complementary refers to the ability of the peptides
to interact through ionized pairs and/or hydrogen bonds which form between their hydrophilic
side-chains, and structurally compatible refers to the ability of complementary peptides to
maintain a constant distance between their peptide backbones. Peptides having these properties
participate in intermolecular interactions which result in the formation and ization of betasheets
at the secondary structure level and interwoven filaments at the tertiary structure level.
Examples include, but are not d to, peptide family members, RAD 16-1 ((RADA)(4); SEQ
ID NO:2) RAD 16-11 ((RARADADA)(2); SEQ ID NO:3), KFE-8 ((FKFE)(2); SEQ ID NO:4),
or KLD-12 ((KLDL)(3); SEQ ID NO:5). See, for example, U.S. Patent 483; Holmes et al,
2000, Proc Natl Acad Sci USA; 97(12):6728-33; Yokoi et al, 2005, Proc Natl Acad Sci USA;
102(24):8414-9; Liu et al, 2012, Nanoscale; 4(8):2720-7, and BD PuraMatrix™ Peptide
Hydrogel, Guidelines for Use, Catalog Number 354250 (SPCG rev 2.0; BD Biosciences,
Bedford, MA). In some aspects, a peptide hydrogel includes the peptide scaffold self-assembling
building blocks of arginine-alanine-aspartate-alanine (RADA; SEQ ID NO:1). In some aspects, a
e hydrogel includes DARADARADA (SEQ ID NO:2), or a derivative thereof.
In some aspects, the peptide el includes PURAMATRIX, or a derivative thereof. See, for
example, U.S. Patent 5,670,483; Holmes et al, 2000, Proc Natl Acad Sci USA; 97(12):6728-33;
Yokoi et al, 2005, Proc Natl Acad Sci USA; 102(24):8414-9; Liu et al, 2012, Nanoscale;
4(8):2720-7, and BD PuraMatrix™ Peptide Hydrogel, ines for Use, Catalog Number
354250 (SPCG rev 2.0; BD Biosciences, Bedford, MA), each of which are incorporated
herein in their entireties.
In some embodiments, a biomedical polymer hydrogel may be a polyethylene glycol
(PEG) hydrogel that rizes spontaneously in vivo.
In some embodiments, a slurry matrix, in on to gelling at vertebrate or ian
body temperature and/or logical salt concentrations, is a bioresorbable synthetic polymer
that degrades and ves with time. Such compounds are naturally degraded in the body by
hydrolysis and absorbed as water-soluble monomers. Examples include, polylactic acid,
polylactide (PLA), poly (L-lactic acid), poly-D-lactide, polyglycolic acid (PGA), polyglycolide
and its copolymers (poly(lactic-co-glycolic acid) with lactic acid, homo- and copolymers of lactic
acid and glycolic acid, poly (DL-lactic lycine) copolymers, poly (DL-lacticco-glycolic
acid) (PLGA), poly (DL-lacticco-glycolic acid) , porous poly(DL-lactic-co-glycolic acid)
foams, poly(amino acids) poly[ox(l-oxo-l,2-ethanediyl)] 02)n; Biovek),
poly(glycolide-co-caprolactone), poly(glycolide-co-trimethylene ate), polydioxanone
(PDO, PDS), poly-p-dioxanone, caprolactone (also referred to as 2-oxepanone), epsiloncaprolactone
, 6-hexanolactone, hexanolactone, l-oxaoxocycloheptane polyglactin 910,
polyanhydrides, and polyorthoester films formed from poly (D,L-lactic-co-glycolic acid, 88: 12)
(PLGA) or from a 50/50 (W/W) blend of PLGA and poly (L-lactic acid) (PLLA). See, for
example, Schakenraad and Dijkstra, 1991, Clin Mater; 53-69; Mooney et al., 1997, J
Biomed Mater Res; 4 1 3-20; and Lu et al., 2000, Biomaterials; 21(18): 1837-45.
Compositions of the present invention e one or more antigenic agents (also referred
to herein as an gen). An antigenic agent may be any of the great variety of agents that
are administered to a subject to elicit an immune response in the subject. An nic agent
may be an immunogen derived from a pathogen. The antigenic agent may be, for example, a
peptide or protein antigen, a viral antigen or polypeptide, an inactivated virus, a recombinant
virus, a bacterial or parasitic antigen, an inactivated bacteria or parasite, a Whole cell, a
genetically modified cell, a tumor associated antigen or tumor cell, or a carbohydrate antigen. In
some applications an antigen is not a living cell. In some embodiments, an antigenic agent is a
soluble antigen.
A composition as described herein may include as an antigenic agent any of the great
variety of immunogenic agents available as vaccine components. Such vaccines may include,
but are not limited to, antigenic vaccines components directed against various infectious, viral,
and tic diseases and anti-tumor vaccine components. Antitumor vaccines include, but are
not limited to, peptide vaccines, whole cell vaccines, genetically modified Whole cell vaccines,
recombinant protein vaccines or vaccines based on expression of tumor associated antigens by
recombinant viral s. In some embodiments, an antigenic agent is a soluble n.
An antigenic agent includes a bacterial antigen from, for example, Haemopholis
influenza, za virus types A or B, Streptococcus pneumonia, Staphylococcus aureus,
us cis antigen (such as, for example, PA).
An antigenic agent includes a parasite antigen from, for example, a malaria parasite or a
schistosome parasite. Malaria antigens e, but are not d to antigens from the
plasmodium species Plasmoclium vivax, Plasmodiumfalciparum, and Plasmoclium knowlesi,
Plasmoclium ovaleancl, and Plasmodium malariae. Schistosome parasites e, but are not
limited to, Schistosomajaponicum, Schistosoma i, and Schistosoma haematobium. A
schistosome antigen may be a osome triose phosphate isomerase (CTPI) protein, or
antigenic fragment or derivative thereof, including, but not limited to a S. japom'cum, S. monsoni,
or S. haematobium CTPI protein, or antigenic nt or derivative thereof. A schistosome
antigen may be a schistosome tetraspin 23 kDa integral membrane protein (C23), or antigenic
fragment or tive thereof, including, but not limited to a S. japom'cum, S. monsoni, or S.
haematobium C23 protein, or antigenic fragment or derivative thereof Such a schistosome
antigen may be a chimeric polypeptide, fused to one or more additional antigenic determinants,
such as for e, a heat shock protein, or nic fragment or derivative thereof, including,
but not limited to, bovine heat shock protein 70 (Hsp70). Schistosome antigens include, for
example, SjCTPI, SjCTPI-Hsp70, SjC23, and SjC23-Hsp70 polypeptides. Antigens may be
form any of a variety of other parasites, including, but not limited to, kinetoplastid protozoa,
such as for example, protozoa of the Blastocrz'thz'dz'a, Crithz'dz'a, Endotrypanum, Herpetomonas,
Leishmam’a, Leptomonas, Phytomonas, Trypanosoma, and Wallaceina genera. In preferred
embodiments, the protozoan is of the genus Trypanosoma, including, but not limited to, T. cruzi,
T. brucez’, T.b. gambiense, and T.b. rhodesz'ense. In some ments, the protozoan is of the
genus am'a, including, for example, Leishmania major. Notable trypanosomal es
include trypanosomiasis an Sleeping Sickness and South American Chagas Disease,
caused by species of osoma) and leishmaniasis (caused by species of Leishmania).
An antigenic agent includes a viral antigen from, for e, hepatitis, such as for
example, hepatitis C, hepatitis B, or tis A, influenza, for example, the M2, hemaglutinin,
and/or neuraminidase ns of an influenza virus, including, for example, influenza A
(including, but not d to, the H5N1 and HlNl subtypes), influenza B, and za C,
respiratory syncytial virus (RSV), rabies, papilloma virus, measles, a, varicella, rotavirus,
polio, variscella zoster virus (VZV), and negative stranded RNA viruses, such as for example, a
virus of the family Paramyxoviridae. Examples of a virus of the family Paramyxoviridae
include, but are not limited to, human parainfluenza virus 1, human parainfluenza virus 2, human
parainfluenza virus 3, human parainfluenza virus 4, parainfluenza virus 5, mumps virus, measles
virus, human metapneumovirus, human respiratory syncytial virus, bovine respiratory syncytial
virus rinderpest virus, canine distemper virus, phocine distemper virus, Newcastle disease virus,
avian pneumovirus, Peste des Petits Ruminants virus (PPRV), Sendai virus, le virus,
Tupaia paramyxovirus, Tioman virus, Tuhokovirus l, Tuhokovirus 2, Tuhokovirus 3,
Hendravirus, Nipahvirus, Fer-de-Lance virus, Nariva virus, Salem virus, J virus, Mossman virus,
and Beilong virus.
An antigenic agent may include one or more gens derived from pathogens
infectious to poultry. Such immunogens may be derived from, for example, infectious
bronchitis virus (IBV), Newcastle disease virus (NDV), Marek's disease (MDV), infectious
bursal disease (IBD) virus, infectious laryngotracheitis (1LT), avian reovirus, cholera, fowl pox,
mycoplasmosis, turkey and n Coryza, avian influenza, avian alomyelitis (AE),
avian rhinotracheitis (ART), duck virus hepatitis, haemorrhagic enteritis, goose parvovirus,
Paramyxovirus 3, chicken a virus (CAV), E. coli, Erysipelas, Reimerella, Mycoplasma
gallisepticam, Pastearella maltocida, Salmonella enteritidis, Salmonella zjiphimariam,
coccidiosis, egg drop syndrome (EDS) virus, turkey rhinotracheitis virus (TRTV), and poxvirus.
An nic agent may include one or more immunogens derived from pathogens
infectious to bovoids, including, but not limited to, domestic , water buffalo, African
buffalo, bison, and yaks. Such immunogens may be derived from, for example, bovine
respiratory disease (BRD) vaccine, including, but not limited to BVDV types I and 11, bovine
herpes virus 1 (BHV-l) vaccine, including, but not limited to, subunit vaccines that would not
result in latent virus, Haemophilus somnas e, Mannheimia haemolytica vaccine,
Mycoplasma bovis vaccine, bovine rus vaccine, Escherichia coli K99 e, bovine
coronavirus (BCV) vaccine, Clostridiam ei (black leg) vaccine, Clostridiam am
vaccine, Clostridiam li (malignant edema) vaccine, Clostridiam novyi (black disease)
vaccine, Clostridiam perfringens otoxemia) vaccine, infectious bovine keratoconjunctivitis
(pink eye) vaccine, including, but not limited to, lla bovis, chlamydia, mycoplasma,
acholeplasma, or infectious bovine rhinotracheitis (1BR) virus vaccines, is vaccines,
including, but not limited to, Escherichia coli J5 vaccine.
An antigenic agent may include one or more immunogens derived from pathogens
infectious to swine, including, but are not limited to, porcine circovirus type 2 (PCV2), porcine
uctive and respiratory syndrome (PRRSV), respiratory mycoplasma, Streptococcus sais,
porcine coronavirus, rotavirus, enterotoxigenic Escherichia coli (K88), Actinobacillus
plearopneamonia (APP), and swine influenza.
An nic agent may include one or more immunogens derived from the Barkholderia
genus, a group of virtually ubiquitous gram-negative, motile, obligatory aerobic rod-shaped
bacteria including both animal/human and plant pathogens as well as some environmentally
important s. Burkholderz’a is best known for its pathogenic members. Burkholderz’a mallez'
is responsible for glanders, a disease that occurs mostly in horses and related animals.
Burkholderia mallei is the causative agent of melioidosis (also called Whitmore's
e), an infectious disease predominately of tropical climates that can infect humans or
animals, especially in Southeast Asia and rn Australia. Burkholderz'a cepacia is an
important en of pulmonary infections in people with cystic fibrosis. Due to their
antibiotic resistance and the high mortality rate from their associated diseases Burkholderz’a
mallez' and Burkholderia pseudomallei are considered to be potential biological warfare agents,
targeting livestock and humans. Burkholderia antigens include, for example, any of three
burkholderia recombinant proteins (the burkholderia 4-9 n, the burkholderia 22-11 protein,
and the burkholderia 42 protein). Such deria antigens may be administered separately or
as a cocktail of any two or three antigens.
An antigenic agent may be one or more of those currently used in the combination
measles-mumps-rubella (MMR) and measles-mumps-rubella-varicella (MMRV) vaccines.
In some embodiments, the antigenic agent is a polynucleotide vaccine, that is, the
antigenic agent is delivered as a vector construct, such as a plasmid, that results in the expression
of a polypeptide antigen upon delivery to a subject. As used , the term "polynucleotide"
refers to a polymeric form of nucleotides of any length, either ribonucleotides or
deoxynucleotides, and es both double- and single-stranded RNA and DNA. A
polynucleotide can be obtained directly from a natural , or can be ed with the aid of
recombinant, enzymatic, or chemical techniques. A cleotide can be linear or circular in
topology. A polynucleotide may be, for example, a portion of a vector, such as an expression or
g vector, or a fragment. A polynucleotide may include nucleotide sequences having
different fianctions, including, for ce, coding regions, and ding regions such as
regulatory regions. Any suitable vector or delivery vehicle may be utilized. Various vectors are
publicly available. The vector may, for example, be in the form of a plasmid, cosmid, viral
particle, or phage. A vector may be an expression vector. The appropriate nucleic acid sequence
may be inserted into the vector by a variety of ures. In general, DNA is inserted into an
appropriate restriction endonuclease site(s) using techniques known in the art. Vector
components generally include, but are not limited to, one or more of a signal sequence, an origin
of replication, one or more marker genes, an enhancer element, a promoter, and a ription
termination sequence. Construction of le vectors containing one or more of these
components employs standard ligation techniques which are known to those of skill in the art.
A composition as described herein may be useful as a vaccine. The vaccine can be a
prophylactic or protective vaccine.
A composition of the present invention may include one or more compounds with
adjuvant activity. Such an adjuvant stimulates the immune system and increases the response to
a vaccine antigen, without having any specific antigenic effect in itself. An adjuvant acts to
accelerate, prolong, or enhance antigen-specific immune responses when used in ation
with specific vaccine antigens. le compounds or compositions for this e include,
but are not limited to, an aluminum based adjuvant, such as, for example, aluminum phosphate,
aluminum hydroxide (also referred to as alum), aluminum hydroxyl-phosphate, and aluminum
hydroxyl-phosphate-sulfate, and non-aluminum adjuvants, such as, for example, QSZl, MF59,
Lipid-A, neutral lipsomes, microparticles, a ne such as, for example, IL-l2, plant oils,
animal oils, oil-in-water or water-in-oil emulsion based on, for example a mineral oil, such as
Bayol FTM or Marcol 52““, Complete Freund's adjuvant, incomplete Freund's adjuvant, a
vegetable oil such as, for e, vitamin E acetate, a saponin, squalene, a lipidated amino acid
(“LAA”), and/or a TLR agonist.
In some embodiments, an adjuvant component is a toll-like receptor (TLR) ligand. TLRs
in mammals were f1rstidentif1edin 1997. They constitute the first line of defense against many
pathogens and play a crucial role in the function of the innate immune system. There are many
known subclasses of Toll-like receptors, including, TLRl, TLR2, TLR3, TLR4, TLRS, TLR6,
TLR7, TLR8, TLR9, TLRlO, TLRl l, TLRlZ, TLRl3, TLRl4, TLRlS, and TLRl6, and their
ligands exhibit significant ural variation. A TLR t is a molecular ligand for one of
the s Toll-like receptors (TLRs). Known TLRs include: TLRl (TLRl s include
triacyl oteins); TLR2 (TLR2 ligands include oteins, gram positive peptidoglycan,
lipoteichoic acids, fungi, and viral glycoproteins); TLR3 (TLR3 ligands include -stranded
RNA, as found in certain viruses, and poly I:C); TLR4 (TLR4 ligands include lipopolysaccharide
and viral glycoproteins); TLRS (TLRS ligands include flagellin); TLR6 (TLR6 ligands e
diacyl lipoproteins); TLR7 (TLR7 ligands include small tic immune modifiers (such as
imiquimod, R-848, loxoribine, and bropirimine) and single-stranded RNA); TLR8 (TLR8
ligands include small synthetic compounds and -stranded RNA); and TLR9 (TLR9 ligands
include unmethylated CpG DNA motifs). Some TLR ligands are described herein, but it should
be understood that such listings do not limit the invention in any way. TLR ligands are widely
available commercially.
Preferred TLR agonists include TLR2 agonists, TLR4 agonists, TLR7 agonists, TLR8
agonists, and TLR9 agonists. LR2 is involved in the recognition of a wide array of microbial
molecules from Gram-positive and Gram-negative ia, as well as mycoplasma and yeast.
TLR2 ligands include lipoglycans, lipopolysaccharides, ichoic acids and peptidoglycans.
TLR4 recognizes Gram-negative lipopolysaccharide (LPS) and lipid A, its toxic moiety.
TLR4 agonists include, but are not d to, lipopolysaccharide (LPS), Viral glycoproteins,
monophosphoryl lipid A (MPL) (Anderson et al., 2010, Colloids SurfB Bioz'nterfaces;
75(1): 123-32), Glucopyranosyl Lipid nt—Stable on (GLA-SE) (Coler et al., 2010,
PL0S One; 5(10):e13677), and the synthetic hexaacylated lipid A derivative, denoted as
glucopyranosyl lipid adjuvant (GLA) (Coler et al., 2011, PLOS One; 6(1):e16333).
TLR9 is activated by unmethylated ntaining sequences, including those found in
bacterial DNA or synthetic oligonucleotides (ODNs). Such ylated CpG containing
sequences are present at high frequency in bacterial DNA, but are rare in mammalian DNA.
Thus, unmethylated CpG sequences distinguish microbial DNA from ian DNA. A
TLR9 agonist may be a ation of microbial DNA, including, but not limited to, E. 6011'
DNA, endotoxin free E. coli DNA, or endotoxin-free bacterial DNA from E. coli K12. A TLR9
agonist may be a synthetic oligonucleotide containing unmethylated CpG motifs, also referred to
herein as “a igodeoxynucleotide,” “CpGODNs,” “ODN,” or “CpG.” CpG ODNs are
short, single stranded, DNA molecules that contain a ne (“C” nucleotide) followed by a
guanine (“G” nucleotide). The “p” typically refers to the phosphodiester backbone of DNA. A
TLR9 agonist of the present invention may include any of the at least three types of stimulatory
ODNs have been described, type A, type B, and type C. igodeoxynucleotides may be
produced by standard methods for chemical synthesis of polynucleotides or purchased
commercially. For example, CPG ODNs can be purchased through oGen (San Diego,
CA).
The compositions as described herein may include one or more cytokines. Cytokines
may include, but are not limited to, IL-lot, IL-lB, IL-2, IL-3, IL-4, IL-6, IL-8, IL-9, IL-10, IL-12,
IL- 1 3 IL- 1 5 IL- 1 9, IL-20, IFN-(x, IFN—B, IFN—y, tumor necrosis factor (TNF),
, , IL-18,
transforming growth factor-B (TGF-B), granulocyte colony stimulating factor (G-CSF),
macrophage colony stimulating factor (M-CSF), granulocyte-macrophage colony stimulating
factor (GM-CSF), and or Flt-3 ligand. In some applications, one or more cytokines may serve as
an adjuvant.
The present invention also includes methods of inducing an immune response in a subject
by administering a composition as described herein to the t. The immune response may or
may not confer protective immunity. An immune response may include, for example, a humoral
response and/or a cell mediated immune response. A humoral immune response may include an
IgG ding IgGl, IgG2 (including IgG2a and/or , IgG3, and/or IgG4), IgM, IgA, IgD,
IgE, and/or IgY response. A ar immune response may include T cell activation and/or
cytokine production. The determination of a humoral or cellular immune response may be
determined by any of a variety of methods known in the immunological arts, including, but not
limited to, any of those described herein. The induction of an immune response may include the
priming and/or the stimulation of the immune system to a filture nge with an infectious
agent, providing immunity to future infections. The ion of such an immune response may
serve as a protective response, generally resulting in a reduction of the ms. The immune
response may enhance an innate and/or adaptive immune response. The immune response may
demonstrate higher concentrations of antibodies with a single, primary immunization. The
immune se may show altered immunoglobulin ratios and/or altered induction of
inflammatory cytokines, type I interferons, and/or chemokines, compared to immunization
without the slurry matrix. Such alteration may be an increase or a decrease. For example, a
higher ratio of one isotype of immunoglobulin compared to another immunoglobulin isotype (for
example, any one of IgM, IgA, IgD, IgG, or IgE compared to any one of IgM, IgA, IgD, IgG, or
IgE) or a higher ratio of one IgG subclass compared to r IgG subclass (for example, any
one of IgG1, IgG2a, IgG2b, IgG3, or IgG4 compared to any one of IgG1, IgG2a, IgG2b, IgG3,
or IgG4) may be obtained.
The present invention also includes methods of vaccinating a subject by administering a
ition as described herein to the subject. Such vaccination may result in a reduction or
mitigation of the symptoms of filture infection and may prevent a filture ion. The
compositions described herein may have therapeutic and/or lactic applications as
immunogenic compositions in preventing and/or ameliorating infection, such that resistance to
new infection will be enhanced and/or the clinical severity of the e reduced. Such
protection may be demonstrated by either a reduction or lack of the symptoms associated with
RSS, including, but not limited to, any of those described herein. Any of a wide variety of
available assays may be used to determine the effectiveness of the vaccination method of the
t ion, including, but not d to, any of those described herein
In some applications, an immunologically effective amount of at least one immunogen is
employed in such amount to cause a substantial reduction in the course of the normal ion.
Immunogenicity and effectiveness may be assayed in any of a variety ofknown experimental
systems, including, but not limited to, any of those described herein.
The compositions and methods described herein may be administered to a subject for the
treatment and/or prevention of viral diseases, infectious diseases, including, but not limited to
bacterial, fungal and parasitic infections, cancer, and other diseases in which the administration
of one or more immunogens is therapeutically desired. With the methods of the present
disclosure, the efficacy of the administration of one or more agents may be assessed by any of a
variety of parameters known in the art, including, but not limited to, any of those described
herein. This includes, for example, determinations of an increase in the delayed type
hypersensitivity reaction to tumor antigen, determinations of a delay in the time to relapse of the
post-treatment malignancy, determinations of an increase in relapse-free survival time,
determinations of an increase in post-treatment survival, determination of tumor size,
determination of the number of reactive T cells that are activated upon exposure to the
vaccinating antigens by a number of methods including ELISPOT, FACS analysis, cytokine
release, or T cell proliferation assays.
For example, the compositions and methods described herein may be stered to a
patient for the treatment of cancer. mor vaccines include, but are not limited to, peptide
vaccines, whole cell vaccines, genetically modified whole cell es, recombinant n
es or vaccines based on expression of tumor associated antigens by recombinant viral
vectors. Cancers to be treated include, but are not limited to, melanoma, basal cell oma,
colorectal cancer, atic , breast cancer, prostate cancer, lung cancer (including small-
cell lung carcinoma and non-small-cell carcinoma), leukemia, lymphoma, sarcoma, ovarian
cancer, 's a, n's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,
neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,
small-cell lung tumors, primary brain tumors, stomach cancer, malignant pancreatic insulanoma,
malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer,
lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer,
malignant hypercalcemia, cervical cancer, endometrial cancer, glioblastoma, and adrenal cortical
cancer. In some aspects, the cancer is a primary cancer. In some aspects, the cancer is
metastatic. As used herein, “tumor” refers to all types of cancers, neoplasms, or malignant
tumors found in mammals.
The efficacy of treatment of a cancer may be assessed by any of various parameters well
known in the art. This includes, but is not limited to, inations of a reduction in tumor size,
determinations of the tion of the growth, spread, veness, vascularization,
angiogenesis, and/or metastasis of a tumor, determinations of the inhibition of the growth,
spread, veness and/or vascularization of any atic lesions, determinations of tumor
infiltrations by immune system cells, and/or determinations of an increased delayed type
hypersensitivity reaction to tumor antigen. The efficacy of treatment may also be ed by the
determination of a delay in relapse or a delay in tumor progression in the subject or by a
determination of survival rate of the subject, for example, an increased al rate at one or
five years post ent. As used , a relapse is the return of a tumor or neoplasm after its
apparent cessation.
As used herein, unless the context makes clear otherwise, “treatment,” and similar word
such as “treated,” “treating,” etc., is an approach for obtaining beneficial or desired results,
including and preferably clinical results. A ent may include therapeutic and/or
prophylactic treatments. Desirable effects of treatment e preventing occurrence or
recurrence of disease, alleviation of symptoms, diminishment of one or more direct or indirect
pathological consequences of the e, decreasing the rate of e progression,
amelioration or palliation of the disease state, and ion or improved prognosis. In some
ations, a composition as described may demonstrate an improvement in one or more
desired results of at least about 10%, at least about 15%, at least about 20%, or at least about
%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at
least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about
95%.
As used herein, an “effective amount” or a peutically ive amount” of a
substance is that amount sufficient to affect a desired biological , such as beneficial results,
including clinical results. Therapeutically effective concentrations and amounts may be
determined for each application herein empirically by testing the compounds in known in vitro
and in vivo systems, ing any of those described herein. Dosages for humans or other
animals may then be extrapolated therefrom. With the methods of the present invention, the
efficacy of the administration of one or more interventions may be assessed by any of a variety
of parameters well known in the art.
In some embodiments, an “effective amount” is an amount that results in a reduction of at
least one pathological parameter. Thus, for example, an amount that is effective to achieve a
reduction of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%,
at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about
75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%, compared
to the expected ion in the parameter in an individual not receiving ent.
The present invention also includes s of making and using the vaccine
compositions described herein. The compositions of the present sure may be formulated in
pharmaceutical preparations in a variety of forms adapted to the chosen route of administration.
Any of a variety of modes of administration may be used. For example, administration may be
intravenous, topical, oral, intranasal, subcutaneous, intraperitoneal, intramuscular, or intratumor.
A vaccine ition as described herein may take the form of an implant. Such an
implant may be implanted within the tumor. Delivery may be lished by any of a variety
of available technologies, including, for example, injection, infilsion, instillation, l
application, delivery by a , and/or delivery by a catheter. Delivery may be by the use of a
delivery device or tool, such as a needle or catheter. Such delivery devices are included in the
present invention.
A composition of the present invention may be administered with one or more additional
therapeutic interventions. Additional therapeutic treatments include, but are not limited to,
surgical ion, radiation therapy, chemotherapy, hormone therapy, anti-tumor vaccines,
antibody based therapies, whole body irradiation, bone marrow transplantation, eral blood
stem cell lantation, the administration of cytokines, antibiotics, antimicrobial agents,
ral agents, such as AZT, ddI or ddC, the administration of herapeutic agents, such
as, for example, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, vincristine,
ifosfamide, cisplatin, gemcitabine, busulfan, ara-C, adriamycin, mitomycin, cytoxan,
methotrexate, and combinations thereof. Such stration may take place before, during,
and/or after the administration of a vaccine ition as described.
As used herein, the term “subject” includes, but is not limited to, humans and non-human
vertebrates. In some embodiments, a subject is a mammal, ularly a human. A subject may
be an “individual,” “patient,” or “host.” A subject may include, for example, a human, a higher
primate, a non-human primate, domestic livestock and domestic pets (such as dogs, cats, cattle,
horses, pigs, sheep, goats, mules, donkeys, mink, and poultry), laboratory s (such as for
example, mice, rats, hamsters, guinea pigs, and rabbits), and wild life. In some embodiments, a
vaccine composition, as described herein is administered to a bovine, including, but not limited
to, domestic cattle, water o, African o, bison, and yaks.
The vaccine compositions described herein may be administered to poultry, including, for
example, chickens, turkeys, guinea fowl, partridges, and water fowl, such as, for example, ducks
and geese. Chickens include, but are not limited to, hens, roosters, broilers, rs, r, the
offspring of breeder hens, and layers. The vaccine of the present invention may be stered
to poultry before or after hatching. Poultry may receive a vaccine at a variety of ages. For
example, broilers may be vaccinated in ovo, at one-day-old, in ovo, or at 2-3 weeks of age.
Laying stock or reproduction stock may be vaccinated, for example, at about 6-12 weeks of age
and boosted at about 16-20 weeks of age. Such laying stock or reproduction stock may be
ated at about 6, at about 7, at about 8, at about 9, at about 10, at about 11, or at about 12
weeks of age. Such laying stock or reproduction stock may be boosted at about 16, at about 17,
at about 18, at about 19, or at about 20 weeks of age. The offspring of such laying stock or
reproduction stock may demonstrate an antibody titer to the administered immunogen(s), which
may prevent or mitigate the ms of an infection in the offspring.
The compositions of the present invention may be formulated according to methods
known and used in the art. A vaccine composition of the present invention may include salts,
buffers, preservatives, or other substances designed to improve or stabilize the composition. A
vaccine composition may include a pharmaceutically acceptable excipient or carrier. As used
herein, the term “pharmaceutically acceptable carrier” refers to a substance suitable for
administration to a human or other vertebrate animal. For administration, a composition as
described herein may be ly buffered if necessary and the composition rendered isotonic
with sufficient saline or glucose. In this connection, sterile aqueous media that can be employed
will be known to those of skill in the art. Moreover, for human stration, preparations
should meet sterility, pyrogenicity, and general safety and purity standards as ed by the
FDA. Such preparation may be pyrogen-free, may be sterile, and/or endotoxin-free.
A composition of the present invention may also n one or more stabilizers. Any
suitable stabilizer can be used including carbohydrates such as sorbitol, mannitol, starch, e,
dextrin, or e; proteins such as albumin or ; and buffers such as alkaline metal
phosphate and the like. A stabilizer is particularly advantageous when a dry vaccine preparation
is prepared by lyophilization. Such a composition may include pharmaceutically acceptable
carriers or diluents. Carriers include, for example, stabilizers, preservatives and buffers. Suitable
stabilizers include, for example, SPGA, ydrates (such as sorbitol, mannitol, starch,
sucrose, dextran, glutamate or glucose), proteins (such as dried milk serum, n or casein) or
degradation products thereof. Suitable buffers e, for example, alkali metal phosphates.
Suitable preservatives include, for example, thimerosal, merthiolate and gentamicin. ts,
include, but are not limited to, water, aqueous buffer (such as buffered saline), alcohols, and
s (such as ol).
Any of a wide variety of modulating agents may be included in the methods and
compositions described herein. As used herein, a "modulating agen " is an agent that has a
therapeutic effect on living tissue. Modulatory agents include, for example, therapeutic agents
which are effective to prevent and/or overcome disease and/or promote recovery.
The vaccine of the present ion may be administered to a subject by any ofmany
ent routes. For example, the e may be administered intravenously, intraperitonealy,
aneously, intranasally, orally, transdermally, and/or intramuscularly. Suitable dosing
s may be determined by taking into account factors well known in the art including, for
example, the age, weight, sex, and medical condition of the subject; the route of administration;
the desired effect; and the particular conjugate and formulation employed. The vaccine may be
administered as either a single does or multiple doses. When administered in a multi-dose
vaccination format, the timing of the doses may follow schedules known in the art. For
example, after an initial stration, one or more booster doses may subsequently me
administered to in antibody titers and/or immunologic memory.
The methods of the t invention may e in vitro, ex vivo, or in vivo methods.
As used herein “in vitro” is in cell culture and “in vivo” is within the body of a subject. With the
present invention, an isolated immunogen or agent may be delivered. As used herein, “isolated”
refers to material that has been either removed from its natural nment, produced using
recombinant techniques, or chemically or enzymatically synthesized, and thus is altered “by the
hand ofman” from its natural state.
The present invention includes kits employing one or more of the compositions bed
herein. Such kits may provide for the administration of an immunogen to a subject in order to
elicit an immune response. Kits of the present invention may include other reagents such as
buffers and solutions needed to ce the invention are also included. Optionally associated
with such container(s) can be a notice or printed instructions. As used herein, the phrase
“packaging material” refers to one or more al structures used to house the contents of the
kit. The packaging material is constructed by known methods, preferably to provide a sterile,
contaminant-free environment. As used herein, the term “package” refers to a solid matrix or
al such as glass, c, paper, foil, and the like, capable of holding within fixed limits a
polypeptide. Kits of the t invention may also e ctions for use. Instructions for
use typically include a tangible expression describing the reagent concentration or at least one
assay method parameter, such as the relative amounts of reagent and sample to be admixed,
maintenance time periods for reagent/sample admixtures, temperature, buffer ions, and the
like.
Unless otherwise indicated, all numbers expressing quantities of components, molecular
weights, and so forth used in the specification and claims are to be understood as being modified
in all instances by the term “about.” Accordingly, unless otherwise indicated to the contrary, the
numerical parameters set forth in the specification and claims are approximations that may vary
depending upon the desired properties sought to be obtained by the present ion. At the
very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims,
each numerical parameter should at least be construed in light of the number of reported
significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope
of the invention are approximations, the numerical values set forth in the specific examples are
reported as precisely as possible. All numerical values, however, inherently contain a range
necessarily resulting from the standard ion found in their respective testing measurements.
The ption exemplifies illustrative embodiments. In several places throughout the
application, guidance is provided through lists of examples, which examples can be used in
various combinations. In each instance, the recited list serves only as a entative group and
should not be reted as an ive list.
The present invention is illustrated by the following examples. It is to be understood that
the particular examples, als, amounts, and procedures are to be interpreted broadly in
accordance with the scope and spirit of the invention as set forth herein. All headings are for the
ience of the reader and should not be used to limit the g of the text that follows the
heading, unless so specified.
EXAMPLES
Example 1
New vaccination delivery regimen drives enhanced,
vaccine-specific immune ses
To enhance vaccine delivery over that seen when conventional delivery methods are
used, this example focused on providing antigen, plus or minus CpG adjuvant, along with a
component which is in liquid state at room temperature, but that forms a gel-depot under
physiological conditions, after ion at 35°C. This allows for the antigen and adjuvant to be
delivered in a concentrated form, enhancing antigen presenting cell activity, and leading to pro-
inflammatory, vaccine-specific responses. Recombinant hepatitis B antigen (rHepBag) was used
as the antigen for vaccination, and the delivery method evaluated along with seven different
vaccine delivery s for the ability to induce Hepatitis B specific antibodies and cytokines.
Mice were vaccinated with rHepBag in two different types of gel slurries (PURAMATRIX, also
referred to herein as “P1,” and MATRIGEL, also referred to herein as “P2”), or with rHepBag in
ALHYDROGEL (aluminum salt) or rHepBAg mixed with Complete Freund's adjuvant (CFA).
Gel slurries and ALHYDROGEL were mixed +/- with the murine CpG ODN 1826.
Results showed that mice vaccinated with either gel slurry plus ODN had significantly
higher TNF production 24 to 48 hours after primary ation, while P1 was significantly
superior to ALHYDROGEL at 24 hours. Adjuvant P2 presented a promising Th2 inhibition
after 48 hours with the reduction of IL-4, IL-5 and IL-10 levels coincident with increased
antigen-specific IgG2a production in serum.
The is of vaccine-specific dies showed that P1 drove high vaccine-specific
IgA, IgM and IgG titers 14 days post-prime with or without using ODN and the high IgA and
IgG titers was maintained for 35 days. As both of the gel slurry systems tested in this study was
superior to the conventional adjuvants, this new gel slurry vaccine delivery system will have
broad utility for enhancing responses to numerous current vaccines that are currently marginally
fianctional. The use of this new vaccine ry system will be further investigated in the
development of es for any of a wide variety of infectious diseases, fiom parasitic to viral
infection.
Material and Methods
Vaccines and Route of Administration. The experimental vaccine used in this study was
produced from a recombinant Hepatitis B antigen, , rHepBag (Fitzgerald Industries, Inc.
Massachusetts, USA). 90 6- to 8-week-old female BALB/c mice were evenly divided into 9
groups and respectively received a prime subcutaneous injection (sc) on the back and, a boost 4
weeks later, of 0.1 ml solution containing 5 ug of rHepBag, 0.1 ml of 50 ug ODN 1826
(InvivoGen, Inc. California, USA) with 5 ug of rHepBag, 0.4 ml solution of PURAMATRIX
(P1) and 5 ug of g with or without ODN 1826, 0.4 ml of MATRIGEL (P2) and 5 ug of
rHepBag with or without ODN 1826, 0.1 ml solution of 250 ug alum (Thermo Fisher Scientific,
Inc. Pennsylvania, USA) and 5 ug of g with or without ODN 1826 and, 0.1 ml of
te Freund's Adjuvant (Sigma-Aldrich Co. Missouri, USA) with 5 ug of rHepBag (1 :2).
To prepare one dose of the slurry, 5 ug of rHBsAg antigen, with or without prior mixing with 50
ug CpG, was brought to a final volume of 400 ul with MATRIGEL or PURAMATRIX and
mixed thoroughly before subcutaneous injection. Amounts were scaled up depending on the
number of doses needed. MATRIGEL and PURAMATRIX were sed from BD (Franklin
Lakes, NJ).
Cytokines and antibody evaluation. Splenocytes were isolated one week after boost for
cytolcines evaluation. Single cell suspensions (1.5 10 6/ml) were prepared and suspended in
1640 medium (RPMI 1640 Thermo Scientific Hyclone, Utah, USA) with penicillin—streptomycin
(final trations of 100 U/ml and 100 ug/ml respectively) (Sigma—Aldrich. St. Louis, MO,
USA). 0.5 ml ofthe single cell suspension was added to 48—well plates (Sigma-Aldrich. St.
Louis, MO, USA) with 0.5 ml ofmedia, 0.5 ml of l rig/ml of Concanavalin A (ConA) or 0.5 ml
of 5 rig/ml ofrHepBag and cultured at 37°C with 5% C02. The levels ofTNF were quantified
after 24 and 48 hours culture, IL~4 and IL-5 after 48 hours, IL—4 and lL-lO after 72 hours, each in
triplicate. The percentages of cytokine-positive mice were finther transformed using a two—step
platform that consisted of (l) to calculate the global median for each cytokine considering the
whole range of values obtained for each group; and (2) to establish for each group the concept of
'low' and 'high'—cytokine producers using the global median percentage of cytokine—positive cells
as the cut-off edge to ate the individuals into two categories named as 'low’ and 'high'—
cytokine ers. It is important to highlight that the overall cytokine profile for each group
was constructed by giving the same weight to all cytokines and producing cell populations.
IFN gamma ELISpot was also performed with 3 X 105 and 1.5 x 105 splenocytes after 24
hours of culture, as described by the manufacturer (BD Biosciences (San Francisco, CA, USA)
using 1 rig/ml of ConA as positive control. The orming unit (SFU) value was expressed as
mean ofthe triplicate cultures minus the mean value of its individual background.
Blood samples from mice were collected weekly from 1 to 6 weeks, including the day
prior to the primary zation. Sera collected from these bleeds were used in ULISA assays
for the detection and quantification of antibodies.
Synthetic Peptides for T—cell analysis for flow cytometry. Synthetic peptides Were
synthesized by Biosynthesis, Inc, and were ed based on relevant literature. The S 228—39
peptide (IPQSLDSWWTSL; SEQ ID NO:6) is H2~Ld—restricted and the dominant e in
Balb/c mice. The splenocytes from five mice per group were individually ated with 5 uM
peptide and 40 U/ml IL-2 for flow cytometry.
Statistical analyses. For antibody evaluation, comparisons were ed by Mann—
Whitney or t's t test using ad PRISM software, version 4.0 (GraphPad Software,
California, USA), after Kolmogorov-Smimov normality test. A difference was considered as
statistically significant when a P-value was 5 0.05. Chi squared-test was used for comparisons
of 'low' and 'high'-cytokine producers frequencies among groups and cance considered at P
S 0.05. Comparison of radar graphs axes and polygon areas were considered significant for
ratios two times lower in magnitude. Data is for the results presented in the radar chart
format was performed by ing the central polygon areas among cytokine-producers
categories intra and inter . Significant differences were considered for ratios indicating
axes and polygon areas two times lower or higher in size.
Results
Initial results showed mice vaccinated with either gel slurry plus Cst had significantly
higher vaccine-specific IgG2a 14 days after the prime, and IgA, IgM at 28 days post inoculation
than mice vaccinated with alum or CFA. One gel slurry delivery drove significantly higher
vaccine-specific IgG titers 14 days post-prime than the other delivery methods did oost,
suggesting that the boost was unnecessary. Recall assays showed upregulated IL-lO and IL-4
from cytes of mice vaccinated with OGEL or CFA compared to cells from gel-
slurry + CpG vaccinated mice. CpG use reduced levels of IL-5 to background in all groups
compared to elevated levels in CFA. No ences in levels of IFN or TNF were seen.
Figure 1 shows the kinetics of IgA anti-HBsAg antibody titers. Data shown is pooled
from two independent experiments for total n=l 0.
Figure 2 shows the kinetics of IgM anti-HBsAg antibody titers. Data shown is pooled
from two independent experiments for total n=l 0.
Figure 3 shows the kinetics of IgG anti-HBsAg antibody titers. Data shown is pooled
from two independent experiments for total n=l 0.
Figure 4 shows the kinetics of IgG1 anti-HBsAg antibody titers. Data shown is pooled
from two independent experiments for total n=l 0.
Figure 5 shows the kinetics of Inga anti-HBsAg antibody . Data shown is pooled
from two independent experiments for total n=l 0.
Figure 6 shows higher anti-HBsAg antibody titers after single vaccination (21 days).
Data shown is pooled from two independent experiments for total n=lO; 5, **p<0.0l,
**p<0.00l, ****p<0.0001 compared to n alone using two-way ANOVA with Bonferroni
post-test.
Figure 7 shows higher anti-HBsAg antibody titers after single vaccination (35 days).
Data shown is pooled fiom two ndent ments for total n=lO; *p<0.05 compared to
antigen alone using two-way ANOVA with Bonferroni post-test.
Figure 8 shows cytokine profile twenty-four hours after HBsAg re-stimulation of
splenocytes. Data shown is representative of one experiment, n=5; *p<0.05, ****p<0.0001
compared to antigen alone using two-way ANOVA with Bonferroni post-test.
Figure 9 shows ne profile forty-eight hours after HBsAg mulation of
splenocytes. Data shown is pooled from two independent experiments for total n=lO (n=5 for
adjuvants only); no statistical differences seen (p<0.05) compared to antigen alone using two-
way ANOVA with Bonferroni post-test.
Figure 10 shows cytokine profile seventy-two hours after HBsAg re-stimulation of
splenocytes. Data shown is pooled from two independent experiments for total n=lO (n=5 for
adjuvants only); 0l compared to antigen alone using two-way ANOVA with Bonferroni
post-test.
Figure ll shows increased HBsAg-specific cell-mediated immunity by ELISpot in
specific T cell responses. Data shown is pooled from two independent experiments for
total n=lO; *p<0.05 compared to antigen alone using two-way ANOVA with Bonferroni post-
test.
Figure 12 shows increased HBsAg-specific T cell-mediated immunity by flow cytometry.
Data shown is pooled from two independent experiments for total n=lO; **p<0.0l compared to
antigen alone using two-way ANOVA with Bonferroni post-test.
Increase of cytokines secretion by splenocytes with stimulation of rHepBag. In order to
measure the cellular immune response induced by the vaccines, mice were sacrificed one week
after boost and splenocytes were ed with or without 5 ug/ml final concentration of
rHepBag. nes levels were measured by ELISA. The concept of low and high ers
was applied to igate a broader range of cytokines and assess ex vivo cytokine profiles of
circulating ytes. For this purpose, the global median for each cytokine-positive cell subset
was calculated, taking the whole range of values obtained for each group, as described elsewhere
(Vitelli-Avelar et al., 2008, Scand J Immunol; 68(5):5 16-25). The global median percentage of
each cytokine-positive cell population was used as the cut-off edge to segregate the individuals
into two categories named 'low' and 'high'-cytokine producers, as shown in Table l.
The data demonstrated that none of the mice inoculated with ODN 1826 showed TNF
production in 24 hours, but when ODN 1826 was associated with adjuvants P1 or P2, a
significant proportion of mice displayed values of TNF above the cut-off edge, as shown in Fig.
13 (P < 0.011). gh ALHYDROGEL, when associated or not to ODN 1826, induced a
significant amount of 'high'-TNF producers, all of the mice inoculated with adjuvant Pl without
CpG displayed values above the cut-off, and this value was cantly higher than all
Alhydrogel groups (P < 0.001). This same result was not observed after 48 hours when
adjuvants Pl, P2, ALHYDROGEL and Freund showed a comparable number of 'high'-TNF
ers (Fig. 14A and 14B) (P < 0.001).
Moreover, interesting data was found for IL-4 and IL-5 production after 48 hours when
most of the mice immunized with adjuvant P2 fell into a region of 'low'-IL-4 and IL-5 producers
(P < 0.05). Differently, most of the mice inoculated with adjuvant Pl presented a high
production of both cytokines (P < 0.002). As shown in Fig. 15, the adjuvant Pl continued to
present 'high'-IL-4 ers after 72 hours, in association or not with ODN 1826 and this same
result was found after ALHYDROGEL or Freund immunization (P < 0.001). Also, the data
demonstrated that most of the mice previously zed with adjuvant P2 or adjuvant P2 plus
ODN l826 displayed values of IL-lO below the cut-off edge, cantly lower than mice
immunized with rHepBag, associated or not to ODN 1826 (P < 0.05).
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Sustained humoral response in mice vaccinated with rHepBag and adjuvants Pl and P2.
Sera were collected weekly before and after zation to test c isotypes antibody titer
by ELISA. Mice vaccinated with both adjuvants Pl and P2 developed an anti-rHepBag IgG
antibody in 2 weeks after prime inoculation (P < 0.002). The highest anti-rHepBag antibody
titers were reached in mice vaccinated with Pl associated or not to ODN, and these responses
were significantly greater than immunization with ODN, Alum or Freund's adjuvants (P <
0.001). The IgGl :IgG2a ratio elicited in vivo represents different patterns for both adjuvants.
Adjuvant Pl drives to a Th2 response with high levels of IgGl in 14 to 35 days post-prime
inoculation. Whereas, the response elicited by P2 plus ODN is a mixed system rather than a pure
Thl or Th2 response, wherein the IgGl and IgG2a levels were upregulated during all the
ne. See Fig. l7A-l7D.
The combination of adjuvant Pl +/- ODN d the upregulation of IgA and IgM titers
as soon as 14 days post-prime inoculation and this humoral response was maintained until 35 and
21 days, respectively (P < 0.04). This adjuvant was superior to Freund's during 14 and 35 days
and to ALHYDROGEL for the first 3 weeks for the production of IgA, IgM and IgG (P < 0.02).
Additionally, both adjuvants Pl and P2 demonstrated to be superior to Freund's adjuvant for the
production of all Ig after boost (P < 0.02). See Figs.l6A-l6D.
Discussion
This e showed that mice ated with either a Pl or P2 gel slurry plus ODN
had significantly higher TNF tion 24 to 48 hours after primary inoculation, while Pl was
significantly superior to ALHYDROGEL at 24 hours. nt P2 presented a promising Th2
inhibition after 48 hours with the reduction of IL-4, IL-5 and IL-lO levels coincident with
increased antigen-specific IgG2a production in serum.
The analysis of vaccine-specific antibodies showed that Pl drove high vaccine-specific
IgA, IgM and IgG titers 14 days post-prime with or without using ODN and the high IgA and
IgG titers was maintained for 35 days. As both of the gel slurry s tested in this study were
superior to the conventional adjuvants, this new gel slurry e delivery system will have
broad utility for enhancing responses to numerous current vaccines that are currently marginally
fianctional. The use of this new vaccine ry system will be r investigated in the
development of vaccines for any kind of infectious diseases, from parasitic to viral infection.
Example 2
Influenza Vaccination
Following methods described in more detail in the previous examples, C57/BL and
Balb/c mice were immunized with the recombinant nucleoprotein (rNP) influenza virus antigen
administered with alum, CpG, or a slurry of PURAMATRIX and CpG. To e one dose of
the slurry, 10 ug rNP antigen, with or without prior mixing with 50 ug CpG, was t to a
final volume of 200 ul with PURAMATRIX and mixed thoroughly before subcutaneous
injection. Amounts were scaled up depending on the number of doses needed. As shown in Fig.
18B, anti-influenza IgG titers were increased Balb/c mice vaccinated with rNP administered as a
slurry with PURAMATRIX and CpG, as compared to mice vaccinated with rNP administered
with the adjuvant alum or CpG. Fig. 18A shows anti-influenza IgG titers in C57BL/6 mice.
Anti-influenza IgG titers were determined four weeks post-last vaccination (wplv).
Again, ing methods described in more detail in the previous examples, C57Bl/6
mice were immunized with whole inactivated influenza A virus (HlNl) strain PR8 administered
with alum, as a PURAMATRIX slurry, or as a slurry ofPURAMATRIX and CpG. As a control,
additional mice were zed with PR8 whole inactivated virus (WIV) only. To prepare one
dose of the , 15 ug of PR8 antigen, with or without prior mixing with 50 ug CpG, was
brought to a final volume of 200 ul with PURAMATRIX and mixed thoroughly before
subcutaneous injection. Amounts were scaled up ing on the number of doses needed.
PR8 (WIV) is formalin-inactivated influenza /34 (HlNl) from Charles River rNP is
inant human Influenza A (A/PlV8/34/Mount Sinai (HlNl) segment 5) nuclear protein NP
from Imgenex.
As shown in Fig. 19, serum anti-influenza IgG titers were increased in C57Bl/6 mice
vaccinated with PR8 WIV administered with as a slurry of PURAMATRIX and CpG, as
compared to mice vaccinated with PR8 WIV administered with the adjuvant alum or as a slurry
with PURAMATRIX alone, without CpG. Anti-influenza IgG titers were determined four weeks
post-last vaccination (wplv). Fig. 19 shows results from two independent experiments.
As show in Fig. 20, enhanced tion from lethal challenge was observed in C57Bl/6
mice vaccinated with PR8 WIV. Fig. 20A shows results from an ndent experiment with
lethal challenge at 30 LD50 and Fig. 20B shows results from an independent experiment with
lethal nge at 1000 LD50.
Example 3
Burkholderia Vaccination
Following methods described in more detail in the previous e, mice were
immunized with a cocktail of three different burkholderia recombinant ns (burkholderia 4-
9 protein, the burkholderia 22-ll protein, and the burkholderia 42 protein) administered with one
of three ent adjuvants preparation, alum, Complete Freund’s Adjuvant (CFA), or slurry of
PURAMATRIX and CpG. To prepare one dose of the PURAMATRIX + CpG slurry, 75 ug of
Burkholderia proteins antigen, with or without prior mixing with 50 ug CpG, was brought to a
final volume of 200 ul PURAMATRIX and mixed thoroughly before subcutaneous injection.
s were scaled up ing on the number of doses needed. As controls, additional mice
were immunized with alum only, CFA only, or PURAMATRIX + CpG slurry, without antigen.
The Burkholderz’a (previously part ofPseudomonas) genus name refers to a group of
virtually tous gram-negative, motile, obligatory aerobic rod-shaped bacteria including both
animal/human and plant pathogens as well as some environmentally important species.
Burkholderia is best known for its pathogenic members. Burkholderz’a mallez' is responsible for
rs, a disease that occurs mostly in horses and related animals. Burkholderia pseudomallei
is the causative agent of dosis (also called re's disease), an infectious disease
predominately of tropical climates that can infect humans or animals, especially in Southeast
Asia and northern Australia. Burkholderz’a cepacz’a is an important pathogen of pulmonary
infections in people with cystic fibrosis. Due to their otic ance and the high mortality
rate from their associated diseases Burkholderz’a mallez' and Burkholderia pseudomallei are
considered to be potential biological warfare agents, targeting livestock and humans.
Fig. 21 shows anti-burkholderia IgG titers in mice immunized with a cocktail of three
burkholderia recombinant proteins (burkholderia 4-9 protein, the burkholderia 22-ll protein, and
the burkholderia 42 protein). Fig. 21B shows anti-burkholderia protein 4-9 IgG titers in
immunized mice. Fig. 21A shows anti-burkholderia protein 22-ll IgG titers in immunized mice.
Fig. 21C shows anti-burkholderia protein 42 IgG titers in zed mice. Antibody titers after
immunization with alum only, alum + protein cocktail, complete Freund’s adjuvant (CFA) only,
CFA + protein cocktail, TRIX + CpG slurry only, and PURAMATRIX gel + protein
il are shown. An increased immune response as ed by specific serum antibody
levels were observed against two of the three proteins administered as a gel vaccine ition
with puramatrix compared with vaccination with alum or CFA. Specifically, increased anti-
burkholderia IgG titers were observed t the burkholderia 4-9 protein (Fig. 21B) and the
burkholderia 22-11 protein (Fig. ZlAB) when administered as a gel vaccine with
PURAMATRIX, compared with vaccination with alum or CFA. Challenge data is being
Example 4
Veterinary Vaccines
ing procedures described in more detail in the previous examples, the present
invention may be used with any of a variety of veterinary vaccines. The vaccine compositions,
delivery methods, and delivery system of the present invention will provide many advantages
and better value for the commercial livestock ry, ing, but not limited to, improved
efficacy, delivery early in the production cycle, and efficacy with the administration of only a
single dose to provide protection throughout the production cycle.
The compositions, delivery methods, and delivery systems of the present invention may
be used in the zation of swine. Vaccines that may be administered to swine using the
compositions, methods and systems of the present invention include, but are not limited to,
porcine circovirus type 2 (PCV2) vaccine, porcine reproductive and respiratory syndrome
(PRRSV), respiratory mycoplasma vaccine, Streptococcus suis vaccine, porcine coronavirus
vaccine, rotavirus vaccine, enterotoxigenic Escherichia coli (K88) vaccine, bacz'llus
pleurapneumom’a (APP) vaccine, and swine influenza vaccine. See, for example, the world wide
web at merck—animal—health.com/s ecies/ igsx’vaccinesas x, “Vaccinations for the Swine Herd,”
Alabama Cooperative Extension System Publication 2, Alabama A&M and Auburn
Universities (available on the world wide web at aces.edu/pubs/docs/A/ANR-0902/ ANR-
0902.pdf), and “Pig vaccination ms,” PRIME FACT publication 944, September 2009
(available on the world wide web at dpi.nsw.gov.au/_data/assets/pdf_file/0009 /301500/Pig-
vaccination-programs.pdf) for more detailed information on available vaccines and the
administration of such vaccines to swine.
The compositions, delivery methods, and delivery s of the present invention may
be used in the immunization of bovine, including, but not limited to, domestic cattle, water
buffalo, African buffalo, bison, and yaks. Vaccines that may be administered to bovines, using
the compositions, methods and s of the present invention include, but are not limited to,
bovine respiratory disease (BRD) vaccine, including, but not limited to BVDV types I and 11,
bovine herpes virus 1 (BHV-l) vaccine, including, but not limited to, subunit vaccines that
would not result in latent virus, Haemophilus somnus vaccine, Mannheimia haemolytica vaccine,
Mycoplasma bovis vaccine, bovine rus vaccine, Escherichia coli K99 vaccine, bovine
coronavirus (BCV) e, Clostridium chauvoei (black leg) vaccine, Clostridium septicum
vaccine, Clostridium sordelli (malignant edema) vaccine, Clostridium novyi (black disease)
vaccine, Clostridium perfringens (enterotoxemia) vaccine, ious bovine keratoconjunctivitis
(pink eye) vaccine, including, but not limited to, Moraxella bovis, chlamydia, mycoplasma,
acholeplasma, or infectious bovine rhinotracheitis (1BR) virus vaccines, mastitis vaccines,
including, but not limited to, Escherichia coli J5 e.
In some applications, the compositions, delivery s, and ry systems of the
present invention may be used for the administration of one or more schistosomiasis antigens to
a bovoid. Such a schistosome n may be derived from, for example, Schistosoma
japonicum, Schistosoma monsoni, or Schistosoma haematobium. A schistosome antigen may be
a schistosome triose phosphate isomerase (CTPI) protein, or nic nt or derivative
thereof, including, but not limited to a S. japonicum, S. monsoni, or S. haematobium CTPI
protein, or antigenic fragment or derivative thereof. A schistosome antigen may be a
schistosome tetraspin 23 kDa integral membrane protein (C23), or antigenic fragment or
derivative thereof, including, but not limited to a S. japonicum, S. monsoni, or S. haematobium
C23 protein, or antigenic fragment or tive thereof Such a schistosome antigen may be a
chimeric polypeptide, fiased to one or more onal antigenic determinants, such as for
example, a heat shock n, or antigenic fragment or tive thereof, including, but not
limited to, bovine heat shock protein 70 (Hsp70).
See, for example, “Beef Cattle Herd Health Vaccination le” Powell et al.,
sity of Arkansas, Division of lture, Agriculture and Natural Resources publication
FSA3009 (available on the world wide web at uaex.edu/Other_Areas/publications/PDF/FSA-
3009.pdf), “How to ate,” ma Cooperative Extension Service, Division of
Agricultural Sciences and Natural Resources, Publication No. 350 (available on the world wide
web at ansci.colostate.edu/pdf_files/YLE/Dairy7_vaccinate.pdf), and “Cattle Vaccines and Their
Use,” Beef Cattle Handbook publication BCH-3015 (available on the world wide web at
iowabeefcenter.org/Beef%20Cattle%20Handbook/Vaccines_Cattle.pdf) for more detailed
information on available vaccines and the stration of such vaccines to cattle.
The vaccine compositions, delivery methods, and delivery system of the present
invention may also be used in the vaccination of companion animals, including, but not limited
to cats and dogs, such as, for example, for the immunization of dogs with irus vaccine for
transfer of maternal immunity.
Routes of administration include, but are not limited to, subcutaneous (sc) or
intramuscular (im) ion. Vaccination with the composition, methods, and ry systems
of the present invention will yield rapid, longer g protection after administration of a single
dose.
Example 5
Poultry Vaccines
ing procedures described in more detail in the previous examples, the present
invention may be used as a delivery system for any of a variety of poultry vaccines, including,
but not limited to, vaccines for infectious bronchitis (1B), Newcastle disease (ND), Marek’s
diseases, infectious bursal disease (IBD) virus, infectious laryngotracheitis (1LT), avian
reovirus, cholera, fowl pox, asmosis, turkey and n Coryza, avian influenza, avian
encephalomyelitis (AE), avian rhinotracheitis (ART), duck virus hepatitis, haemorrhagic
enteritis, goose parvovirus, Paramyxovirus 3, chicken anaemia virus (CAV), E. coli, Erysipelas,
Reimerella, asma galliseptz'cam, Pastearella maltocz'da, Salmonella enteritidis,
Salmonella typhz'marz’am, and coccidiosis.
Routes of administration include, but are not limited to, subcutaneous (sc) or
intramuscular (im) injection. With subcutaneous ion, vaccine is injected into the space
between the skin and underlying tissues. Typically the site of application used in poultry in the
loose skin at the back of the neck. With intramuscular injection, the vaccine preparation is
deposited within a mass of muscle. Typically, either the breast muscle or the thigh muscle is
used for this purpose. Vaccination may include the vaccination of day old hatchlings, s,
layers, breeders, broilers, and/or show birds. lly layers and breeders get vaccinated prior
to the laying , and then every 6 to 8 weeks with inactivated vaccines during the laying
period. This not only protects them from disease but passes on maternal antibodies to the
progeny. Poultry that may be vaccinated include, but are not limited to, chickens, turkeys, and
waterfowl, such as, for example, ducks and geese.
Example 6
Schistosomiasis Immunization
Mice were immunized with the schistosome protein antigen CCA in either complete
Freund’s adjuvant or in MATRIGEL plus Cst. Anti-CCA IgG antibody titers were ined
by ELISA The data is shown in Fig. 22A (CCA in complete Freund’s adjuvant) and Fig. 22B
(CCA in EL plus Cst). Two mice were immunized for each n preparation.
Sera samples were collected at 0, 8, l6, and 19 days post immunization for mice immunized with
CCA in te ’s adjuvant and at 0, 8, 16, 24, 32, and 40 days post immunization for
mice immunized with CCA in MATRIGEL plus Cst. The ELISA data clearly shows higher
titers of CCA specific antibodies in mice immunized with MATRIGEL plus Cst.
Example 7
Schistosomiasis Vaccination of Water Buffalo
Schistosomiasis is a parasitic disease affecting more than 200 million people worldwide.
Reassessment of schistosomiasis-related disability, combined with recent ation on the
global prevalence of schistosome infection indicates that the true burden of osomiasis is
substantially greater than previously appreciated. In Asia, ularly China, the causative agent
is Schistosomajaponicum. Unlike the African species, S. mansoni and S. haematobium, S.
japom'cum is a zoonotic parasite, with bovines, particularly water buffaloes accounting for about
75% of schistosome transmission to humans in China. Interventions that reduce schistosome
infection in water buffaloes will enhance their health simultaneously reducing disease
transmission to humans. Current control programs in many areas of China include simultaneous
uantel (PZQ) ent of humans and water buffaloes; while this has shown a reduction in
the overall prevalence, it requires continued mass ents that are both time consuming and
expensive. A more sustainable option would be development of a vaccine which reduces
transmission of S. japanicum from bovines to replace bovine herapy. Indeed
mathematical modeling (Williams et al., 2002, Acta Trap; 82(2):253-262) has demonstrated that
reducing S. japanicum infection in bovine reservoirs using prophylactic es with 45%
cy alone or in combination with PZQ should over time reduce the equilibrium prevalence
and potentially lead to long-term sustainable control of osomiasis. This two-pronged base
intervention would significantly reduce ission of schistosomiasis for the long term,
increase bovine health and growth and would likely reduce l ity in village
populations. See Da’Dara et al., 2008, Vaccine; 26(29-30):36l7-3625, which is herein
incorporated by reference in its entirety.
Antigen-PURAMATRIX compositions as described herein will be used to immunize
livestock with S. japonicum antigens. For these trials, all animals will be given a primary
vaccination with a SjCTPI-Hsp70 plasmid DNA vaccine (as described in more detail in Da’Dara
et al., 2008, Vaccine; 26(29-30):36l7-3625). Water buffalo will be boosted with a composition
of recombinant SjCTPI protein, PURAMATRIX and bovine CpG. Specifically, 100 ug of
recombinant SjCTPI plus bovine CpG will be mixed in PURAMATRIX for a total injection
volume of approximately 0.50 ml/animal. This will be injected into the shoulder of buffalo/and
cattle. Only a single booster vaccination will be stered to an .
The elicitation of a l and cellular immune responses, including anti-SjCTPI IgG
antibody response, will be determined. After boosting, animals will be challenged were
challenged with cercariae and vaccine efficacy determined by measuring the reduction in the
number of eggs per gram feces, reduction in eggs in liver tissues, reduction in miracidial
hatching, and reduction in worm burden. Methods for these determinations are described in
more detail in a et al., 2008, Vaccine; 26(29-30):36l7-3625.
A first trial in the pines is already in Year 2 in the Philippines, with 400 water
buffalo or cattle having been boosted, as described above. A second trial in Samar, Philippines,
will include 1500 water buffalo or cattle. A third trail in China will include 600 water buffalo or
cattle.
Immunization of water buffalo and cattle with compositions of schistosome polypeptides,
such as for e, SjCTPI, SjCTPI-Hsp70, SjC23, or SjC23-Hsp70 polypeptides, in a
puramatrix composition, with or t adjuvants, such as for example, CpG or IL-l2, may
serve as the basis for new control programs for schistosomiasis in Asia. Such a program, in
addition to treatment with uantel (PZQ), would include vaccination of water buffaloes with
partially protective vaccines such SjC23-Hsp70 and SjCTPI-Hsp70 as a means to reduce
numbers of egg-laying parasites in ock, g to measurable declines in prevalence,
intensity and transmission of S. japom'cum.
The complete disclosure of all patents, patent applications, and publications, and
electronically available material (including, for instance, nucleotide sequence submissions in,
e. g., GenBank and RefSeq, and amino acid sequence submissions in, e.g., rot, PIR, PRF,
PDB, and translations from annotated coding regions in GenBank and RefSeq) cited herein are
incorporated by reference. In the event that any inconsistency exists between the disclosure of
the present application and the disclosure(s) of any document incorporated herein by reference,
the sure of the present ation shall govern. The foregoing detailed description and
examples have been given for clarity of understanding only. No unnecessary limitations are to
be tood therefrom. The ion is not limited to the exact details shown and described,
for variations obvious to one skilled in the art will be included within the invention defined by
the . All headings are for the convenience of the reader and should not be used to limit the
meaning of the text that follows the heading, unless so specified.
Claims
Claims (31)
1. A composition comprising: a self assembling peptide that forms a stable hydrogel at physiological salt concentrations; 10 an adjuvant, wherein the adjuvant comprises a Toll-Like Receptor (TLR) agonist; and one or more antigens.
2. The composition of claim 1, wherein the self assembling peptide is selected from the group consisting of RADARADARADARADA (SEQ ID NO:2), RA16-II (SEQ ID NO:3), 15 KFE-8 (SEQ ID NO:4), and KLD-12 (SEQ ID NO:5).
3. The composition of claim 2, wherein the self assembling peptide comprises RADARADARADARADA (SEQ ID NO:2). 20
4. The composition of any one of claims 1 to 3, wherein the antigen comprises a bacterial antigen, a viral n, a parasitic antigen, a toxin, and/or an anti-tumor vaccine component.
5. The composition of any one of claims 1 to 4, wherein the TLR agonist comprises a TLR4 and/or TLR9 agonist.
6. The composition of claim 5, n the TLR9 agonist comprises a CpG oligodeoxynucleotide (ODN).
7. The ition of any one of claims 1 to 6, wherein the n comprises a tis 30 antigen, an influenza antigen, a schistosomiasis antigen, and/or a lderia antigen, or an antigenic fragment thereof.
8. Use of a ition of any one of claims 1 to 7 in the manufacture of a ment for producing an immune response in a subject.
9. Use of a ition of any one of claims 1 to 7 in the manufacture of a medicament for 5 immunizing a subject.
10. Use of a composition of any one of claims 1 to 7 in the manufacture of a medicament for treating a subject with one or more immunogenic antigens. 10
11. Use of a composition of any one of claims 1 to 7 in the manufacture of a medicament for treating a subject with one or more therapeutic antigens.
12. A method of delivering one or more immunogenic antigens to domestic livestock or a companion animal, the method sing administering a composition of any one of claims 1 to 15 7 to the domestic livestock or the companion animal.
13. A method of delivering one or more immunogenic antigens to poultry, the method comprising administering a composition of any one of claims 1 to 7 to the poultry. 20
14. Use of a composition of any one of claims 1 to 7 in the manufacture of a medicament for treatment involving subcutaneous (sc) injection and/or uscular (im) injection.
15. Use of a composition of any one of claims 1 to 7 in the manufacture of a medicament for a primary and/or booster ation.
16. Use of a composition of any one of claims 1 to 7 in the manufacture of a medicament for a booster vaccination.
17. Use of a composition of any one of claims 1 to 7 in the manufacture of a medicament for 30 a booster vaccination after a primary vaccination with a polypeptide vaccine or a d DNA vaccine.
18. A method of producing an anti-schistosome immune response in a bovoid, the method comprising stering a composition of any one of claims 1 to 10 to the bovoid, wherein one or more antigen comprises a schistosome antigen.
19. A method of osomiasis vaccination in a , the method comprising administering a composition of any one of claims 1 to 10 to the bovoid, wherein the one or more antigen ses a schistosome antigen. 10
20. The method of any one of claims 18 or 19, wherein the composition further comprises one or more adjuvants.
21. The method of any one of claims 18 to 20, wherein the composition further ses a Toll-Like Receptor (TLR) agonist and/or a cytokine.
22. The method of claim 21, wherein the TLR agonist comprises a TLR4 and/or TLR9 agonist.
23. The method of claim 22, wherein the TLR9 agonist comprises a CpG 20 oligodeoxynucleotide (ODN).
24. The method of claim 23, wherein the CpG ODN comprises bovine CpG.
25. The method of any one of claims 20 to 24, n the adjuvant comprises IL-12.
26. The method of any one of claims 18 to 25, wherein the schistosome antigen comprises a Schistosoma japonicum antigen, or an antigenic fragment thereof.
27. The method of any one of claims 18 to 26, wherein the schistosome antigen comprises a 30 SjCTPI polypeptide, a SjCTPI-Hsp70 polypeptide, a SjC23 polypeptide, and/or a SjC23-Hsp70 polypeptide, or an antigenic fragment thereof.
28. The method of any one of claims 18 to 27, wherein administration of the composition comprises a primary and/or a booster vaccination. 5
29. The method of any one of claims 18 to 28, wherein administration of the composition comprises a r administered after a primary vaccination with a SjCTPI-Hsp70 plasmid DNA vaccine.
30. The method of any one of claims 18 to 29, r comprising the administration of one 10 or more anti-schistosome chemotherapeutic agents.
31. The method of any one of claims 18 to 30, demonstrating at least 45% efficacy in the prevention of infection with a osome parasite.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161476431P | 2011-04-18 | 2011-04-18 | |
US61/476,431 | 2011-04-18 | ||
PCT/US2012/034012 WO2012145355A1 (en) | 2011-04-18 | 2012-04-18 | Vaccine delivery method |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ616804A NZ616804A (en) | 2015-12-24 |
NZ616804B2 true NZ616804B2 (en) | 2016-03-30 |
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