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Infection and Immunity, December 2000, p. 7212-7213, Vol. 68, No. 12
0019-9567/00/$04.00+0
LETTERS TO THE EDITOR
Outer Surface Protein A and Arthritis in Hamsters
 |
LETTER |
In the February issue of Infection and Immunity, Croke et al.
(1) report that hamsters vaccinated with recombinant OspA (rOspA) following infection with Borrelia burgdorferi
develop inflammatory arthritis. The authors suggest that these reports are important because an rOspA vaccine was approved by the Food and
Drug Administration for use in humans.
We vigorously disagree that the findings of Croke et al. have
implications for potential vaccinees on the basis of the study design,
methodologies, and the lack of confirmation that this model is
predictive and applicable to humans.
In the study, hamsters (weighing 
150 g) were administered one, two,
or four times the human adult recommended dose. The formulation of the
OspA vaccine administered to the hamsters was different (nonlipidated, fused to a carrier protein, and adsorbed to a
different aluminum hydroxide preparation) than the currently marketed
SmithKline Beecham (SB) product, LYMErix [Lyme disease vaccine
(recombinant OspA)]. The hamsters were infected with
107 organisms, which is 10-fold higher than that stated in
the Discussion section and three logs higher than that required to
repeatedly induce infection in our laboratory. In some cases it was
apparently necessary to reinoculate the hamsters, introducing yet
another variable.
Table 1 is misleading in its statement that no nonvaccinated hamster
developed arthritis; in footnote b to Table 1, Results, and
Fig. 1, it is stated that an unknown percentage of the
nonvaccinated, challenged animals developed arthritis. Since the
control hamsters developed arthritis, the induction of inflammatory
arthritis is therefore independent of vaccination status. In
addition, if this were an immune response-mediated arthritis, one would
expect systemic involvement including other joints,
which the authors have not demonstrated. The data do not support an
autoimmune process, but even if cross-reactivity were noted in
hamsters, extrapolation to other species should not be assumed due to
protein differences. Inexplicably, the animals that received the
highest dose of OspA had the lowest percentage of swelling among
vaccinees. The statistical evaluation of the swelling is based on the
gross morphologic size and not on a validated microscopic pathological
scale. Due to the small sample sizes (n = 4), no
definite conclusion regarding the differences can be ascertained.
The same laboratory has also reported the induction of arthritis
due to infection with B. burgdorferi alone using the same strain of hamsters (2). Induction of arthritis may be a
species-specific effect since these changes cannot be reliably produced
in other species, including other rodents, dogs, and monkeys.
Available human data contradicts the authors' results. In the pivotal
efficacy trial involving about 11,000 subjects, an outside, independent
data safety monitoring board (DSMB) reviewed the safety data and found
no evidence of an association between LYMErix and autoimmune arthritis.
Moreover, neither the independent DSMB nor SB found evidence of a
higher incidence of arthritis among the recipients of LYMErix than
among the recipients of a placebo. No evidence of an association
between vaccination with LYMErix and inflammatory arthritis has been
found in any of SB's other clinical trials. Since launch, over
1,000,000 doses of LYMErix have been distributed and no unusual
patterns of adverse events have been noted in postmarketing surveillance.
The study by Croke et al. demonstrates that challenging a specific
strain of hamsters with an overwhelming number of organisms induces
local synovial inflammation, independent of vaccination status. We
believe that the data obtained from the model cannot be extrapolated to
humans and that there are currently no data to support the authors'
contention that these results have implications for vaccinees.
| |
FOOTNOTES |
*
Present address: Musculoskeletal, Clinical
Affairs, Global Medical Affairs Department, Wyeth-Ayerst
Pharmaceuticals, 555 E. Lancaster Ave., St. Davids, PA 19087. Phone: (610) 971-4172. Fax: (610) 995-4698. E-mail:
Parenti{at}labs.wyeth.com.
| |
REFERENCES |
| 1.
|
Croke, C. L.,
E. L. Munson,
S. D. Lovrich,
J. A. Christopherson,
M. C. Remington,
D. M. England,
S. M. Callister, and R. F. Schell.
2000.
Occurrence of severe destructive Lyme arthritis in hamsters vaccinated with outer surface protein A and challenged with Borrelia burgdorferi.
Infect. Immun.
68:658-663[Abstract/Free Full Text].
|
| 2.
|
Lim, L. C. L.,
D. M. England,
B. K. DuChateau,
N. J. Glowacki,
J. R. Creson,
S. D. Lovrich,
S. M. Callister,
D. A. Jobe, and R. F. Schell.
1994.
Development of destructive arthritis in vaccinated hamsters challenged with Borrelia burgdorferi.
Infect. Immun.
62:2825-2833[Abstract/Free Full Text].
|
| | | | |
Dennis L. Parenti*
Adult Vaccines
Clinical Research & Development and
Medical Affairs, N.A.
SmithKline Beecham
1250 S. Collegeville Road
Collegeville, Pennsylvania 19476
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| |
AUTHORS' REPLY |
There is considerable indirect evidence that outer surface protein
(Osp)A induces arthritis in humans. Steere and colleagues (1,
5) showed that the antibody response to OspA and OspB correlates
with severe and prolonged Lyme arthritis in humans. The level of
anti-OspA immunoglobulin G, especially to the C-terminal epitope of
OspA, correlates with maximum arthritis (1). Kalish et al.
(5) also showed that the cellular immune response to OspA was elevated in genetically susceptible persons (HLA-DR4 specificity). These patients have antibiotic-resistant arthritis. In
addition, Gross et al. (4) identified an immunodominant epitope of OspA that might be responsible for treatment-resistant Lyme arthritis. Furthermore, 298 reports of adverse reactions to Lyme
disease vaccination have been reported to the Food and Drug
Administration. Of these, 10% of patients have reported symptoms of
arthritis. This latter information was published in several major newspapers.
Although these reports have implicated OspA as an arthritogen, direct
evidence has been lacking. We showed in numerous publications (2,
3, 6, 7) that severe destructive arthritis develops in hamsters
vaccinated with whole-cell vaccines when challenged with Borrelia
burgdorferi. Our current results present direct evidence that
recombinant OspA (rOspA) also induces severe destructive arthritis when
OspA-vaccinated hamsters are infected with B. burgdorferi (2). The hamster may be the best animal model for
determining the arthritogenic potential of Lyme disease vaccines.
A major concern is whether the arthritic response obtained with
hamsters or the lack of this arthritic response with other animals,
particularly the mouse, can be applied to humans. We believe there are
similarities between the hamster model and human Lyme disease. For
example, humans and hamsters make a similar antibody response to
vaccination. In hamsters vaccinated with 120 µg of rOspA, the
protective anti-OspA borreliacidal antibody response rose to protective
levels but waned rapidly. No borreliacidal antibody was detected
10 weeks after vaccination; however, the nonprotective anti-OspA
antibody remained elevated (9). We observed virtually
identical results in human volunteers vaccinated with 30 µg of
rOspA. All volunteers developed borreliacidal antibody; however, only one volunteer had detectable anti-OspA
borreliacidal antibody 180 days after vaccination. In addition, the
level of nonprotective antibody to rOspA remained elevated
(9). These results suggest humans and hamsters make a
similar response to rOspA, despite differences in vaccine dosages.
Our latest findings demonstrate that rOspA vaccination primes hamsters
for severe destructive arthritis if the animals are challenged during
periods of low borreliacidal antibody activity (2).
Nonvaccinated hamsters (see Table 1 in Reference 2) developed only mild tenosynovitis and mild soft-tissue swelling of the hind paws when infected with B. burgdorferi. In
contrast, hamsters vaccinated with rOspA (two different preparations)
and infected with B. burgdorferi developed severe
destructive arthritis characterized by prominent focal tenosynovitis
with subsynovial inflammation, pannus formation, erosion of
subchrondrial bone, and gross swelling of the hind paws. Therefore,
vaccination with rOspA greatly augmented the severity of the mild
tenosynovitis normally induced in hamsters by infection with B. burgdorferi.
A number of variables were suggested to question our findings. We
disagree. The severe destructive arthritic response is not limited to
the site of infection (8). Swelling of the front paws occurs
25 to 35 days after challenge of vaccinated hamsters with
106 B. burgdorferi organisms in the hind paws.
Vaccinated hamsters also develop a generalized arthritis involving all
paws and hip joints after intradermal, subcutaneous, intraperitoneal,
or intravenous infection with B. burgdorferi. The level of
challenge does affect the onset, duration, and severity of the
arthritic response. Vaccinated hamsters infected with fewer
(102 to 104) B. burgdorferi
organisms still develop a more severe histopathologic response than
nonvaccinated hamsters challenged with these inocula of B. burgdorferi. In addition, the arthritic response is not dependent
upon the type of adjuvant used for vaccination (6). Furthermore, development of severe destructive arthritis is not a
nonspecific response. Hamsters vaccinated with Escherichia
coli, Staphylococcus aureus, or Treponema
pallidum in alum and challenged with the viable homologous agent
do not develop arthritis.
Presently, three vaccinations with rOspA (30 µg each in alum) are
recommended to induce protection in humans (10, 11). However, the duration of protection is unknown and annual vaccinations may be required to ensure protective anti-OspA borreliacidal antibody (10, 11). Our vaccination dosages were appropriate. We
vaccinated hamsters with 30, 60, and 120 µg of rOspA. Most
importantly, these dosages yielded protective antibody responses in
hamsters that were identical to those in humans.
When hamsters were vaccinated with 120 µg of rOspA, anti-OspA
borreliacidal antibody was produced. However, the levels of borreliacidal antibody were insufficient to prevent 50% of the OspA-vaccinated hamsters from developing arthritis when infected with
B. burgdorferi. The remaining concentrations (30 and 60 µg) failed to induce protective borreliacidal antibody, but were
sufficient to vaccinate (prime) hamsters for development of arthritis
when challenged with B. burgdorferi. We used a high inoculum
of B. burgdorferi to overcome the presence of local
borreliacidal antibody. Sufficient borreliacidal antibody, however, was
not produced to prevent the development of severe destructive
arthritis. We could have used lower inocula for infection. The same
changes would occur; however, they would require verification by
histopathologic examination.
In conclusion, our results confirm that vaccination with
rOspA can prime hamsters for development of severe destructive
arthritis. Although we cannot directly apply our results to humans, our
findings do support the indirect evidence obtained by Steere and
colleagues (1, 4, 5). We believe the hamster model provides
valuable insight into the immunologic responses which currently
confound the understanding of human Lyme disease. Our findings suggest that the human rOspA vaccine should be modified to eliminate
epitopes responsible for arthritis.
| |
FOOTNOTES |
*
Phone: (608) 262-3634
Fax: (608) 262-3257
E-mail: rfschell{at}facstaff.wisc.edu
| |
REFERENCES |
| 1.
|
Akin, E.,
G. L. McHugh,
R. A. Flavell,
E. Fikrig, and A. C. Steere.
1999.
The immunoglobulin (IgG) antibody response to OspA and OspB correlates with severe and prolonged Lyme arthritis and the IgG response to P35 correlates with mild and brief arthritis.
Infect. Immun.
67:173-181[Abstract/Free Full Text].
|
| 2.
|
Croke, C. L.,
E. L. Munson,
S. D. Lovrich,
J. A. Christopherson,
M. C. Remington,
D. M. England,
S. M. Callister, and R. F. Schell.
2000.
Occurrence of severe destructive Lyme arthritis in hamsters vaccinated with outer surface protein A and challenged with Borrelia burgdorferi.
Infect. Immun.
68:658-663.
|
| 3.
|
DuChateau, B. K.,
E. L. Munson,
D. M. England,
S. D. Lovrich,
S. M. Callister,
J. R. Jensen, and R. F. Schell.
1999.
Macrophages interact with enriched populations of distinct T lymphocyte subsets for the induction of severe destructive Lyme arthritis.
J. Leukoc. Biol.
65:162-170[Abstract].
|
| 4.
|
Gross, D. M.,
T. Forsthuber,
M. Tary-Lehmann,
C. Etling,
K. Ito,
Z. A. Nagy,
J. A. Field,
A. C. Steere, and B. Huber.
1998.
Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis.
Science
281:703-706[Abstract/Free Full Text].
|
| 5.
|
Kalish, R. A.,
J. M. Leong, and A. C. Steere.
1993.
Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi.
Infect. Immun.
61:2774-2779[Abstract/Free Full Text].
|
| 6.
|
Lim, L. C. L.,
D. M. England,
B. K. DuChateau,
N. J. Glowacki,
J. R. Creson,
S. D. Lovrich,
S. M. Callister,
D. A. Jobe, and R. F. Schell.
1994.
Development of destructive arthritis in vaccinated hamsters challenged with Borrelia burgdorferi.
Infect. Immun.
62:2825-2833.
|
| 7.
|
Lim, L. C. L.,
D. M. England,
N. J. Glowacki,
B. K. DuChateau, and R. F. Schell.
1995.
Involvement of CD4+ T lymphocytes in induction of severe destructive Lyme arthritis in inbred LSH hamsters.
Infect. Immun.
63:4818-4825[Abstract].
|
| 8.
|
Munson, E. L.,
B. K. DuChateau,
D. A. Jobe,
M. L. Padilla,
S. D. Lovrich,
J. R. Jansen,
L. C. L. Lim,
J. L. Schmitz,
S. M. Callister, and R. F. Schell.
1996.
Hamster model of Lyme borreliosis.
J. Spirochet. Tick-Borne Dis.
3:15-21.
|
| 9.
|
Padilla, M. L.,
S. M. Callister,
R. F. Schell,
G. L. Bryant,
D. A. Job,
S. D. Lovrich,
B. K. DuChateau, and J. R. Jensen.
1996.
Characterization of the protective borreliacidal antibody response in humans and hamsters after vaccination with a Borrelia burgdorferi outer surface protein A vaccine.
J. Infect. Dis.
174:739-746[Medline].
|
| 10.
|
Sigal, L. H.,
J. M. Zahradnik,
P. Lavin,
S. J. Patella,
G. Bryant,
R. Haselby,
E. Hilton,
M. Kunkel,
D. Adler-Klein,
T. Doherty,
J. Evans, and S. Malawista.
1998.
A vaccine consisting of recombinant Borrelia burgdorferi outer surface protein A to prevent Lyme disease.
N. Engl. J. Med.
339:216-222[Abstract/Free Full Text].
|
| 11.
|
Steere, A. C.,
V. Sikand,
F. Meurice,
D. L. Parenti,
E. Fikrig,
R. T. Schoen,
J. Nowakowski,
C. H. Schmid,
S. Laukamp,
C. Buscarino, and D. S. Krause.
1998.
Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer surface lipoprotein A with adjuvant.
N. Engl. J. Med.
339:209-215[Abstract/Free Full Text].
|
| | | | |
Ronald F. Schell*
University of Wisconsin Medical School
Wisconsin State Laboratory of Hygiene
465 Henry Mall
Madison, Wisconsin 53706
|
| | | | |
Steven M. Callister
Steven D. Lovrich
Gundersen/Lutheran Medical Center
La Crosse, Wisconsin 54601
|
Infection and Immunity, December 2000, p. 7212-7213, Vol. 68, No. 12
0019-9567/00/$04.00+0
