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Table 1
Level of interferon alpha (pg/ml) in the sera of patients during the course of treatment.
Patients Mode of treatment Period after vaccination
Number Gender Age 0 day 24 hours 21 day
1 male 30 Vaccine alone (group 1) 0 10.8 13.4
2 male 40 6.6 0 5.4
3 male 35 0 0 8.6
4 male 20 25.3 39.4 ND*
5 male 44 17.8 0 0
6 male 29 18.5 2.7 ND*
7 male 26 158 0 5
8 female 46 0 0 0
9 female 45 18.4 0 9.1
10 female 38 0 0 24
Mean 24.5 5.2 8.2
SD 47.9 12.5 7.8
11 female 32 Vaccine + vitamin C (group 2) 0 45.6 21
12 female 26 0 11.2 5.4
13 male 28 0 20.2 0
14 male 29 19.5 11.5 0
15 female 30 0 91.3 13.8
16 female 20 124 514 37
Mean 23.9 115.6 12.9
SD 49.6 197.5 14.4
*ND = not done
Vitamin C – a challenge in
the management of rabies
Mirjana Stantic-Pavlinic
a*
, Stanko Banic
b
,
Jozica Marin
b
, Polona Klamenc
b
a
Institute for Public Health of Ljubljana,
Ljubljana, Slovenia
b
Institute of Microbiology and Immunol-
ogy, Medical Faculty, Ljubljana, Slovenia
Studies in experimental animals have
shown that protection from rabies seems to be
related not only to the high antigenicity of the
vaccine but also to induction of interferon
[1–4]. It has also been established that vitamin
C enhances the interferon response to the
chemical interferon inducers poly (rI) and
poly (rC) [3, 5] as well as to some viruses [2].
Our study was conducted on humans in
the course of post-exposure treatment of
rabies in a region endemic for animal rabies.
The aim of the study was to establish whether
an enhancing effect of vitamin C on inter-
feron induction could be demonstrated in
patients vaccinated against rabies. As vaccina-
tion alone is not always effective in treated
patients [6], a further improvement of the
post-exposure treatment of rabies would be
welcome. The existence of a huge reservoir of
rabies in animals almost all over the world and
the occurrence of human cases of rabies are
reasons for continuing research on protection
against rabies [7, 8].
The course of the study
Sixteen healthy adult patients entered
the study. The mean age of the patients was
32 years (minimum 20 years, maximum 46
years, median 30 years). Written informed
consent was obtained. The patients were ran-
domly allotted to two groups and were treated
with the vaccine alone (group 1) or vaccine
plus vitamin C (group 2).
Risk of infection with rabies virus was
assessed using a standardised questionnaire.
The criteria for exposure to rabies demanded
that the patients had a break in the skin due
to the bite of an animal with an unknown
owner or an animal suspected to be rabid in
the endemic animal rabies area. The patients
were not previously vaccinated against rabies
and they had no immunodeficiency disorders
or immunosuppressive treatment. Commer-
cially available inactivated rabies vaccine
prepared in human diploid cells, Vaccine
Rabique (Pasteur Mérieux, Lyon, France) was
used in the study. Rabies immunoglobulins
were not added. All patients were immunized
with 2 ml – 1 ml 1 ml on the days 0,7 and 21
[9]. The second group received a single oral
dose of 2 g of vitamin C powder dissolved in
water in addition to the first dose of vaccine.
Alpha interferon levels were measured in
the sera before the start of the treatment, at
24 hours and at 21 days after the start of the
vaccinations. Assessment of the level of alpha
interferon was done using interferon alpha
ELISA assay (Endogen Inc, USA). Statistical
analysis was done by EPI-Info 6.
Baseline mean level of interferon in
groups 1 and 2 of patients (Table 1) was
comparable, being 24.5 in group 1 and 23.9 in
group 2. 24 hours after the start of the treat-
ment, mean interferon alpha level had in-
creased only in the group 2.
Vitamin C has a significant influence on
the production of interferon alpha in patients
vaccinated against rabies on the first day after
the start of the treatment (Odds ratio 23.20;
95% confidence limits for OR 7.49 <OR
<83.52; Chi-Squares Yates corrected 47.69;
P-values highly significant <0.001).
21 days after the start of the treatment
the influence of vitamin C on the level of
interferon alpha was not statistically apparent
(Odds ratio 1.63; confidence limits for OR
0.51 <OR <5.38; Chi-Squares Yates corrected
0.42; P-values 0.52).
The immunization with human diploid
cell vaccines against rabies is the gold stan-
dard for prevention of rabies in exposed per-
sons [10]. However, some deaths in treated
patients have been reported [6, 11, 12].
We have demonstrated that vitamin C is
an effective stimulator of interferon produc-
tion in humans and could therefore be used
for stimulation of an enhanced interferon
response to rabies vaccine. Simultaneous in-
oculation of rabies vaccine and administration
of vitamin C could improve the post-exposure
immunization especially in the case of rabies
immunoglobulin shortage.
We assume that at the beginning of treat-
ment, when the antibody levels against rabies
virus are not present or are not protective, a
high level of interferon could have protective
role.
Correspondence:
Mirjana Stantic-Pavlinic
Institute for Public Health of Ljubljana
Zaloška 29
1000 Ljubljana,
Slovenia
E-Mail: stantic@bigfoot.com
References
1 Wiktor TJ, Postic B, Ho M, Koprowski H. Role
of Interferon Induction in the Protective Activity
of Rabies Vaccines. J Infect Dis 1972;126:408–18.
2 Siegel BV. Enhanced interferon response to
Murine Leukemia Virus by Ascorbic Acid. Infect
Immun 1974;10:409–10.
3 Siegel BV. Enhancement of interferon produc-
tion by poly (rI)
.
poly(rC) in mouse cell cultures
by ascorbic acid. Nature 1975;254:531–2.
4 Wiktor TJ, Koprowski H, Mitchell JR, Merigan
TC. Role of Interferon in Prophylaxis of Rabies
after Exposure. J Infect Dis 1976;133(Suppl.):
A260–A265.
SWISS MED WKLY 2004;134:326–327 · www.smw.ch
327
5 Fenje P, Postic B. Prophylaxis of experimental ra-
bies with the poly-riboinosinic-polyribocytidylic
acid complex. J Infect Dis 1971;123:426–8.
6 Wilde H, Sirikawin S, Sabcharoen A, Kingnate
D, Tantawichien T, Harischandra PAL, et al.
Failure of Postexposure Treatment of Rabies in
Children. Clin Infect Dis 1996;22:228–32.
7 Stantic-Pavlinic M: How dangerous is the Euro-
pean bat lyssavirus? Wien Klin Wochenschr
2003;115:1–3.
8 Stantic-Pavlinic M. Rabies treatment of health
care staff. Swiss Med Wkly 2002;132:129–31.
9 WHO: Recommendations on Rabies Post-Expo-
sure Treatment and the Correct Technique
of Intradermal Immunization against Rabies.
WHO/EMZlZOO.96.6,1997.
10 WHO: Current Strategy for Human Rabies Vac-
cination and WHO Position. Rabies Bulletin
Europe 2002;26:14–6.
11 Wilde H, Choomkasien P, Hemachudha T,
Supich Ch, Chutivongse S. Failure of rabies post
exposure treatment in Thailand. Vaccine 1989;7:
49–52.
12 Shill M, Baynes RD, Miller SD. Fatal rabies en-
cephalitis despite appropriate post-exposure pro-
phylaxis. A case report. N Engl J Med 1987;316:
1257–8.
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