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Original article
SWISS MED WKLY 2004;134:326–327 ·
Peer reviewed article
Letter to the editor
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
, Stanko Banic
Jozica Marin
, Polona Klamenc
Institute for Public Health of Ljubljana,
Ljubljana, Slovenia
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
Mirjana Stantic-Pavlinic
Institute for Public Health of Ljubljana
Zaloška 29
1000 Ljubljana,
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.):
SWISS MED WKLY 2004;134:326–327 ·
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
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.
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:
12 Shill M, Baynes RD, Miller SD. Fatal rabies en-
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Rhesus monkeys were completely protected from rabies by a single dose of experimental, highly concentrated, rabies virus vaccine prepared from virus propagated in cultures of human diploid cells and administered several hours after infection with street rabies virus. Protection seemed to be related to the high antigenicity of the vaccine and to its ability to induce interferon in vaccinated animals. Only partial protection was afforded by one or three inoculations of less concentrated vaccines that were prepared from cultures of human diploid cells or primary hamster kidney cells and that were not capable of inducing interferon. The level of virus-neutralizing antibody induced by vaccination could not be correlated with the final outcome of the disease. The simultaneous inoculation of vaccine and interferon inducers (polyribocytidylic acid homopolymer pair or Newcastle disease virus) did not improve the results obtained with vaccine alone, a fact which indicates that factors other than interferon and antibody may play an important role in the treatment of rabies after exposure.
WE have reported1 an increased response to interferon induction in mice fed a diet containing vitamin C, and have now found a similar phenomenon in vitro. Addition of L-ascorbate to cultures of mouse cells (transformed L cells and normal embryonic fibroblasts) stimulated with polyinosinic acid . polycytidylic acid (poly(rI).poly(rC)) resulted in increased synthesis of interferon.
Three failures of postexposure rabies treatment using imported purified duck embryo cell and Vero cell rabies vaccines are reported from Thailand. Reference is made to eight additional previously reported Thai patients, six of whom had received human diploid cell vaccine. An analysis of these cases reveals that there were serious flaws in management in all of these patients. It is stressed that 45% of human rabies deaths in Thailand occur within 20 days of being bitten and 71% are dead within 28 days. This short incubation period does not allow much time to start immunotherapy. Of Bangkok dogs found to have rabies at autopsy, approximately 8% have a rabies immunization history. Once a dog has bitten a patient immunotherapy should not be delayed in countries with a high incidence of dog rabies. Patients with chronic disease, alcoholics and drug addicts may have an impaired immune response to postexposure rabies vaccines.
Here we document an apparent case of failure of a seemingly adequate regimen of human diploid-cell vaccine and rabies immune globulin.
BALB/cJ mice, on an ad libitum regimen of 250 mg% l-ascorbate in their drinking water, displayed augmented levels of circulating interferon after stimulation with murine leukemia virus.
Inactivated rabies vaccine of tissue-culture origin, Kern Canyon vaccine, or influenza-virus vaccine, given shortly before or immediately after challenge with street rabies virus, protected the majority of hamsters against death. All three vaccines stimulated circulating interferon. Hamsters treated with bacterial endotoxin and given rabies vaccine 24 hr before challenge were not as well protected and produced less interferon. When vaccination preceded challenge by five days or more, only rabies virus vaccine rendered the animals immune and resistant to infection. These results suggest that interferon induced by vaccines administered at or near the time of challenge may play a role in protection from rabies. Concentrated rabies vaccines also induced interferon in rabbits and in cell cultures of human and rabbit origin. Live-virus vaccine induced more interferon than did inactivated vaccine. Interferon was not induced by the administration of rabies vaccine to rabies-immune rabbits. In hamster and human cell cultures treated with homologous interferon, growth of rabies virus was inhibited; treatment with heterologous interferon did not have this effect. Thus, rabies virus was also shown to be susceptible in vitro to the antiviral effect of interferon.