VIEWPOINTS

Postexposure Treatment of Rabies Infection:

Can It Be Done without Immunoglobulin?

Downloaded from https://academic.oup.com/cid/article-abstract/34/4/477/412337 by guest on 24 September 2018

Henry Wilde, Pakamatz Khawplod, Thiravat Hemachudha, and Visith Sitprija
Queen Saovabha Memorial Institute (Thai Red Cross Society) and Department of Medicine, Chulalongkorn University, Bangkok, Thailand

The last remaining international manufacturer of equine rabies immunoglobulin (ERIG) discontinued production in 2001.
However, ERIG remains an essential biological that has no substitute other than human rabies immunoglobulin (HRIG),
which is in short supply and virtually unaffordable in developing countries. Physicians in regions where canine rabies is
endemic and neither ERIG nor HRIG is available are providing less-than-optimal treatment to patients exposed to rabies. If
no immunoglobulin is available, they have only 1 therapy option: use of a vaccine schedule that produces the highest and,
hopefully, earliest neutralizing antibody response. However, treatment failures must still be expected. Early, aggressive wound
cleansing and more intensive efforts at canine control and are ever more important. Countries that have the resources to
manufacture their own rabies immunoglobulins must be encouraged to do so.

More than 5 decades have passed since
Habel, Koprowski, Baltazard, and others
[1–4] first demonstrated the need for
equine rabies antiserum as part of the
initial optimal treatment of severely ra-
bies-exposed patients (those with bleed-
ing wounds or mucous-membrane ex-
posure to rabies virus). Their work has
been confirmed in numerous additional
experimental and field studies. The use
of human rabies immunoglobulins
(HRIG) and of purified pepsin-digested
equine products (equine rabies immu-
noglobulin, or ERIG) have since saved
the lives of countless patients who would
have died if treated with vaccine alone
[5]. Two problems, however, have con-
tinued to plague postexposure rabies
Received 18 April 2001; revised 6 August 2001; elec-
tronically published 7 January 2002.
Reprints or correspondence: Dr. Henry Wilde, Queen
Saovabha Memorial Institute, 1871 Rama IV Rd., Bangkok,
10330, Thailand (henry@mail.redcross.or.th).
Clinical Infectious Diseases 2002; 34:477–80
 2002 by the Infectious Diseases Society of America. All
rights reserved.
1058-4838/2002/3404-0008$03.00
treatment (PET). It is very expensive and
not readily available where it is needed
the most, in poor, countries where canine
rabies is endemic [6]. Optimal PET is
therefore virtually unaffordable in most
of the developing world [6]. ERIG, which
replaced the crude and adverse reac-
tion–prone unpurified antiserum sam-
ples, sold at ∼20% of the cost of HRIG
in Asian countries [6]. Therefore, it was
almost affordable. Most of the 8 million
PETs administered annually worldwide
annually, however, still use dangerous
and often poorly immunogenic brain tis-
sue–derived vaccines without rabies im-
munoglobulin (RIG) [7]. No accurate
worldwide statistics of rabies vaccine
treatment failures have been compiled,
but numbers are thought to be signifi-
cant. Most failures have been in subjects
who have not received RIG [8, 9]. Good
wound care and potent vaccines, admin-
istered promptly without RIG, have no
doubt saved the lives of countless indi-
viduals exposed to rabies [7, 10, 11]. We
do not know, however, which patient is
doomed if not given HRIG or ERIG as
well as vaccine [8, 9, 11]. RIG serves to
neutralize virus at the inoculation (e.g.,
bite) sites. It reduces the virus load that
can replicate in muscle cells and later in-
vade nerve endings. RIG thus closes the
gap until endogenous antibodies elicited
by active immunization appear [8, 9, 11].
It is for these reasons that the World
Health Organization (WHO) Rabies
Expert Committee recommended the use
of RIG in all severe rabies exposures such
as single or multiple transdermal wounds
regardless of body site [7, 12]. RIG must
be injected into and around the wounds,
ideally at the time of the first vaccine dose
[7, 12]. ERIG and HRIG have therefore
been placed on the WHO list of essential
drugs and biologicals [13].
ERIG and HRIG are in short supply
worldwide [14]. Many rabies-control
clinics in developing countries have had
to wait months for orders to be filled,
and some remain unfilled. Thus, count-
less patients worldwide who should re-
ceive HRIG or ERIG are being treated

Postexposure Rabies Treatment • CID 2002:34 (15 February) • 477

 Table 1. Humoral immune response for human diploid cell vaccine (potency, 3.16 IU/mL) given intramuscularly and intradermally.

Seroconversion
GMT of antibody (range), IU/mL, by day after vaccination
No. of on day 7,
Regimen patients 7 14 28 91 % of patients
a
Intramuscular ⫻ 5 22 0.17 (!.02–1.3) 10.99 (1.5–71.6) 12.98 (1.4–60.73) 2.8 (0.23–9.2) 7
b
Intradermal 4-4-4-0-1-1 19 0.32 (!0.2–1.64) 9.88 (4.09–48.45) 9.34 (3.71–30.96) 3.57 (1.04–10.42) 27

NOTE. Data are from Ubol et al. [25]. GMT, geometric mean titer.
a
The Essen regimen: 1 full dose of vaccine injected intramuscularly on days 0, 3, 7, 14, and 28.
b
Double-dose Thai Red Cross regimen: 0.1 mL of vaccine injected intradermally at 4 different lymphatic drainage sites on days 0, 3, and 7, none on day
14, and 0.1 mL of vaccine injected intradermally at 1 site on days 28 and 90.

Downloaded from https://academic.oup.com/cid/article-abstract/34/4/477/412337 by guest on 24 September 2018

with vaccine alone [7]. Production of
HRIG hinges on the availability of hu-
man donors who have been immunized
against rabies and requires an expensive
screening and production process. Pro-
duction of ERIG requires a constant sup-
ply of serum from horses that have been
immunized against rabies. Large multi-
national manufacturers have been reluc-
tant to maintain such facilities because of
pressures from animal rights groups, in-
creasing production costs, and ever more
complex directives from national regu-
latory authorities [14]. ERIG is used only
in developing countries, where patients
are usually unable to pay a price for it
that would generate enough profit for in-
ternational firms to cover current pro-
duction costs. Three major European
manufacturers (Behring, Sclavo, and Ber-
na) have discontinued production of
ERIG during the past 2 decades. The
last remaining manufacturer, Aventis-
Pasteur, announced that it will not be
able to fill orders after the end of 2001.
A new chromatography-purified and
heat-treated ERIG is now in the final de-
velopment phase, but when it will appear
on the market and whether it is as effec-
tive in neutralizing virus as the older
products are not known [15, 16]. This
leaves only a few small producers in de-
veloping countries. Most of them are not
manufacturing ERIG using current
“good manufacturing practices” stan-
dards and in sufficient quantity to satisfy
home-country requirements. To the best
of our knowledge, among Asian nations,
only Thailand has been producing a
moderate quantity of HRIG, from unpaid
volunteer donors at the Thai Red Cross
National Blood Center in Bangkok [17].
This critical situation was discussed at
the WHO “Rabies in Asia” conference at
Hanoi, Viet Nam, in March 2001, and
again at Geneva, Switzerland, in July
2001. The consensus opinion was that
countries where canine rabies is endemic
would have to develop their own ERIG
and HRIG manufacturing capabilities in
order to provide optimal PET in the fu-
ture. This will require motivation, in-
vestment, and technology transfer. Only
a few nations will be willing and able to
muster the needed efforts. It should,
however, be possible to produce ERIG in
existing plants that make purified equine
or ovine antisnake serum samples. Some
larger blood banks, which can process
blood components, could also produce
HRIG. The Thai Red Cross, in spite of
serious economic difficulties facing the
nation in the late 20th century, is up-
grading and enlarging its snake antivenin
plant and horse farm in order to man-
ufacture purified and pepsin-digested
ERIG.
How can one approach patients who,
under present guidelines, require RIG
when none is available? Wound care be-
comes ever more important and must be
carried out rigorously with scrupulous
cleansing and deep irrigation, followed
by application of a potent antiseptic
agent [18]. The question also arises of
whether the risk of rabies can be reduced
by using an accelerated vaccine schedule,
which induces higher antibody titers and
perhaps even an earlier cellular response
than the “gold standard” 5-dose intra-
muscular (“Essen”) schedule or the
WHO-approved Thai Red Cross intra-
dermal treatment schedule [12]. Could
such a regimen reduce the number of
vaccine failures that one must expect in
severe exposures when no immunoglob-
ulin is administered? Studies elsewhere
[19–25] have shown that a higher neu-
tralizing antibody response could be in-
duced by injecting multiple intradermal
doses of vaccine at different lymphatic
drainage sites. This led to WHO approval
of 2 intradermal postexposure schedules
[7, 12]. Both have been extensively tested
and are in daily use in some Asian and
African countries. They have been found
effective, but, like the Essen regimen,
only when used together with rabies im-
munoglobulin [19–23]. The Thai Red
Cross regimen (TRC-ID) consists of 0.1
mL of any potent tissue culture vaccine
injected at 2 different sites intradermally
on days 0, 3, and 7 and 0.1 mL at 1 site
on days 28 and 90 [12]. The Oxford, or
8-site, regimen consists of 0.1. mL in-
jected intradermally at 8 sites on day 0,
at 4 sites on day 7, and at 1 site on days
28 and 90 [12]. TRC-ID has now been
used for 11 decade in Southeast Asian
countries and in well over 100,000
courses of postexposure treatment; how-
ever, no accurate data are available on
how many severely exposed patients have
received 1 of the 2 WHO-approved in-
tradermal vaccine regimens without RIG.
The risk for and number of treatment
failures in such cases are not known.
Phanuphak et al. [21] have also shown
that TRC-ID induces an earlier cellular
immune response than does the standard

478 • CID 2002:34 (15 February) • Wilde et al.

 Table 2. Humoral immune response for purified chick embryo vaccine (potency, 7.5 IU/mL) given intramuscularly and
intradermally.
No. of
Regimen patients
a
Intramuscular ⫻ 5 15
Intradermal 8-0-4-0-1-1b 15
c
Intradermal 4-0-4-0-1-1 15
NOTE. Data from Suntharasamai et al. [24].
a
The Essen regimen: 1 full dose of vaccine injected intramuscularly on days 0, 3, 7, 14, and 28.
b
The Oxford regimen: 0.1. mL of vaccine injected intradermally at 8 sites on day 0, none on day 3, at 4 sites on day 7, and at 1 site on
days 28 and 90.
c
0.1. mL of vaccine injected intradermally at 4 sites on day 0, none on day 3, at 4 sites on day 7, and at 1 site on days 28 and 90.
Essen intramuscular regimen. The anti-
body response is equivalent to that of the
intramuscular Essen schedule. The Ox-
ford 8-site regimen induces higher but
not earlier neutralizing antibodies by day
7 when compared to the Essen or the
WHO-approved 2-site TRC-ID regimens
[20, 24]. Modifying the TRC-ID by dou-
bling the number of intradermal injec-
tions on days 0, 3, and 7 also resulted in
a higher, but not earlier, humoral im-
mune response. It was equivalent to that
of the 8-site regimen [20, 24] (tables 1
and 2). Other investigators have hypoth-
esized that virus within peripheral nerves
is in an immune-protected environment
[11]. If that is true, the fate of a patient
with an inoculum into a nerve-rich area
may be decided by day 7, unless the re-
gion is injected with RIG [9, 11]. Thus,
one should expect that the “8-site” or the
“double-dose TRC-ID” regimens, used
without RIG, may still result in treatment
failures. We can use these 2 regimens
without RIG only as desperate, last-resort
measures. It is possible, however, that
these “accelerated” schedules might close
the gap in the early critical period after
a severe bite injury and thus save a few
more patients who would otherwise be
doomed.
We do not have any prospective studies
that show that increasing the dose of an-
tigen or the number of intradermal in-
jections will reduce treatment failures
when no RIG is administered. Phanu-
phak et al.’s work, showing that the cel-
GMT of antibody (range), IU/mL, by day after vaccination
7 14 28
0.02 (!.01–0.2) 3.1 (0.3–16.7) 10.3 (2.1–35.9)
0.04 (!0.1–0.3) 5.4 (1.8–16.7) 5.8 (2.4–13.4)
0.02 (!0.1–0.3) 7.2 (1.8–26.0) 7.2 (1.5–23.2)
lular immune response is induced earlier
with multisite intradermal rabies vacci-
nation, however, may provide some hope
and needs to be investigated further [21].
Because we have now reached a crisis sit-
uation regarding RIG availability, we sug-
gest that, when absolutely no HRIG or
ERIG is available, one should apply one
of the regimens that offer the highest
neutralizing antibody responses and that
may induce earlier cellular immunity.
This would either be the “double-dose”
TRC-ID schedule (4-site 0.1 mL on days
0, 3, and 7 and at 1 site on days 28 and
90) or the 8-site Oxford regimen.
We anticipate that physicians in the de-
veloping world will continue to be faced
with having to provide less-than-optimal
postexposure rabies treatment. Some
Asian countries (notably China, Myan-
mar, Nepal, some Indian states, and for-
mer Soviet Central Asian republics) have
made the calculated decision to accept
treatment failures, because of other pri-
orities and the unavailability of RIG. En-
ergetic and innovative dog control mea-
sures are now ever more important. They
have not been implemented in many
parts of Asia. There were suggestions at
the 2 WHO “Rabies in Asia” conferences
(March 2001 and July 2001) that preex-
posure rabies vaccination of selected
high-risk children, in regions with a large
canine rabies problem, should be consid-
ered if it becomes economically feasible.
Approximately 40% of exposures and
human rabies deaths in developing coun-
Postexposure Rabies Treatment • CID 2002:34 (15 February) • 479
Seroconversion
on day 7,
91 % of patients
4.9 (1.4–9.6) 7
2.7 (0.8–10.2) 7
2.7 (0.9–5.9) 20
Downloaded from https://academic.oup.com/cid/article-abstract/34/4/477/412337 by guest on 24 September 2018
tries are of children !15 years of age [7,
9]. Preexposure vaccination would be
particularly appropriate for countries
that have been unable to manage their
large stray dog populations because of
religious and cultural barriers (Thailand,
Laos, Myanmar, Cambodia, India, and
Nepal). Such public sector preexposure
vaccination can be carried out, however,
only if present tissue culture vaccine costs
could be dramatically reduced. The in-
troduction of such vaccines in liquid
form and as multiple dose vials might be
one approach that could reduce the cost.
There is fear, however, that such efforts
might detract from more intensive dog-
population control programs and vacci-
nation programs, which must remain the
primary objectives in worldwide rabies
eradication.
C. E. Rupprecht and others have stud-
ied monoclonal antibodies (MABs) and
have shown that they can be very effective
in neutralizing a wide range of Lyssavirus
strains in experimental animals [15, 26].
Further research and industrial applica-
tion of this promising work might even-
tually offer an alternative to HRIG and
ERIG, but antirabies MABs are not likely
to appear on the market in time to solve
the present crisis.
Acknowledgments
Rabies research and production of bi-
ologicals at the Queen Saovabha Me-
morial Institute, a WHO collaborating
center for research in rabies, are sup-
ported by the Thai Red Cross Society. We
are grateful to the Institutes Pasteur and
Mérieux, of France, to the Swiss Serum
and Vaccine Institute, of Bern, to the
Behringwerke of Marburg, Germany, and
to the Netherlands Red Cross, for the
generous technical assistance that they
have rendered freely over the past decade.
References
1. Habel K, Koprowski H. Laboratory data sup-
porting the clinical trial of antirabies serum
in persons bitten by a rabid wolf. Bull World
Health Organ 1955; 13:773–9.
2. Koprowski H, Van der Sheer J, Black J. Use
of hyperimmune antirabies serum concen-
trates in experimental rabies. Am J Med
1950; 8:412–20.
3. Baltazard M, Bahmanyar M, Ghodessi M, et
al. Practical trial of antirabies serum in bites
by rabid wolves. Bull World Health Organ
1955; 13:747–72.
4. Selimov M, Boltucijl, Semenova E, et al. An-
wendung des Antirabies Gammaglobulins
bei Menschen, die von tollwuetigen Woelfen
oder anderen Tieren schwer gebissen wur-
den. J Hyg Epidemiol Microbiol Immunol
1959; 3:168–80.
5. Wilde H, Chomchey P, Punyaratabandhu P,
et al. Purified equine rabies immune glob-
ulin: a safe and affordable alternative to hu-
man rabies immune globulin. Bull World
Health Organ 1989; 87:731–6.
6. Wilde H, Tipkong P, Khawplod P. Economic
issues in post-exposure rabies treatment. J
Travel Med 1999; 6:238–42.
7. World Health Organization (WHO). Eighth
report of the expert committee on rabies.
480 • CID 2002:34 (15 February) • Wilde et al.
Technical report series 824. Geneva: WHO,
1992.
8. Wilde H, Choomkasien P, Hemachudha T,
et al. Failure of rabies post-exposure treat-
ment in Thailand. Vaccine 1989; 7:49–52.
9. Wilde H, Sirikawin S, Kingnate D, et al. Ra-
bies post-exposure treatment failures in
Children. Clin Infect Dis 1996; 22:228–32.
10. Sitthi-Amorn C, Jiratanavattana V, Keoyoo
J, et al. The diagnostic properties of labo-
ratory tests for rabies. Int J Epidemiol
1987; 16:602–5.
11. Hemachudha T, Mitrabhakdi E. Rabies. In:
Davis LE, Kennedy PGE, eds. Infectious dis-
eases of the nervous system. Oxford: But-
terworth & Heinemann, 2000:401–44.
12. World Health Organization (WHO). Rec-
ommendations on rabies postexposure treat-
ment and the correct technique of intrader-
mal immunization against rabies. Geneva:
WHO/EMC.ZOO 96.6, 1996.
13. World Health Organization (WHO). The use
of essential drug. WHO Tech Rep Ser
2000; 895:1–61.
14. Wilde H, Thipkong P, Sitprija S, et al. Het-
erologous antisera are essential biologicals:
perspectives of a worldwide crisis. Ann In-
tern Med 1996; 125:233–6.
15. Lang J, Attanath P, Quiambao B, et al. Eval-
uation of the safety, immunogenicity and
pharmacokinetic profile of a new, highly pu-
rified, heat-treated equine rabies immuno-
globulin, administered either alone or in as-
sociation with a purified, Vero-cell rabies
vaccine. Acta Trop 1998; 70:317–33.
16. Hanlon CA, Niezgoda M, Morrill PA, et al.
The incurable wound revisited: progress in
human rabies prevention. Vaccine 2001; 19:
2273–9.
17. Chantanakajornfung A, Naraporn N, Khum-
phai W, et al. A study of human rabies im-
mune globulin manufactured by the Thai
Red Cross. Vaccine 1999; 17:979–98.
18. Cabasso VJ Local wound treatment and pas-
sive immunization. In: Bear G, ed. The nat-
ural history of rabies. 2nd ed. Boca Raton,
FL: CRC Press, 1991:551–70.
19. Nicholson KG, Prestage H, Cole PJ, et al.
Multisite intradermal antirabies vaccination:
Immune responses in man and protection of
rabbits against death from street virus by
postexposure administration of human dip-
loid-cell-strain rabies vaccine. Lancet 1981;
2(8252):915–8.
20. Warrell MJ, Warrell DA, Suntharasamai P, et
al. An economical regimen of human diploid
cell strain anti-rabies vaccine for post-ex-
posure prophylaxis. Lancet 1983; 2(8345):
301–4.
Downloaded from https://academic.oup.com/cid/article-abstract/34/4/477/412337 by guest on 24 September 2018
21. Phanuphak P, Khawplod P, Sirivichayakul S,
et al. Humoral and cell-mediated immune
responses to various economical regimens of
purified Vero-cell rabies vaccine. Asian Pac
J Allergy Immunol 1987; 5:33–7.
22. Chutivongse S, Wilde H, Supich C, et al.
Postexposure prophylaxis for rabies with an-
tiserum and intradermal vaccination. Lancet
1990; 335(8694):896–8.
23. Centers for Disease Control. Rabies postex-
posure immunization regimens: Thailand.
MMWR Morb Mortal Wkly Rep 1990; 39:
759–62.
24. Suntharasamai P, Warrell MJ, Viravan C, et
al. Purified chick embryo cell rabies vaccine:
economical multisite intradermal regimen
for post-exposure prophylaxis. Epidemiol
Infect 1987; 99:755–65.
25. Ubol S, Phanuphak P. An effective econom-
ical intradermal regimen of human diploid
cell rabies vaccination for post-exposure
treatment. Clin Exp Immunol 1986; 63:
491–7.
26. Champion JM, Ruppreacht CE, NAtkins, et
al. The development of monoclonal human
retrovirus–neutralizing antibodies as a sub-
stitute for pooled human immune globulin
in the prophylactic treatment of rabies virus
exposure. J Immunol Meth 2000; 235:81-90.