Vaccine 37 (2019) A94–A98

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Introduction of intradermal rabies vaccination – A paradigm shift in

improving post-exposure prophylaxis in Asia
Gyanendra Gongal a,⇑,1, Gadey Sampath b,2
a
WHO Regional Office for South East Asia, New Delhi, India
b
Institute of Preventive Medicine, Hyderabad, India

a r t i c l e i n f o a b s t r a c t

Article history: The cost of cell culture vaccines for intramuscular administration limits their widespread use in many
Available online 24 August 2018 areas where rabies is present. The innovation of cost-effective multi-site intradermal (ID) vaccination
technique was an impetus for high burden countries to phase out production and use of rabies vaccine
Keywords: of nerve tissue origin in public hospitals in subsequent years. The WHO Expert Committee in 1991
Rabies recommended intradermal application of modern rabies vaccines for post-exposure prophylaxis. There
Asia are many challenges in promotion of ID schedule. Poor patient compliance due to the need for several
Post-exposure prophylaxis
clinic visits is one of the drawbacks of the presently recommended ID rabies vaccination regimens. A
Vaccine
Intradermal
series of clinical trial and field observations in past 3 decade have generated enough evidence-based
Intramuscular information to recommend one week ID schedule. Off label use of commercially available human rabies
vaccine for ID administration is an issue. The national authority should consider revision of ID vaccination
schedule in line with new WHO guidelines.
Ó 2018 Published by Elsevier Ltd. This is an open access article under the CC BY IGO license. (http://crea-
tivecommons.org/licenses/by/3.0/igo/).

1. Introduction
Rabies is still a major public health concern in Asian countries
and most countries in Asia are rabies endemic, except a few island
countries as shown in Fig. 1 [1]. An estimated 59,000 deaths occur
due to human rabies annually in the world, of which 35,172 deaths
occur in Asia.
There has been no major shift in rabies control and/or elimina-
tion due to the lack of effective dog rabies control in endemic
countries. On the other hand, dog population is proportional to
human population. As a result, the number of people seeking
post-exposure prophylaxis after a dog bite is increasing as no
one wants to risk contracting a 100% fatal disease. The cost of cell
culture vaccines (CCVs) for intramuscular administration limits
their widespread use in many areas where rabies is endemic [2].
Most Asian countries with a high rabies burden were producing
or importing nerve-tissue vaccine (NTV) to provide post-exposure
prophylaxis (PEP) in public hospitals as CCVs were out of reach. In
1984, WHO recommended the discontinuation of NTV production
and use for PEP and the 2004 WHO Expert Consultation on Rabies
issued a definitive statement advising that NTVs should be discon-
⇑ Corresponding author.
E-mail address: gn_gongal@yahoo.com (G. Gongal).
1
Technical Officer (PCB).
2
Formerly Deputy Civil Surgeon.
tinued and that only CCVs should be used in humans [3]. The inno-
vation of a cost-effective, multi-site intradermal (ID) vaccination
technique by the Queen Saobabha Memorial Institute of Thailand
in 1986 was an impetus for countries with a high rabies burden
to phase out production and use of NTV in public hospitals in
subsequent years. The phasing out of NTVs and the introduction
of a cost-effective ID schedule in major rabies endemic countries
of Asia is shown in Table 1.
The WHO Expert Committee in 1991 recommended intradermal
administration of modern rabies vaccines for PEP [4]. The multisite
ID regimen pioneered in Thailand is popularly known as Thai Red
Cross (TRC) regimen. The intradermal regimen is approved for both
post-exposure (PEP) and pre-exposure prophylaxis (PrEP) [7].
When compared with standard intramuscular vaccination,
intradermal vaccination offers an equally safe and immunogenic
alternative that requires only 1–2 vials of vaccine to complete a full
course of PEP, thereby reducing the volume used and the direct
cost of vaccine by 60–80% [2].
The cost of PEP can be reduced dramatically if the intramuscular
(IM) regimen is replaced in a progressive manner with the ID
regimen [5]. A conservative cost estimate for human rabies
prophylaxis of 4 million patients using IM versus ID regimens over
a period of five years in Southeast Asia region was done. Fig. 2 illus-
trates the estimated cost when using varying proportions of ID and
IM vaccine for PEP [5].

https://doi.org/10.1016/j.vaccine.2018.08.034
0264-410X/Ó 2018 Published by Elsevier Ltd.
This is an open access article under the CC BY IGO license. (http://creativecommons.org/licenses/by/3.0/igo/).
 G. Gongal, G. Sampath / Vaccine 37 (2019) A94–A98 A95

Fig. 1. Rabies endemicity (Number of Human rabies deaths per 100,000 population). Source: Hampson et al. [1].

Table 1 WHO Regional Office for South-East Asia (WHO SEARO) has pro-
List of Asian countries phasing out use of NTV and introduction of ID schedule. Source: moted the adoption of a cost-effective intradermal regimen in
WHO.
Member States through policy advocacy and capacity building. It
Countries Year is one of the strategic approaches under Regional Strategic Frame-
Last NTV use ID introduced work for elimination of human rabies transmitted by dogs to
Thailand 1992 1990
improve accessibility, affordability and availability of modern
Sri Lanka 1995 1997 rabies vaccines.
Bhutan 1996 2014
Philippines 1997 1998
Cambodia 2005 2000 2. General considerations for introduction of intradermal
India 2005 2006 vaccination
Nepal 2006 2017
Vietnam 2007 2007
The decision to implement economical intradermal post-
Bangladesh 2011 2010
Myanmar 2012 2013
exposure prophylaxis rests with government agencies that define
Pakistan 2015 2016 rabies prevention and prophylaxis policies in their own countries.
Any country willing to adopt an ID regimen of proven efficacy with
the recommended vaccines need not repeat immunogenicity
studies in their own population. When the intradermal route is
800 705 used, precautions should include staff training, implementation
Estimated cost of PEP provision

700 of appropriate vaccine storage protocols following reconstitution

586 and the use of appropriate 1 mL syringes with short hypodermic
600
needles. Health workers can easily learn this technique based on
in millions US$

500 466
past experience of administration of BCG vaccine and performing
400 347
the Tuberculin skin test. However, appropriate training should be
300 226.5 given to ensure complete intradermal instillation of the vaccine
200 and to avoid accidental subcutaneous injection. It should be noted
100 that many commercially available human rabies vaccines are
0 labelled for IM use and off label use of vaccines for ID administra-
100% 25% ID, 50% ID, 75% ID, 100% ID tion should be mentioned in national guidelines for PEP. There are
75% IM 50% IM 25% IM some vaccine brands which are labeled for both IM and ID use. The
Proportion of ID PEP to IM PEP (%) ID schedule should be introduced in major anti-rabies clinics
where the number of patients seeking PEP exceeds five or more
Fig. 2. Estimated costs of providing varying proportions of intradermal (ID) versus
(on any working day). Following reconstitution with the accompa-
intramuscular (IM) rabies post-exposure prophylaxis (PEP) to 4 million dog bite
patients.
nying sterile diluent, the vaccines should either be stored at +2 °C
to +8 °C and used within 6–8 h, or used immediately [8].

As shown in Fig. 2, if the intramuscular (IM) PEP regimen is used
over a period of 5 years, the estimated cost is US $705 million. In
contrast, if the intradermal (ID) PEP protocol is practiced, the esti-
mated cost will be almost two thirds less, at US $226.5 million. This
demonstrates the cost-effectiveness of ID versus IM PEP protocols.
Over 95% of patients are provided PEP using an ID regimen in Sri
Lanka (personal communication, Dr. Omala Wimalaratna).
3. Evolution of intradermal rabies vaccination
The ID route of vaccination against rabies was first licensed in
USA in 1986 for pre-exposure immunization. The evolution of
multisite intradermal regimen for post-exposure prophylaxis
(PEP) over the past 3 decades is presented in Fig. 3. The eight-
site regimen, also known as Oxford regimen [13] was introduced
A96 G. Gongal, G. Sampath / Vaccine 37 (2019) A94–A98

Fig. 3. Evolution of intradermal vaccination schedule.

in the 1980s, but due to the large number of inoculations required
on days 0 and 7 it was difficult to persuade patients, particularly
children, to undergo the full vaccination course and as such the
regimen did not gain popularity. The original TRC regimen was
designed to give a full vaccination course over a period of
3 months. This has been improvised in the last three decades in
regards to dose, frequency of vaccination and duration of vaccina-
tion to improve acceptance by health professionals and compliance
by patients, without compromising vaccine efficacy. The original
Thai Red Cross Regimen has been replaced with a one month
schedule, with two doses of vaccine given on days 0, 3, 7, and 28
(‘‘2-2-2-0-2” regimen), as per the recommendation of the eighth
WHO Expert Consultation [3]. The modified Thai Red Cross Regi-
men considerably improves compliance rates as patients receive
the full course of vaccine within a period of one month. In 2017,
the Strategic Advisory Group of Experts (SAGE) Working Group
on rabies vaccine, recommended a one week ID vaccination sched-
ule taking into consideration evidence-based information gener-
ated in Asian countries [8]. The WHO Expert Consultation on
Rabies, Third Report 2018, has also recommended a one week ID
schedule [9].
Different options are available for PEP of previously vaccinated
people. One intradermal dose of 0.1 mL per site is recommended
on days 0 and 3. As an alternative to this regimen, the patient
 G. Gongal, G. Sampath / Vaccine 37 (2019) A94–A98
Table 2
Currently recommended ID regimens [9].
Category I Exposure Category II Exposure
Post exposure prophylaxis
Washing of exposed skin surfaces Wound washing
No PEP required Immediate vaccination:
2 sites ID on days 0, 3 and 7 RIG is not indicated
Re –exposure (previously immunized individuals)
Category I Exposure Category II Exposure
Washing of exposed skin surfaces Wound washing
No PEP required Immediate vaccination: 1 site ID on days 0 and 3
(or) 4-sites ID on day 0 RIG is not indicated
Pre-exposure prophylaxis
2 Visits: 2 sites ID on days 0 and 7
RIG - Rabies immunoglobulin, PEP - Post-exposure prophylaxis, ID - Intradermal.
may be offered a single-visit 4-site intradermal regimen consisting
of 4 injections of 0.1 mL equally distributed over left and right del-
toids, if there is a time constraint. The currently recommended ID
regimen categories for PEP, re-exposure and PrEP are summarized
in Table 2.
4. Method of ID administration
Insulin syringes with a fixed needle of gauge 28 or more are
used for ID administration of the rabies vaccine. After reconstitu-
tion of the vaccine with the diluent supplied, 0.2 mL of the same
is loaded in the Insulin syringe. The needle is inserted into the skin,
almost parallel to the skin, with the bevel pointed upwards. 0.1 mL
of the reconstituted vaccine is injected into the dermis. Initially a
resistance is felt. If the vaccine is injected into the dermis, it results
in a blanched papule on the surface of the skin and finally a Peau
d’Orange appearance. The remaining 0.1 mL is injected into the
other site.
The sites recommended for ID vaccination are the deltoids,
suprascapular region and anterolateral part of the thigh. If the 2
site regimen is used, 0.1 mL is injected into each of the upper arms
(deltoid area).
5. Scientific basis
The skin is endowed with a network of dendritic cells, with
extensive connections to the lymphatic tissues. Once the vaccine
is injected via the ID route, the dendritic cells or the antigen pre-
senting cells capture, process the antigen and present it to the
immune effector T cells. By direct delivery of the antigen to the
immune system of the skin, a potentially greater immunogenicity
is achieved by the ID route, with a smaller dose of the vaccine,
when compared to IM or subcutaneous routes [12,13].
6. Issues and challenges
There are many challenges in the promotion of an ID schedule
as health workers are comfortable using a single dose IM regimen.
Although millions of people have received PEP using an ID regimen
in several Asian countries, health authorities in some countries
insist on performing clinical trials in indigenous populations which
is expensive and may be considered as lost opportunities to reduce
the cost of vaccination in public hospitals. There is some misunder-
standing or confusion among health workers that a different rabies
vaccine is used for the ID regimen. The vaccine used for ID admin-
istration is the same human rabies vaccine that is produced and
commercially available for the IM regimen.
A97
Category III Exposure
Wound washing Immediate vaccination:
2 sites ID on days 0, 3 and 7
RIG administration is recommended
Category III Exposure
Wound washing
Immediate vaccination: 1 site ID on
days 0 and 3 (or) 4-sites ID on day 0 RIG is not indicated
Previous WHO guidelines for intradermal administration of a
rabies vaccine in post-exposure situations clearly stated that the
volume of the ID dose is one fifth of the IM dose per ID site [6].
It varies according to that of the IM dose. i.e. if the IM dose is
0.5 mL, the ID dose is 0.1 mL/site. If the IM dose is 1 mL, the ID dose
is 0.2 mL per site [6,9]. There has been further WHO consultation
with rabies experts in subsequent years and it was recommended
that one ID dose is 0.1 mL of vaccine and one IM dose is an entire
vial of vaccine, irrespective of the vial size [8]. This was also based
on clinical studies [14].
Since the recommendation of the ID schedule by the WHO,
there has been significant discussion regarding potency require-
ments (antigenic content) of rabies vaccines for ID use. The
national regulatory authorities monitoring the procurement of
rabies vaccines for ID administration in certain countries, including
Sri Lanka, Philippines and Thailand, have requested greater
potency than the WHO-recommended value for rabies vaccine
used for ID/PEP [11]. WHO recommended a uniform ID dose of
0.1 mL for all CCVs having potency equal to or greater than 2.5 IU
per IM dose, based on well-designed clinical trials in 2004 [3].
Vaccine wastage is expected with the ID regimen due to the
short shelf life of the vaccine after reconstitution and fewer
patients at the time of vaccination. Once opened, vials should be
stored for no longer than 6–8 h, which will result in some wastage,
dependent on the open vial policy in some countries [7].To mini-
mize wastage of vaccines, at least 4 patients, new and repeat cases
put together, should attend the clinic on a given working day
within a period of 8 h after reconstitution of the vaccine. However
if adequate number of patients do not attend the clinic on a given
day, the remaining reconstituted vaccine can be used for PrEP of
other individuals.
Off label use of commercially available human rabies vaccine
for ID administration is an issue and labelling of human rabies vac-
cine for ID use is under jurisdiction of the respective National Drug
Regulatory Authority.
Only two WHO prequalified vaccines—purified Vero cell rabies
vaccine and purified chick embryo cell vaccine have been shown
to be safe and effective when administered intradermally at a dose
of 0.1 mL in a WHO recommended pre- or post-exposure prophy-
laxis regimen [7]. Intradermal vaccination was not recommended
in immunocompromised individuals due to impaired antibody
response in the past [10]. However, the current WHO position
paper recommends both IM and ID regimens in immunocompro-
mised individuals with sero-monitoring.
Poor patient compliance due to the need for several clinic visits
is one of the drawbacks of the currently recommended ID rabies
vaccination regimens. A series of clinical trial and field observations
over the past 3 decades have generated enough evidence-based
A98 G. Gongal, G. Sampath / Vaccine 37 (2019) A94–A98
information to recommend a one week ID schedule, helping to
address the issue of poor patient compliance.
The WHO expert consultation on rabies held in 2012 recom-
mended the development of appropriate, inexpensive devices
and pre-filled syringes to facilitate pre- and post-exposure prophy-
laxis for rabies [6]. The Programme for Appropriate Technology in
Health (PATH) came up with an innovative idea of developing ID
devices in India, in response to WHO recommendations, but it
had to abandon technology development in the final stages due
to legal and administrative barriers.
7. Future task
In 2015, the World Health Organization (WHO), Food and
Agriculture Organization of the United Nations (FAO), World
Organization for Animal Health (OIE) and the Global Alliance for
Rabies Control (GARC) set a goal of zero human deaths, worldwide,
due to dog-mediated rabies by 2030: Zero by 30. The ID adminis-
tration of rabies vaccines provides a cost-saving and dose-sparing
alternative to IM vaccination and should therefore be encouraged
in regions where affordability is a deterrent to accessing PEP. It is
extremely useful in those countries which are facing chronic short-
age of expensive human rabies vaccine and where government is
committed to ensuring universal health coverage and the achieve-
ment of zero human rabies deaths in an accelerated manner, i.e.
long before 2030.
The national authorities should consider revision of ID vaccina-
tion schedules in line with new WHO guidelines. Labelling of
commercially available human rabies vaccine for ID use should
be considered by the National Drug Regulatory Authority in coun-
tries where vaccine is produced for domestic consumption as well
as export to rabies endemic countries. Pharmaceutical companies
should be encouraged to undergo WHO pre-qualification proce-
dure to ensure GMP, as most rabies endemic countries rely on
them for quality assurance. It is important to develop intradermal
vaccination devices with proper dosing to promote ID schedules in
resource-poor rabies endemic countries.
Conflict of interest
All authors have no conflict of interest.
References
[1] Hampson K, Coudeville L, Lembo T, Sambo M, Kieffer A, et al. Estimating the
global burden of endemic canine rabies. PLoS Negl Trop Dis 2015;9(4):. ,
https://www.ncbi.nlm.nih.gov/pubmed/25881058. https://doi.org/10.1371/
journal.pntd.0003709e0003709.
[2] WHO. Rabies vaccines WHO position paper. Weekly epidemiological report,
vol. 85; 2010. p. 309–20.
[3] WHO expert consultation on rabies. First report. Tech rep series 931. Geneva
(Switzerland): World Health Organization; 2005.
[4] WHO expert committee on rabies. Tech rep series 824. Geneva (Switzerland);
1992.
[5] Gongal G, Wright AE. Human rabies in the WHO southeast Asia region:
forward steps for elimination. Adv Prevent Med 2011. https://doi.org/10.4061/
2011/383870 [5 pages]383870.
[6] WHO. Report of a WHO consultation on intradermal application of human
rabies vaccines, Geneva, Switzerland; 1995.
[7] WHO. WHO expert consultation on rabies. Second report, tech rep series 982.
Geneva (Switzerland): World Health Organization; 2013.
[8] WHO. Rabies vaccines and immunoglobulins: WHO position. WHO/CDS/NTD/
NZD/2018.04.
[9] WHO. WHO expert consultation on rabies. Third report TRS1012. Geneva
(Switzerland): World Health Organization; 2018.
[10] Kopel E et al. Inadequate antibody response to rabies vaccine in
immunocompromised patient. Emerg Infect Dis 2012;18:1493–5.
[11] Madhusudana S, Mani R. Expert Rev Vaccines 2014;13(5):641–55.
[12] Teunissen MB, Haniffa M, Collin MP. Insight into the immunobiology of human
skin and functional specialization of skin dendritic cell subsets to innovate ID
vaccination design. Curr Top Microbiol Immunol 2012;351:25–76.
[13] Warrell MJ, Suntharasamai P, Nicholson KG, et al. Multi-site ID and multi-site
subcutaneous rabies vaccination: improved economical regimens. Lancet
1984;1(8382):874–6.
[14] Briggs DJ, Banzhoff A, Nicolay U, et al. Antibody response of patients after post-
exposure rabies vaccination with small ID doses of purified chick embryo cell
vaccine or purified Vero cell rabies vaccine. Bull World Health Organ 2000;78
(5):693–8.