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Evaluating Rabies Pre‐exposure Prophylaxis 

Vaccination Schedules: 

PATRICK SOENTJENS

CHIEF PHYSICIAN, POLYCLINIC, ITM, ANTWERPCHAIR, BELGIAN STUDY GROUP TRAVEL MEDICINE

MED LT COL, HEAD, CENTER FOR INFECTIOUS DISEASES, MILITARY HOSPITAL BRUSSELS

No disclosures     

Disclosures

Background

Rabies PrEP

Rabies PrEP: prospective studies

Rabies PrEP: retrospective studies

Discussion

Conclusion

Rabies

“The Belgium experience” Rabies causes fatal encephalitis

‐ an estimated 59.000 ‐ 70.000 human deaths every year in endemic regions

‐ estimated risk for an animal bite in travellers: 

calculated 0,4 % per month staying in an endemic country

‐ 3 deaths per year in travellers

Background

Hampson et al. PloS Negl Trop Dis 2015WHO Wkly Epidemiol Rec 2010Gautret: JTravelMed 2012; Vaccine 2012; CurrOpin Infect Dis 2012

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Institut Pasteur de Paris

The 10th of October 2017 

Un cas de rage importé en France chez un enfant

Hospitalisé à Lyon, le garçon de 10 ans avait été mordu par un chien contaminé lors d’un séjour en août 2017 au Sri Lanka.

Background

Only the seventh known case in the United Kingdom since 2000.

England's health service issued a reminder Monday for travellers to avoid coming into contact with animals when travelling to rabies affected countries, particularly those in Asia and Africa

The 12th of Nov 201858 old Briton dies from rabies after cat bite in Morocco

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The 6th of May 2019

Norwegian woman dies from rabiesafter Philippines puppy bite

Birgitte Kallestad, 24 year old, was on holiday withfriends when they found the puppy on a street.

She fell ill soon after returning to Norway, and died on Monday at the hospital where she worked.

Family statement of Brigitte the 15th of May at www.promed.org

"Our dear Birgitte loved animals. Our fear is that such fate may happen to others who have a warm heart like her. We want rabies vaccine to be included in the program for travellers to locations where the disease is present, and that people become more aware of the danger. If we manage to achieve this, the death of our sunbeam can save others. Warm greetings from the family."

Rabies risk during travel: low risk – animal bite: high risk

Background

Steffen: J Travel Med 2015 and adapted 2018

Start PEPimmediately

Rabies risk: prevention

Increase awareness

Avoid contact with street dogs, monkeys and other mammals

Background

Shlim: J Travel Med 2019

Rabies risk: have a back‐up plan

Travel insurance 

Background

Shlim: J Travel Med 2019

Rabies risk: start Rabies PEP procedure in time

Washing ‐ Soap ‐ Desinfection

Respective PEP schedule and HRIG   

Background

WHO report 2018

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Rabies risk: difficulties with Human Rabies Immunoglobulins (HRIG)

In time ‐ Availability ‐ Costs?

Equine Rabies Immunoglobulins?

Background

Belgian Rabies PEP data 2017 with use of HRIG in BE 

N = 75

44 of the cases (58%) were female. 

Mean age was 33 years (interquartile range 24 ‐ 51; range: 4 ‐ 85). 

Mean time delay between exposure and the administered HRIG was 8.7 days: 

‐ 9.6 days (IQR 2,5 ‐ 9) for abroad travel‐ 6 days (IQR 1 ‐ 4) for inland bat‐related risks. 

Mean time delay between exposure and the first administered dose of rabies vaccine was 7.7 days: 

‐ 8.3 days (IQR 0 ‐ 8,5) for abroad travel‐ 6 days (IQR 1 ‐ 4) for inland bat‐related risks

Background

Soentjens et al Acta Clin Belgica 2019

Immunescence following Rabies PEP: research gaps

Belgian Rabies PEP data 2017 ITMN = 63 (of 75)

One single patient had no response (RFFIT < 0.5 IU/mL) after a full 51IM PEP schedule with HRIG

The timing of the vaccinations and the serology test were in accordance 

Age = 80 years

Serology testing (RFFIT) is crucial in Rabies PEP when decreasing PrEP and PEP doses

Background

Soentjens et al Acta Clin Belgica 2019 Clin Infect Dis 2012

Concept BOOST

Rabies pre‐ and postexposure prophylaxis (PEP without PrEP) 

‘Adequate immune response = lifelong antibodies RFFIT > 0.5 IU/mL’

No PrEP schedule

RFFIT > 0.5 IU/mlWHO guideline

Risk cat III PEP IM schedule

Naive B‐cells

Rabies PEP schedules in Belgium (2019)

Schedules D0 D3 D7 D14 D21 D28 D+10 IndicationsRabies PEP after PrEPSchedule 1: 

2 intramuscular njections / 2 visits

1 x 1 x No RFFIT Contact category II en III 

4 intradermal injections / 1  visit

1 injection = 0.1 mL

Rabies PEP without previous PrEPSchedule 2:

4 intramuscular injections / 3 visits

2 x 1 x 1 x No RFFIT Contact category II 

Exception to do RFFIT on D31 if:

‐ vaccination schedule startedoverseas

‐ in ‘vulnerable’ patients

Schedule 3:

5 intramuscular injections / 5 visits

+ Human rabies immunoglobulins

(HRIG)

1 x 1 x 1 x 1 x 1 x RFFIT

D38

Contact category III

Result RFFIT > 3.0 IU/ml

Result RFFIT > 5.0 IU/ml 

(if bat‐related or immunosuppression)

1 x

PEP: post‐ exposure prophylaxis – PrEP: pre‐exposure prophylaxis – RFFIT: rabies rapid fluorescent focus inhibition test

RFFIT: rabies rapid fluorescent focus inhibition test is key in rabies prevention procedures

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New BE guideline 2019: sparing HRIG

HRIGonly in wound ‐ same dosage (20 IU/kg) or less

inject minimal 2 mL

Rabies PEP 2019

https://www.itg.be/Files/docs/Reisgeneeskunde/PEP_Rabies_ENG.pdf

Concept BOOST

Rabies pre‐ and postexposure prophylaxis (PEP without PrEP) 

‘Adequate immune response = lifelong antibodies RFFIT > 0.5 IU/mL’

No PrEP schedule

RFFIT > 0.5 IU/mlWHO guideline

Risk cat III PEP schedule

RFFIT > 3.0 IU/mlBE guideline

Rabies risk: promote pre‐exposure vaccination

Revised WHO recommendations for rabies pre‐exposure prophylaxis in travellers: avoid bumpy roads, select the highway!

Background

Knopf, Steffen: J Travel Med 2019

Tackling the high rabies human case fatality rate

To use newer practical regimens ‐ 1 deceased 10 y France

‐ 1 deceased 58 y UK

‐ 1 deceased 24 y Norway

Background

PrEP + PEP 2ID mL

PrEP 2 0.4 mL

PEP 1 0.4 mL

Total visits 3 0.8 mL

Intradermal

Background

Rabies PrEP

Rabies PrEP: prospective studies

Rabies PrEP: retrospective studies

Discussion

Conclusion

Rabies

“The Belgium experience”

New WHO publication since the 17th of April 2018:

Technical Report

Rabies PrEP

Guidelines on PrEP and PEP

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WHO publication of the 17th of Apr 2018:

Promote intradermal (ID) schedules‐ ID as effective as IM injection

‐ Technical guidance: ID technique is not difficult

‐ Use always single‐dose injections on two sites during each visit

But ID schedules are off‐label…

Background

= 

WHO guidelines > 2‐visit regimen for rabies PrEP: 2ID or 2IM 

Rabies PrEP

21IM

2²ID

WHO guidelines: BE guideline from 1st May 2018: two‐visit regimens

New Rabies PrEP regimens that are recommended in first line 

for individuals of all ages are:

‐ 2‐site ID vaccine administration on day 0 and 7

2²ID double dose 2x 0.1 ml on day 0 and day 7

‐ 1‐site IM vaccine administration on day 0 and 7 

21IM single dose 1x ampoule (1ml) on day 0 and day 7 

Rabies PrEP

Day 0 Day 7

Rabies PrEP completed, additional vaccines needed

after bite / risk

WHO guidelines: 1‐visit regimen: 1ID or 1IM

Rabies PrEP

1²ID11IM

Preferred rabies PrEP schedule: two‐visit schedules

Use a one visit rabies PrEP schedule in last‐minute travelers

‐ ID0.1ml d 0 ID (double dose)  > d X ID after travel (double dose)

‐ IM1.0 ml  d 0 IM  > d X after travel

Rabies PrEP guideline in BE (from 1st of May 2018)

Changing the PrEP strategy from strictly 3 visits to 2 visits > to 1 visit as an option 

Rabies PrEP completed, additional vaccines neededafter bite / risk

Add stamp

Who is using this PrEP regimens? Off‐label

No guideline to use off‐label: optional by practitioner

2²ID Ireland?, Australia?, New Zealand?

21IM Germany

Guideline to use off‐label

2²ID Belgium, The Netherlands, Canada, Japan, …

21IM Belgium, Denmark, The Netherlands, Canada,…

1²ID or 11IM Belgium,…

Guidelines on 2IM + booster

Adapted 31IM: 21IM + 11IM Switzerland

Unchanged guidelines on 3IM + booster

Adapted 31IM + booster 11IM UK, USA, Germany, France, Italy, Spain,…

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Langedijck et al. Clin Infect Dis 2018

22 studies included in meta‐analysis

N Age Rabies PreP IM PEP IMDay 0 (‐ 3)

RFFIT ≥ 0,5IU/ml

GMTMeanIU/ml

Strady2009N = 274

42 years(12‐79) 33% F

2IM HDCV‐PVRV

2IM HDCV‐PVRVafter 10 y 

100% 35.6 D14

Vien2008N = 86

2 ‐ 4 m50% F

2IM PVRV2 months

1IMPVRVafter 1 y

100% 35,0D14

Rabies 2-visit IM: prime and boost

D0 D56

D0 D3D7D0

D0

N = 360 subjects 2IM

N Age Rabies PreP ID PEP IDDay 0 ( ‐ 3)

RFFIT ≥ 0,5IU/ml

GMTMeanIU/ml

Kamoltham2007N = 84

5‐8 yearsF 46%

PCECV2ID 0,1 ml

1 year PCECV2ID 0,1 ml

D7 96%

D14 100%

D7  4.69

D14  10.76

Pengsaa2009N = 44

12‐18 months

PCECV2ID 0,1 ml

1 year PCECV1ID 0,1ml

D7 100% 13.0

Wongsaroj2013N = 36

18‐24 years

PVRV2ID 2x0,1 ml

1 year PVRV1ID 0,1 ml

D14 100% 14.38

PrEP rabies 2-visit ID: prime and boost

D28 D3

D0 D28

D0 D0

D0

D21 D0 D3D0

N = 164 subjects 2ID 

N Age Rabies PreP ID % > 0.5 IU/ml GMTMeanIU/ml

Mills2011N = 420

10‐65 yearsF: 54%

HDCV2ID 0,1 ml

ELISA After D14 to D21

94,5%

No data

Lau2013N = 54

Years10‐49 yearsF: 50%

PCECV2ID 0,1 ml

ELISAAfter 21 days

94,4%

De Pijper2018N = 430

18‐48 yearsM: 97%

PVRV2ID 2x0,1 ml

RFFITAfter 14 days

99,3%

After 14 days6.25 (80%)

After 21 days15.65 (20%)

Other rabies 2-visit ID: prime without boost

D28

D0 D28

D0

D7

0,5 ml

D0

N = 904 subjects 2ID

IM versus single-dose ID regimens

PrEP IM 3x 1.0 mL << >> ID 3x 0.1 ID d0 ‐ d7 ‐ d28 (single dose)

S. Recuenco et al. Vaccine 2017.

PrEP IM

PrEP ID

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IM versus single-dose ID regimens

PEP 1IM (1 mL) versus 1ID (0.1 mL) (single dose!) 

S. Recuenco et al. Vaccine 2017.

PEP IM

PEP ID

• Those who spend long periods in at‐risk areas or in remote areas where nomedical assistance is available promptly.

• Those who often travel to endemic regions or will do so frequently in thefuture.

• Travellers who undertake long cycle rides or joggers in endemic regions.

• Children who go and live with their parents in endemic regions.

• Those with an increased risk due to their profession or activities, such asvets, foresters, veterinary students or bat protection volunteers.

• Military personnel who go to endemic regions on missions.

• Laboratory staff or experts who come into contact with the virus forprofessional reasons (e.g. laboratory activities).

Recommendation of Belgian Superior Health Council:Preventive vaccination is recommended for the following people:

Rabies PrEP and PEP schedules (Belgium 2019) SchedulePrEP

Volume Day 0

Day 7

Day X

Day Y

SchedulePEP

Volume Day 0

Day3

Day7

Day 14‐21

Day 28

TotalVolume

New standard PrEP ID (2 visits) with PEP ID (1 visit) 

2²ID 4 x 0,1 mL

14ID  4 x 0,1 mL 0.8 mL

Alternative PrEP ID (1 visit + 1 visit X) with PEP ID (1 visit) in travellers

2²ID 4 x 0,1 mL

14ID  4 x 0,1 mL 0.8 mL

New standard PrEP IM (2 visits) with PEP IM (2 visits) 

21IM  2 x 1.0 mL

21IM  2 x 1.0 mL 4.0 mL

Alternative PrEP ID (1 visit + 1 visit X) with PEP ID (1 visit) in travellers

11IM  1 x 1.0 mL

2 x 1.0 mL 4.0 mL

Standard PEP IM (3 visits) without MARIG

41IM 4 x 0.1 mL 4.0 mL

Standard PEP IM (5 visits) with MARIG

51IM 

+HRIG

5 x 1.0 mL 5.0 mL+2 ‐ 8 mL

+ RFFIT

RFFIT Rabies Fluorescent Focus Inhibition Test

Background

Rabies PrEP

Rabies PrEP: prospective studies

Rabies PrEP: retrospective studies

Discussion

Conclusion

Rabies

“The Belgium experience”

Rabies vaccination schedules in Belgian soldiers: “it started as a small project”

Shortage of immunoglobulins

‐ Advise pre‐exposure vaccination in high risk or long‐term travelers

Shortage of vaccine ‐ Promote volume‐sparing intradermal vaccination

High cost of primary vaccination 

‐ Promote low cost intradermal vaccination

Lack of preparation time 

‐ Evaluate shorter schedules of intradermal pre‐exposure vaccination

Rationale to use simplified intradermal (ID) regimens

Lembo PlosNTD 2010Wilde JTravel Med 2013; Bourhy Eurosurveil 2009Khawlplod JTravelMed 2002 - 2007; Vaccine 2012Mills JTravelMed 2011

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Rationale for simplified ID regimens Intradermal Rabies PrEP in BE troopsID injection by stimulating dendritic cells in the skin and lymph nodes

Reduced dose ‐ volume

‐ 1/10th of 1 ml IM dose: 1 x 0.1 ml ID                            0.1ID 11ID

‐ 1/5th of 1 ml IM dose: 2 x 0.1 ml ID                              2x 0.1ID 1²ID

Shortening priming schedules

More than N = 10.000 subjects are vaccinated

Number of visits Priming schedule

41ID: 4 visits: single shots of 0.1 ml

31ID: 3 visits: single shots of 0.1 ml

2²ID: 2 visits: two shots of 0.1 ml 

1²ID: 1 visit: two shots of 0.1 ml

Reference centers for ID use for technical reasons???

ID technique = easy to learn

‐ always double‐dose ID regimens

‐ use syringes for diabetic use

‐ prepare 0,10 – 0,13 mL for each injection site 

‐ inject always in both (fore)arms

‐ check the size of the papule (> 6 mm is fine, if not sure – revaccinate)

‐ add a stamp in the vaccination card (necessary due the different regimens used worldwide)

Technical problems with ID use Prospective RCTs on ID Rabies PrEP and PEP schedules in BE Armed Forces

HealthyBE soldiers

PrEP Volume Day 0 Day 7 Day 28

%RFFIT> 0.5 IU/mL

GMT PEP Volume Day 0

%RFFIT

> 0.5 IU/mLDay 7

GMT

RCT 1 

N = 250 2²ID 4 x 0.1 mL 100% 13 11ID  1 x 0,1 mL 100% 37

N = 250  31ID 3 x 0.1 mL 100% 18 11ID 1 x 0.1 mL 100% 25

RCT 2 

N = 151

1²ID 2 x 0.1 mL

83,5%D14

1.3 14ID  4 x 0.1 mL 99,3% 20

N = 151 1²ID  2 x 0.1 mL 99,3% 14

ImiQ: application of topical Imiquimod at time of injection during 6 hours Intramuscular injection and rabies immunoglobulines

Intradermal injection

P. Soentjens Clin Infect Dis 2018 P. Soentjens Clin Infect Dis 2019

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Prospective RCTs on ID Rabies PrEP and PEP schedules in BE Armed Forces

HealthyBE soldiers

PrEP Volume Day 0 Day 7 Day 28

%RFFIT> 0.5 IU/mL

GMT PEP Volume Day 0

%RFFIT

> 0.5 IU/mLDay 7

GMT

RCT 1 

N = 250 2²ID 4 x 0.1 mL 100% 13 11ID  1 x 0,1 mL 100% 37

N = 250  31ID 3 x 0.1 mL 100% 18 11ID 1 x 0.1 mL 100% 25

RCT 2 

N = 151

1²ID 2 x 0.1 mL

83%D14

1.3 14ID  4 x 0.1 mL 99,3% 20

N = 151 1²ID  2 x 0.1 mL 99,3% 14

ImiQ: application of topical Imiquimod at time of injection during 6 hours Intramuscular injection and rabies immunoglobulines

Intradermal injection

Prospective RCTs on ID Rabies PrEP and PEP schedules in BE Armed Forces

HealthyBE soldiers

PrEP Volume Day 0 Day 7 Day 28

%RFFIT> 0.5 IU/mL

GMT PEP Volume Day 0

%RFFIT

> 0.5 IU/mLDay 7

GMT

RCT 1 

N = 250 2²ID 4 x 0.1 mL 100% 13 11ID  1 x 0,1 mL 100% 37

N = 250  31ID 3 x 0.1 mL 100% 18 11ID 1 x 0.1 mL 100% 25

RCT 2 

N = 151

1²ID 2 x 0.1 mL

83%D14

1.3 14ID  4 x 0.1 mL 99,3% 20

N = 151 1²ID  2 x 0.1 mL 99,3% 14

ImiQ: application of topical Imiquimod at time of injection during 6 hours Intramuscular injection and rabies immunoglobulines

Intradermal injection

50%VAX‐ID

Novosanis

VAX‐ID device

RCT3: 1²ID: Evaluating the VAX-ID™ device

Easier in use?More effective?Lesser pain?

Background

Rabies PrEP

Rabies PrEP: prospective studies

Rabies PrEP: retrospective studies

Discussion

Conclusion

Rabies

“The Belgium experience”

Retrospective studies on ID Rabies PrEP (and PEP) schedules in Belgian Armed Forces

BE soldiers

PrEP VolumeDay0

Day 7

Day 28

Day 365

%RFFIT

> 0.5 IU/mL

%RFFIT> 3.0 IU/mL

PEPBE soldiers

VolumeDay 0

%RFFIT> 0.5 IU/mLDay 7

%RFFIT

> 3.0 IU/mL

Retro 1 

N= 881  41ID 4 x 0.1 mL

100%mean = 145drange 7 – 1603

96,6%

Retro2 N= 489 31ID 3 x 0,1 

mL82%

Mean = 405d 

35%Mean = 405d 

11ID  N = 43 1 x 0.1 mL

100%

Retro 3

N= 2112 31ID 3 x 0,1 mL

99,9% 83,9%

Retro 4

N= 301 2²ID 2 x 2 x 0.1 mL

98,8% 81,7%

Intradermal injection of 0,1 mL of rabies vaccine

B.Damanet et al. CISTM 2019

N = 3783

Background

Rabies PrEP

Rabies PrEP: prospective studies

Rabies PrEP: retrospective studies

Discussion

Conclusion

Rabies

“The Belgium experience”

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Discussion: schedule needs to be 100% effective

Use a regimen that is 100% preventable

Discussion

Among all the infectious diseases, rabies is the most easy to prevent’

Use a regimen that is 100% preventible

Discussion

9IM

PrEP 0

PEP 9

Totalvisits

9

To use a regimen that is 100% preventable

Discussion

9IM 5IM 3IM 6ID6IM

5ID5IM

4ID4IM

3ID3IM

3ID3IM

2ID2IM

PrEP 0 0 0 4 3 2 2 1 1

PEP 9 5 3 2 2 2 1 2 1

Totalvisits

9 5 3 6 5 4 3 3 2

Use a regimen that is 100% preventable

Discussion

4IM

PrEP 2

PEP 2

Totalvisits

4

3ID

PrEP 2

PEP 1

Totalvisits

3

Intradermal OK Intramuscular OK

Discussion: future studies

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Subject

‐ Older age (> 50 years)

‐ Vulnerable population like immunosuppressed

‐ Children

Booster studies after primary vaccination with some larger time delay

Immunological studies: B‐ cell and T‐cell function

Use of enhancers, like adjuvants

Use of devices or patches      

Future studies on 1²ID - 2²ID - 1IM - 2IM

Leo Vissers’ team Leiden (NL)1²ID ‐ 2²ID ‐ 1IM ‐ 2IMB‐cell and T‐cellOlder age

Discussion: long-lasting immunityPersistance of Antibodies

JTM 2007

Malerczyk

Vaccine 2006

Suwansrinon

Vaccine2008Brown

Vaccine2011Fayaz

N 15 118 89 26

IM or ID IM/IDPrEP

IM/IDPrEP

IDPrEP

IMPEP

RFFIT> 0,5 IU/ml

22% 100 % 100 %

RFFIT> 0,5 IU/mlAfter booster

100%1 x 1 mL IM

100%d0 0,1 mL IDd3 0,1 mL ID

100 %+ 1 booster IM (65%)

Time intervalAfter PrEP/PEP

15 years 21 years 10 years 32 years

Discussion: increase in use 13 BE clinics: 2‐visit ID and IM regimen (mostly 2IM)

2 BE centers: 2‐visit ID rabies regimen Discussion: costs

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Costs of 3IM – 2IM – 2²ID  Discussion: vaccine volume

Limited vaccine volume

Vaccine stock of every travel clinic = limited(related to pharmaceutical production = limited worldwide)

Travel clinic stockN= 1000 vaccines 1 ml

Subjects reached by IM

Subjects reached by ID

3‐visit 333 > 3000Single dose/visit

2‐visit 500 > 2000Double dose/visit

1‐visit (1000) (+/‐ 5000)Double dose/visit

What are the barriers?

• ID: off‐label ‐ difficult technique ‐ painful ‐ research on single‐visit regimens 

• Vaccine: more stock ‐ cost ‐more potent (single‐visit) ‐ no cold chain ‐more production ‐ small incubator

• Devices: needle‐free – others

• Surveillance

Discussion

Off-label intradermal schedules for Rabies

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Used since 1960

Recommended by WHO since 1984

Packaging containing 1/10 (0,1 ml), approved by the US FDA in 1984 but withdrawn

Still recommended by WHO in 2013

Not recommended anymore by the UK and the US authorities

Since 2018 recommended by WHO only as double-dose during each visit

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Conclusion

‐ Have a plan for rabies: rabies low‐risk – rabies PEP procedures high risk

‐ Off‐label use is a regulatory barrier in some countries.

‐ The studies on two‐visit rabies PrEP regimens = highway  ‐ Double‐dose single‐visit 1²ID and double‐dose two‐visit 2²ID are 

schedules, that are easy in use, safe, and at low cost.‐ Single‐visit 1²ID PrEP schedule provides an adequate immune response 7 

days after booster doses.

‐ Investment once in a lifetime!

Many thanks

Collaborators

Institute of Tropical Medicine Antwerp Yven Van Herreweghe, PhDNatacha HerssensBart SmekensAchilleas TsoumanisChristophe Burm

Military Hospital Queen Astrid Brussels,Belgian Defense

Petra AndriesBenjamin DamanetKatrien De KoninckEric Dooms, MDPeter Vanbrabant, MDMony Hing, MDQuentin Ledure, PhaKatrijn Ghoos, MDSarah Djebara, MD

Scientific Institute of Public Health Brussels

Steven Van Gucht, Vet PhDSanne Terryn, Vet PhD

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