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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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