Updated on Regimens for Post-Exposure Prophylaxis Rabies-Free... · Flury LP PM-strain b PM-strain PM-strain b Human culture Fibroblasts Chick embryo cell Vero cell inactivated Vero

Prof. Terapong Tantawichien, MD.

President of Infectious Diseases

Association of Thailand

Head of Division of Infectious Diseases,

Department of Medicine,

Chulalongkorn University

Assistant Director of Queen Savabha

Memorial Institute, Thaialnd

Updated on Regimens for Post-Exposure Prophylaxis

Post-Exposure Prophylaxis ( PEP) for Possible Rabies Exposure

Any animal bite or scratch should receive prompt local first aid by

thorough cleansing of wound with soap and povidone iodine.

Non-immunized patient will need to obtain full PEP in the event of

a possible exposure to a proven or suspected rabid animal. RIG and a

series of vaccination for severe exposure.

Concern: - RIG or rabies vaccine may not be available in

the destination country.

- Different post-exposure vaccine schedules,

alternative routes of administration, and other

rabies vaccines may be used abroad.

Immunized patient (who have completed a pre-exposure or post-

exposure rabies immunization) received the only booster vaccination

and do not require RIG.

Regimen Day 0-Day 3-Day 7-Day 14-Day 28-Day 90

Essen IM

Zagreb

(2-1-1) IM

TRC-ID

Booster

Vaccination

For pre-immunized host WHO 2013

1-1-1-1-1-0 or

1-1-1-1-0-0

( US, alternative WHO - Healthy, fully immune

competent host-WHO (vial/site)

2-0-1-0-1-0 (vial/site)

2-2-2-0-2 (0.1 ml/site)-modified

WHO- not definite potency for ID dose

REGIMENS FOR POST-EXPOSURE TREATMENT

1-1 IM or ID 4-site ID on single day

WHO recommendation: two doses of intramuscular (IM) or intradermal

(ID) vaccination on days 0 and 3.

As an alternative regimen, the patient may be offered a single-visit 4-

site ID regimen consisting of 4 injections of 0.1 mL of CCV equally

distributed over deltoids or anterior thighs.

Time

Primary vaccination

(tissue-culture vaccines) day 0 day 3

4-site ID:

Detoid and

Thigh or suprascrapular area

1 site ID

IM

1 site ID

IM

WHO Position Paper : Wkly Epidemiol Rec 2010(August 6) WHO 2013

RABIES EXPOSURE

Conventional Booster

vaccination

Alternative Booster vaccination

Rabies Vaccines and Immunoglobulin for Humans

Vaccine name Virus strain Substrate Type

Cell-culture

Human diploid cell culture

(HDCV)

Purified chick embryo cell

(PCECV)

Purified Vero cell (PVRV)

VERORAB, ABHAYRAB

Chromatographic

Purified Vero cell (CPRV)

Purified duck embryo (PDEV)

PM-strain

Flury LP

PM-strain

PM-strain

PM-strain

Human culture

Fibroblasts

Chick embryo cell

Vero cell

Vero cell

Duck embryo

b-Propiolactone-

inactivated

b-Propiolactone-

inactivated

b-Propiolactone-

inactivated

b-Propiolactone-

inactivated

b-Propiolactone-

inactivated

Highly purified equine RIG (ERIG) are now being manufactured in

Europe, Thailand, India, China and South America. HRIG – local products ( The Thai Red Cross Society,….)

Future Regimens for Post-Exposure Prophylaxis ?

Shorten regimens Reduced cost of vaccine High immunogenicity

Less visits

Safe and less side effects

Day 0 3 7 14

A control group received 2-site intradermal injections on days 0, 3, and 7 and 1 injection on days 28 and 90 ( standard TRC-ID) with equine rabies immunoglobulin. Results. All subjects in all groups had NAb value 0.5 IU/mL on days 14 and 28. The percentages of subjects who had a NAb value 0.5 IU/mL from days 0 through 360 were not significantly different among the 3 groups. GMTs for subjects receiving the 4-site intradermal regimen, with or without ERIG, had significantly higher NAb values than did the control group on day 14 and 28 . Clin Infect Dis 2010

4-site intradermal injections of 0.1 mL of PVRV to the deltoids and thighs on days 0, 3, and 7, with and without equine rabies immunoglobulin (40 IU/kg).

4-site ID

Evaluation of a one week intradermal regimen for rabies post-

exposure prophylaxis: Results of a randomized, open label,

active-controlled trial in healthy adult volunteers in India Sudarshan MK ; Human Vaccine Immunotherapeutic 2012 80 adult volunteers were enrolled and randomly either to PCECV or PVRV,

Each subject received intradermally one of the vaccines, using the one week regimen (4–4-4). Blood samples were collected on Days 0, 7, 14, 28,180 and 365

Rabies virus neutralizing antibody response following “single visit – 4 sites” ID booster

vaccination with PCECV and PVRV

Days Vaccine No. of

subjects

Range

of

RVNA

conc.

GMC

95% Confidence

Interval for GMC

t-value

P-value

(two-

tailed) Lower

Bound

Upper

Bound

Day 7 PCECV 8 2.5–5.5 3.81 3.13 4.64

0.515 0.612 PVRV 14 2.5–5.7 3.60 3.11 4.17

Day 14 PCECV 8 7.5–10.5 8.93 7.92 10.08

0.495 0.626 PVRV 14 6.5–10.6 8.62 7.81 9.51

Comparison of safety and immunogenicity of 2 WHO

prequalified rabies vaccines administered by one week,

4 site intra dermal regimen (4-4-4-0-0) in animal bite cases Narayana A; Human Vaccine Immunotherapeutic 2015 Comparative, open label, phase III, randomized clinical trial conducted in India.

90 subjects with CAT II/III exposures: ERIG was administered to CAT III exposures.

0.1 mL of either PCECV or PVRV was administered intradermally into 4 sites on days 0, 3 and 7 to all subjects.

Day of

blood

sample

Vaccine No. of

subjects

Range

(IU/mL)

GMC

(IU/mL)

95% CI t-value P value

Lower

Bound

Upper

Bound

14 Rabipur 45 4.5–16.5 14.50 13.50 15.57 0.095 0.924

Verorab 44 4.5–16.5 14.43 13.41 15.53

90 Rabipur 42 6.5–14.5 11.78 11.27 12.31 0.432 0.667

Verorab 43 10.5–14.5 11.93 11.47 12.40

365 Rabipur 32 4.5–8.5 5.95 5.50 6.44 0.933 0.354

Verorab 38 4.5–7.5 5.67 5.29 6.08

Comparison of geometric mean RVNA concentration following administration of Rabipur or Verorab using one week, 4 site ID regimen in animal bite cases

WHO recommendation (2013):

- 1 dose of IM or intradermal (ID) vaccination on days 0 and 3.

- Alternative regimen, a single-visit 4-site ID regimen consisting of

4 injections of 0.1 mL of CCV equally distributed over deltoids

or anterior thighs.

Time

Primary vaccination

(cell-culture vaccines) day 0 day 3

4-site ID:

Detoid and

Thigh or suprascrapular area

1 site ID

IM

1 site ID

IM

WHO Position Paper : Wkly Epidemiol Rec 2010(August 6) WHO 2013

RABIES EXPOSURE

Conventional Booster

vaccination

Alternative Booster vaccination

Clin Infect Dis 2001

Clin Infect Dis 2010

The period from 1998 through 2008 at QSMI, 5116 patients who received the

4-site booster vaccinations. 3335 patients (65.2%) had WHO category III risk

253 (4.95%) of the 5116 patients were bitten by animals with proven rabies.

No treatment failure, reduced direct and indirect cost of treatment

We conducted a prospective study of neutralizing antibody (Nab)

response after single-visit booster regimens compared with

conventional IM booster vaccination for PEP.

New Single-Visit Booster Regimens:

Time

Primary vaccination

(cell--culture vaccines) day 0 day 3

1 site ID

IM

1 site ID

IM

RABIES EXPOSURE

Alternative booster vaccination ?

• 2-site ID booster regimen with CCV administered on day 0

(may reduce the volume of vaccine and adverse reaction).

• One intramuscular booster with CCV dissolved in aluminium-

adjuvanted tetanus toxoid on day 0 (Phanuphak P, et al. Immunoenhancement

with combined rabies and aluminium-adjuvanted tetanus vaccines. Vaccine 1989; 7:249-52).

Time

Pre-exposure vaccination

(PVRV) day 0 day 3

Single-visit booster Group A (n=22) - 0.1 mL x 2 ID injections (total= 0.2mL)

Group B (n=22) - 0.2 mL x 2 ID injections (total= 0.4mL)

Group C (n=20) - 0.5 mL x 1 IM injection (dissolved in adjuvented TT)

Conventional booster (control)

Group D(n=22) – conventional 2 doses IM

0.5 mL x 1 IM injection on days 0 and 3

1 site IM 1 site IM

1 year later and no rabies exposure

Materials and Methods

A group of 86 healthy subjects (age range 19-20 years) who had received an

intradermal pre-exposure vaccination with purified Vero cell rabies vaccine

(PVRV; Verorab®: Sanofi Pasteur, France; batch number E0316-; potency, 13.1

IU/0.5 mL) 1 year earlier were recruited and randomly divided into 4 groups:

PVRV (Verorab®; Sanofi Pasteur, France; batch E0316;potency of 13.1 IU per ampule

and contains 0.5 mL of the diluent volume (potency, 2.6 IU /0.1 mL, 5.2 IU/0.2 mL).

Table 1. GMTs and range of titers of rabies Nab following different

booster regimens ( gr. A, gr B, gr C ) and conventional intramuscular

booster vaccination ( gr. D )

Days after booster vaccination

Group,finding 0 5 14 30** 180 360

Group A: 2-site 0.1ml ID day 0(n=22):GMT 0.7 2.2 18.5* 21.3 12.9 9.3

Range of Nab .3-3.9 .3-26.1 4.6-118 5.3-136 2.7-218 1.8-80.5

Subjects Nab <0.5 IU/ml 6 1 0 0 0 0

Group B: 2-site 0.2ml ID day0(n=22):GMT 0.7 2.2 40.5 39.6 27.0 13.2

Range of Nab titers .2-2.3 .7-9.2 9.6-648 3.3-569 1.3-336 2.1-218

Subjects Nab <0.5 IU/ml 7 0 0 0 0 0

Group C: 0ne IM+TT days 0 (n=20): GMT 0.6 1.4 37.0 32.1 ND 6.15

Range of Nab titers .07-2.2 0.1-5.7 8.5-147 10.5-147 ND 1.4-29.7

Subjects Nab <0.5 IU/ml 2 0 0 0 ND 0

Group D: control IM days 0,3 (n=22): GMT 0.7 1.1 40.9 25.8 16.8 6.3

Range of Nab titers .2-2.2 .3-5.0 6.2-208 4.8-136 2.7-175 1.2-45.5

Subjects Nab <0.5 IU/ml 6 2 0 0 0 0

*p<.05 gr. A vs. gr. B, C and D(control), **P< .05 gr. B vs. gr. A and D(control)

GMT of Nab group A was sig. lower than group B, C and D on day 14 (P <.05).

GMTs of Nab in group B (0.2 mL/ID site) were significantly higher than group A

(0.1 mL/ID site) and D on days 30 (P<.05).

There was no significant diff. between group C and group D (p > .05).

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