National Center for Emerging and Zoonotic 

Infectious Diseases

Rabies immune globulin

Agam Rao, MD

CAPT, United States Public Health Service

CDC Lead for Rabies ACIP Workgroup

Advisory Committee on Immunization Practices meeting

June 24, 2021
Viral pathogenesis of rabies

 Neurotrophic virus

– Enters peripheral nerves

– Travels centripetally to Central 

Nervous System 

– Flows centrifugally to innervated 

organs, including salivary glands 

 Incubation period usually weeks to 

months

 Death typically within 2 weeks of 

illness onset

Site of 

animal 

bite
Role of rabies immune globulin (RIG) in 

preventing rabies

 Provide passive immunity before vaccine-induced 

humoral immunity occurs

 Given only to persons who have not received PrEP or 

previous PEP

 Does not negate the need for PEP vaccines because at 

least some rabies virus is expected to travel to the CNS
• First exposure to 

rabies virus

• Wound washing 

& PEP = RIG + 

vaccines IM [0, 

3, 7, 14 days]

Time (years)

21 33 40

Indications for Rabies Immune Globulin

A) Persons who did not previously receive complete series 

of recommended PrEP or PEP
Indications for Rabies Immune Globulin

B) For persons who received previous 2-dose PrEP but:

Did not receive titer or booster within 3 years (newly passed 

ACIP recommendations)

Time since 2-dose PrEP series

Days 0 and 7

PrEP

> 3 years

Rabies 

exposure

Wound washing + to be cautious:

PEP = RIG + vaccine IM[0, 3, 7, 14 days]
Rabies virus 

concentration

Days after an exposure

Rabies 

Exposure

0 3 7 14

Virus present 

at entry site

Incubation period

(5 days to > 2 years)

Prodrome

(0-10 

days)

Acute 

neurologic 

period (2-7 

days)

Coma

(5-14 

days)

Death

CNS 

virus

Salivary 

glands 

virus

Spread and replication of virus in the absence 

of appropriate PEP

Rabies virus concentration without PEP
response

Antibody 

Days post-exposure

Rabies 

Exposure

0 3 7 14

Virus present 

at entry site

Zone of PEP mediated 

virus neutralization at 

the site of infection

Vaccine induced 

humoral immune 

response

No signs or symptoms of rabies

Passive immunity - HRIG

Rabies vaccine on days 0, 3, 7, 

and 14

Rabies antibody response with PEP
2008 ACIP recommendations

 RIG products licensed in U.S. equally efficacious: 

HyperRabTM S/D and Imogam® Rabies-HT

 RIG administration within first 7 days of initiation of first 

rabies vaccine

 Administer 20 IU/kg, regardless of age

 Infiltrate maximal amount around wound that is 

anatomically feasible

 Remainder should be administered IM at location 

different from where vaccine is administered 

 For large / multiple wounds, RIG can be diluted
2018 WHO considerations

 RIG in limited supply internationally 

– It is estimated that worldwide, <2% of persons with serious 

wounds (i.e., WHO Category III), receive RIG

– RIG is very expensive 

 Dog bites are most common rabies exposures 

– Wounds are large

– Large proportion of RIG infiltrated around wound 

– Benefits from IM administration of remaining RIG may be 

limited
2018 WHO Position Statement

 Prioritize limited RIG

– High risk (WHO Category III) exposures

– Multiple bites

– Deep wounds

– Bites to highly innervated body parts

– Persons with severe immunodeficiency

– Exposures from confirmed or probable rabies case

– Exposures from bats

 Limit RIG infiltration to RIG that can be infiltrated into 

and around the wound; no IM administration of leftover

 Maximum dose: 20 IU/kg 

 Dilute RIG if there are multiple wounds
Human immunoglobulins licensed in U.S.

Product name Manufacturer Administration Potency Dose

Imogam® Sanofi Pasteur

Infiltrated around 

wound and 

remainder 

administered 

intramuscularly

150 IU/mL 20 IU/kg

KedrabTM/ 

Kedrion

Biopharma 

and Kamada

Ltd

150 IU/mL 20 IU/kg

HyperRabTM 

S/D

Grifols

150 IU/mL 20 IU/kg 

HyperRab® 300 IU/mL 20 IU/kg 
Human immunoglobulins licensed in U.S.

Product name Manufacturer Administration Potency Dose

Imogam® Sanofi Pasteur

Infiltrated around 

wound and 

remainder 

administered 

intramuscularly

150 IU/mL 20 IU/kg

KedrabTM/ 

Kedrion

Biopharma 

and Kamada

Ltd

150 IU/mL 20 IU/kg

HyperRabTM 

S/D

Grifols

150 IU/mL 20 IU/kg 

HyperRab® 300 IU/mL 20 IU/kg 
ACIP WG considerations

 Two newly licensed RIGs: Are these new formulations 

or new products?

 RIG administration limited to wound

– What is the data?

– In the U.S., exposure wounds are often small (i.e., from 

bat). What are the U.S. implications?

 Is there data to support any other changes to RIG 

recommendations?
Newly licensed RIG products in U.S.
Human immunoglobulins licensed in U.S.

Product name Manufacturer Administration Potency Dose

Imogam® Sanofi Pasteur

Infiltrated around 

wound and 

remainder 

administered 

intramuscularly

150 IU/mL 20 IU/kg

KedrabTM/ 

Kedrion

Biopharma 

and Kamada

Ltd

150 IU/mL 20 IU/kg

HyperRabTM 

S/D

Grifols

150 IU/mL 20 IU/kg 

HyperRab® 300 IU/mL 20 IU/kg 
KedrabTM/ Kedrion

 Licensed by FDA in 2017

 Indicated for

– Passive, transient post-exposure prophylaxis 

– To persons of all ages 

– Given immediately after contact with a rabid or 

possibly rabid animal

 Clinical study design and trial results similar to 

previously licensed RIG products

 No referral of BLA submission was made to Blood 

Products Advisory Committee because no concerns
HyperRab®

 Licensed by FDA in 2018

 Indicated for PEP along with rabies vaccine 

 Higher potency formulation of HyperRabTM S/D

– Greater concentration of anti-rabies virus antibodies 

within each mL of volume

– Less volume needed to administer recommended amount

 No FDA post-licensure requirements because 

considered to be new formulation (not new product)

 Improved production and manufacturing processes 

over the years

 Requires dilution with Dextrose 5% in Water (D5W) 

rather than normal saline
WG Assessment of KedrabTM and 

HyperRab®

 Both prepared from plasma of donors who were 

hyperimmunized with rabies vaccine

 Safety and efficacy: Similar to previously licensed RIGs

 WG conclusions

– Newly licensed products are not “new”

– Desirable to have multiple licensed RIG products 

because shortages have occurred

– HyperRab® is twice as concentrated resulting in less 

volume administered compared to other RIGs

– Products equally efficacious so WG 

– No preferential recommendation of a specific RIG
Selection of RIG product

 Indications same for all

 More concentrated product could be preferable for small 

wounds (e.g., those from a bat bite)

 Given differences in potency between products, oversight 

needed to ensure correct volume administered for a 

particular product

 Clinicians should be aware that D5W is the 

recommended diluent for HyperRab® even though it is 

not provided with the product

 Individual facilities can determine which product to stock 
WG discussions about RIG administration 

around wound
U.S. and RIG considerations

 Role for RIG

– Studies indicate it can be advantageous

– It is not difficult to access in U.S.

 Most rabies cases are from bat exposures 

– These create small or barely visible wounds

– Very little RIG is administered around a wound

 Immunogenicity data suggests that IM RIG is detected in sera 

24 hours later; there may be benefit
Pathophysiology

 RIG infiltrated around wound likely remains at site of 

injection

– Limited data cited in WHO Position Statement*

– Unclear whether IM administration of RIG provides 

significant benefit

 Data insufficient for WG to propose change to current 

ACIP recommendations 

*Madhusudana et al, Saesow et al, and Wilde et al included in background documents
Conclusion

 Two newly licensed RIGs (2017): Are these new 

formulations or new products? New formulations

 RIG administration limited to wound

– What is the data? WHO considerations different from ACIP’s

– In the U.S., exposure wounds are typically small (i.e., from 

bat). What are the U.S. implications? Small wounds would 

result in very small (if any) RIG infiltrated around wound

 Is there data to support any other changes to RIG 

recommendations? No changes to any RIG recs; clinical 

guidance will be presented at the October ACIP meeting 
Acknowledgements

 Rabies WG

 RIG product sponsors

– Grifols

– Biopharma and Kamada Ltd
National Center for Emerging and Zoonotic 

Infectious Diseases

Thank you