Systematic Review: Rabies Pre-exposure Prophylaxis immunogenicity - - PowerPoint PPT Presentation

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Systematic Review: Rabies Pre-exposure Prophylaxis immunogenicity - - PowerPoint PPT Presentation

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National Center for Emerging and Zoonotic Infectious Diseases Systematic Review: Rabies Pre-exposure Prophylaxis immunogenicity Jesse Blanton, DrPH Co-Lead, ACIP Rabies WG Advisory Committee on Immunization Practices February 27, 2020 CDC

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National Center for Emerging and Zoonotic Infectious Diseases

Systematic Review: Rabies Pre-exposure Prophylaxis immunogenicity

Jesse Blanton, DrPH Co-Lead, ACIP Rabies WG

Advisory Committee on Immunization Practices February 27, 2020

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CDC Rabies PreEP Systematic Review and Meta- Analysis

  • Review of immunologic response to rabies PreEP

– – – – – Primary Response, duration of immunity, and booster response

  • Started 2017, Updated through 2019
  • Review Question

Population: Persons at risk of rabies exposure Interventions: 1) Persons receiving alternate rabies vaccination schedules using modern cell culture vaccines; 2) Persons receiving rabies vaccination by alternate routes using modern cell culture vaccines (i.e. ID) Comparison: Persons receiving ACIP recommended rabies pre- exposure prophylaxis regimen by the IM route using modern cell culture vaccines Outcomes: Rabies neutralizing antibodies reported as IU/mL 1-3 weeks after primary vaccination, 1 year post vaccination, and after booster

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Literature Search

  • Databases: MEDLINE, Embase, Cochrane Library, WHO Index Medicus,

citation sampling

  • Jan 1965 – Dec 2019
  • Search Term:

(rabies OR rabies vaccine) AND (antibodies) AND (human) AND (preexposure OR pre-exposure) Results: 258 Unique papers

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Selection Criteria

*not a licensed vaccine or ever evaluated by WHO; RFFIT: Rapid Fluorescent Focus Inhibition Test; GMT: geometric mean titer

  • Exclusion Criteria

– – – – – Use of nervous tissue or experimental vaccines* Immunocompromised populations

  • Inclusion Criteria

Subjects received PrEP (schedule of 1-3 doses) Immune response to vaccination measured by RFFIT Findings reported as GMT (IU/mL) or as a seroconversion rate to a stated cut-off (e.g. 0.5 IU/mL)

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Study Selection

  • Selected Studies

– – – 1978 – 2019 146 Cohorts (study arms) 11,608 Subjects

  • Avg: 79.5 / cohort
  • Med: 32 / cohort
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Study Characteristics

  • Study Types

– – – – – – – – – Randomized clinical trial (59%) Controlled clinical trial (16%) Cohort study (13%) Case/Time series (12%)

  • Study Locations

Asia (41%) North America (29%) Europe (25%) South America (3%) Africa (2%)

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Primary Response – Cohort Characteristics

  • Schedules (cohorts)

– – – – – Single dose 2-dose: day 0,28; day 0,60; day 0,7 3-dose: day 0,3,7; day 0,7,14; day 0,7,21/28

  • Vaccines (cohort)

PVRV, PCEC, HDCV, and Others

  • Route (cohorts)

IM, ID, SC

Purified Vero Rabies Vaccine (PVRV), Purified Chick Embryo Cell Vaccine (PCEC), Human Diploid Cell Vaccine (HDC

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Primary Seroconversion of ACIP recommended schedule

  • Day 0,7,21/28 schedule well established with broad

evidence base – – Recommended schedule for >40 years High (>97%) seroconversion regardless of vaccine or administration route

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Primary titer response of ACIP recommended schedule

  • Heterogeneity

between studies higher for GMT

  • IM produces

significantly higher GMT – Not clinically significant

  • Primary IM GMT

>13.99 IU/mL (lowest 95% CI)

  • Primary ID GMT >4.50

IU/mL (lowest 95% CI)

ID Studies IM Studies GMT: Geometric Mean Titer, IM: intramuscular, ID: intradermal

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Rabies Pre-exposure Prophylaxis 2-dose, 1 week Schedule (day 0 and 7)

Primary Response

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Study Characteristics – primary immunogenicity

Study Study Original Study Original Study Type(1) Type(1) Population Population Intervention(1,2) Intervention(1,2) Comparison(1,2) Comparison(1,2) Study Study Subjects (in Subjects (in analysis) analysis)

Ajjan Ajjan , 1989 , 1989 CCT CCT Europe, veterinary Europe, veterinary students students HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] 144 (72) 144 (72) Jaijaroensup Jaijaroensup , 1999 , 1999 RCT RCT Asia, veterinary Asia, veterinary students students PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] PCEC PCEC

  • 2xID [0,7,21/28]

2xID [0,7,21/28] PCEC PCEC

  • IM [0,7,21/28]

IM [0,7,21/28] 138 (84) 138 (84) Arora, 2004 Arora, 2004 RCT RCT North America, North America, veterinary students veterinary students HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] 135 (44) 135 (44) Sabchareon Sabchareon, 1999 , 1999 RCT RCT Asia, children Asia, children HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] 400 (190) 400 (190) Briggs, 1996 Briggs, 1996 Case Series Case Series North America, North America, veterinary students veterinary students HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] n/a n/a 157 157 Hacibektasoglu, 1992 Hacibektasoglu, 1992 RCT RCT Europe, at risk Europe, at risk population population HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] 60 (30) 60 (30) Kitala Kitala, 1990 , 1990 CCT CCT Africa, veterinary Africa, veterinary students students HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] 80 (37) 80 (37) Vodopija, 1986 Vodopija, 1986 RCT RCT Europe, general Europe, general population population HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] 92 (46) 92 (46) Cramer, 2016 Cramer, 2016 RCT RCT Europe, general Europe, general population population PCEC PCEC

  • IM [0,7,21/28]

IM [0,7,21/28] 605 (371) 605 (371) Recuenco, 2017 Recuenco, 2017 CCT CCT North America, at risk North America, at risk population population PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] PCEC PCEC

  • IM [0,7,21/28]

IM [0,7,21/28] 66 (30) 66 (30) Soentjens Soentjens, 2019 , 2019 RCT RCT Europe, military Europe, military HDCV HDCV-2xID [0,7] 2xID [0,7] HDCV HDCV-ID [0,7,21/28] ID [0,7,21/28] 500 (242) 500 (242) Endy, 2019 Endy, 2019 RCT RCT North America, North America, general population general population PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] PCEC PCEC

  • ID [0,7]

ID [0,7] PCEC PCEC

  • IM [0,7]

IM [0,7] PCEC PCEC

  • IM [0,7,21/28]

IM [0,7,21/28] 60 (35) 60 (35)

1: Individual study arms were treated as observational cohorts for pooled analysis. 2: Serology data taken between day 14-28 (before 3rd dose administered in [0,7,21/28] cohorts) used as proxy of [0,7] schedule

PCEC PCEC

  • IM [0,3,7]

IM [0,3,7] PCEC PCEC

  • IM [0,7,21/28]

IM [0,7,21/28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] FBKC FBKC

  • IM [0,7,21/28]

IM [0,7,21/28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28]

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Primary Immunogenicity –GMT by serology day [2dose]

  • 2 doses of vaccine

days 0 and 7

  • Comparable primary

titer response to 3- dose schudule

  • Limited number of

studies, but similar heterogeneity as

  • bserved in 3-dose

ACIP meta-analysis

Day 14-21 Day 28

ID ID

GMT: Geometric Mean Titer

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Primary Immunogenicity – SCR by serology day [2dose]

  • High SCR (98%) achieved 7-

14 days after second dose (day 7)

  • No significant difference at

between serology periods

  • SCR consistent across

studies (little heterogeneity)

Day 14 – 21 Day 28

ID ID ID

SCR: Seroconversion Rate (>0.5IU/mL)

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Primary Immunogenicity – SCR 3-dose vs 2-dose

  • 30-60 days post vaccination

– – No significant difference in SCR between 3-dose and 2-dose schedules Limited number of 2-dose studies with small cohort sizes

[0,7,21/28] Schedule – 3 doses received [0,7] Schedule - 2 doses received

ID SCR: Seroconversion Rate (>0.5IU/mL)

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Duration of Immunogenicity and response to booster

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Study Characteristics – Duration of immunogenicity

Study Study Study Study Type(1) Type(1) Population Population Intervention(1,2) Intervention(1,2) Comparison( Comparison( 1,2) 1,2) Time @ Time @ Booster Booster (m) (m) Total Total follow follow -up up (m) (m) N @ N @ booster booster

Pengsa Pengsa, 2009 , 2009 RCT RCT Asia, Children Asia, Children PCEC PCEC

  • 0.5IM [0,7,21/28]

0.5IM [0,7,21/28] PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] PCEC PCEC

  • ID [0,28]

ID [0,28] PCEC PCEC

  • IM

IM [0,7,21/28] [0,7,21/28] 12 12 36 36 176 176 Ajjan Ajjan , 1989 , 1989 CCT CCT Europe, veterinary Europe, veterinary students students HDCV HDCV-IM IM [0,7,21/28] [0,7,21/28] n/a n/a 21 21 98 98 Jaijaroensup Jaijaroensup , , 1999 1999 RCT RCT Asia, veterinary Asia, veterinary students students PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] PCEC PCEC

  • 2xID [0,7,21/28]

2xID [0,7,21/28] PCEC PCEC

  • IM

IM [0,7,21/28] [0,7,21/28] 12 12 12+(14d) 12+(14d) 110 110 Kamoltham Kamoltham , 2007 , 2007 RCT RCT Asia, Children Asia, Children PCEC PCEC

  • ID

ID [0,7,21/28] [0,7,21/28] 12 12 24 24 147 147 Sabchareon Sabchareon, 1999 , 1999 RCT RCT Asia, children Asia, children HDCV HDCV-IM IM [0,7,21/28] [0,7,21/28] 12 12 12+(14d) 12+(14d) 310 310 Strady Strady, 1998 , 1998 RCT RCT Europe, at risk Europe, at risk population population HDCV HDCV-IM IM [0,7,21/28] [0,7,21/28] 12 12 120 120 120+(14d) 120+(14d) 286 286 Briggs, 1996 Briggs, 1996 Case Case Series Series North America, North America, veterinary students veterinary students HDCV HDCV-IM [0,7,21/28] IM [0,7,21/28] n/a n/a 12 12 12+(14d) 12+(14d) 146 146 Dreesen, 1989 Dreesen, 1989 RCT RCT North America, general North America, general population population HDCV HDCV-ID [0,7,21/28] ID [0,7,21/28] PCEC PCEC

  • IM [0,7,21/28]

IM [0,7,21/28] PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] HDCV HDCV-IM IM [0,7,21/28] [0,7,21/28] 24 24 24+(7d) 24+(7d) 69 69 Bernard, 1987 Bernard, 1987 RCT RCT North America, North America, veterinary students veterinary students HDCV HDCV-ID [0,7,21/28] ID [0,7,21/28] HDCV HDCV-SC [0,7,21/28] SC [0,7,21/28] HDCV HDCV-IM IM [0,7,21/28] [0,7,21/28] 12 12 24 24 24+(21d) 24+(21d) 48 48 Cramer, 2016 Cramer, 2016 RCT RCT Europe, general Europe, general population population PCEC PCEC

  • IM

IM [0,7,21/28] [0,7,21/28] n/a n/a 12 12 584 584 Chatchen, 2017 Chatchen, 2017 RCT RCT Asia, Children Asia, Children PCEC PCEC

  • 0.5IM [0,7,21/28]

0.5IM [0,7,21/28] PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] PCEC PCEC

  • IM

IM [0,7,21/28] [0,7,21/28] 12 12 96 96 68 68 Endy Endy, 2019 , 2019 RCT RCT North America, general North America, general population population PCEC PCEC

  • ID [0,7,21/28]

ID [0,7,21/28] PCEC PCEC

  • ID [0,7]

ID [0,7] PCEC PCEC

  • IM [0,7]

IM [0,7] PCEC PCEC

  • IM

IM [0,7,21/28] [0,7,21/28] 12 12 12+(7d) 12+(7d) 42 42 Soentjens Soentjens, 2019 , 2019 RCT RCT Europe, military Europe, military HDCV HDCV-2xID [0,7] 2xID [0,7] HDCV HDCV-ID ID [0,7,21/28] [0,7,21/28] ~18 ~18 ~18+(7d) ~18+(7d) 411 411

1: Individual study arms were treated as observational cohorts for pooled analysis. 2: Serology data taken between day 14-28 (before 3rd dose administered in [0,7,21/28] cohorts) used as proxy of [0,7] schedule

PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] PCEC PCEC

  • 2xID [0,28]

2xID [0,28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] HDCV HDCV-IM [0,28] IM [0,28] PVRV PVRV

  • IM [0,7,21/28]

IM [0,7,21/28] PVRV PVRV

  • IM [0,28]

IM [0,28] PCEC PCEC

  • IM [0,3,7]

IM [0,3,7]

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1 year immunogenicity and response to booster - GMT

1 Year post vaccination [0,7,21/28] Schedule [0,7] Schedule

  • Lower GMT in 2 dose (day 0,7) recipients

– not significantly different from 3 dose recipients

  • Anamnestic response observed post booster in both 2 and 3 dose cohorts

– GMT in 3 dose recipients significantly higher

ID ID

GMT: Geometric Mean Titer

7-14 days post booster [0,7] Schedule [0,7,21/28] Schedule

ID ID

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1 year immunogenicity and response to booster - SCR

[0,7,21/28] Schedule [0,7] Schedule 1 Year post vaccination

ID

[0,7,21/28] Schedule [0,7] Schedule 7-14 days post booster (at 1 year)

ID ID

SCR: Seroconversion Rate (>0.5IU/mL)

  • Lower proportion of 2 dose (day 0,7) recipients w/ adequate titer at 1 year:

59%

  • Anamnestic response post booster

– All recipients achieve adequate antibody level, no significant difference between groups

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Summary

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2-dose (day 0,7) schedule study summary

  • Soentjens et al. (n=183) ID

– –

– –

–

Pre-booster (1-3 years post vaccination): 2-dose ID GMT (3.4 IU/mL) was significantly higher compared to 3-dose ID (2.0 IU/mL) 100% of both groups had an adequate titer (>0.5 IU/mL) after booster

  • Endy et al. (n=22) IM/ID

Compared to 3-dose IM series, no significant difference observed in the GMT at day 365 for 2-dose IM or 2-dose ID 40-50% of 2-dose recipients had a titer of >0.5 IU/mL at day 365

100% of recipients had an adequate titer after receiving booster at 1 year

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Duration and kinetics of antibody response

  • Most studies evaluated 3 dose (day 0,7,21/28) schedule (IM and ID)
  • Rapid decay during first 6 months post vaccination

– – – Slows to plateau between 6 months to 1 year Decay more rapid when administered by ID route

  • ID >1.5 times more likely to not have an adequate titer at 1-2

years post vaccination

  • Post booster response typically greater than primary response

Decay slower after booster

Banga et al. Vaccine. 2014; 32:979 Brown et al. Vaccine. 2008; 26:3909 Mansfield et al. Vaccine. 2016; 34:5959 Strady et al. JID. 1998; 177:1290

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Booster effect on duration of immunogenicity

Years post vaccination

(15 cohorts) (5) (6) (3) (4)

Average Percent ≥0.5 IU/mL* [0,7,21/28] Schedule, IM route

*Random effects model

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Acknowledgements

Rabies Vaccine Work Group

Sharon Frey (chair) Lynn Bahta José R. Romero Deborah Briggs James Stevermer Matt Zahn Karl Hess Paula Agger Jesse Blanton Robin Levis Katie Brown Elizabeth Barnett Sally Slavinski Greg Moran Michael Pentella Susan Moore David Shlim Julie Emili Linlu Zhao Pedro Moro Kristina Angelo Eun-Chung Park

CDC Technical Team

Jesse Blanton Brett Petersen Ryan Wallace Sathesh Panayampalli James Ellison Erin Whitehouse Anna Mandra Jesse Bonwitt Caroline Schrodt

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National Center for Emerging and Zoonotic Infectious Diseases

Thank you

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Additional Slides

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Titer cut-offs

  • 0.5 IU/mL aligns with WHO.

– Corresponds closer to assay threshold across laboratories

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Meta-Analysis Summary

  • *Pooled SCR by random effects model.
  • **Cochran’s Q Test.
  • † Significant difference between vaccines types (p<0.01).
  • ‡Significant difference between vaccination routes (p<0.01)

IM IM – Route Route ID ID – Route Route Schedule Schedule

Cohorts Cohorts (Subjects) (Subjects) SCR† SCR† 95% CI 95% CI I2 I2 p- value** value** Cohorts Cohorts (Subjects) (Subjects) SCR SCR 95% CI 95% CI I2 I2 p- value* value* * [0,7,21/28] [0,7,21/28] 45 (2,899) 99% (98%

  • 99%)

0% 1.0 21 (876) 98% (97%

  • 99%)

0% 1.0 [0,3,7] [0,3,7] 3 (209) 98% (92%

  • 100%)

22% 0.29

  • [0,7]

[0,7] 25 (1,909) 98% (97%

  • 99%)

41% 0.02 9 (653) 97% (93%

  • 99%)

38% 0.12 [0,28] [0,28] 3 (224) 99% (94%

  • 100%)

20% 0.29 3 (126) 98% (94%

  • 100%)

87% <0.01 [0] [0] 9 (574) 17% (9%

  • 32%)

87% <0.01

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Primary Immunogenicity – Schedule Comparison

  • 2 weeks post vaccination
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Neutralizing Antibody as Surrogate of Protection

Rabies Virus Antibodies from Oral Vaccination as Correlate of Protection against Lethal Infection in Wildlife Moore S, et al. (2017). Trop Med Infect Dis.,

  • 0.5 IU/mL rabies

neutralizing antibodies (RFFIT)

– – – Not a measure of protection Measure of adequate response Reliable detection limit of assays

  • Correlation between

antibody titer and survival

  • Variability between species
  • Adequate antibody

response after primary vaccination and anamnestic response post challenge is best surrogate of survival

Survived Challenge Succumbed