Document text
The HibVax Study
Immunogenicity of H. influenzae type b PRP -OMP
vaccines in American Indian and Alaska Native infants
Laura Hammitt, MD
Associate Professor, JHSPH
Infectious Disease Program Lead, Center for Indigenous Health
Johns Hopkins Bloomberg School of Public Health
On behalf of the study team in Navajo Nation and Anchorage, Alaska
Disclosures/Disclaimers
▪This study was supported in part by a research grant from the Investigator -
Initiated Studies Program of Merck Sharp & Dohme LLC, a subsidiary of Merck
& Co., Inc. Rahway, NJ 07065 USA, acting on behalf of a joint venture with Sanofi
known as MSP Vaccine Company.
▪Research grants to my institution from AstraZeneca, Merck, Pfizer, CDC, NIH.
▪The findings and conclusions in this report are those of the authors and do not
necessarily represent the official position of the Indian Health Service or the
Centers for Disease Control and Prevention.
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Preferential recommendation for PRP -OMP Hib
conjugate vaccines in AI/AN infants
▪Disease at a young age in the
pre-vaccine era
▪Robust protection following
the first dose
▪Immunogenicity
▪Efficacy
▪Re-emergence of Hib disease
in AN infants following use of
non -PRP -OMP vaccines 050010001500200025003000
0-1 2-3 4-5 6-7 8-9 10-11 12-23 24-48Cases per 100,000
Age (months)Alaska Native Navajo Nation General US
Ward JI et al., Lancet , 1981; 1281 -1284.H. influenzae meningitis in children <5 years,
1971-1977
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Preferential recommendation for PRP -OMP Hib
conjugate vaccines in AI/AN infants
Table 3. Efficacy Analysis of H. influenzae Type b OMPC Vaccine*
Time of Disease OnsetCases of H.
influenzae Efficacy
Estimatep-value95% CI
Vaccine Placebo
(n/total) (%)
At least 1 dose
Onset before 18 mo. 1/2588 22/2602 95 <0.001 72-99
Onset before 15 mo. 0/2588 21/2602 100 <0.001 81-100
Onset before 2nd dose 0/2588 8/2602 100 0.005 41-100
Two doses
Onset before 18 mo. 1/2056 14/2105 93 <0.001 53-98
Onset before 15 mo. 0/2056 13/2105 100 <0.001 67-100
*Intention -to-treat analysis - included all infants enrolled.
Santosham et al., N Engl J Med 1991; 324:1767 -17724▪Disease at a young age in the
pre-vaccine era
▪Robust protection following
the first dose
▪Immunogenicity
▪Efficacy
▪Re-emergence of Hib disease
in AN infants following use of
non -PRP -OMP vaccines
Preferential recommendation for PRP -OMP Hib
conjugate vaccines in AI/AN infants
Invasive Hib Disease Children Aged <5 Years
Alaska, 1980 - 2018
Figure courtesy of Rosalyn Singleton; Singleton, et al. J Pediatr 2000; 137:313 -205▪Disease at a young age in the
pre-vaccine era
▪Robust protection following
the first dose
▪Immunogenicity
▪Efficacy
▪Re-emergence of Hib disease
in AN infants following use of
non -PRP -OMP vaccines
Invasive Hib disease in children <5 years
020406080100Incidence
(cases/per 100,000)Navajo Nation General US*Hib PRP -OMP
vaccine introductionAverage number Hib cases in U5 children
per year in Navajo Nation:
1988 - 1990: 19 cases/ yr
1993 - 2023: <2 cases/yr
90%
decline
CIH/Navajo Epidemiology Center Active Bacterial Surveillance data; Navajo Research Conference 20216
Invasive Hib disease in AI/AN children <5 years
Navajo Nation and White Mountain Apache Tribal Lands
2004 -2023 (N=25)
0102030405060Age (months)Vaccination history in Hib cases
<5 years
Un-
vaccinated
(n=4)Up to date
for age
(n=7)Fully
vaccinated
(n=14)Average age 21 months
Median age
(IQR)14 months
(9-37 months)
Age range 2-52 months
Clinical
syndromeMeningitis: 28%
Pneumonia: 40%
7IQR: interquartile range
Combination vaccines → fewer shots, fewer missed doses,
lower administrative burdenPedvaxHIB ®
(PRP -OMP Hib vaccine)Vaxelis®
(DTaP -IPV-Hib-HepB )
Contents Single Antigen Hexavalent
Use in AI/AN
infantsCurrently recommended Hib
vaccine for AI/AN infantsCurrently recommended for
general U.S. infants; not yet
preferentially recommended
for AI/AN infants
Hib Antigen and
Conjugate7.5 µg PRP
OMP3.0 µg PRP
OMP
Primary Series 2-dose (2, 4 months) 3-dose (2, 4, 6 months)
Post -dose 1
immunogenicityHigh ???
8PRP: Hib polyribosylribitol phosphate ; OMP: outer membrane protein of Neisseria meningitidis
HibVax Study: Primary objective
Do Hib antibody levels in AI/AN infants m eet
non-inferiority criteria 30 days after dose 1 of
Vaxelis ® compared to PedvaxHIB ®?
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HibVax Study Overview
Phase IV, prospective, open label, RCT
2 months
Visit 1
Day 13 months
Visit 2
Day 31
6 months
Visit 4
Day 1217 months
Visit 5
Day 151
4 months
Visit 3
Day 61
Physical exam
Questionnaire
Receive vaccinesBlood draw
Collection Window30-48 Days
Post Dose 156-90 Days
Post Dose 230-48 Days
Post Dose 3Prior to
Dose 1Safety monitoring
NCT04978818; JHSPH IRB #11170; Navajo Nation Human Research Review Board #20.374; Alaska Area IRB #2020 -20-01110
HibVax Study Overview
Phase IV, prospective, open label, RCT
2 months
Visit 1
Day 13 months
Visit 2
Day 31
6 months
Visit 4
Day 1217 months
Visit 5
Day 151
4 months
Visit 3
Day 61
Physical exam
Questionnaire
Receive vaccinesBlood draw
Collection Window30-48 Days
Post Dose 156-90 Days
Post Dose 230-48 Days
Post Dose 3Prior to
Dose 1Safety monitoring
NCT04978818; JHSPH IRB #11170; Navajo Nation Human Research Review Board #20.374; Alaska Area IRB #2020 -20-01111
HibVax Study Overview
Phase IV, prospective, open label, RCT
2 months
Visit 1
Day 13 months
Visit 2
Day 31
6 months
Visit 4
Day 1217 months
Visit 5
Day 151
4 months
Visit 3
Day 61
Physical exam
Questionnaire
Receive vaccinesBlood draw
Collection Window30-48 Days
Post Dose 156-90 Days
Post Dose 230-48 Days
Post Dose 3Prior to
Dose 1Safety monitoring
NCT04978818; JHSPH IRB #11170; Navajo Nation Human Research Review Board #20.374; Alaska Area IRB #2020 -20-01112
Inclusion Criteria
•Healthy AI/AN infant born at gestational age of ≥35 weeks
•Between 6 to 12 weeks of age
•Written informed consent provided by parent(s)/Legally
Authorized Representative(s)
Exclusion Criteria (selected)
•Prior receipt of infant vaccines other than birth dose hepatitis B
vaccine
•History of receipt of blood, blood products, or antibody products
•Immunocompromised
•Allergy to any vaccine component, or to latex
•Acute illness and/or fever ≥38.0ºC (time -limited exclusion)
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Methods
▪Anti -Hib IgG antibody levels measured by commercially available
ELISA assay at CDC/Arctic Investigations Program, Anchorage, AK
▪Geometric mean concentrations (GMCs) assessed using
constrained longitudinal analysis (cLDA)
▪Assumes groups have equal anti -Hib GMC at baseline based on the
randomized study design
▪Results are presented for all evaluable participants complying
with the procedures and intervals between primary doses, as
defined in the protocol
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Study Enrollment
▪Enrollment began in Jan 2022 in
Anchorage, AK and four sites in the
Navajo Nation (Southwest US)
▪All s tudy visits competed by Oct 2023
Total enrollment 333
Anchorage, AK 26
Chinle , AZ 61
Fort Defiance, AZ 115
Gallup, NM 81
Shiprock, NM 50
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Study Visit Completion
2 months
Day 1
N3 months
Day 31
N4 months
Day 61
N6 months
Day 121
N7 months
Day 151
N
Completed Visit 333 319 314 300 296
Evaluable Sample 321 307 - 272 270
Evaluable Sample in ATP Cohort 321 298 - 255 245
ATP: According to protocol
No specimens were collected at Day 61, in accordance with the protocol
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Participant Characteristics
PedvaxHIB ® (N=166) Vaxelis ® (N=167)
Median age in days at Dose 1,
(interquartile range)56 (45 -63) 60 (46 -63)
Male, n (%) 74 (44.6) 84 (50.3)
Site, n (%)
Anchorage, AK 13 (7.8) 13 (7.8)
Chinle, AZ 30 (18.1) 31 (18.6)
Fort Defiance, AZ 57 (34.3) 58 (34.7)
Gallup, NM 40 (24.1) 41 (24.6)
Shiprock, NM 26 (15.7) 24 (14.4)
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Serious Adverse Events (SAEs)
▪25 SAEs were detected during study follow up in 21 individuals.
▪No SAEs were associated with study participation.
▪The most common SAE was acute respiratory infection (n=21).PedvaxHIB ®
N=166Vaxelis ®
N=167Total
SAEs, n 15 10 25
Participants, n (%) 12 (7%) 9 (5%) 21 (6%)
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Primary Outcome: Anti -Hib IgG Geometric Mean
Concentration (GMC) 30 Days Post -Dose 1
PedvaxHIB ® Vaxelis ®
Anti -Hib Antibody GMC
µg/mL (95% CI)Observed Data0.39
(0.31 - 0.50)0.41
(0.33 - 0.52)
Modeled by
cLDA0.40
(0.31 - 0.50)0.41
(0.33 - 0.51)
Ratio of GMCs ( Vaxelis : PedvaxHib )
1.03 (0.75 - 1.41)
The pre -specified non -inferiority criterion was met based on the lower bound of
the 95% confidence interval (CI) around the antibody concentration ratio
[Vaxelis / PedvaxHIB] being > 0.67CI: confidence interval; cLDA : constrained longitudinal data analysis
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Anti -Hib IgG Geometric Mean Concentration
Day 1 and Day 31
Output from constrained longitudinal data analysis20Putative Correlates of Protection
Long -term
Short -term
Dose 2Dose 3 (Vaxelis Only)Dose 1Anti -Hib IgG Geometric Mean Concentration
Days 1, 31, 121, and 151
Putative Correlates of Protection
Long -term
Short -term
Output from constrained longitudinal data analysis21
020406080100
Day 1 Day 31 Day 121 Day 151ProportionPedvaxHIB
VaxelisProportion with Anti -Hib Concentration ≥0.15 µg/mL
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020406080100
Day 1 Day 31 Day 121 Day 151ProportionPedvaxHIB
Vaxelis
* χ2 p-value <0.05*Proportion with Anti -Hib Concentration ≥1.0 µg/mL
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020406080100
Day 31:Day 1 Day 121:Day 1 Day 151:Day 1ProportionPedvaxHIB
VaxelisProportion with 4-fold rise in Anti -Hib Concentration
from Day 1
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Limitations
▪Participant follow -up ended at 7 months
▪Over 90% of participants had anti -Hib antibody above the
putative correlate of short -term protection
▪The proportion of participants with anti -Hib antibody
concentrations above the putative correlate of long -term
protection and the anti -Hib GMC were greater in the Vaxelis ®
group
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Protection Post -Booster
▪Median age of Hib disease in AI/AN children in the
Southwest US: 14 months
▪Majority of cases occur in fully vaccinated children
▪Current booster strategy for AI/AN children: PedvaxHib at 12 -
15 months
▪Robust immunogenicity seen in heterologous schedules of
PRP -OMP followed by conjugate vaccines with different
carrier proteins (e.g. PRP -TT, HbOC )
Reid et al. , 1993; Decker et al., 1993; Decker and Edwards, 1998; Greenberg et al., 1995; Wilck et al., 202126
Wilck MB et al. Vaccine. 2021;39(9):1428 -1434. doi:10.1016/j.vaccine.2021.01.046Significantly
higher
post -booster
anti-Hib GMC
with a
heterologous
booster
dose
Vaxelis +
PRP -TT4 doses
PRP -TT
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Conclusions
▪Post -dose 1 anti -Hib GMCs following Vaxelis ® met the
pre-specified criteria for non -inferiority.
▪Including Vaxelis ® among the vaccines with a
preferential recommendation would expand the
available options for AI/AN children.
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Acknowledgements
▪Study participants and their families
▪Institutional Review Boards
▪Navajo Nation Human Research Review Board (NNR -20.374)
▪Fort Defiance Indian Hospital IRB
▪Johns Hopkins Bloomberg School of Public Health IRB (IRB00011170)
▪Alaska Area IRB (2020 -02-011-4)
▪Southcentral Foundation Executive Committee
▪Alaska Native Tribal Health Consortium Human Research Review Committee
▪Indian Health Service, Tséhootsooí Medical Center, Alaska Native
Medical Center, CDC/Arctic Investigations Program
▪Study Team – Bianca Jackson, Bob Weatherholtz , Scott Zeger , Ros
Singleton, Karen Miernyk , Jonathan Steinberg, James Keck, Study
Nurses, Study Physicians, Regulatory Coordinators, Research
Assistants
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