Immunogenicity of H. Influenzae Type b PRP-OMP Vaccines in American Indian and Alaska Native Children (the HibVax Study)
Condition: Haemophilus Influenzae Type B Infection
MeSH terms: Influenza, Human; Haemophilus Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      The main goal of this study is to compare the Haemophilus influenzae type b antibody response
      in American Indian / Alaska Native (AI/AN) infants to two licensed vaccines: Vaxelis and
      PedvaxHIB.
    

Detailed description: 
      Historically, American Indian and Alaska Native (AI/AN) children aged <5 years have
      experienced invasive H. influenzae type b (Hib) disease at a rate that is at least 5 times
      higher than the general U.S. population. In the pre-vaccine era, the incidence of Hib disease
      peaked earlier for AI/AN children at 4-5 months than general US children at 6-9 months.
      Therefore, prevention efforts for AI/AN populations focused on identifying a vaccine that
      would protect against disease in early infancy. Studies in AI/AN children revealed that the
      Hib conjugate vaccine with the capsular polysaccharide (polyribosylribitol phosphate
      polysaccharide [PRP]) coupled to the outer membrane protein complex of Neisseria meningitidis
      (OMP) induced anti-PRP IgG titers that correlated with protection (GMC ≥0.15 μg/mL) and
      demonstrated high efficacy after a single dose in infancy. Hib PRP-OMP was licensed in 1991
      as PedvaxHIB; following introduction of a two-dose primary series and a booster dose, the
      rate of Hib disease decreased substantially among AI/AN children. The importance of PRP-OMP
      vaccine to disease control was highlighted in the 1990s in Alaska when use of a non-PRP OMP
      Hib vaccine was associated with an increase in disease incidence in AN children. In 1999, the
      American Academy of Pediatrics Committee for Native American Child Health released its
      official preference for Hib PRP-OMP for use in AI/AN populations.

      In spite of Hib vaccine coverage similar to or greater than the national average, AI/AN
      populations periodically experience pediatric cases of invasive Hib disease. In contrast to
      the pre-Hib vaccine era, a majority of these cases occur in fully vaccinated children beyond
      the first year of life. This epidemiologic shift in the age at which disease occurs may
      indicate ongoing transmission in the presence of waning immunity following vaccination.

      Vaxelis is a licensed hexavalent combination vaccine that contains Hib PRP-OMP and antigens
      (Hepatitis B surface antigen, Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis [DTaP],
      and Inactivated Polio Virus [IPV]) to protect against diseases caused by 5 other organisms.
      Vaxelis contains 3.0 µg/mL of PRP-OMP antigen, compared to 7.5 µg/mL in PedvaxHIB. This lower
      concentration of PRP-OMP has been shown to be less reactogenic and similarly immunogenic to
      higher doses. Vaxelis is approved for administration as a 3-dose primary series at 2, 4, and
      6 months of age. A booster dose with a different licensed Hib vaccine (e.g., PedvaxHIB,
      ActHib) is required at 12-15 months. Vaxelis Hib PRP-OMP was found to be highly immunogenic
      post-dose 2 at 4 months and post-dose 3 at 6 months. However, immunogenicity post-dose 1 was
      not measured in the phase 3 clinical trials of this vaccine.

      In June 2019, the CDC's Advisory Committee on Immunization Practices (ACIP) passed a
      resolution supporting inclusion of Vaxelis in the Vaccines For Children Program for the
      general U.S. population. This vaccine was made available for routine use in the U.S. in 2021.
      A preferential recommendation for use of this vaccine in AI/AN children was not given because
      post-dose 1 immunogenicity data were not available. To support policy recommendations to
      protect the health of the AI/AN community, a study is needed to assess non-inferiority of the
      post-dose 1 immune response to Vaxelis compared to the current recommended product
      (PedvaxHIB). It is important to demonstrate that infants vaccinated with Vaxelis will be
      protected early in life, given the historic early peak of Hib disease and the evidence that
      Hib still circulates in village-based and reservation-based AI/AN communities.

      If this study finds that Vaxelis and PedvaxHIB provide comparable protection after one dose,
      this would support the ACIP making a preferential recommendation for Vaxelis for AI/AN
      infants. This would expand the options of preferred vaccines for AI/AN infants and
      potentially provide more long-lasting protection given that 3 doses would be given as part of
      the primary series.

      This study is a prospective, randomized, unblinded, phase IV study of the immunogenicity of
      two licensed Hib vaccines among AI/AN infants. The study will enroll approximately 330 AI/AN
      infants on Navajo Nation, on White Mountain Apache (WMA) Tribal lands, and in Anchorage,
      Alaska who are 6-12 weeks of age and due to receive their first set of routine infant
      immunizations. Eligible infants whose parents provide written informed consent will be block
      randomized to one of two study arms - either Vaxelis or PedvaxHIB. Participants will make 5
      study visits over the course of approximately 5 months. Participants randomized to the
      Vaxelis group will receive the vaccination at 2, 4 and 6 months of age, and randomized to the
      PedvaxHIB group will receive the vaccination at 2 and 4 months of age.

      Four blood samples will be collected: at ages 2, 3, 6, and 7 months. These specimens will be
      tested by ELISA to assess anti-PRP antibody levels. Among infants vaccinated at 2 months of
      age, the anti-PRP IgG GMC 30 days post dose 1 of Vaxelis will be considered non-inferior if
      the ratio of the GMC in the Vaxelis group relative to the PedvaxHIB group is >0.67. The
      statistical criterion we are using to define non-inferiority corresponds to the lower bound
      of the two-sided 95% confidence interval (CI) on the anti-PRP IgG GMC ratio [Vaxelis /
      PedvaxHIB] being >0.67. A sample size of 150 evaluable children per group will provide at
      least 80% power to detect non-inferiority using constrained longitudinal analysis.

      Each participant will also be given other routine pediatric immunizations that are not part
      of the study regimen, per ACIP schedule and recommendations, (e.g., DTaP and IPV at 2, 4 and
      6 months, and hepatitis B vaccine at 2 and 6 months, for participants randomized to
      PedvaxHIB; Prevnar13 at 2, 4 and 6 months, and the rotavirus vaccine series at either 2, 4
      and 6 months (if given RotaTeq) or 2 and 4 months (if given Rotarix). Inactivated influenza
      vaccine will be offered at 6 months of age, as appropriate based on season.
    

Intervention name(s): Vaxelis; PedvaxHIB
Intervention type(s): Drug; Drug
Intervention description(s): Eligible infants will be block randomized to one of two study arms.; Eligible infants will be block randomized to one of two study arms.
Other intervention name(s): Intervention; Comparator
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomization of participants will be done at the site level. Participants will be assigned randomly 1:1, to the Vaxelis arm or the PedvaxHIB arm. This is an unblinded study. Study staff will log into a secure system to randomize the participant. The study vaccine associated with that randomization will be selected. A verifier will confirm that the correct vaccine was selected. After verification, study staff will administer the dose.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Native American; Vaccine