Immunogenicity of H. Influenzae Type b PRP-OMP Vaccines in American Indian and Alaska Native Children (the HibVax Study)

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Born at gestational age of ≥35 weeks
* AI/AN infant between 6 to 12 weeks of age (42-90 days) at the time of the first vaccination (i.e., Study Day 1)
* Written informed consent provided by parent(s)/Legally Authorized Representative(s) (LARs)
* Investigators believe that the parent(s)/LARs can and will comply with the requirements of the protocol (i.e., return for follow-up visits, recall of adverse events)
* Infant is available to complete the follow-up period of 5 months
* Healthy infant, as established by medical history and clinical examination before entering the study

Exclusion Criteria:

* History of receipt of blood, blood products, or immunoglobulin products since birth or expected receipt through the duration of the study
* Chronic seizure or evolving or unstable neurologic disorder
* Congenital Heart Disease, except for uncomplicated CHD (e.g., PDA, small septal defect)
* Infant of mother with HIV infection
* History of reaction or hypersensitivity likely to be exacerbated by any vaccine component, or to latex
* Infant with confirmed or suspected immunocompromising medical condition, based on medical history, including chronic administration (more than 14 days in the lifetime) of immunosuppressants or other immune-modifying drugs since birth
* Administration of infant vaccines other than birth dose Hepatitis B, prior to the time of enrollment
* Any condition which might interfere with the evaluation of the investigational product, or interpretation of subject safety or study results, in the opinion of the investigator
* Child of an employee of the sponsor, clinical study site, or any other individual involved with the conduct of the study, or an immediate family member of such individuals
* Acute illness and/or fever (temperature ≥100.4 F or ≥38.0 C) at time of enrollment (Note: Participant with fever may be enrolled at later date if symptoms have resolved and all other criteria for inclusion are met at that time)
* Current (or within the past 7 days) or expected receipt of immunosuppressive agents, including steroids, except topical or inhaled steroids (Note: For oral corticosteroids, this will mean prednisone (≥ 0.5 mg/kg/day, or equivalent; participant may be enrolled at a later date if medication use ends and all other criteria for inclusion are met at that time)