ACIP Evidence to Recommendations Regarding Use of Haemophilus influenzae Type b-Containing Vaccines Among American Indian and Alaska Native Infants

Policy Question: Should DTaP-IPV-Hib-HepB (Vaxelis) be included with monovalent PRP-OMP (PedvaxHIB) in the preferential recommendation for American Indian and Alaska Native infants based on the Haemophilus influenzae type b (Hib) component?

Population: American Indian and Alaska Native infants

Intervention: DTaP-IPV-Hib-HepB (Vaxelis)

Comparison: Monovalent PRP-OMP (PedvaxHIB)

Outcomes: Invasive Hib disease, post-dose 1 immunity, post-primary series immunity, serious adverse events

Background: Invasive Haemophilus influenzae type b (Hib) disease is a rare but serious bacterial infection that disproportionally affects American Indian/Alaska Native populations. Before routine Hib vaccination began, the incidence of H. influenzae meningitis peaked at a younger age among American Indian/Alaska Native infants (4–6 months) than among other U.S. infant populations (6–7 months).¹Hib vaccination with monovalent PRP-OMP (PedvaxHIB, Merck & Co, Inc.) has historically been preferred for American Indian/Alaska Native infants because it provides a protective antibody response after the first dose.²DTaP-IPV-Hib-HepB (Vaxelis, MSP Vaccine Company (a U.S.-based partnership between Merck, known as MSD outside the United States and Canada, and Sanofi)) contains PRP-OMP but has not previously had a preferential recommendation for American Indian/Alaska Native infants because the dose is lower than PedvaxHIB and post-dose 1 immunogenicity data were not previously available.³Given recently available data comparing post-dose 1 immunogenicity of DTaP-IPV-Hib-HepB and monovalent PRP-OMP among American Indian/Alaska Native infants, ACIP re-evaluated the Hib vaccine preferential recommendation for American Indian/Alaska Native infants.

Public Health Importance

Problem
Criteria	Work Group Judgements	Evidence	Additional Information
Is invasive Hib disease among American Indian and Alaska Native infants a problem of public health importance?	Yes	Before the introduction of effective vaccines, Hib was the leading cause of bacterial meningitis and other invasive bacterial disease in the United States, primarily among children aged <5 years.² The most common clinical syndromes of invasive Hib disease in the post-vaccine era are bacteremic pneumonia, bacteremia without a focus, and meningitis.⁴ The incidence of invasive Hib disease among children aged <5 years declined >99% with introduction of Hib vaccines.² However, American Indian/Alaska Native children aged <5 years still have a 31-fold higher incidence of invasive Hib disease than non-native children.⁵	None.

Benefits and Harms

Benefits and Harms
Criteria	Work Group Judgements	Evidence	Additional Information
How substantial are the desirable anticipated effects overall and for each main outcome for which there is a desirable effect?	Moderate	The anti-Hib IgG GMC ratio (DTaP-IPV-Hib-HepB vs. monovalent PRP-OMP) 30 days post-dose 1 modeled by constrained longitudinal data analysis was 1.03 (95% CI: 0.75–1.41) and met the non-inferiority criterion.⁶ The proportion of infants with anti-Hib concentration above the putative correlate of short-term protection (≥0.15 µg/mL) 30 days post-dose 1 was similar in the DTaP-IPV-Hib-HepB group (75.7%) and the monovalent PRP-OMP group (71.2%, p=0.39).⁶ The proportion of infants with anti-Hib concentration above the putative correlate of long-term protection (≥1.0 µg/mL) 150 days post-dose 1 was higher in the Vaxelis group (83.6%) than in the PedvaxHIB group (71.7%, p=0.03).⁶	None.
How substantial are the undesirable anticipated effects overall and for each main outcome for which there is an undesirable effect?	Minimal	The frequency of serious adverse events* was similar in the DTaP-IPV-Hib-HepB group (5.4%) and the monovalent PRP-OMP group (7.2%, p=0.49).⁶ The most common serious adverse event was acute respiratory infection (21/25; 84%). No SAEs were deemed related to study participation.	None.
Do desirable effects outweigh undesirable effects?	Favors both: DTaP-IPV-Hib-HepB (Vaxelis) and monovalent PRP-OMP (PedvaxHIB)	For the critical outcomes of post-dose 1 immunity and serious adverse events, the DTaP-IPV-Hib-HepB and monovalent PRP-OMP groups were similar. Although the DTaP-IPV-Hib-HepB group had a more favorable antibody response than the monovalent PRP-OMP group for the important outcome of post-primary series immunity, Work Group members felt that this was outweighed by other advantages of having two Hib vaccine options available for this population, including improved reliability of the vaccine supply and ability to maintain flexibility for parents/guardians and providers.	None.
What is the overall certainty of this evidence for the critical outcomes?	Moderate	There are two critical outcomes with data available: post-dose 1 immunity and serious adverse events. The certainty of evidence for both outcomes began as high because the study design was a randomized controlled trial. For each critical outcome, the certainty of evidence was downgraded for serious indirectness because of the wide confidence interval around the effect estimate for absolute risk, reflecting the relatively small sample size (n=333).	The study was conducted among Navajo Nation and Alaska Native infants and may not be generalizable to other American Indian populations; Work Group members determined this did not warrant a downgrade.

*Serious adverse events defined as hospitalization, death, life-threatening drug experience, or prolonging of hospitalization.

Values

Values
Criteria	Work Group Judgements	Evidence	Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects?	Probably yes or yes	DTaP-IPV-Hib-HepB would provide an additional option for American Indian and Alaska Native infants. In collaboration with CDC’s Office of Tribal Affairs and Strategic Alliances, the National Center for Immunization and Respiratory Diseases held a listening session with tribal communities in January 2024. Among 80 attendees, 9 were from tribes or tribal serving organizations, and 46 were from Indian Health Service. Key questions and concerns raised by participants for Work Group consideration were: whether Vaxelis will offer the same protection as PedvaxHIB, the need to monitor for possible breakthrough cases, and the importance of considering data on safety and side effects. The Work Group has incorporated these considerations into the evidence to recommendations framework.	None.
Is there important uncertainty about or variability in how much people value the main outcomes?	Probably no, probably yes, or don’t know	The Work Group did not achieve a majority consensus, with the plurality favoring probably no, and others favoring don’t know or probably yes. Some Work Group members noted it was difficult to assess the degree of certainty given the limited number of American Indian/Alaska Native participants in the listening session.	None.

Acceptability

Acceptability
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention acceptable to key stakeholders?	Probably yes	Limited data were available. DTaP-IPV-Hib-HepB would reduce the number of injections to complete the childhood immunization series for those who receive it and may therefore improve acceptability for parents/guardians and medical providers. CDC’s General Best Practice Guidance for Immunization and the American Academy of Pediatrics Red Book both state a general preference for combination vaccines over separate injections of equivalent component vaccines.^7,8 Including DTaP-IPV-Hib-HepB as a preferred Hib product adds flexibility for providers caring for American Indian/Alaska Native infants.	According to CDC’s General Best Practice Guidance for Immunization, potential advantages of combination vaccines include improved vaccine coverage rates, timely catch-up immunizations, reduced shipping and stocking costs, reduced costs for extra health care visits necessitated by deferral of vaccination, and facilitation of additional new vaccines into vaccination programs; potential disadvantages of combination vaccines include adverse events that might occur more frequently with combination vaccines than with individual components, confusion and uncertainty about selection of vaccine combinations and schedules for subsequent doses, and extra doses of certain antigens in the combination product.⁷

Resource Use

Resource Use
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention a reasonable and efficient allocation of resources?	Yes	The cost is similar for DTaP-IPV-Hib-HepB and other vaccine options that cover the same pathogens, accounting for administration costs. Using DTaP-IPV-Hib-HepB has been considered acceptable for the general U.S. population, and it would therefore be equitable to use the same standard for American Indian/Alaska Native children.	Based on the most recent pediatric Vaccines for Children (VFC) Program price list, costs were estimated for three options to complete the childhood immunization series for diphtheria, tetanus, pertussis, polio, Hib, and hepatitis B using DTaP-IPV-Hib-HepB or monovalent PRP-OMP and varying the extent of combination vaccine use.*⁹ Option 1 used Vaxelis (3 doses), PedvaxHIB (1 dose), and DTaP (1 dose). Option 2 used Pediarix (3 doses), PedvaxHIB (3 doses), and DTaP (1 dose). Option 3 used the individual component vaccines PedvaxHIB (3 doses), DTaP (4 doses), IPV (3 doses), and HepB (2 doses). The total public sector cost (vaccines and administration) was $419.01-419.04 for option 1, $368.45–368.48 for option 2, and $365.58–371.28 for option 3.The total private sector cost (vaccines and administration) was $669.90–670.41 for option 1, $612.12–612.63 for option 2, and $690.37–695.01 for option 3.

* Private sector administration cost was assumed to be $34.53 for first vaccine based on estimates from a 2014 study, adjusted for inflation.10 A factor of 0.6 was used to calculate the private sector administration cost of $20.72 for subsequent doses at the same visit based a 2019 study.11 Public sector administration costs were assumed to be half of private sector costs.12 Vaccine cost ranges reflect different costs for DTaP (Daptacel vs. Infanrix) and HepB (Engerix B vs. Recombivax HB).

Resource Use
Criteria	Work Group Judgements	Evidence	Additional Information
What would be the impact on health equity?	Moderate	Limited data were available. The option to use a combination vaccine may improve equity by improving reliability of the vaccine supply and improving Hib vaccination uptake among American Indian and Alaska Native populations, who are disproportionately at risk for invasive Hib disease.	None.

Feasibility

Feasibility
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention feasible to implement?	Yes	DTaP-IPV-Hib-HepB has been widely used in the general U.S. population with >7.4 million doses distributed in the United States (as of quarter 1 of 2024).* Adding DTaP-IPV-Hib-HepB to the preferential recommendation for American Indian/Alaska Native infants would increase flexibility for patients and providers and reduce the number of injections to complete the childhood immunization series for those who receive it. Neither DTaP-IPV-Hib-HepB nor monovalent PRP-OMP require reconstitution.^13,14 The shelf life of Vaxelis (4 years) is longer than that of PedvaxHIB (3 years).*	DTaP-IPV-Hib-HepB cannot be used for the booster dose of Hib, DTaP, or IPV.³ Clinics will need to stock additional products for the booster doses. Stocking monovalent PRP-OMP for the Hib booster dose would maintain parent/guardian and provider flexibility to choose this for doses 1–3. Stocking a tetanus-toxoid conjugate Hib vaccine (PRP-T) is also an option. A group of 124 AI/AN infants who took part in a phase 3 study of DTaP-IPV-Hib-HepB primary series with a heterologous Hib booster (PRP-T), demonstrated a robust immune response.^15. However, stocking PRP-T creates a potential risk of inadvertent administration of PRP-T for doses 1–3 with a less robust immune response following dose 1 and 2 compared with PRP-OMP vaccines.

*Personal communication with MSP Vaccine Company.

Balance of Consequences

A majority of Work Group members thought desirable consequences probably outweigh undesirable consequences in most settings. A majority of Work Group members thought there is sufficient information to move forward with a recommendation.

Policy option for ACIP consideration

ACIP recommends DTaP-IPV-Hib-HepB (Vaxelis®) should be included with monovalent PRP-OMP (PedvaxHIB®) in the preferential recommendation for American Indian and Alaska Native infants based on the Haemophilus influenzae type b (Hib) component.

Final ACIP recommendation

References

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Briere EC, Rubin L, Moro PL, Cohn A, Clark T, Messonier N. Prevention and Control of Haemophilus influenzae Type b Disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2014;63:1–14.
Oliver SE, Moore KL. Licensure of a Diphtheria and Tetanus Toxoids and Acellular Pertussis, Inactivated Poliovirus, Haemophilus influenzae Type b Conjugate, and Hepatitis B Vaccine and Guidance for Use in Infants. MMWR Morb Mortal Wkly Rep 2020;69:136–9
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General Best Practice Guidelines for Immunization. Best Practice Guidance of the ACIP. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html
American Academy of Pediatrics. Red Book 2018 Report of the Committee on Infectious Diseases. 31st Edition.
VFC price list VFC | Current CDC Vaccine Price List | CDC
Tsai Y et al. Insurance reimbursements for human papillomavirus vaccination in the private sector, 2007–2014. Prev Med Rep. 2019.15:100917.
Tsai Y et al. Insurance reimbursements for routinely recommended adult vaccines in the private sector. Am J Prev Med. 2019;57:180-190.
Tsai Y. Payments and Utilization of Immunization Services Among Children Enrolled in Fee-for-Service Medicaid. Med Care. 2018;56: 54–61.
Food and Drug Administration. Package Insert: Vaxelis. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2020. https://www.fda.gov/media/119465/download
Food and Drug Administration. Package Insert: PedvaxHIB. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 1998. https://www.fda.gov/media/80438/download
Wilck MB, Xu ZJ, Stek JE, Goveia G, Lee AW. Protective immune responses against Haemophilus influenzae type b elicited by a fully-liquid DTaP-IPV-Hib-HepB vaccine (Vaxelis^TM). Vaccine 2021;39:1428-34.

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