Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Use Haemophilus influenzae Type b-Containing Vaccines among American Indian and Alaska Native Infants

Introduction

On December 21, 2018, the U.S. Food and Drug Administration licensed a hexavalent combined diphtheria and tetanus toxoids and acellular pertussis (DTaP) adsorbed, inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib) conjugate, and hepatitis B (HepB) recombinant vaccine, DTaP-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)) for use as a 3-dose series in infants at ages 2, 4, and 6 months.¹ On June 26, 2019, CDC’s Advisory Committee on Immunization Practices (ACIP) voted to include DTaP-IPV-Hib-HepB in the federal Vaccines for Children (VFC) program.² This decision was based on review of data from clinical trials comparing immunogenicity and safety of DTaP-IPV-Hib-HepB and licensed comparator vaccines among healthy infants in the general U.S. population.

Hib vaccination with monovalent PRP-OMP (PedvaxHIB, Merck & Co, Inc.) has been preferred for American Indian/Alaska Native infants because it provides a protective antibody response after the first dose.³ This is important because 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).⁴ Vaxelis contains PRP-OMP but the dose is lower than PedvaxHIB, and data on post-dose 1 antibody responses were not previously available. At the time of the VFC vote for DTaP-IPV-Hib-HepB, ACIP did not include it in the preferential recommendation for American Indian/Alaska Native infants given the lack of post-dose 1 immunogenicity data.

Given 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. A systematic review and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to inform ACIP’s deliberations regarding use of DTaP-IPV-Hib-HepB among American Indian and Alaska Native infants. The policy question under consideration was “Should DTaP-IPV-Hib-HepB (Vaxelis) be included with monovalent PRP-OMP (PedvaxHIB) in the preferential recommendation for American Indian/Alaska Native infants based on the Haemophilus influenzae type b (Hib) component”? (Table 1).

Methods

Members of ACIP’s Meningococcal/Hib Vaccines Work Group (“Work Group”) selected the policy question and specified and rated the importance of relevant outcomes (including benefits and harms) before the GRADE assessment (Table 1, Table 2). All Work Group members and CDC staff participating in the GRADE assessment met ACIP requirements for reporting conflicts of interest.

A systematic literature search was conducted using Medline, Embase, Cochrane Library, CINAHL (EBSCOHost), Scopus, and clinicaltrials.gov databases. Efforts also were made to obtain unpublished or other relevant data. Two reviewers screened titles, abstracts, and full-text records, as indicated, to determine whether records should be included. Records were included if they presented primary data on use of DTaP-IPV-Hib-HepB among American Indian/Alaska Native infants pertinent to one or more of the PICO outcomes. Characteristics of all included studies are shown in Appendix 1, and evidence retrieval methods are shown in Appendix 2.⁵

The GRADE evidence certainty assessment addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The evidence certainty categories were high, moderate, low, or very low certainty.

Results

A summary of the GRADE assessment was presented to ACIP on June 26, 2024. Overall, 2,332 records were identified and screened; 2,290 records were excluded based on the title, and 41 records were excluded based on review of the abstract or full text. The remaining record described results from one phase IV, prospective, open-label, randomized controlled clinical trial comparing DTaP-IPV-Hib-HepB and monovalent PRP-OMP among American Indian/Alaska Native infants and was included in the evidence synthesis and GRADE assessment (Appendix 1). ⁵ No data were identified regarding the outcome invasive Hib disease. Data on the remaining outcomes are summarized in the tables below.

Summary

For all three outcomes with available data, the initial evidence level was high because the available data were from a randomized controlled trial. For post-dose 1 immunity, the proportion of participants with anti-Hib concentration ≥0.15 µg/mL (the putative correlate of short-term protection) 30 days post-dose 1 was similar among infants in the DTaP-IPV-Hib-HepB group and the monovalent PRP-OMP group. For post-primary series immunity, the proportion of participants with anti-Hib concentration ≥1.0 µg/mL (the putative correlate of long-term protection) 150 days post-dose 1 was higher in the DTaP-IPV-Hib-HepB group than in the monovalent PRP-OMP group. Antibody titers were not available beyond day 150 post-dose 1. The proportion of serious adverse events was similar between groups, and no serious adverse events were deemed related to study participation. All outcomes were downgraded for imprecision based on wide confidence intervals surrounding the absolute risks, resulting in a final evidence certainty of moderate for each outcome.

Table 1: Policy Question and PICO

Table 2: Outcomes and Rankings

Table 3: Summary of Studies Reporting Outcomes of Interest

Table 4: Grade Summary of Findings Table

Table 5: Summary of Evidence for Outcomes of Interest

References

1. Food and Drug Administration. Vaxelis (Diphtheria and Tetanus Toxoids and Acellular Pertussis, Inactivated Poliovirus, Haemophilus b conjugate and Hepatitis B Vaccine). [Package insert]. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2018. https://www.fda.gov/media/119465/download
2. 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.
3. Briere EC, Rubin L, Moro PL, Cohn A, Clark T, Messonnier 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.
4. Ward JI, Margolis HS, Lum MK, Fraser DW, Bender TR, Anderson P. Haemophilus influenzae disease in Alaskan Eskimos: characteristics of a population with an unusual incidence of invasive disease. Lancet. 1981;1:1281–5.
5. Hammitt L. The HibVax Study: Immunogenicity of influenzae type b PRP-OMP vaccines in American Indian and Alaska Native infants [Presentation slides]. Presented at the Advisory Committee on Immunization Practices meeting, Atlanta, GA; February 29, 2024. Atlanta, GA: US Department of Health and Human Services, CDC; 2024 https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2024-02-28-29/03-Vaxelis-Hammitt-508.pdf

Appendix 1. Studies Included in the Review of Evidence

Appendix 2: Search Strategies