Immunogenicity of co-administered vaccine antigens with whole-cell or acellular pertussis vaccines in infancy: a randomised controlled trial
Authors: Pérez Chacón Gladymar , McAlister Sonia , Totterdell James , Estcourt Marie J. , Marsh Julie A. , Jones Mark , Perrett Kirsten P. , Campbell Dianne E. , Wood Nicholas , Gold Michael , Waddington Claire S. , O’Sullivan Michael , Curtis Nigel , Wadia Ushma , McIntyre Peter B. , Holt Patrick G. , Snelling Tom , Richmond Peter C. 
Published: February 2025

Background

Whole-cell pertussis (wP) and acellular pertussis (aP) vaccines evoke different immune responses to pertussis vaccine antigens. We compared the effect of a heterologous wP/aP/aP primary series (hereafter mixed wP/aP) versus a homologous aP/aP/aP primary schedule (hereafter aP-only) on antibody responses to co-administered vaccine antigens in infants and toddlers.

Methods

We randomised Australian infants in a 1:1 ratio to receive either a mixed wP/aP schedule (pentavalent diphtheria-tetanus-wP-hepatitis B-Haemophilus influenzaetype b; DTwP-HepB-Hib vaccine at 6 weeks old followed by hexavalent DTaP-inactivated poliovirus vaccine (IPV)-HepB-Hib vaccine at 4 and 6 months old) or to aP-only priming doses of hexavalent DTaP-IPV-HepB-Hib vaccine at the same ages. All infants received 13-valent pneumococcal conjugate vaccine (13vPCV) at 6 weeks, 4 and 12 months of age and DTaP-IPV and Hib vaccine boosters at 18 months. We estimated the ratio (GMR) of IgG geometric mean concentrations (GMCs) in the wP/aP and aP-only groups for the serotypes included in the 13vPCV, for Hib capsular polysaccharide polyribosylribitol phosphate (PRP), and for hepatitis B surface antigen (HBsAg) at 6, 7, 18, and 19 months. We assessed whether the wP/aP schedule is non-inferior to the aP-only schedule for co-administered vaccine antigens (GMR>2/3). Trial registration: ACTRN12617000065392p.

Results

Between March 2018 and January 2020, 150 infants were randomised (75 per study arm). Responses to all 13vPCV serotypes and Hib-PRP at 6, 7, 18, and 19 months old, as well as HBsAg at 6 and 7 months old were non-inferior (>90% probability). Sera GMCs were higher for each 13vPCV serotype, Hib-PRP, and HBsAg at each timepoint in the wP/aP group than in the aP-only group.

Interpretation

A mixed wP/aP schedule resulted in non-inferior IgG responses to co-administered vaccine antigens compared to the standard aP-only schedule for pertussis primary immunisation.

Funding

Telethon New Children’s Hospital Research Fund and National Health and Medical Research Council.

Research in context

Evidence before this study

Combination vaccines incorporate antigens that protect against multiple diseases into a single injection. Most low- and middle-income countries (LMICs) currently use wP combination vaccines. Due to the need for periodic boosters to protect older children, adolescents, and adults, these countries may consider moving to the less reactogenic aP combination vaccines that are routinely used in most high-income countries. We searched for evidence about whether a mixed wP/aP primary schedule impacts the immunogenicity of co-administered vaccines. We were particularly interested in evidence for impacts on 13vPCV 2 + 1 schedule and other pneumococcal dose-sparing schedules. We searched PubMed on May 23, 2024, for randomised controlled trials using the following search terms “pneumococcal”, “routine vaccin*”, and “pertussis” combined with Boolean operators, without date or language restrictions. We failed to identify any head-to-head randomised comparisons of the effect of heterologous (mixed) versus homologous pertussis vaccine primary series on co-administered vaccine antigens. Our previous meta-analysis reviewed 15 randomised controlled studies that compared serious adverse events among infants receiving wP versus aP as a first dose before 6 months of age. Few studies reported immune responses to non-DTP co-administered antigens. These findings suggest enhanced Hib responses among recipients of a three-dose primary series of wP compared to those who received three primary aP doses, non-inferior Hib-PRP seroprotection among aP compared to wP vaccinees, and mixed results regarding HBsAg-IgG levels post-wP priming. Both wP and aP groups exhibited weaker Hib-PRP IgG responses when DTP-Hib vaccines were co-administered with meningococcal serogroup C vaccine conjugated to cross-reactive material 197 (CRM197) compared to the meningococcal serogroup C vaccine conjugated to tetanus toxoid (TT).

Added value of this study

This paper is the first reported evidence of a mixed wP/aP schedule resulting in non-inferior IgG responses to co-administered vaccine antigens compared to the standard homologous aP-only schedule for pertussis primary immunisation. In addition, enhanced immune responses were observed to all serotypes included in the 13vPCV and Hib-PRP vaccines in children receiving the mixed wP/aP vaccination strategy versus those vaccinated with a standard aP-only schedule.

Implications of all the available evidence

In settings transitioning from using wP to aP multi-component vaccines, infants receiving a mixed schedule (with wP as the first dose) can be expected have non-inferior, and possibly superior, antibody responses to concomitant vaccine antigens. To better understand the underlying mechanisms of our findings, the assessment of opsonophagocytic activity response rates and serotype-specific memory B cell immune responses to PCV antigens is required. Large population-based studies, particularly in countries where pneumococcal and Hib disease burdens remain high, should be conducted to determine if the observed effects on immune responses translate into differences in protection against disease.