Immune response to the hepatitis B antigen in the RTS,S/AS01 malaria vaccine, and co-administration with pneumococcal conjugate and rotavirus vaccines in African children: A randomized controlled trial

Abstract

The RTS,S/AS01 malaria vaccine (Mosquirix) reduces the incidence of Plasmodium falciparum malaria and is intended for routine administration to infants in Sub-Saharan Africa. We evaluated the immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix) and human rotavirus vaccine (HRV; Rotarix) when co-administered with RTS,S/AS01 ( www.clinicaltrials.gov NCT01345240) in African infants. 705 healthy infants aged 8-12 weeks were randomized to receive three doses of either RTS,S/AS01 or licensed hepatitis B (HBV; Engerix B) vaccine (control) co-administered with diphtheria-tetanus-acellular pertussis-Haemophilus influenzae type-b-conjugate vaccine (DTaP/Hib) and trivalent oral poliovirus vaccine at 8-12-16 weeks of age, because DTaP/Hib was not indicated before 8 weeks of age. The vaccination schedule can still be considered broadly applicable because it was within the age range recommended for EPI vaccination. PHiD-CV or HRV were either administered together with the study vaccines, or after a 2-week interval. Booster doses of PHiD-CV and DTaP/Hib were administered at age 18 months. Non-inferiority of anti-HBV surface antigen antibody seroprotection rates following co-administration with RTS,S/AS01 was demonstrated compared to the control group (primary objective). Pre-specified non-inferiority criteria were reached for PHiD-CV (for 9/10 vaccine serotypes), HRV, and aP antigens co-administered with RTS,S/AS01 as compared to HBV co-administration (secondary objectives). RTS,S/AS01 induced a response to circumsporozoite protein in all groups. Pain and low grade fever were reported more frequently in the PHiD-CV group co-administered with RTS,S/AS01 than PHiD-CV co-administered with HBV. No serious adverse events were considered to be vaccine-related. RTS,S/AS01 co-administered with pediatric vaccines had an acceptable safety profile. Immune responses to RTS,S/AS01 and to co-administered PHiD-CV, pertussis antigens and HRV were satisfactory.

Keywords: RTS,S; co-administration; hepatitis B; immunogenicity; malaria; plasmodium falciparum; pneumococcal conjugate vaccine; vaccine.

Figures

Figure 1.

Study flow per co-administration vaccination regimen from week 0 until month 26.Group R1 received RTS,S/AS01 + (DTaP/Hib + tOPV + PHiD-CV), and HRV 2 weeks later, Group R2 received RTS,S/AS01 + (DTaP/Hib + tOPV + HRV), and PHiD-CV 2 weeks later, Group R3 received RTS,S/AS01 + (DTaP/Hib + tOPV), and (PHiD-CV + HRV) 2 weeks later, Group C1 received HBV + (DTaP/Hib + tOPV + PHiD-CV), and HRV 2 weeks later, Group C2 received HBV + (DTaP/Hib + tOPV + HRV), and PHiD-CV 2 weeks later, * Other: five consent withdrawal, two recruitment target reached in SBIR, one down syndrome, and one end of inclusion (recruitment was completed), ** Protocol violation: three screening expired and one child received recommended vaccines before enrolment, DTaP/Hib = diphtheria-tetanus-acellular-pertussis-Haemophilus influenzae type-b-conjugate vaccine, tOPV = trivalent oral poliovirus vaccine, PHiD-CV = 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine, HRV = human rotavirus vaccine.

Figure 2.

Anti-pneumococcal antibody concentrations and OPA titers after primary vaccination with PHiD-CV (with or without RTS,S/AS01 co-administration) and booster vaccination (according to protocol immunogenicity cohort at each time point). Vertical lines indicate 95% confidence intervals, OPA = opsonophagocytic activity, PHiD-CV = 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine, GMC/T = geometric mean antibody concentration/titer.

Figure 3.

Focus on Patient Section.