Immunogenicity and safety of the RTS,S/AS01 malaria vaccine co-administered with measles, rubella and yellow fever vaccines in Ghanaian children: A phase IIIb, multi-center, non-inferiority, randomized, open, controlled trial

Highlights

• First RTS,S/AS01 dose was given with Vitamin A supplementation at 6 months of age.

• Third RTS,S/AS01 dose was given with yellow fever and measles-rubella vaccines at 9 months.

• Immune responses following co-administration met all non-inferiority criteria.

• The safety profile of the vaccines was clinically acceptable when co-administered.

• RTS,S/AS01 can be given with Vitamin A, yellow fever and measles-rubella vaccines.

Abstract

Background

To optimize vaccine implementation visits for young children, it could be efficient to administer the first RTS,S/AS01 malaria vaccine dose during the Expanded Programme on Immunization (EPI) visit at 6 months of age together with Vitamin A supplementation and the third RTS,S/AS01 dose on the same day as yellow fever (YF), measles and rubella vaccines at 9 months of age. We evaluated the safety and immunogenicity of RTS,S/AS01 when co-administered with YF and combined measles-rubella (MR) vaccines.

Methods

In this phase 3b, open-label, controlled study (NCT02699099), 709 Ghanaian children were randomized (1:1:1) to receive RTS,S/AS01 at 6, 7.5 and 9 months of age, and YF and MR vaccines at 9 or 10.5 months of age (RTS,S coad and RTS,S alone groups, respectively). The third group received YF and MR vaccines at 9 months of age and will receive RTS,S/AS01 at 10.5, 11.5 and 12.5 months of age (Control group). All children received Vitamin A at 6 months of age. Non-inferiority of immune responses to the vaccine antigens was evaluated 1 month following co-administration versus RTS,S/AS01 or EPI vaccines (YF and MR vaccines) alone using pre-defined non-inferiority criteria. Safety was assessed until Study month 4.5.

Results

Non-inferiority of antibody responses to the anti-circumsporozoite and anti-hepatitis B virus surface antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus RTS,S/AS01 alone was demonstrated. Non-inferiority of antibody responses to the measles, rubella, and YF antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus YF and MR vaccines alone was demonstrated. The safety profile of all vaccines was clinically acceptable in all groups.

Conclusions

RTS,S/AS01 can be co-administered with Vitamin A at 6 months and with YF and MR vaccines at 9 months of age during EPI visits, without immune response impairment to any vaccine antigen or negative safety effect.

Introduction

An estimated 219 million malaria cases and 435 000 deaths from malaria occurred worldwide in 2017 [1]. Africa accounted for more than 90% of malaria cases and deaths, and children younger than five years were the most vulnerable age group [1], [2]. Current malaria control measures rely on chemoprophylaxis and vector control interventions [1], [3]. Although these methods have contributed to the decline in the number of malaria cases, complementary tools, such as vaccines, are needed, especially since anti-malarial drug and insecticide resistance continue to increase [1].

In this context, the pre-erythrocytic Plasmodium falciparum malaria vaccine (RTS,S/AS01, GSK vaccine) has been developed [4]. RTS,S/AS01 has received a positive scientific opinion from the European Medicines Agency under an Article 58 regulatory procedure in July 2015 [5]. The WHO recommended pilot implementation of RTS,S/AS01 as a four-dose regimen in African settings with moderate-to-high malaria transmission [6]. The first dose should be administered after the age of 5 months and should be followed by the second and third doses with a minimum interval of 4 weeks and the third dose completed by 9 months of age. The fourth dose should be given around the second birthday.

The EPI delivery system is an effective means of achieving rapid high vaccination coverage in Africa. Co-administration of multiple vaccines ensures that children are protected when they need it most, reduces the number of vaccination visits required, and allows an easier incorporation of new vaccines into existing schedules. However, the risks of immune interference or enhancing effects of the co-administered vaccines always need to be evaluated before their incorporation into an existing immunization program [7], [8], [9], [10], [11]. In sub-Saharan Africa, measles, rubella and yellow fever (YF) vaccines are given at 9 months of age [12]. A previous phase 4 study conducted in The Gambia has shown that the co-administration of a combined measles-rubella (MR) vaccine and a YF vaccine at 9 months of age was associated with a reduction in the anti-rubella and anti-YF antibody levels, which were further reduced by the concomitant administration of the IPV vaccine, but that seroconversion rates were maintained to both antigens [13]. In regions with Vitamin A deficiency, the WHO recommends Vitamin A supplementation twice yearly for children 6–59 months of age [14]. Co-administration with Vitamin A and with MR and YF vaccines would therefore facilitate the implementation of RTS,S/AS01. In a previous study, the co-administration of RTS,S/AS01 with YF and measles vaccines at 9 months of age did not show immunological interferences for the YF and measles immune responses [11]. However, the study design did not allow for the evaluation of the impact of co-administration on the anti-CS antibody response and was conducted in infants 6 weeks of age at the first dose with co-administration of RTS,S/AS01 with rubella vaccine not assessed. The present study evaluated the immunogenicity, safety and reactogenicity of RTS,S/AS01 in co-administration with a YF and a MR vaccine in Ghanaian children. A summary contextualizing the results, the potential clinical research relevance, and the impact of our study is described in the Plain Language Summary (Fig. 1).