Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial

Abstract

Background: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya.

Methods: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)-Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks-4 months, 5-17 months), and by baseline CD4% (<10, 10-14, 15-19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459.

Findings: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6-51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3-46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8-1·6). 20 (20·2%, 95% CI 12·8-29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3-19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7-11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1-9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients).

Interpretation: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes.

Funding: GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.

Figure 1:. Trial profile

177 participants completed the study (87 assigned to RTS,S/AS01, reasons for 12 withdrawals were: five had a fatal SAE, one withdrew consent, three migrated, two were lost to follow-up, and one refused; and 90 assigned to rabies vaccine, reasons for 11 withdrawals were: four had a fatal SAE, six migrated, and one had non-compliance with study procedures). ATP=according-to-protocol. SAE=serious adverse event. ITT=intention-to-treat.

Figure 2. Overall incidence of solicited and grade 3 solicited adverse events

: Absolute data: pain: RTS,S/AS01 52/288, rabies vaccine 18/298; redness: RTS,S/AS01 20/288, rabies vaccine 9/298; swelling: RTS,S/AS01 31/288, rabies vaccine 13/298; drowsiness: RTS,S/AS01 32/288, rabies vaccine 15/298; irritability: RTS,S/AS01 73/288, rabies vaccine 32/298; loss of appetite: RTS,S/AS01 51/288, rabies vaccine 26/298; fever: RTS,S/AS01 120/288, rabies vaccine 56/298. Data were reported during the 7-day post-vaccination periods in the intention-to-treat population. Error bars represent 95% CIs. Grade 3 pain=crying when limb was moved or the limb was spontaneously painful. Grade 3 redness or swelling=diameter larger than 20 mm. Grade 3 drowsiness=preventing everyday activity. Grade 3 irritability=preventing everyday activity and crying inconsolably. Grade 3 loss of appetite=not eating at all. Grade 3 fever=axillary temperature greater than39·0°C. Any fever=axillary temperature ≥37·5°C.