Malaria is a significant public health threat in sub-Saharan Africa, particularly among children. The RTS,S/AS01 malaria vaccine reduces the risk and severity of malaria in children. RTS,S/AS01 was piloted in three African countries, Ghana, Kenya and Malawi, to assess safety, feasibility and cost-effectiveness in real-world settings. A qualitative longitudinal study was conducted as part of the feasibility assessment. This analysis explores RTS,S/AS01 vaccination barriers and identifies potential motivators among caregivers in three sub-counties in western Kenya.
A cohort of 63 caregivers with a malaria vaccine eligible child was interviewed at three time points over 24 months. A sub-set of 11 caregivers whose eligible children were either partially or non-vaccinated were selected for this sub-analysis. The 5A Taxonomy for root causes of under-vaccination was used to organise the inductively-coded data into categories (awareness, acceptance, access, affordability, and activation) and identify the factors influencing uptake across caregivers. A trajectory analysis was conducted to understand changes in factors over time within each caregiver experience. Caregiver narratives are used to illustrate how the factors influencing uptake were interrelated and changed over time.
Lack of awareness, previous negative experiences with routine childhood immunisations and the burden of getting to the health facility contributed to caregivers initially delaying uptake of the vaccine. Over time concerns about vaccine side effects diminished and anticipated vaccination benefits strongly motivated caregivers to vaccinate their children. Persistent health system barriers (e.g., healthcare provider strikes, vaccine stockouts, negative provider attitudes) meant some children missed the first-dose eligibility window by aging-out.
Caregivers in this study believed the RTS,S/AS01 to be effective and were motivated to have their children vaccinated. Despite these positive perceptions of the malaria vaccine, uptake was substantially hindered by persistent health system constraints. Negative provider attitudes emerged as a powerful deterrent to attending immunisation services and hampered uptake of the vaccine. Strategies that focus on improving interpersonal communication skills among healthcare providers are needed.

BACKGROUND: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses.
METHODS: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months.
RESULTS: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge.
CONCLUSIONS: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria.
BACKGROUND: NCT01857869.

BACKGROUND: For regulatory approval, consistency in manufacturing of vaccine lots is expected to be demonstrated in confirmatory immunogenicity studies using two-sided equivalence trials. This randomized, double-blind study (NCT01323972) assessed consistency of three RTS,S/AS01 malaria vaccine batches formulated from commercial-scale purified antigen bulk lots in terms of anti-CS-responses induced.
METHODS: Healthy children aged 5-17 months were randomized (1:1:1:1) to receive RTS,S/AS01 at 0-1-2 months from one of three commercial-scale purified antigen bulk lots (1600 litres-fermentation scale; commercial-scale lots), or a comparator vaccine batch made from pilot-scale purified antigen bulk lot (20 litres-fermentation scale; pilot-scale lot). The co-primary objectives were to first demonstrate consistency of antibody responses against circumsporozoite (CS) protein at one month post-dose 3 for the three commercial-scale lots and second demonstrate non-inferiority of anti-CS antibody responses at one month post-dose 3 for the commercial-scale lots compared to the pilot-scale lot. Safety and reactogenicity were evaluated as secondary endpoints.
RESULTS: One month post-dose-3, anti-CS antibody geometric mean titres (GMT) for the 3 commercial scale lots were 319.6 EU/ml (95% confidence interval (CI): 268.9-379.8), 241.4 EU/ml (207.6-280.7), and 302.3 EU/ml (259.4-352.3). Consistency for the RTS,S/AS01 commercial-scale lots was demonstrated as the two-sided 95% CI of the anti-CS antibody GMT ratio between each pair of lots was within the range of 0.5-2.0. GMT of the pooled commercial-scale lots (285.8 EU/ml (260.7-313.3)) was non-inferior to the pilot-scale lot (271.7 EU/ml (228.5-323.1)). Each RTS,S/AS01 lot had an acceptable tolerability profile, with infrequent reports of grade 3 solicited symptoms. No safety signals were identified and no serious adverse events were considered related to vaccination.
CONCLUSIONS: RTS,S/AS01 lots formulated from commercial-scale purified antigen bulk batches induced a consistent anti-CS antibody response, and the anti-CS GMT of pooled commercial-scale lots was non-inferior to that of a lot formulated from a pilot-scale antigen bulk batch.