Malaria Vaccine Pilot Evaluation: results of safety data analysis 24 months after RTS,S/AS01 introduction

The objectives of the 24-month primary analysis was to evaluate if there was an association between RTS,S/AS01 introduction and the incidence of hospital admission with meningitis, or severe malaria, including cerebral malaria and incidence of gender-specific mortality (all cause, except injuries) in the vaccinating areas. Using the combined data from the 3 countries, sufficient events had accrued by April 2021 to address safety signals and to assess effectiveness against hospital admission with severe malaria with sufficient (90%) power. Overall 13/28 (46.4%) of age-eligible children hospitalized with meningitis had received at least one dose of RTS,S/AS01 compared with 2506/4684 (53.5%) of those who were hospitalized for other reasons (odds ratio 0.92 (95% CI: 0.43, 1.97)). In the 3 countries, there were 28 and 23 cases of hospitalized meningitis among the age-eligible and non-eligible children in the vaccinating areas, compared with 23 and 36, respectively, in the nonvaccinating areas. The rate ratio was 1.0 (95% CI: 0.50, 1.97), excluding the association of RTS,S/AS01 introduction with the increased incidence of meningitis reported in the phase III trial. Of the patients with cerebral malaria in vaccine-eligible age groups from implementation areas, 44% (23/52) had received RTS,S/AS01 vaccine, compared to 54% (2496/4662) of all other admissions in this age group from implementation areas (odds ratio 0.81 (95% CI: 0.46, 1.42)). In the 3 countries, there were 52 and 227 cases of cerebral malaria among the age-eligible and non-eligible children in the vaccinating areas, compared with 54 and 227 respectively, in the nonvaccinating areas. The rate ratio was 1.1 (95% CI: 0.73, 1.69), excluding the association of RTS,S/AS01 introduction with the increased incidence of cerebral malaria reported in the phase III trial. Using the data collected up to 31 March 2021 by the network of village-based reporters who collected data from verbal autopsies that classed the death as due to injury or other causes, and from hospital records for hospital deaths in Malawi, cause of death was established for 4280/4729 (90.5%) deaths in vaccine eligible age groups. In Malawi, using data from the 2018 census to estimate the denominator, the mortality rate was 4.38/1000 person-years, similar to that reported in the census, i.e., 5.08/1000 person years. In the 3 countries, there were 1421 and 4218 deaths among the age-eligible and non-eligible children, respectively in the vaccinating areas, compared with 1443 and 3874, respectively, in the non-vaccinating areas. The rate ratio was 0.93 (95% CI: 0.84, 1.03) which, while the upper 95% CI limit is >1, is compatible with the reduction expected from the reduction reported in clinical trials. The rate ratio for female to male mortality was 1.08 (95% CI: 0.93, 1.25), p=0.321, and this was similar by age group. Among the deaths in the vaccinating area, there were 495/841 (58.9%) age-eligible girls and 502/881 (57%) age-eligible boys who had received at least one dose of RTS,S/AS01.