This paper further contributes key information on the safety, immunogenicity and efficacy profile over a 20 month follow up period of the candidate malaria RTS,S adjuvanted vaccine when co-administered to infants alongside routine immunizations included in the Expanded Programme of Immunization.
This study shows that, over 12 and 18 months of follow up post vaccination: vaccine efficacy against multiple episodes of malaria disease was 50.7% and 26.7%, respectively, in the ATP population. Vaccine efficacy against multiple episodes of malaria disease in the ITT population, starting at first dose of vaccine, was lower (14%). Including ITT analysis provides fair comparisons among the vaccinated population, but perfect adherence to the protocol, especially for phase II studies, is crucial. Results from ATP analyses aim to predict the true biological efficacy of the vaccine.
Initial results demonstrated that RTS,S/AS02D has an acceptable safety profile, that it can be given in co-administration with EPI vaccines and provides protection against first P. falciparum infection of approximately 65% (p = 0.01) over 6 months of follow up .
As an exploratory endpoint in this follow up study, vaccine efficacy against multiple episodes of clinical disease was 51%, though not achieving statistical significance (p = 0.072), and 54% against first or only episode of clinical disease (p = 0.026), over 12 months post-vaccination. These results are consistent with those of a trial evaluating safety, immunogenicity and efficacy of RTS,S/AS01 in co-administration with EPI vaccines in infants . Similar levels of protection have been observed in children 5–17 months old upon first RTS,S/AS01 vaccination in a Phase II trial conducted in Tanzania and Kenya .
However, the large multi-country, multi-site RTS,S/AS01 Phase III trial showed that in young infants the vaccine provided modest protection against malaria when co-administered with EPI vaccines . The fact that most of the participants in the Phase III study come from high transmission areas indicates that RTS,S protection may be influenced by other factors including level of transmission.
While CIs are wide, and models, including time-varying covariates and Schoenfeld residuals (p = 0.192), do not support waning in vaccine efficacy, a longer follow-up of infants post-vaccination showed lower levels of protection in this trial (27% over 18 months), which was not significant at the 5% level (p = 0.307). This is in contrast with a study with the RTS,S/AS01 formulation in infants, which showed protection of 59% over 19 months of follow up (p < 0.001) .
The reduction in the level of protection observed after 18 months, when compared to the level observed at 12 months, was also reported in a study with 45 months of follow up . While it is not impossible that the close follow up during the ADI period may have impacted VE estimates in this trial, a possible explanation could be due to a combination of (i) true decay in vaccine-induced protection over the period of follow up, (ii) the decline in the number of susceptible subjects due to rapid acquisition of immunity, and/or (iii) variability in malaria transmission and exposure. Similar observations were made in recent long-term follow-up studies of RTS,S/AS02 [6, 7, 9–12, 20, 21].
The assessment of anti-CS antibody titres shows that at 18 months post vaccination 71.8% of RTS,S/AS02 recipients remain seropositive. While remaining higher than those seen in the control group, antibody levels are much lower than early after vaccination. Although no protective threshold has been established, anti-CS antibody levels have been shown to be associated with protection [18, 22, 23]. The relatively low immune responses of RTS,S/AS02 to anti-CS observed in this trial, compared to the AS01E formulation, may have also contributed to the apparent drop in long-term protection.
As seen in other studies of RTS,S/AS02 and RTS,S/AS01 [3–13, 22, 23], post vaccination anti-HBs seroprotection rates and GMTs are high. In this study, at month 20 they remained greater than in recipients of hepatitis B vaccine. This supports the fact that the RTS,S candidate vaccine also confers protection against Hepatitis B virus (HBV).
The observation of an acceptable safety profile of RTS,S/ASO2D over 20 months of follow up is consistent with long term safety follow up of RTS,S/AS01 in infants . No safety concerns appeared upon SAE review over the duration of follow up. Few children died and severe malaria rates were lower than expected in this setting, which may be due to close follow up of this cohort. Clinically diagnosed pneumonia, reported as SAEs and classified by MedDRA preferred terms , tended to be more frequently reported among hospitalized participants in the hepatitis B vaccine group at 9 months post vaccination , and this effect was less marked in the current data set to 20 months. A tendency for pneumonia rates to be lower may be due to a variety of reasons, including chance findings, lack of accurate diagnosis for pneumonia and/or the possibility that the malaria candidate vaccine reduced the indirect consequences of malaria. A more rigorous assessment of the co-morbidities is ongoing in the Phase III trial [17, 22].
The acceptable vaccine safety profile and the efficacy data obtained in this trial in the context of co-administration of EPI vaccines adds to the growing body of evidence that, if approved, the RTS,S candidate vaccine could contribute to the reduction of the malaria disease burden in infants and children and become an additional component of integrated malaria control strategies.
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GSK Study ID number: 104298 (Malaria-040).