Alonso, P.L. et al. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 366, 2012-2018

Eduardo Mondlane University, Lourenço Marques, Maputo City, Mozambique
The Lancet (Impact Factor: 45.22). 01/2006; 366(9502):2012-8. DOI: 10.1016/S0140-6736(05)67669-6
Source: PubMed


RTS,S/AS02A is a pre-erythrocytic stage malaria vaccine that provides partial protection against infection in malaria-naive adult volunteers and hyperimmune adults. A previous report showed that this vaccine reduced risk of clinical malaria, delayed time to new infection, and reduced episodes of severe malaria over 6 months in African children. An important remaining issue is the durability of protection against clinical disease in these children.
We did a randomised, controlled, phase IIb trial of RTS,S/AS02A given at 0, 1, and 2 months in 2022 Mozambican children aged 1-4 years. We previously determined vaccine efficacy (VE) against clinical malaria in a double-blind phase that included study months 2.5-8.5 (VE(2.5-8.5)). We now report VE in a single-blind phase up to month 21 (VE(8.5-21)). The primary endpoint was time to first or only clinical episode of Plasmodium falciparum malaria (axillary temperature 37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) detected through a passive case detection system. We also determined VE for other case definitions and for episodes of severe malaria. This study is registered with the identifier NCT00197041.
During the single-blind phase, VE(8.5-21) was 28.9% (95% CI 8.4-44.8; p=0.008). At month 21, prevalence of P falciparum infection was 29% lower in the RTS,S/AS02A group than in the control (p=0.017). Considering the entire study period, VE(2.5-21) was 35.3% (95% CI 21.6-46.6; p<0.0001) and VE(2.5-21) for severe malaria was 48.6% (95% CI 12.3-71.0; p=0.02).
These results show that RTS,S/AS02A confers partial protection in African children aged 1-4 years living in rural endemic areas against a range of clinical disease caused by P falciparum for at least 18 months, and confirm the potential of malaria vaccines to become credible control tools for public-health use.

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    • "The most clinically advanced malaria vaccine candidate, RTS,S, targets the circumsporozoite protein (CSP) on the surface of sporozoites—the parasite stage transmitted from mosquitos to humans (Regules et al., 2011). RTS,S induces relatively short-lived CSP-specific antibody responses (Alonso et al., 2005; Riley and Stewart, 2013) and confers only partial, shortterm protection from malaria in children (Rts, 2014). In light of our findings here, it is noteworthy that RTS,S induces Th1- skewed CS-specific CD4 + T cells in children residing in malaria-endemic areas (White et al., 2013). "
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    • "Whilst the holy grail for malaria eradication is the development of a cheap, effective vaccine, currently none exists and the most promising candidate to date has, at best, only a moderate impact on the incidence of malaria [123]. Despite this, significant progress against morbidity and mortality is possible with the tools we already have. "
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    • "Although some of them showed potent protection at pre-clinical trials (Schwartz et al., 2012), none to date conferred complete protection against both clinical and severe malaria. The only vaccine to reach stage 3b, RTS,S/AS01E, showed approximately 50% efficacy for 18 months (Alonso et al., 2005) but immunity was significantly diminished within 4 years (Olotu et al., 2013). Notably, protection declined over time and with increasing malaria exposure. "
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    ABSTRACT: Malaria is a significant global burden but after >30 years of effort there is no vaccine on the market. While the complex life cycle of the parasite presents several challenges, many years of research have also identified several mechanisms of immune evasion by Plasmodium spp. Recent research on malaria, has investigated the programmed cell death-1 (PD-1) pathway which mediates exhaustion of T cells, characterized by poor effector functions and recall responses and in some cases loss of the cells by apoptosis. Such studies have shown exhaustion of CD4(+) T cells and an unappreciated role for CD8(+) T cells in promoting sterile immunity against blood stage malaria. This is because PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8(+) T cells, thus masking their role in protection. The role of T cell exhaustion during malaria provides an explanation for the absence of sterile immunity following the clearance of acute disease which will be relevant to future malaria-vaccine design and suggests the need for novel therapeutic solutions. This review will thus examine the role of PD-1-mediated T cell exhaustion in preventing lasting immunity against malaria.
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