Waiting for the Malaria Vaccine: The Complex Epidemiological Transition Toward Malaria Elimination

(See the Major Article by Akech et al on pages 372–80.)

Malaria remains a public health threat, even if its burden has been declining in the recent past from 239 million cases and 607 000 deaths to 219 million cases and 435 000 deaths estimated in 2010 and 2017 respectively [1]. This reduction has occurred as a possible result of different preventive and curative interventions such as the use of insecticide-treated nets (ITN, especially long lasting), indoor residual spraying (IRS), larvicides, and intermittent preventive therapy in pregnant women and seasonal chemoprophylaxis in children, as well as the use of rapid diagnostic tests (RDT) and artemisinin-based combination therapies (ACT). However, evidence exists that a decrease in malaria transmission has occurred even before the large-scale implementation of those strategies [2]. Since 2015, the decreasing trend has plateaued, and the 10 countries with the largest malaria burden in Africa, by far the most affected continent, has registered a slight increase of cases in 2017 in comparison to 2016 [1]. The stop of the decreasing trend poses the 2030 ambitious goal of 90% reduction in malaria incidence and mortality rate in comparison to 2015, set by the Global Technical Strategy for Malaria 2016–2030 [3], at risk. The causes of this stagnation are not completely clear so far, but the suboptimal implementation of the interventions due to insufficient funding, emergence of vector resistance to insecticides, and parasite resistance to ACT drugs (the latter fortunately not yet registered in Africa) could play a role. In addition, a worrying shift toward older children of malaria morbidity and mortality because of decreased transmission and slower appearance of functional immunity in childhood has been reported [4].

The availability of an effective antimalaria vaccine could add a substantial weapon to the present set of interventions in view of the final goal of malaria elimination. The vaccine in the most advanced stage of development is the GSK RTS,S/A01, which requires a primary cycle of 3 doses followed by a booster 18 months apart. Its intention-to-treat efficacy after 48 months of follow-up has been reported to be 36.3% (clinical malaria) and 32.2% (severe malaria) in children aged 5–17 months in a large multicentric study involving 11 sites with different malaria transmission patterns. The efficacy obtained when younger infants (6–12 weeks) were vaccinated was significantly lower [5]. Disturbingly, the trial reported a higher incidence of meningitis and cerebral malaria in the vaccinated group in comparison to controls [6]. Later long-term follow-up (7 years) analysis of children vaccinated (3 doses only) in 2 high transmission trial sites in Kenya and Tanzania have shown a trend toward the vanishing of vaccine protection starting from the fifth year [7]. Similar results were issued by a recent long term (7 years) follow-up study carried out in children vaccinated in 3 study sites in Kenya, Burkina Faso, and Tanzania that confirmed the overall clinical protection but without additional benefit after month 48. Reassuringly, the trial failed to identify an excess of cerebral malaria in the 3 additional year of follow-up [8].

Despite its shortcomings, the RTS,S vaccine has been granted positive regulatory assessment by the European Medicine Agency (EMA) in 2015. However, in order to further assess in real life, the additional impact of 4 doses RTS,S vaccine on severe malaria and all causes mortality and to characterize vaccine safety, the World Health Organization (WHO) has issue a position paper calling for a large-scale pilot implementation phase, funded by the GAVI Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis, and Malaria; and Unitaid. The implementation phase is due to start in 2019 in moderate-to-high transmission areas of Ghana, Kenya, and Malawi, using the Expanded Programme for Immunization (EPI) platform and starting the primary cycle at 5–6 months with a booster dose 18 months apart [9]. The knowledge of the baseline epidemiological situation in the selected vaccination areas is therefore crucial to precisely appreciate vaccine attributable efficacy.

Starting from the 90s, Kenya has done dramatic progresses to control malaria, and today nearly 50% of the counties has a P. falciparum Parasite Prevalence (PfPR) below 1% in children 2–10 years of age, even if high PfPR areas over 30% still exist in western Counties near Lake Victoria [10].

The paper by Akech and colleagues in this issue of Clinical Infectious Diseases [11] is a large retrospective analysis of the incidence of uncomplicated and severe malaria and malaria attributable deaths in 1 month to 15-year-old children in the years 2015–2017 in 4 County hospitals near Lake Victoria, a high transmission area that is targeted by the pilot introduction of the RTS,S vaccine.

Briefly, when compared to a previous assessment performed in the 90s [12], a shift toward an older age of malaria infection was observed, with as many as one third of malaria admissions, severe malaria cases, and deaths reported in children aged 5–15 years. A higher proportion of cerebral malaria cases was also reported in comparison to the past. Disturbingly, a number of deaths was recorded in older children for whom no signs of severe malaria was retrieved in the surveillance system. Despite the observed shift, however, the burden of malaria remained concentrated in children below the age of 5 years.

Although the authors have done a commendable effort to present reliable data, the obvious limitation of the study lies in its retrospective design that could have led to possible misclassification of malaria cases and prompted a slightly different definition of severe malaria phenotype as compared to WHO. Furthermore, the analysis has covered the 2015–2017 period, before and after a strike of health workers [13], whose impact on the implementation of malaria control activities and hospitals’ data collection is difficult to appreciate.

Even with these limitations, the work by Akech and colleagues is particularly timely and important, providing an essential baseline scenario against which the epidemiological impact of the vaccine introduction will have to be assessed. If the ongoing trend of malaria clinical presentation toward older ages will continue in the future, given the administration of the RTS,S vaccine within the frame of the EPI schedule and its vanishing efficacy with time, concerns exist about its effective protection at the right time to prevent severe malaria in childhood as long as malaria transmission in the moderate-to-high transmission areas is above a certain threshold. The clinical impact of the persisting vaccine-induced reduction of blood-stage immunity still has to be elucidated [14].

The complex epidemiological transition we are witnessing requires expanding surveillance efforts, also including children of older age and adolescents, and intensifying control interventions. The exact assessment of epidemiological dynamics, also including the role of chronic submicroscopic asymptomatic carriers of parasites to sustain transmission [15], is crucial now more than ever [16] to precisely quantify the attributable fraction of vaccine introduction to curb malaria burden and provide generalized policy indications after the pilot implementation phase expected in 2023.

RTS,S malaria vaccine is the result of a long-term research effort to eventually eliminate malaria. However, its suboptimal efficacy requires its use in combination with intense antimalarial control efforts (with particular regard to ITN use), especially in moderate to high transmission areas, to accelerate the reduction of malaria transmission and avoid dangerous rebound effects. Adequate funding is requested, now more than ever, to facilitate the successful future transition toward effective malaria control and, eventually, elimination.

Notes

Potential conflicts of interest. The author reports no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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