Seasonal vaccination against malaria: a potential use for an imperfect malaria vaccine.

In many parts of the African Sahel and sub-Sahel, where malaria remains a major cause of mortality and morbidity, transmission of the infection is highly seasonal. Seasonal malaria chemoprevention (SMC), which involves administration of a full course of malaria treatment to young children at monthly intervals during the high transmission season, is proving to be an effective malaria control measure in these areas. However, SMC does not provide complete protection and it is demanding to deliver for both families and healthcare givers. Furthermore, there is a risk of the emergence in the future of resistance to the drugs, sulfadoxine-pyrimethamine and amodiaquine, that are currently being used for SMC. Substantial progress has been made in the development of malaria vaccines during the past decade and one malaria vaccine, RTS,S/AS01, has received a positive opinion from the European Medicines Authority and will soon be deployed in large-scale, pilot implementation projects in sub-Saharan Africa. A characteristic feature of this vaccine, and potentially of some of the other malaria vaccines under development, is that they provide a high level of efficacy during the period immediately after vaccination, but that this wanes rapidly, perhaps because it is difficult to develop effective immunological memory to malaria antigens in subjects exposed previously to malaria infection. A potentially effective way of using malaria vaccines with high initial efficacy but which provide only a short period of protection could be annual, mass vaccination campaigns shortly before each malaria transmission season in areas where malaria transmission is confined largely to a few months of the year

Malaria Transmission-Blocking Vaccines: Present Status and Future Perspectives

Transmission-blocking vaccines (TBVs) utilize Plasmodium sexual stage proteins to induce antibodies that prevent parasites from infecting blood-fed mosquitoes. This type of vaccine, which can be considered a “vaccine of solidarity,” reduces Plasmodium infections within communities without conferring direct protective immunity to the vaccine recipients. The leading TBV candidates have advanced to field clinical trials, where vaccine-induced antibody function has been demonstrated in mosquito-feeding assays. However, the duration of functional antibody responses has been short-lived; hence current development has focused on improved adjuvant and vaccine delivery systems to generate long-lasting immune responses. For the future implementation of TBVs, community perceptions and understandings should be considered, and education should be provided on the concept and its value. Implementation will need to be undertaken in harmony with current malaria control policies

Dispersible formulation of artemether/lumefantrine: specifically developed for infants and young children

Infants and children under five years of age are the most vulnerable to malaria with over 1,700 deaths per day from malaria in this group. However, until recently, there were no WHO-endorsed paediatric anti-malarial formulations available

Plasmodium falciparum Plasmepsin 2 Duplications, West Africa

Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as antimalaria drug in Africa. We report the detection in Mali of Plasmodium falciparum infections carrying plasmepsin 2 duplications (associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.This work was supported by a Swedish Research Council Grant (no. VR-2014-3134). The WANECAM study is funded by the European and Developing Countries Clinical Trial Partnership and by the Medicines for Malaria Venture (Geneva, Switzerland) and is co-funded by the United Kingdom Medical Research Councils, the Swedish International Development Cooperation Agency, the German Ministry for Education and Research, the University Claude Bernard (Lyon, France), the University of Science, Techniques, and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), the Institut de Recherche en Sciences de la Sante (Bobo-Dioulasso, Burkina Faso), and the Centre National de Formation et de Recherche en Sante Rurale (Guinea).J.I. was supported by EuroInkaNet/Erasmus Mundus Program. Fundacao para a Ciencia e Tecnologia supports M.S. (grant no. SFRH/BD/129769/2017), M.I.V. (grant no. SFRH/BPD/76614/2011), and P.E.F. (grant no. IF/00143/2015)

Evaluation of seasonal malaria chemoprevention in two areas of intense seasonal malaria transmission: Secondary analysis of a household-randomised, placebo-controlled trial in Houndé District, Burkina Faso and Bougouni District, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is now widely deployed in the Sahel, including several countries that are major contributors to the global burden of malaria. Consequently, it is important to understand whether SMC continues to provide a high level of protection and how SMC might be improved. SMC was evaluated using data from a large, household-randomised trial in Houndé, Burkina Faso and Bougouni, Mali. METHODS AND FINDINGS: The parent trial evaluated monthly SMC plus either azithromycin (AZ) or placebo, administered as directly observed therapy 4 times per year between August and November (2014-2016). In July 2014, 19,578 children aged 3-59 months were randomised by household to study group. Children who remained within the age range 3-59 months in August each year, plus children born into study households or who moved into the study area, received study drugs in 2015 and 2016. These analyses focus on the approximately 10,000 children (5,000 per country) under observation each year in the SMC plus placebo group. Despite high coverage and high adherence to SMC, the incidence of hospitalisations or deaths due to malaria and uncomplicated clinical malaria remained high in the study areas (overall incidence rates 12.5 [95% confidence interval (CI): 11.2, 14.1] and 871.1 [95% CI: 852.3, 890.6] cases per 1,000 person-years, respectively) and peaked in July each year, before SMC delivery began in August. The incidence rate ratio comparing SMC within the past 28 days with SMC more than 35 days ago-adjusted for age, country, and household clustering-was 0.13 (95% CI: 0.08, 0.20), P < 0.001 for malaria hospitalisations and deaths from malaria and 0.21 (95% CI 0.20, 0.23), P < 0.001 for uncomplicated malaria, indicating protective efficacy of 87.4% (95% CI: 79.6%, 92.2%) and 78.3% (95% CI: 76.8%, 79.6%), respectively. The prevalence of malaria parasitaemia at weekly surveys during the rainy season and at the end of the transmission season was several times higher in children who missed the SMC course preceding the survey contact, and the smallest prevalence ratio observed was 2.98 (95% CI: 1.95, 4.54), P < 0.001. The frequency of molecular markers of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance did not increase markedly over the study period either amongst study children or amongst school-age children resident in the study areas. After 3 years of SMC deployment, the day 28 PCR-unadjusted adequate clinical and parasitological response rate of the SP + AQ regimen in children with asymptomatic malaria was 98.3% (95% CI: 88.6%, 99.8%) in Burkina Faso and 96.1% (95% CI: 91.5%, 98.2%) in Mali. Key limitations of this study are the potential overdiagnosis of uncomplicated malaria by rapid diagnostic tests and the potential for residual confounding from factors related to adherence to the monthly SMC schedule. CONCLUSION: Despite strong evidence that SMC is providing a high level of protection, the burden of malaria remains substantial in the 2 study areas. These results emphasise the need for continuing support of SMC programmes. A fifth monthly SMC course is needed to adequately cover the whole transmission season in the study areas and in settings with similar epidemiology. TRIAL REGISTRATION: The AZ-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT02211729

Quinine Treatment Selects the pfnhe-1 ms4760-1 Polymorphism in Malian Patients with Falciparum Malaria

Background. The mechanism of Plasmodium falciparum resistance to quinine is not known. In vitro quantitative trait loci mapping suggests involvement of a predicted P. falciparum sodium-hydrogen exchanger (pfnhe-1) on chromosome 13. Methods. We conducted prospective quinine efficacy studies in 2 villages, Kolle and Faladie, Mali. Cases of clinical malaria requiring intravenous therapy were treated with standard doses of quinine and followed for 28 days. Treatment outcomes were classified using modified World Health Organization protocols. Molecular markers of parasite polymorphisms were used to distinguish recrudescent parasites from new infections. The prevalence of pfnhe-1 ms4760-1 among parasites before versus after quinine treatment was determined by direct sequencing. Results. Overall, 163 patients were enrolled and successfully followed. Without molecular correction, the mean adequate clinical and parasitological response (ACPR) was 50.3% (n = 163). After polymerase chain reaction correction to account for new infections, the corrected ACPR was 100%. The prevalence of ms4760-1 increased significantly, from 26.2% (n = 107) before quinine treatment to 46.3% (n = 54) after therapy (P = .01). In a control sulfadoxine-pyrimethamine study, the prevalence of ms4760-1 was similar before and after treatment. Conclusions. This study supports a role for pfnhe-1 in decreased susceptibility of P. falciparum to quinine in the field.Howard Hughes Medical Institute [55005502]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; European and Developing Countries Clinical Trials Partnership [EDCTP IP_07_31060_002]info:eu-repo/semantics/publishedVersio

Cost-effectiveness of district-wide seasonal malaria chemoprevention when implemented through routine malaria control programme in Kita, Mali using fixed point distribution

Background Seasonal malaria chemoprevention (SMC) is a strategy for malaria control recommended by the World Health Organization (WHO) since 2012 for Sahelian countries. The Mali National Malaria Control Programme adopted a plan for pilot implementation and nationwide scale-up by 2016. Given that SMC is a relatively new approach, there is an urgent need to assess the costs and cost effectiveness of SMC when implemented through the routine health system to inform decisions on resource allocation. Methods Cost data were collected from pilot implementation of SMC in Kita district, which targeted 77,497 children aged 3–59 months. Starting in August 2014, SMC was delivered by fixed point distribution in villages with the first dose observed each month. Treatment consisted of sulfadoxine-pyrimethamine and amodiaquine once a month for four consecutive months, or rounds. Economic and financial costs were collected from the provider perspective using an ingredients approach. Effectiveness estimates were based upon a published mathematical transmission model calibrated to local epidemiology, rainfall patterns and scale-up of interventions. Incremental cost effectiveness ratios were calculated for the cost per malaria episode averted, cost per disability adjusted life years (DALYs) averted, and cost per death averted. Results The total economic cost of the intervention in the district of Kita was US $357,494. Drug costs and personnel costs accounted for 34$0.73 and US $0.86, respectively; total annual financial and economic costs per child receiving SMC were US$2.92 and US $3.43, respectively. Accounting for coverage, the economic cost per child fully adherent (receiving all four rounds) was US$6.38 and US $4.69, if weighted highly adherent, (receiving 3 or 4 rounds of SMC). When costs were combined with modelled effects, the economic cost per malaria episode averted in children was US$4.26 (uncertainty bound 2.83–7.17), US $144 (135–153) per DALY averted and US$ 14,503 (13,604–15,402) per death averted. Conclusions When implemented at fixed point distribution through the routine health system in Mali, SMC was highly cost-effective. As in previous SMC implementation studies, financial incentives were a large cost component

Efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria: revisiting molecular markers in an area of emerging AQ and SP resistance in Mali

<p>Abstract</p> <p>Background</p> <p>To update the National Malaria Control Programme of Mali on the efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated <it>falciparum </it>malaria.</p> <p>Methods</p> <p>During the malaria transmission seasons of 2002 and 2003, 455 children – between six and 59 months of age, with uncomplicated malaria in Kolle, Mali, were randomly assigned to one of three treatment arms. <it>In vivo </it>outcomes were assessed using WHO standard protocols. Genotyping of <it>msp1</it>, <it>msp2 </it>and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites (molecular correction).</p> <p>Results</p> <p>Day 28 adequate clinical and parasitological responses (ACPR) were 14.1%, 62.3% and 88.9% in 2002 and 18.2%, 60% and 85.2% in 2003 for chloroquine, amodiaquine and sulphadoxine-pyrimethamine, respectively. After molecular correction, ACPRs (cACPR) were 63.2%, 88.5% and 98.0% in 2002 and 75.5%, 85.2% and 96.6% in 2003 for CQ, AQ and SP, respectively. Amodiaquine was the most effective on fever. Amodiaquine therapy selected molecular markers for chloroquine resistance, while in the sulphadoxine-pyrimethamine arm the level of <it>dhfr </it>triple mutant and <it>dhfr</it>/<it>dhps </it>quadruple mutant increased from 31.5% and 3.8% in 2002 to 42.9% and 8.9% in 2003, respectively. No infection with <it>dhps </it>540E was found.</p> <p>Conclusion</p> <p>In this study, treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine. The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy.</p