*Traditional approaches to malaria control:Vector controlindoor pesticide treatments (spray walls)elimination of breeding sitesSurveillanceTreatment of active cases (e.g. chloroquine)4) More surveillanceEntomological problems:Surveillance systems have degeneratedVector control infrastructure has degeneratedInsecticide resistanceAlmost all older insecticides are now of little effect, forcing the use of much moreexpensive chemicals.Common problem in public health:As control strategies are successful in reducing a disease, and concern about the disease wanes, itbecomes harder to justify the expense of maintaining the program. Scarce dollars are shifted toother pressing problems. But eventually the disease returns, sometimes now with resistance tothe original insecticides and drugs.Chloroquine: based on chemical structure of quinineInitially remarkably inexpensive (~4 cents/dose) and effective.Resistance appeared first in 1957 in an area on the Thailand-Cambodia border. Miningattracted many non-immune workers to the area, and also created lots of ditches/ponds/etc thatbred lots of Anopheles mosquitoes, leading to frequent malaria epidemics. To combat this publichealth officials started a program where chloroquine was added to table salt (attempt to treatpeople with a prophylactic dose). Resistance, based on an ability to rapidly excrete the drug viaan ABC transporter (40X faster than wild type parasites), appeared, then spread throughout SEAsia, then into Africa, now everywhere. Consequence of failure to consider what would happenwhen parasites are exposed to a drug for a long time (i.e. failure to account for evolution).New drugs?Little interest from the big pharmaceutical companies*“orphan diseases”: most who require the drugs are too poor to pay much, so little economicincentive to invest in R&D (common problem in many tropical diseases)Most effort now funded by WHO, Gates Foundation, similar NGOsSome newer drugs available (eg. atovaquone-proguanil (Malarone), sulfadoxine-pyrimethamine(Fansidar), doxycyclineAll are many times more expensive than chloroquineSome new drugs based on traditional cureseg. Artimisin from Chinese Artemesia plantsArtemisin combination therapy (ACT) now the standard, but resistance has already appeared,especially in Thailand/Myanmar border areaNew developments: Entomological PerspectiveResidual indoor spraying of insecticides is still used, but much less frequently due to insecticideresistance.Nets are treated with permethrin or other fast-acting contact insecticide. Odor of sleeping peopledraws in mosquitoes that contact the net and are killed. Practical considerations: cost of nets,ease/cost of replenishing insecticide treatment of nets.**Our best current tool: insecticide-treated bednets!Insecticide-treated bednets reduce the number of infectious bites (open bars: bitesprevented; filled bars: bites received). Note that night time (peak at 3 am) is when thethreat is the greatest.Vaccine developmentAnti-sporozoiteAnti-gametocyteAnti-merozoiteMulti-functional vaccine contains peptides fromseveral different stages of the parasiteVery dificult problem, with no real success until very recently. Why?Parasites mostly cryptic inside host cellsTremendous amount of genetic diversity, very hard tofind “universal” antigensParasites selected for ability to evade host immunityField trials of candidate vaccines ongoing.ResultsIn the 14 months after the first dose of vaccine, the incidence of first episodes ofclinical malaria in the first 6000 children in the older age category was 0.32 episodes perperson-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, foran efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treatpopulation and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacyagainst severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severemalaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocolpopulation during an average follow-up of 11 months. Serious adverse events occurred with asimilar frequency in the two study groups. Among children in the older age category, the rate ofgeneralized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI,0.62 to 1.64).1st malaria vaccine to show efficacy in field trials!!!!Update:After four doses, protection (reduction in cases) over 4 years was:Clinical malaria 39%Severe malaria 29%Malaria hospitalization 37%Immunity fades over time, but natural immunity due to malaria exposure builds up.WHO & the Vaccine Alliance sponsoring a widespread vaccination campaign across the mostendemic areas of sub-Saharan Africa between 2022 and 2025. 1st vaccine to be deployed in thefield.Update 2:BioNTech is leading an effort to develop a mRNA vaccine for malaria in 2022. BioNTech (withPfizer) previously developed a highly effective mRNA vaccine for Covid-19. Possiblecomplication: mRNA vaccines require a “cold chain” with storage on dry ice, hard to accomplishin rural sub-Saharan Africa.Lymphatic FilariasisLymphatic filariasis*Also called “elephantiasis”1.2 billion people at riskAbout 120 million infected in 72 countriesOver 40 million disabledNote: “Filariasis” is a general term for infection with nematodeparasites (River blindness is another example)Nematode Parasites:Wuchereria bancrofti (most common worldwide)Brugia malayi (southeast Asia)Brugia timori (southeast Asia)*Reservoirs:Only humans are known as reservoirs (anthroponosis)So very few animal models are available to study