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The World Health Organization (WHO) has certified Cabo Verde as a malaria-free country, marking a significant achievement in global health. With this announcement, Cabo Verde joins the ranks of 43 countries and 1 territory that WHO has awarded this certification.

Cabo Verde is an island nation about 250 west of Senegal. It “is the third country to be certified in the WHO African region, joining Mauritius and Algeria which were certified in 1973 and 2019 respectively.

“Certification of malaria elimination is the official recognition by WHO of a country’s malaria-free status. The certification is granted when a country has shown – with rigorous, credible evidence – that the chain of indigenous malaria transmission by Anopheles mosquitoes has been interrupted nationwide for at least the past three consecutive years.  A country must also demonstrate the capacity to prevent the re-establishment of transmission.”

https://www.who.int/news/item/12-01-2024-who-certifies-cabo-verde-as-malaria-free–marking-a-historic-milestone-in-the-fight-against-malaria

PEER REVIEWED ARTICLES (see notes after citations from non-peer-reviewed publications)

Prevention

Vaccines

Aderinto N & al., A Perspective on Oxford’s R21/Matrix-M™ Malaria Vaccine and the Future of Global Eradication Efforts, Malaria J, 2024 Jan 12, 23:16, https://doi.org/10.1186/s12936-024-04846-w#Sec2 is a review of the results of the Phase II and Phase III testing of the vaccine and the conclusions that can be drawn from them: (1) “Vaccine Efficacy (VE) [was] 75% in locations characterized by seasonal variations, while it registered at 68% in standard locations.” (2) “A distinguishing feature of this vaccine is the inclusion of Novavax’s Matrix-M, a saponin-based adjuvant known for enhancing immune responses, resulting in greater effectiveness and durability. Matrix-M stimulates the recruitment of antigen-presenting cells at the injection site and improves antigen presentation in local lymph nodes.” (3) “The 5–17-month age group demonstrated significantly higher antibody titers than 18–36-month-olds … Specifically, when comparing the two age groups, VE was significantly higher in the younger age group (78%) than in the older age group (70%).” (4) “A parallel decline in efficacy over the initial year of follow-up was observed at both seasonal and standard sites” and (5) “According to the WHO, the R21 vaccine has been proven safe in clinical trials…” The authors caution that “[w]hile the R21/Matrix-M Malaria Vaccine is a promising tool, it cannot work in isolation. Malaria control should encompass a range of interventions, including vector control, prompt diagnosis and treatment, community education, and infrastructure development.”

“Seasonal vaccination with the RTS,S/AS01E vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either intervention given alone over a 3 year period.” The objective of Dicko A & al., Children up to the Age of 5 Years in Burkina Faso and Mali: A Double-Blind, Randomised, Controlled, Phase 3 Trial, Lancet Infect Dis. 2024 Jan; 24(1):75-86, https://doi.org/10.1016/s1473-3099(23)00368-7 was “to establish whether the added protection provided by the combination could be sustained for a further 2 years … The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57·7% … and versus RTS/AS01E-alone being 59·0% … Hospital admissions for WHO-defined severe malaria were reduced by 66·8% (95% CI 40·3 to 81·5), for malarial anaemia by 65·9% (34·1 to 82·4), for blood transfusion by 68·1% …, for all-cause deaths by 44·5% …, for deaths excluding external causes or surgery by 41·1% …, and for deaths from malaria by 66·8% … in the combined group compared with the SMC alone group.”

In Can Incorporating Genotyping Data into Efficacy Estimators Improve Efficiency of Early Phase Malaria Vaccine Trials? Malaria J, 2023 Dec 19, 22:383, https://doi.org/10.1186/s12936-023-04802-0, Potter GE, & al. review a proposal of a different method of calculating vaccine efficacy while conducting trials of malaria vaccines.  The method involves “[g]enotyping information [which] can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power.”  Ultimately their study of this issue leads them to conclude that the “power gain from the genotyping methods depends on the context.”  

RTS,S/AS01 and R21 are the two malaria vaccines approved by WHO and in use today.  They target the Plasmodium falciparum circumsporozoite protein which is the first form of the malaria parasite entering the human body. Thomson-Luque R & al., Plasmodium falciparum Merozoite Surface Protein 1 as Asexual Blood Stage Malaria Vaccine Candidate, Expert Rev Vaccines. 2023 Dec 15, https://doi.org/10.1080/14760584.2023.2295430 reviews research targeting another stage of the parasite using merozoite surface protein 1 (MSP1) … “to provide immune protection against asexual blood-stage malaria. Successful immunization studies in monkey models involved the use of the full-length MSP1 as vaccine construct. Vaccines using full-length MSP1 for immunization have the potential benefit of including numerous conserved B-cell and T-cell epitopes. This could result in improved parasite strain-transcending, protective immunity in the field. [the authors review] outcomes of clinical trials that utilized a variety of MSP1 constructs and formulations, including full-length MSP1, either alone or in combination with other antigens, in both animal models and humans.”

PfSPZ vaccines have been the subject of much research. In Safety and Protective Efficacy of PfSPZ Vaccine Administered to HIV Negative and Positive Tanzanian Adults, J Clin Invest. 2024 Jan 9:e169060, https://doi.org/10.1172/jci169060, Jongo S, & al. claim that “Sanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria” even though the WHO has not endorsed its use and its 2023 World Malaria report does not mention it. The paper reports on a “randomized, double blind, placebo-controlled trial enrolled 18-45-year-old HIV negative (HIV-) and well-controlled HIV+ Tanzanians.” After analyzing the results, the authors conclude that” PfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective.” As well, James ER & al. claim over 90% effectiveness of the vaccine “for up to 12 weeks,” which is said to make it suitable for preventing malaria for travelers. The paper, Piloting Delivery of PfSPZ Vaccines for Malaria Through a Cryogenic Vaccine Cold Chain to Travel and Military Medicine Clinics, J Travel Med, 2024 Jan 11: Taae007, https://doi.org/10.1093/Jtm/Taae007, is focused on the need for cold chain transportation.

Studying a potential transmission-blocking vaccine, Gao W & al. conclude in A Dual-Antigen Malaria Vaccine Targeting Pb22 and Pbg37 Was Able to Induce Robust Transmission-Blocking Activity, Parasit Vectors,  2023 Dec 14; 16(1):455, https://doi.org/10.1186/s13071-023-06071-x that “[d]ual-antigen vaccines, which expand/lengthen the period during which the transmission-blocking antibodies can act during sexual-stage development, can provide a promising higher transmission-reducing activity compared to single antigens.”

Kunkeaw N & al. “report on mRNA vaccines targeting P. vivax and demonstrate that Pvs25 mRNA-LNP outperformed an adjuvanted Pvs25 protein vaccine suggesting that it is a promising candidate for further testing in non-human primates.” The paper is A Pvs25 MRNA Vaccine Induces Complete and Durable Transmission-Blocking Immunity to Plasmodium vivax, NPJ Vaccines. 2023 Dec 14; 8(1):187, https://doi.org/10.1038/s41541-023-00786-9.

Vector control and protection from vectors

 

“The WHO commissioned a systematic review of the literature and synthesis of evidence for reactive indoor residual spraying (IRS) to develop official recommendations for countries.” Gimnig JE & al., Reducing Malaria Transmission Through Reactive Indoor Residual Spraying: A Systematic Review, Am J Trop Med Hyg. 2023 Dec 20: tpmd220745, https://doi.org/10.4269/ajtmh.22-0745 reports on the only two randomized trials published “that meet inclusion criteria for epidemiological outcomes … In the superiority trial, reactive IRS reduced malaria prevalence by 68% (… certainty of evidence: HIGH) compared with no reactive IRS. No difference was observed for clinical malaria (…; certainty of evidence: MODERATE). In the noninferiority study, the mean difference in incidence between reactive IRS and proactive IRS was 0.10 additional case per 1,000 person-years, which was within the prespecified noninferiority bound (…; certainty of evidence: MODERATE).” Based on the above, the authors conclude that “reactive IRS may be a cost-effective tool for the prevention of malaria in elimination settings.” However, they encourage additional high-quality studies.

“Clothianidin, an insecticide with a novel mode of action, has been deployed in the annual indoor residual spraying programme in northern Ghana since March 2021.” Pambit Zong CM & al. collected “baseline data on local Anopheles gambiae sensu lato (s.l.) susceptibility to the clothianidin insecticide” in a village in Northern Ghana. As reported in Baseline Susceptibility of Anopheles gambiae to Clothianidin in Northern Ghana, Malaria J, 2024 Jan 9, 23:12, https://doi.org/10.1186/s12936-023-04769-y#Sec10, “[t]he WHO susceptibility bioassay revealed a delayed killing effect of clothianidin. Mosquitoes exposed to the cone bioassays for 5 min died 120 h after exposure. Slightly higher mortalities were observed in mosquitoes exposed to clothianidin-treated cement wall surfaces than mosquitoes exposed to mud wall surfaces.”

According to Paintsil EK & al., “[t]he most cost-effective malaria prevention and control strategy is the use of a bed net. However, several factors affect the ownership and usage of bed nets among the adult population. [They] aimed to examine socio-demographic factors affecting bed net ownership, usage and malaria transmission among adult patients seeking healthcare in two Ghanaian urban cities.” In a hospital-based study of 550 subjects, using questionnaires, they established that while “53.3% … of participants owned at least one-bed net but only 21.5% … slept under it the previous night… Those married were 2.0 … and 2.4 … times more likely to own and use a bed net respectively than those who never married. Also, pregnant women were 1.3 … and 1.8 … times more likely to own and use a bed net respectively than non-pregnant. Even though income levels were not associated with bed net ownership and usage, students were 0.4 … and 0.2 … times less likely to own and use bed net respectively compared to formally employed persons. The overall malaria prevalence rate was 7.8%. Malaria-negative patients were 1.6 … and 2.4 … times more likely to own and use bed nets respectively than malaria positive. Patients with tertiary education recorded the lowest malaria prevalence … None of those with a monthly income > $300 recorded a case of malaria. On the contrary, majority 83%, … of the malaria-positive patients earned ≤ $150.” The article is Demographic and Socio-Economic Factors Affecting Bed Net Ownership, Usage, and Malaria Transmission Among Adult Patients Seeking Healthcare in Two Ghanaian Urban Cities, BMC Public Health. 2024 Jan 6; 24(1):106, https://doi.org/10.1186/s12889-023-17590-8.

As documented in multiple articles already, Nhangave AV & al. also found that many young women who own long lasting insecticide treated nets (LLINs) do not know how to use them. Based on “in depth interviews” of 48 women, Factors Associated with the Use of Long-Lasting Insecticidal Nets in Pregnant Women and Mothers with Children Under Five Years of Age in Gaza Province, Mozambique, PLoS Glob Public Health, 2024 Jan 16; 4(1):E0002811, https://doi.org/10.1371/Journal.Pgph.0002811 reports that “[m]ost participants recognized the protective effects of long-lasting insecticidal nets in preventing malaria, and understood that women and children were high risk groups. The nets were reported to cause side effects and difficulty breathing by 100% of pregnant women, while 54.2% of mothers with children under 5 reported no side effects. The majority of women in both groups reported that their health professionals did not educate them about how to use or handle the nets properly. Only 16.7% of mothers with children under 5 received correct handling instructions.”

Wheldrake A & al. tested durability of insecticide treated bed nets (ITNs) in 2020 in comparison to similar tests in 2013 and conclude in Physical Durability: Are Bed Nets Getting Any Stronger? Malaria J, 2024 Jan 13, 23:19, https://doi.org/10.1186/s12936-023-04832-8 that “resistance to damage of ITNs has not generally improved from 2013 to 2020, and in some cases performance is worse. … The long-term physical durability of ITN products cannot be expected to improve while their resistance to damage remains so low, and major upgrades to the performance standards of textile materials used to make ITNs, as well as incentives to develop stronger ones are urgently required.”

Kibondo UA & al. “explore factors associated with malaria infection prevalence in children aged 6 months to 14 years in Muleba, where Long Lasting Insecticidal Net (LLIN) combining a pyrethroid insecticide and synergist piperonyl butoxide (PBO) that counteract resistance in the mosquitoes, was first distributed under trial conditions in 2015.” The authors conclude that “[u]sing PBO LLIN reduced the risk of malaria infection.” However, malaria incidence in all communities studied increased over the period of study and that “LLIN usage at individual level was not a significant factor in either study arms, after adjusting for other factors.” {This last quote is from the article, not the abstract.} The paper is Factors Associated with Malaria Infection Among Children After Distribution of PBO-Pyrethroid Synergist-Treated Nets and Indoor Residual Spraying in North-Western Tanzania, PLoS One. 2023 Dec 21; 18(12):e0295800, https://doi.org/10.1371/journal.pone.0295800.

“Pyrethroids are the main insecticides used in vector control for malaria. However, their extensive use in the impregnation of long-lasting insecticidal nets (LLINs) and indoor residual spraying has led to the development of resistance, threatening its success as a tool for malaria control.” Boussougou-Sambe ST & al. assessed “the susceptibility to pyrethroids and organochlorides of malaria vectors from a semi-urban and rural areas … and to determine the frequency of insecticide resistance genes.” They report in Anopheles gambiae s.s. Resistance to Pyrethroids and DDT in Semi-Urban and Rural Areas of the Moyen-Ogooué Province, Gabon, Malaria J. 2023 Dec 18; 22:382, https://doi.org/10.1186/s12936-023-04820-y that Anopheles gambiae sensu stricto (s.s.), which “was the sole species present, … were resistant to pyrethroids and organochlorides. … All the mosquitoes tested were heterozygous or homozygous for the knockdown resistance (Kdr) mutations Vgsc-L1014F and Vgsc-L1014S…”

Akoton R & al. state in Vectorial Competence, Insecticide Resistance in Anopheles funestus and Operational Implications for Malaria Vector Control Strategies in Benin Republic, Malaria J, 2023 Dec 21, 22:385, https://doi.org/10.1186/s12936-023-04815-9 that the vector mentioned has been found to be “resistant to pyrethroid insecticides used for bed nets impregnation and also resistant to bendiocarb which is currently being introduced in indoor residual spraying formulation in malaria endemic regions.” Further, the vector is distributed all through the country and has adapted to biting during the dry season and at dawn.  All of this represents a major challenge to malaria vector control activities.

 

In a massive study (over 250,000 mosquitoes collected), Yovogan B & al. “assessed the efficacy of pyrethroid-pyriproxyfen and pyrethroid-chlorfenapyr LLINs on the density of Anopheles gambiae s.s. and An. coluzzii compared to pyrethroid-only nets in a three-arm cluster randomised control trial in Benin.” They report in The Impact of Pyrethroid-Pyriproxyfen and Pyrethroid-Chlorfenapyr Long-Lasting Insecticidal Nets on Density of Primary Malaria Vectors Anopheles gambiae s.s. and Anopheles coluzzii in Benin: A Secondary Analysis of a Cluster Randomised Controlled Trial, Parasit Vectors. 2024 Jan 4; 17(1):7, https://doi.org/10.1186/s13071-023-06104-5 that after distribution of nets, “[t]here was no evidence of a significant reduction in vector density indoors in either primary vector species” with any of the three types of insecticides. The abstract is silent on the rate of use of the nets.

Akuoko OK & al. collected adult mosquitoes “during the dry and rainy seasons in 2017 and 2018 from five study sites in Ghana in different ecological zones. Indoor- and outdoor-biting mosquitoes were collected per hour from 18:00 to 06:00 h employing the human landing catch (HLC) technique.” Amng the over 33,000 Anopheles mosquitoes collected and identified, Anopheles gambiae s.l. made up more than 90%. They “were more abundant indoors across all ecological zones of Ghana. The frequency of [a resistance marker] was higher indoors than outdoors from all the study sites, but with higher sporozoite rates in outdoor mosquitoes in Dodowa and Kpalsogu. There is, therefore, an urgent need for a supplementary malaria control intervention to control outdoor-biting mosquitoes.” Biting Behaviour, Spatio-Temporal Dynamics, and the Insecticide Resistance Status of Malaria Vectors in Different Ecological Zones in Ghana, Parasit Vectors. 2024 Jan 9; 17(1):16, https://doi.org/10.1186/s13071-023-06065-9 is their paper.

“Much of our understanding of malaria transmission comes from mosquito feeding assays using Anopheles mosquitoes from colonies that are well adapted to membrane feeding. This raises the question whether results from colony mosquitoes lead to overestimates of outcomes in wild Anopheles mosquitoes.” Ayo D & al. compared colonies of wild An. gambiae s.s. to the strain used in most experimental studies and conclude that using the laboratory strains “do not overestimate outcomes in wild An. gambiae s.s. mosquitoes, the mosquito species most relevant to malaria transmission in Uganda.” Their paper is Susceptibility of Anopheles gambiae to Natural Plasmodium falciparum Infection: A Comparison between the Well-Established Anopheles gambiae s.s Line and a Newly Established Ugandan Anopheles gambiae s.s. Line, Am J Trop Med Hyg. 2023 Dec 26: tpmd230203, https://doi.org/10.4269/ajtmh.23-0203

Eligo N & al., Anopheles arabiensis Continues to Be the Primary Vector of Plasmodium falciparum After Decades of Malaria Control in Southwestern Ethiopia, Malaria J, 2024 Jan 9, 23:14, https://doi.org/10.1186/s12936-024-04840-2 is a detailed study of “Anopheles mosquito species distribution and their infection rate in southwestern Ethiopia.” Of approximately 1400 Anopheles collected, about 55% were An. arabiensis; the rest distributed among seven other species.  Only An. arabiensis were found to harbor P. falciparum, but the numbers were exceedingly small (5/785).

Zhou G & al., Anopheles stephensi Ecology and Control in Africa, Trends Parasitol. 2023 Dec 22: S1471-4922(23)00291-X, https://doi.org/10.1016/j.pt.2023.11.011 appears to be an extremely important article about the newly invasive species; regrettably, however, the abstract is brief and non-revealing and the article itself unavailable without a subscription to the journal. Ditto Hemming-Schroeder E & Ahmed A, Anopheles stephensi in Africa: Vector Control Opportunities for Co-Breeding An. stephensi and Aedes Arbovirus Vectors, Trends Parasitol, 2022 Dec 13, S1471-4922(22)00284-7.pdf, https://doi.org/10.1016/j.pt.2022.11.011.

Ismail RBY & al. used modeling to predict “environmental suitability for Anopheles stephensi” in a variety of urban and rural locations in Ghana. “Analysing geospatial and species occurrence data, [they] identified optimal environmental conditions and important factors for its presence. The model’s most important variables guided hotspot prediction across several ecological zones aside from urban and peri-urban regions.” The authors identify the “Greater Accra, Ashanti Central, Upper East, Northern, and North East regions” as being the most likely to be suitable for the vector. The paper is Predicting the Environmental Suitability for Anopheles stephensi Under the Current Conditions in Ghana, Sci Rep, 2024 Jan 11; 14(1):1116, https://doi.org/10.1038/S41598-024-51780-7.

 

Damene E & Massebo F evaluated “the effect of ivermectin administration to cattle … for its effect on mortality, survivorship and [fecundity] of laboratory reared Anopheles arabiensis. They injected calves with the drug, then exposed them to starved laboratory reared female mosquitoes.  As they report in Administration of Ivermectin to Cattle Induced Mortality, Reduced Fecundity and Survivorship of Anopheles arabiensis in Ethiopia: An Implication for Expansion of Vector Control Toolbox, Trop Med Health, 2024 Jan 16; 52(1):11, https://doi.org/10.1186/S41182-023-00575-z, the process “resulted in an average 24-h mortality rate of 81.6% against An. arabiensis on the first day following treatment. 100% An. arabiensis that fed on ivermectin-treated calves on the first day after treatment died within four days. Egg production rate of An. arabiensis that fed on ivermectin-treated calves was significantly lower compared to controls.” They suggest repeating the experiment with wild mosquitoes.

Finda MF & al. administered a structured survey to 180 stakeholders in 25 countries in sub-Saharan Africa, followed by 18 in-depth discussions with selected groups and individuals regarding the role of gene drive modified mosquitoes (GDMMs). They report in Perspectives of African Stakeholders on Gene Drives for Malaria Control and Elimination: A Multi-Country Survey, Malaria J, 2023 Dec 21, 22:384, https://doi.org/10.1186/s12936-023-04787-w that “despite high levels of awareness of GDMMs among the stakeholders (76.7%), there was a relatively low-level of understanding of their key attributes and potential for malaria control (28.3%). When more information about GDMMs was provided to the stakeholders, they readily discussed their insights and concerns, and offered several recommendations to ensure successful research and implementation of the technology. These included: (i) increasing relevant technical expertise within Africa, (ii) generating local evidence on safety, applicability, and effectiveness of GDMMs, and (iii) developing country-specific regulations for safe and effective governance of GDMMs. A majority of the respondents (92.9%) stated that they would support field trials or implementation of GDMMs in their respective countries.”

“Beginning the year 2021, the Pan-African Mosquito Control Association (PAMCA) initiated an exchange programme with American Mosquito Control Association (AMCA) members’ mosquito abatement districts, in efforts coordinated by the University of Notre Dame.” In Ochomo E & al., Mosquito Control by Abatement Programmes in the United States: Perspectives and Lessons for Countries in Sub-Saharan Africa, Malaria J, 2024 Jan 4, 23:8, https://doi.org/10.1186/s12936-023-04829-3, the authors “document observations, experiences, and lessons gathered by the African vector control professionals that participated in exchange visits to thirteen mosquito abatement districts across six states… [They] highlight the key components of mosquito control operations in the United States and compare them to mosquito control programmes in SSA countries endemic for vector-borne diseases, deriving important lessons that could be useful for vector control in SSA.”

Chemoprophylaxis

 

Ibinaiye T & al. found “[s]ignificant urban-rural differences … caregivers’ sociodemographic characteristics, such as age, gender, level of education, occupation status and health-seeking behaviour for febrile childhood illnesses. Disparities were also seen in terms of [seasonal malaria chemoprophylaxis (SMC)] coverage and related outcomes, with lower odds of the receipt of Day 1 dose direct observation of the administration of Day 1 dose by community distributors, receipt of the full three-day course of SMC medicines and receipt of SMC in all cycles of the annual round among children residing in urban areas, compared with those residing in rural areas. Similarly, urban-dwelling caregivers had lower odds of being knowledgeable of SMC and believing in the protective effect of SMC than rural-dwelling caregivers. The paper is Urban–Rural Differences in Seasonal Malaria Chemoprevention Coverage and Characteristics of Target Populations in Nine States of Nigeria: A Comparative Cross-Sectional Study, Malaria J, 2024 Jan 2, 23:4, https://doi.org/10.1186/s12936-023-04825-7.

“Intermittent Preventive Treatment (IPT) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization (WHO) to reduce disease in pregnancy and adverse maternal and newborn outcomes. At least three doses of SP should be taken by pregnant women during antenatal consultation (ANC) beginning from the thirteenth week of pregnancy till parturition.” In Uptake of Intermittent Preventive Treatment of Malaria in Pregnancy and Risk Factors for Maternal Anaemia and Low Birthweight Among HIV-Negative Mothers in Dschang, West Region of Cameroon: A Cross Sectional Study, Malaria J, 2024 Jan 4, 23:6, https://doi.org/10.1186/s12936-023-04816-8, Kamga SLS & al. “assess uptake of IPT during pregnancy and risk factors for maternal anaemia and infant birth weight in Dschang, West region of Cameroon.” They found that a “majority of pregnant women was aged between 24 and 34 years old (59.2%) and had secondary education (58.8%). Uptake of ≥ 3 IPTp was 64.99% … Microscopy (blood smear examination) and PCR-based diagnosis revealed between 0% and 1.57% of parasite-infected placental samples, respectively. Reported malaria in pregnancy predicted maternal anaemia at birth but not birth weight. Only gestational age (< 37 weeks) and bed net use (< 5 months) significantly predicted infant birth weight at delivery.”

“The World Health Organization has suggested intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) to avert malaria infection in pregnant women in malaria-endemic areas, but this intermittent preventive (IP) treatment is at risk of becoming ineffective due to parasite resistance and the contraindication in HIV-infected women.” Eisenberg SL & Krieger AE, A Comprehensive Approach to Optimizing Malaria Prevention in Pregnant Women: Evaluating the Efficacy, Cost-Effectiveness, and Resistance of IPTp-SP and IPTp-DP, Glob Health Action. 2023 Dec 31; 16(1):2231257, https://doi.org/10.1080/16549716.2023.2231257 “argues that alternative IP treatments such as dihydroartemisinin-piperaquine (DP) should be explored, alongside the urgent need to investigate antimalarial cycling strategies. [Also] the cost-effectiveness of IPTp-DP should be evaluated, as well as potential barriers to IP treatment such as medication stockouts, late attendance at antenatal clinics, lack of autonomy and freedom among women, and lack of knowledge about malaria prevention.”

Two articles and an editorial cover the subject of IPTp in women with HIV:

“[I]ntermittent preventive treatment (IPTp) with sulfadoxine–pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. [González R & al.]  assessed whether IPTp with dihydroartemisinin–piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs.” Their report, Safety and Efficacy of Dihydroartemisinin-Piperaquine for Intermittent Preventive Treatment of Malaria in Pregnant women with HIV in Gabon and Mozambique: A Randomized Double-Blind Placebo-Controlled Trial, Lancet Infect Dis, 2024 Jan 12, https://doi.org/10.1016/S1473-3099(23)007380-7 concludes that among the 666 women studied (332 treated, 334 given placebo), “the addition of IPTp with dihydroartemisinin–piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection (miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups.”

In contrast, the “individually randomised, two-arm, placebo-controlled trial [of 904 women] in areas with high-grade sulfadoxine-pyrimethamine resistance in Kenya and Malawi” by Barsosio HC & al., Chemoprevention for Malaria with Monthly Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Pregnant Women Living with HIV on Daily Co-Trimoxazole in Kenya and Malawi: A Randomised, Double-Blind, Placebo-Controlled Trial, Lancet, 2024 Jan 12: S0140-6736(23)02631-4, https://doi.org/10.1016/S0140-6736(23)02631-4 reports that the “incidence of any malaria infection during pregnancy or delivery was 25·4 per 100 person-years in the co-trimoxazole plus dihydroartemisinin-piperaquine group versus 77·3 per 100 person-years in the co-trimoxazole plus placebo group…” However, this paper apparently doesn’t report on asymptomatic parasitemia. The abstract of the associated editorial, Kamya MR & al., Dihydroartemisinin-Piperaquine for Prevention of Malaria in Pregnant Women Living with HIV, Lancet, 2024 Jan 12: S0140-6736(24)00048-5, https://doi.org/10.1016/S0140-6736(24)00048-5 is not accessible.

 

Other

Preventive efficacy of mass drug administration (MDA) is called into question by Schneider ZD & al.’s meta-analysis of 14 randomized controlled studies, Mass Drug Administration to Reduce Malaria Transmission: A Systematic Review and Meta-Analysis, Am J Trop Med Hyg. 2023 Dec 20: tpmd220766, https://doi.org/10.4269/ajtmh.22-0766. “In higher transmission areas, MDA reduced incidence of Pf parasitemia (… moderate certainty) 1 to 3 months after drug administration; no significant effect of MDA on Pf parasitemia prevalence was detected 1 to 3 months post-MDA (…; low certainty). In lower transmission settings, both incidence and prevalence of Pf parasitemia were reduced 1 to 3 months post-MDA … There was no significant effect of MDA at later time points. MDA may have short-term benefits; however, there was no evidence for longer term impact, although none of the trials assessed prolonged interventions.”

Diagnosis

 

General diagnostics

 

In a study of the diagnosis of febrile children Rautman LH & al. report in Fever in Focus: Symptoms Diagnoses and Treatment of Febrile Children in Ghana—A Longitudinal Hospital Study, Trop Med Int Health, 2023 Dec 13, https://doi.org/10.1111/tmi.13962 that while “[m]alaria (n = 581, 73%) and sepsis (n = 373, 47%) were the most prevalent suspected diagnoses on admission, [o]ne-third of malaria suspected diagnoses (n = 192, 33%) were changed on the discharge diagnosis, compared to 84% (n = 315) of sepsis suspected diagnoses. Among malaria-only discharge diagnoses, 98% (n/N = 202/207) received an antimalarial and 33% (n/N = 69/207) an antibiotic; among discharge diagnoses without malaria, 28% (n/N = 108/389) received an antimalarial and 83% (n/N = 324/389) an antibiotic.” The authors are concerned about the overuse of antimalarials without proper indication.

“Light microscopy and rapid diagnostic tests (RDT) have long been the recommended diagnostic methods for malaria. However, in recent years, loop-mediated isothermal amplification (LAMP) techniques have been shown to offer superior performance, in particular concerning low-grade parasitaemia, by delivering higher sensitivity and specificity with low laboratory capacity requirements in little more than an hour.” In Head-To-Head Comparison of Two Loop-Mediated Isothermal Amplification (LAMP) Kits for Diagnosis of Malaria in a Non-Endemic Setting, Malaria J, 2023 Dec 13; 22:377, https://doi.org/10.1186/s12936-023-04809-7, Ivarsson AC & al. report that this “head-to-head comparison showed higher performance indicators of the HumaTurb Loopamp™ Malaria PDT kit compared to the Alethia® illumigene Malaria kit for detection of malaria,” the former showing 100% sensitivity and 100% specificity as compared to qPCR, the latter not.

Amin J & al., Microscopic Parasite Malaria Classification Using Best Feature Selection Based on Generalized Normal Distribution Optimization, PeerJ Comput Sci, 2024 Jan 5: 10:E1744, https://doi.org/10.7717/Peerj-Cs.1744 reflects on the shortcomings of microscopy as a result of human inefficiency and propose a method of computer based microscopy for diagnosis of malaria.

 

Field diagnostics

 

In view of reports of gene deletions that call into question the efficacy of RDTs, Agaba BB & al. investigated RDT positivity (utilizing two kinds RDTs, one depending on histidine rich protein 2 [HRP2] and one on lactic dehydrogenase [LDH]) and gene deletions in patients positively diagnosed with malaria in 40 hospitals in Northern Uganda. In their paper, Limited Threat of Plasmodium falciparum Pfhrp2 and Pfhrp3 Gene Deletion to the Utility of HRP2-Based Malaria RDTs in Northern Uganda, Malaria J, 2024 Jan 2, 23:3, https://doi.org/10.1186/s12936-023-04830-w they report that out of “2435 symptomatic patients tested for malaria, 1504 (61.8%) were positive on pLDH RDT (HRP2-based RDTs actually performed somewhat better, but still less than 70%). Overall, qPCR confirmed single pfhrp2 gene deletion in 1 out of 416 (0.2%) randomly selected samples that were confirmed of P. falciparum mono-infections. They conclude that with the specific gene deletion being so rare, RDT use remains justified. {It is unclear from the abstract whether the 30+ % of patients whose RDT results were negative had malaria or not.}

Despite numerous reports of false negative RDT results elsewhere, Koliopoulos P & al. found that RDT “provided 87% sensitivity and 98% specificity in detecting acute malaria infections,” while microscopy “exhibited 33% sensitivity and 93% specificity.” They state in Challenges in Diagnosing and Treating Acutely Febrile Children with Suspected Malaria at Health Care Facilities in the Lake Mwanza Region of Tanzania, Am J Trop Med Hyg. 2023 Dec 26: tpmd230254, https://doi.org/10.4269/ajtmh.23-0254 that only “7% of malaria-negative children received antimalarials at [the] Hospital when treatment was guided by the results of rapid testing … [while] 75% of malaria-negative patients were treated with antimalarial drugs at health facilities that used blood smears as the standard diagnostic test.” {The question arises whether there were truly that many cases of submicroscopic infections or is there a need to improve microscopy skills in the area studied.}

Nana RRD & al., Rapid Diagnostic Tests for Malaria Diagnosis in Cameroon: Impact of Histidine Rich Protein 2/3 Deletions and Lactate Dehydrogenase Gene Polymorphism, Diagn Microbiol Infect Dis. 2024 Jan; 108(1):116103, https://doi.org/10.1016/j.diagmicrobio.2023.116103 is a study of the prevalence of mutations in three Plasmodium species that might render RDTs unreliable. They report their findings on a small sample (either 25 or 49, unclear from the abstract) to indicate low prevalence of the deletion. Further, they claim that the recently identified species P. ovale curtisi appears to be prevalent over P. ovale wallikeri.

Fulgence KK & al. conducted quality control tests for malaria microscopy on “40 public medical biology laboratories (MBLs) in the Abidjan 1 health region…” They found “a concordance rate of 100% was obtained for slide 1 for Plasmodium falciparum, while this rate was 20% for slide 2 for Plasmodium ovale. For parasite densities < 200/µl, 87.5% of the participating laboratories (PLs) had a performance rate lower than 80%, while 95% of these PLs had a performance rate higher than 80% for parasitaemia > 2000/µl.” The conclusion of their paper, Evaluation of Malaria Microscopy Diagnostic Performance at 40 Public Health Facilities in Abidjan, Côte d’Ivoire in 2020, Acta Parasitol, 2024 Jan 16, https://doi.org/10.1007/s11686-023-00754-2 is that there is a need “to strengthen [adaptation] to low parasitaemia, to improve the biological confirmation of malaria in Côte d’Ivoire.

“Low-density asymptomatic Plasmodium infections are prevalent in endemic areas, but little is known about their natural history. The trajectories of these infections and their propensity to fluctuate to undetectable densities can affect detection in clinical trials and field studies.” Herrgott DEB & al., “aimed to classify the natural history of these infections in a high transmission area over 29 days.” Based on daily collection of dried blood spots from 128 asymptomatic volunteers, they conclude in Assessing the Daily Natural History of Asymptomatic Plasmodium Infections in Adults and Older Children in Katakwi, Uganda: A Longitudinal Cohort Study, Lancet Microbe, 2024 Jan 4, https://doi.org/10.1016/S2666-5247(23)00262-8 that “[p]arasite dynamics and species are highly variable among low-density asymptomatic Plasmodium infections. Sampling every other day or every 3 days detected a similar proportion of infections as daily sampling, whereas testing once per week or even less frequently could misclassify up to a third of the infections.”  A news release from UW, whose scientists conducted the study (Classifying the Natural History of Asymptomatic Malaria, can be accessed from Science Daily at https://www.sciencedaily.com/releases/2024/01/240104210151.htm), goes further and states that the “dynamic lifecycle of this pathogen means that parasite densities can suddenly drop below the level of detection — especially when older, less sensitive tests are used.”

 

New diagnostic methods

 

Ojurongbe TA & al. have developed a “machine-learning model to predict Plasmodium falciparum (Pf) antigen positivity (presence of malaria) based on sociodemographic behaviour, environment, and clinical features … [based on] 200 Nigerian patients [who] were used to develop predictive models using nested cross-validation and sequential backward feature selection (SBFS)…” Their results show that the presence of known symptoms of malaria plus age and environmental factors are more likely to test positive for Pf than negative. The article is Prediction of Malaria Positivity Using Patients’ Demographic and Environmental Features and Clinical Symptoms to Complement Parasitological Confirmation Before Treatment, Trop Dis Travel Med Vaccines. 2023 Dec 15; 9(1):24, https://doi.org/10.1186/s40794-023-00208-7. {Based on the abstract, this reviewer questions whether this method is superior to clinicians using a checklist.}

Other

 

The presence of absence of Duffy blood group is known to have an effect on susceptibility to P. vivax infections. Abagero BR & al., Detection of Duffy Blood Group Genotypes and Submicroscopic Plasmodium Infections Using Molecular Diagnostic Assays in Febrile Malaria Patients, Res Sq. 2023 Dec 6: rs.3.rs-3706814, https://doi.org/10.21203/rs.3.rs-3706814/v1 report that in P. vivax was present in a very small number of Duffy negative patients who presented with fever, but in each instance the density of parasites was so low that they were detected only with qPCR in the study area in Ethiopia, not microscopy. This may have implications for the diagnosis of P. vivax elsewhere in Africa. {This reviewer just became aware that Res Sq, just as BioRxiv mentioned las month, is a journal that does not submit articles to peer review prior to publication.} However, just a week later, Bouyssou I & al., Unveiling P. Vivax Invasion Pathways in Duffy-Negative Individuals, Cell Host Microbe. 2023 Dec 13; 31(12):2080-2092.e5, https://doi.org/10.1016/j.chom.2023.11.007 covers the same issue in a peer reviewed journal and cites the potential mechanisms by which this may occur not just in Ethiopia, but elsewhere in soub-Saharan Africa. These articles could also be cited under Risk factors in Epidemiology. Duffy PE & al., Vivax Malaria and Duffy Antigen: Stop Being So Negative, Cell Host Microbe. 2023 Dec 13; 31(12):1959-1960, https://doi.org/10.1016/j.chom.2023.11.017 is an editorial that comments on the possible causes of Duffy negative individuals acquiring P. vivax infections.

 

Diagnosing asymptomatic malaria is critical in reducing the transmission of the disease. Orish VN & al., Knowledge and Perception of Asymptomatic Malaria in the Volta Region of Ghana, Trans R Soc Trop Med Hyg. 2024 Jan 2; 118(1):33-43, https://doi.org/10.1093/trstmh/trad049 reports that once their study population of 200 (no mention of age & sex distribution) were made aware of the existence of asymptomatic malaria, 90% or more agreed to be tested and treated if found positive.

 

Treatment

 

Treatment results

 

None this month

 

Adherence to guidelines

 

“In 2020, across Africa, only 32% of eligible pregnant women received at least three IPTp [intermittent preventive treatment of pregnancy] doses, despite high antenatal care attendance.” Wolf K & al., “conducted a secondary analysis of data collected during outreach, training, and supportive supervision visits from 2019 to 2020 to assess quality of care and explore factors contributing to providers’ competence in providing IPTp, insecticide-treated nets, malaria case management, and respectful maternity care. Data were collected during observations of provider-patient interactions in six countries…” As reported in Use of Supervision Data to Improve Quality of Care for Malaria in Pregnancy: Experience in Six African Countries, Am J Trop Med Hyg. 2023 Dec 26: tpmd230206, https://doi.org/10.4269/ajtmh.23-0206, “[a]verage competency scores varied across countries: prevention (44-90%), treatment (78-90%), and respectful maternity care (53-93%). The relative association of each factor with competency score varied. Commodity availability, training, and access to job aids correlated positively with competency in multiple countries.” The authors recommend “tailored actions to improve quality [malaria in pregnancy] services.

“The U.S. President’s Malaria Initiative Impact Malaria Project has supported implementation of the outreach training and supportive supervision (OTSS) approach in 11 African countries to improve the quality of malaria care in health facilities through the collection and analysis of observation-based data on health facility readiness and health provider competency in malaria case management.” Bernard YM & al., Clinical Outreach Training and Supportive Supervision Quality-of-Care Analysis: Impact of Readiness Factors on Health Worker Competencies in Malaria Case Management in Cameroon, Mali, and Niger, Am J Trop Med Hyg. 2023 Dec 26: tpmd230479, https://doi.org/10.4269/ajtmh.23-0479 describes “secondary analysis of longitudinal data collected during routine supervision in Cameroon …, Mali …, and Niger … using digitized checklists to assess how service readiness affects health worker competencies in managing patients with fever correctly and providing those with confirmed uncomplicated malaria cases with appropriate treatment and referral … Data from three rounds of OTSS visits in [the three countries] showed a statistically significant positive association between greater facility readiness scores (including the availability of commodities, materials, and trained staff) and health worker competency in case management. These findings provide evidence that health worker performance is likely affected by the tools and training available to them.”

Patients’ adherence to artemisinin-based combination therapy (ACT) is variable, according to a number of published reports. Bawate C & al. “aimed at determining factors influencing patients’ adherence to ACT for malaria in Kamuli, Uganda and report in Factors Influencing Patients’ Adherence to Malaria Artemisinin-Based Combination Therapy in Kamuli District, Uganda, Malaria J, 2024 Jan 2, 23:1, https://doi.org/10.1186/s12936-023-04824-8 that of a total of 844 patients, adherence was 69.7%. “[A]ge …, household head …, employment status …, patients’ preference of ACT to other anti-malarials …, giving a patient/caregiver instructions on how to take the medication …, being satisfied with getting ACT at facility …, patient/caregiver knowing the drug prescribed …, patient history of saving ACT medicines …, and patient ever shared ACT medicines … were all associated with patients’ adherence to ACT.” The authors express concern about the high rate of saving ACT and sharing it with others.

Side effects and complications

 

Ley B & Luzzatto L, Plasmodium vivax Malaria and G6PD Testing, Pathogens. 2023 Dec 13; 12(12):1445, https://doi.org/10.3390/pathogens12121445 is an editorial of an entire issue of the journal devoted to the topic expressed in the title. For review of the difference between P. falciparum and P. vivax infections, as well as the problem addressed by the title, it is worth reading the first two paragraphs of the editorial, which are reproduced in part below:

“… Both are intra-erythrocytic in the human host through an important part of their life cycle, and they resemble each other a lot more than other species belonging to the same genus. Nevertheless, ever since Plasmodium vivax (P. vivax) and P. falciparum have been recognized under the microscope, over a century of studies have brought to light important biological and clinical differences, … [Among others, first,] P. falciparum parasitaemia can range from sub-microscopic to very high, whereby up to 50% of all red cells are parasitized; in contrast, P. vivax infects reticulocytes selectively, and it is rare to see more than 4% of all red cells parasitized. Second, any individual P. falciparum attack, if untreated, is potentially lethal in a non-immune person, whereas mortality from P. vivax is usually the consequence of recurrent attacks. Third, during its development in the human host, P. falciparum has only one major choice to make: after entering the erythrocyte, it will opt for either the asexual or the sexual pathway… on the other hand, … once a [P. vivax] sporozoite has entered a hepatocyte, the parasite has the option to complete schizogony (whereby merozoites will then invade red cells) or stay dormant and become a hypnozoite, that can reactivate weeks to months after the primary infection. … following infection, a significant fraction of parasites develop into hypnozoites, thus setting the stage for one or more relapses in the future.

This last point is very important not only with respect to clinical course and management but also with respect to pharmacogenetics. For the radical cure of P. vivax, it is necessary to administer, in conjunction with schizontocidal treatment, a drug that will effectively remove hypnozoites. The only drugs that can do this hitherto are the 8-aminoquinolines (8AQs) primaquine (PQ) and tafenoquine (TQ). PQ has an elimination half-life of four to six hours and must be given over several days, whereas the elimination half-life of TQ is much longer at 12 to 13 days, and therefore, it can be given as a single dose. While well tolerated in the majority of recipients, 8AQs can cause acute haemolytic anaemia (AHA) in persons who are G6PD deficient, including heterozygous females. …. At one end of the spectrum, there is a view that the public health burden imposed by P. vivax malaria on the population as a whole is so great and eliminating malaria so urgent that there should be no impediment to the use of PQ or TQ, especially since the number of life-threatening drug-induced AHA cases will be small compared to the number of people protected from potentially life-threatening P. vivax relapses. At the other end of the spectrum, standards of good clinical practice—as well as WHO recommendations—demand G6PD testing before providing PQ or TQ and/or daily supervision when administering either of these drugs; this requires significant resources in terms of health personnel and testing facilities.”

Drug resistance

 

In 2023, van Loon W & al. “updated data collected since 2010 on Plasmodium falciparum K13 and MDR1 drug resistance markers in Huye district, southern Rwanda. Artemisinin resistance-associated PfK13 markers occurred in 17.5% of 212 malaria patients …, nearly double the frequency from 2019. PfMDR1 N86, linked with lumefantrine tolerance, was close to fixation at 98%. In southern Rwanda, markers signaling resistance to artemisinin and lumefantrine are increasing, albeit at a relatively slow rate.” The article is Escalating Plasmodium falciparum K13 Marker Prevalence Indicative of Artemisinin Resistance in Southern Rwanda, Antimicrob Agents Chemother. 2023 Dec 11: e0129923, https://doi.org/10.1128/aac.01299-23.

Inidividuals heterozygous for sickle cell anemia (HbAS) are known to be resistant to malaria.  On the other hand, Gnondjui AA & al., In vitro Delayed Response to Dihydroartemisinin of Malaria Parasites Infecting Sickle Cell Erythocytes, Malaria J, 2024 Jan 4, 23:9, https://doi.org/10.1186/s12936-023-04819-5 demonstrates that for those homozygous for the sickle cell hemoglobin (HbSS) parasites seem resistant to dihydroartemisinin (DHA). In their study of red cells with various combinations of sickle cell genes, “the lowest rate of parasitic growth was found with isolates from HbAS red cells. Conversely, a significantly higher survival rate of parasites ranging from 15 to 34% were observed in isolates from HbSS. Isolates with in vitro reduced DHA sensitivity correlate with lower RBC count and haematocrit and higher parasitaemia at inclusion compared to those with isolates with normal DHA sensitivity. However, this decrease of in vitro sensitivity to DHA was not associated with Kelch 13-Propeller gene polymorphism” (which is the usual mechanism of artemisinin resistance in P. falciparum).

Grossman T & al. document that in Israel, travelers returning from sub-Saharan Africa with P. falciparum malaria have shown increasing frequency of artemisinin resistance. “Treatment failure rates were 0% during 2009-2012, 9.1% during 2013-2016 and 17.4% during 2017-2020.” In Emergence of Artemisinin-Based Combination Treatment Failure in Patients Returning from Sub-Saharan Africa with P. falciparum Malaria, J Travel Med. 2023 Dec 28; 30(8):taad114, https://doi.org/10.1093/jtm/taad114 they discuss the results of genetic analysis of the resistant parasites and conclude that is this population of patients, “treatment failure emergence was not associated with mutations in Pfkelch13. However, P76S mutation in the Pfcoronin gene was more frequently present in the treatment-failure group and merits further investigation.” It is unclear where in Africa these patients had acquired the infection.

Schäfer TM & al., The Problem of Antimalarial Resistance and Its Implications for Drug Discovery, Expert Opin Drug Discov. 2023 Dec 18:1-16, https://doi.org/10.1080/17460441.2023.2284820 concludes that ‘[w]hile employing strategies that utilize already approved drugs may offer a prompt and cost-effective approach to counter antimalarial drug resistance, it is crucial to recognize that only continuous efforts into the development of novel antimalarial drugs can ensure the successful treatment of malaria in the future.” The abstract is not enlightening and the article itself is not available for review.

Foo YS & Flegg JA claim in A Spatio-Temporal Model of Multi-Marker Antimalarial Resistance, J R Soc Interface, 2024 Jan; 21(210):20230570, https://doi.org/10.1098/rsif.2023.0570 that they have developed “a Bayesian model to produce spatio-temporal maps that depict the spread of drug resistance, and apply [their] methods for the antimalarial sulfadoxine-pyrimethamine. [They] infer from genetic count data the prevalences over space and time of various malaria parasite haplotypes associated with drug resistance.”

New drug research

Rathi K & al., Recent Advances in the Synthesis and Antimalarial Activity of 1,2,4-Trioxanes, Bioorg Chem. 2023 Dec 19; 143:107043, https://doi.org/10.1016/j.bioorg.2023.107043 is a summary of the state of development of synthetic antimalarials related to artemisinin. Shukla M & al., An Overview on the Antimalarial Activity of 1,2,4-Trioxanes, 1,2,4-Trioxolanes and 1,2,4,5-Tetraoxanes, Med Res Rev. 2024 Jan; 44(1):66-137, https://doi.org/10.1002/med.21979 covers essentially the same topic and is by the same group of authors.

Williams KL & al. identified several antibodies produced by 45 children who were vaccinated by the RTS,S/AS01 vaccine and identified several with potential for efficacy to combat falciparum malaria. They describe in their paper, A Candidate Antibody Drug for Prevention of Malaria, Nat Med. 2024 Jan 2, https://doi.org/10.1038/s41591-023-02659-z testing of two of these antibodies and modifications therein which in their opinion would enable the antibodies to be manufactured. “The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.”

“Natural products make up more than half of the FDA-approved drugs over the last 40 years and have long been an important source of and inspiration for antimicrobials due to their structural diversity.” Chery-Karschney L & al., Tartrolon E, A Secondary Metabolite of a Marine Symbiotic Bacterium, is a Potent Inhibitor of Asexual and Sexual Plasmodium falciparum, Antimicrob Agents Chemother. 2024 Jan 9: e0068423, https://doi.org/10.1128/aac.00684-23 describes “Tartrolon E (TrtE) [which] is a secondary metabolite macrolide polyketide {similar to the antibiotics erythromycin and azithromycin} …. It was isolated from Teredinibacter turnerae, an intracellular endosymbiotic [bacterium] of marine wood-boring bivalve mollusks of the family Teredinidae (shipworms)… [It] is a promising antimalarial because it inhibits the growth of sexual and asexual blood stages of Plasmodium falciparum at sub-nanomolar levels. The potency of TrtE warrants further investigation into its mechanism of action, cytotoxicity, and ease with which parasites may evolve resistance to it.”

Bosc N & al. “developed a machine-learning-based approach to predict compound antimalarial activity, which was trained on the compound collections of several organizations. The resulting prediction platform, MAIP, … offers a solution to prioritize molecules of interest in virtual screening and hit-to-lead optimization.” In their paper, MAIP: An Open-Source Tool to Enrich High-Throughput Screening Output and Identify Novel, Druglike Molecules with Antimalarial Activity, ACS Med Chem Lett. 2023 Nov 20; 14(12):1733-1741, https://doi.org/10.1021/acsmedchemlett.3c00369, the authors “experimentally validate MAIP and demonstrate how the approach was used … to select and purchase compounds from a public library for subsequent experimental screening. [They] observed a 12-fold enrichment compared with a randomly selected set of molecules…”

Plant extracts and traditional treatments

Lithanatudom P & al. studied four plants in the family of “custard apples,” one of which Cananga odorata (ylang-ylang) is used in folk medicine in Southeast Asia. Their paper, In-Vitro Antimalarial Activity of Methanolic Leaf- and Stem-Derived Extracts from Four Annonaceae Plants, BMC Res Notes. 2023 Dec 22; 16(1):381, https://doi.org/10.1186/s13104-023-06664-w reports that extracts of two of these inhibited P. falciparum in vitro, while having no toxic effects on human cells in laboratory testing.

Other

 

Triple Artemisinin-based Combination Therapy has been advocated as means to overcome parasite resistance to one or the other components of standard ACT. Kokori E & al., Triple Artemisinin-Based Combination Therapy (TACT): Advancing Malaria Control and Eradication Efforts, Malaria J, 2024 Jan 18, 23:25, https://doi.org/10.1186/s12936-024-04844-y extols the virtues of this approach, stating “TACT introduces novel dimensions to the fight against malaria that make them a superior choice in several aspects. TACT has been demonstrated to address resistance, offer a broader spectrum of action, reduce the risk of treatment failure, and can be tailored to meet regional needs, strengthening the global effort to combat malaria. However, maximizing these benefits of TACT depends on accessibility, particularly in resource-limited regions where malaria is most prevalent. Collaborative efforts among stakeholders, sustainable pricing strategies, efficient supply chains, and public–private partnerships are essential to ensure that TACT reaches needy populations.”

Matte M & al., Assessment of Pre-Referral Treatment for Malaria, Diarrhea, and Pneumonia by Rural Community Health Workers in Southwestern Uganda: A Cross-Sectional Study, BMC Health Serv Res, 2024 Jan 17; 24(1):95, https://doi.org/10.1186/S12913-024-10598-9 is a descriptive report on actual practice of community health workers, with only the general conclusion that the results “highlight the need to strengthen pre-referral treatment interventions.  With regard to malaria, RDT malaria results “indicated a negative outcome in 83(60%) and positive in 55 (40%) of cases.”

 

Campaigns and Policies

 

“Many countries pursuing malaria elimination implement ‘reactive’ strategies targeting household members and neighbors of index cases to reduce transmission. These strategies include reactive case detection and treatment (RACDT; testing and treating those positive) and reactive drug administration (RDA; providing antimalarials without testing). [Steinhardt LC, & al.] conducted systematic reviews of RACDT and RDA to assess their effect on reducing malaria transmission.” The report, Reactive Case Detection and Treatment and Reactive Drug Administration for Reducing Malaria Transmission: A Systematic Review and Meta-Analysis, Am J Trop Med Hyg. 2023 Dec 20: tpmd220720, https://doi.org/10.4269/ajtmh.22-0720 concludes that “[e]vidence for reactive strategies’ impact on malaria transmission is limited, especially for RACDT, but suggests RDA might be more effective.”

“In settings nearing [malaria] elimination, interventions will be most effective at interrupting transmission when targeted at the residual foci of transmission. These foci may be missed due to asymptomatic infections. To solve this problem, [WHO] recommends reactive case detection (RACD).” Aidoo EK & al., Malaria Elimination in Ghana: Recommendations for Reactive Case Detection Strategy Implementation in a Low Endemic Area of Asutsuare, Ghana, Malaria J, 2024 Jan 2, 23:5, https://doi.org/10.1186/s12936-023-04792-z is a literature review of 22 papers covering RACD. Based on the data in these papers, the authors conclude that in this “low endemic area, the elimination of malaria may require finding individuals with asymptomatic infections. Given the low prevalence of asymptomatic individuals identified in this study and as [documented] in the literature review, which favours RACD, Asutsuare is a possible setting receptive for RACD implementation.”

Asiedu A & al. state that in Ghana, community health officers (CHOs) “play a major role in malaria service delivery… [but] struggle to comply with the World Health Organization’s test, treat, and track initiative guidelines and appropriate referral practices.” In Improving Malaria Case Management and Referral Relationships at the Primary Care Level in Ghana: Evaluation of a Quality Assurance Internship, Glob Health Sci Pract. 2023 Dec 22; 11(6):e2300050, https://doi.org/10.9745/ghsp-d-23-00050 they report on the outcome of a 5-day training program that targeted CHOs from areas deemed poorly performing.  Immediately after the training improvements were noted “in history taking …; fever assessment …; severe malaria assessment and referral …; and knowledge assessment…” Three months after the training the improvements were sustained.

“In 2020, the WHO commissioned 10 systematic reviews of potential interventions in elimination or post-elimination settings to summarize their impact on malaria transmission.” Two articles published this month are of interest in this context. Tusell M & al., Development of Systematic Reviews to Inform WHO’s Recommendations for Elimination and Prevention of Re-Establishment of Malaria: Methodology, Am J Trop Med Hyg. 2023 Dec 20: tpmd220740, https://doi.org/10.4269/ajtmh.22-0740 “describes the general methods used to conduct this series of systematic reviews and notes where individual reviews diverged from the common methodology. The paper also presents lessons learned from conducting the systematic reviews to make similar future efforts more efficient, standardized, and streamlined.” Marsh K & al., Development of WHO Recommendations for the Final Phase of Elimination and Prevention of Re-Establishment of Malaria, Am J Trop Med Hyg. 2023 Dec 20: tpmd220768, https://doi.org/10.4269/ajtmh.22-0768 describes the process by which the recommendations were developed.

Odhiambo JN & al. investigated China’s Hidden Role in Malaria Control and Elimination in Africa, (BMJ Glob Health. 2023 Dec 18; 8(12):e013349, https://doi.org/10.1136/bmjgh-2023-013349). They identified “224 Chinese-funded malaria projects in Sub-Saharan Africa (SSA) committed between 2002 and 2017, [that] mainly focused on three areas: the provision of medical supplies (72.32%), the construction of basic health infrastructure (17.86%) and the deployment of anti-malaria experts (3.57%). Moreover, nearly 39% of the initiatives were concentrated in just four countries: the Democratic Republic of Congo, Central African Republic, Uganda and Liberia.” They conclude that “the extent and direction of China’s support are not adequately tailored to address malaria challenges in different countries.”

Epidemiology

 

Climate change, biodiversity and environment

 

“Climatic factors influence malaria transmission via the effect on the Anopheles vector and Plasmodium parasite. Modelling and understanding the complex effects that climate has on malaria incidence can enable important early warning capabilities.” Pillay MT & al. , Utilizing a Novel High-Resolution Malaria Dataset for Climate-Informed Predictions with a Deep Learning Transformer Model, Sci Rep. 2023 Dec 28; 13(1):23091, https://doi.org/10.1038/s41598-023-50176-3 is a report of comparing several previously published models of climate influence on malaria with a technique called Transformer. {For a reference on Transformer, see https://medium.com/inside-machine-learning/what-is-a-transformer-d07dd1fbec04, which is unfortunately beyond the understanding of this reviewer.}

Abdelkrim O & al. argue in Anopheles Mosquitoes in Morocco: Implication for Public Health and Underlined Challenges for Malaria Re-Establishment Prevention Under Current and Future Climate Conditions, Pest Manag Sci. 2023 Dec 21, https://doi.org/10.1002/ps.7943 that by 2050, malaria may reappear in Morocco.  They base their prediction on the probable reappearance of four species of Anopheles, An. claviger, An. labranchiae, An. multicolor, and An. sergentii in the country. It is unclear, however, whether these species carry Plasmodium parasites and if they do, if they feed on humans.

“The major health threats from climate change include increasing temperatures, air pollution, extreme weather events, changes in the spread of infectious diseases, antimicrobial resistance, emerging pathogens, and an increase in vector-borne disease.” Parums DV, Editorial: Climate Change and the Spread of Vector-Borne Diseases, Including Dengue, Malaria, Lyme Disease, and West Nile Virus Infection, Med Sci Monit. 2024 Jan 1; 29:e943546, https://doi.org/10.12659/msm.943546 “aims to provide an update on the association between climate change and the spread of vector-borne diseases and highlights the urgent need for public health and disease prevention and treatment strategies to control the rise in vector-borne diseases.”

Risk factors

 

“Chronic carriage of asymptomatic low-density Plasmodium falciparum parasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear.” On the contrary, Fogang B & al. report in Asymptomatic Plasmodium falciparum Carriage at the End of the Dry Season is Associated with Subsequent Infection and Clinical Malaria in Eastern Gambia, Malaria J, 2024 Jan 17; 23:22, https://doi.org/10.1186/S12936-024-04836-y that among over 5200 individuals studied over two years, “[a]symptomatic parasite carriage at the end of dry season was associated with a higher risk of infection … and clinical malaria … during the followig transmission season.” The authors are unclear on the reason(s) for this association.

Please see Abagero BR & al., Detection of Duffy Blood Group Genotypes and Submicroscopic Plasmodium Infections Using Molecular Diagnostic Assays in Febrile Malaria Patients, Res Sq. 2023 Dec 6: rs.3.rs-3706814, https://doi.org/10.21203/rs.3.rs-3706814/v1 and Bouyssou I, El Hoss S, Doderer-Lang C & al., Unveiling P. Vivax Invasion Pathways in Duffy-Negative Individuals, Cell Host Microbe. 2023 Dec 13; 31(12):2080-2092.e5, https://doi.org/10.1016/j.chom.2023.11.007 under Other in Diagnosis.

 

General epidemiology

 

Mategula D & Gichuki J, Understanding the Fine-Scale Heterogeneity and Spatial Drivers of Malaria Transmission in Kenya Using Model-Based Geostatistical Methods, PLOS Glob Public Health. 2023 Dec 8; 3(12):e0002260, https://doi.org/10.1371/journal.pgph.0002260 is the description of a sophisticated geospatial modeling method, by which the authors conclude that “elevation, proportion of insecticide treated net (ITN) distributed, rainfall, temperature and urbanization covariates are all significant predictors of malaria transmission. The 5×5 Km resolution maps show that malaria is heterogeneous in Kenya, with hotspot areas in the lake endemic area, the coastal areas, and some parts of the shores of Lake Turkana and Kajiado. The high-resolution malaria prevalence maps produced as part of the analysis have shown that Kenya has additional malaria hotspots, especially in areas least expected.”

Ochieng FO applied a complicated mathematical model to malaria incidence in Kenya and found that it “closely aligns with the recorded malaria incidence data. The optimal values of the model parameters were estimated from the fitting algorithm, and future malaria dynamics were projected for the next decade.” In SEIRS Model for Malaria Transmission Dynamics Incorporating Seasonality and Awareness Campaign, Infect Dis Model. 2023 Dec 9; 9(1):84-102, https://doi.org/10.1016/j.idm.2023.11.010 the author states that the “research findings suggest that social media-based awareness campaigns, coupled with specific optimization control measures and effective management methods, offer the most cost-effective approach to managing malaria.”

Zalwango MG & al. compared three threshold approaches to epidemic declaration “to compare their outbreak-signaling outputs and help identify prioritization approaches and method appropriateness across Uganda.” In Evaluation of Malaria Outbreak Detection Methods, Uganda, 2022, Malaria J, 2024 Jan 13, 23:18, https://doi.org/10.1186/s12936-024-04838-w they report that “[d]uring 2022, > 50% of districts in Uganda were in an epidemic mode according to the 75th percentile method used, resulting in a need to restrict national response to districts with the highest rates of complicated malaria.”

Spatiotemporal studies

Diouf MP & al., Prevalence of Malaria Infection in Pregnant Women Attending Antenatal Clinics in Southern Senegal, Am J Trop Med Hyg. 2024 Jan 2: tpmd230164, https://doi.org/10.4269/ajtmh.23-0164

Kouna LC & al., Malaria Prevalence in Asymptomatic and Symptomatic Children Living in Rural, Semi-Urban and Urban Areas in Eastern Gabon, Acta Parasitol. 2024 Jan 9, https://doi.org/10.1007/s11686-023-00783-x

Tokponnon TF & al., Presence of Plasmodium Vivax in Anopheles gambiae and Absence in Other Malaria Vectors in Cove-Zagnanando-Ouinhi Health Zone in Southern Benin, West Africa, Malaria J, 2024 Jan 15; 23:20. https://doi.org/10.1186/s12936-023-04834-6.

Mbama Ntabi JD & al., Entomological Indicators of Plasmodium Species Transmission in Goma Tsé-Tsé and Madibou Districts, in the Republic of Congo, Malaria J, 2024 Jan 16; 23:21, https://doi.org/10.1186/s12936-023-04823-9.

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