Science & Research Report for March 2022

By Dr. Derick Pasternak, Malaria Science & Research Coordinator, Malaria Partners International 

Readers of these reports will note the steady increase in their length, despite strenuous efforts to include only those of the more than 400 malaria-related articles per month in the professional literature that are of greatest interest to MPI, considering its mission and area of operation.  Feedback from the readers is earnestly sought whether this dimension of the reports is acceptable or needs modification, and if the latter, whether shorter summaries, or even simple listing should be in the report.

Prevention:

Subtopic Vaccines 

Sinnis P, Fidock DA, The RTS,S Vaccine–A Chance to Regain the Upper Hand Against Malaria? Cell, 2022 Mar 3; 185(5):750-754. doi: 10.1016/J.Cell.2022.01.028 lacks a clear abstract.

Looking at the outcomes of effective vaccination and chemoprevention Grant J & al. failed to find mitigation of malnutrition in children, as reported in Impact of Seasonal RTS,S/AS01_E Vaccination Plus Seasonal Malaria Chemoprevention on the Nutritional Status of Children in Burkina Faso and Mali, Malaria J, 2022 Feb 22, vol 21 art 59. https://malariajournal.biomedcentral.com/articles/10.1186/ s12936-022-04077-x.

Sissoko MS & al., Safety and Efficacy of a Three-Dose Regimen of Plasmodium falciparum Sporozoite Vaccine in Adults During an Intense Malaria Transmission Season in Mali: A Randomised, Controlled Phase 1 Trial, Lancet Infect Dis, 2022 Mar; 22(3):377-389. doi: 10.1016/S1473-3099(21)00332-7 and Wahl I, Wardemann H, How to Induce Protective Humoral Immunity Against Plasmodium falciparum Circumsporozoite Protein, J Exp Med, 2022 Feb 7; 219(2):E20201313. doi: 10.1084/Jem.20201313 both state that the efficacy of a whole malaria sporozoite vaccine is demonstrating significant effectiveness (52% after three doses in the first paper above). The evidence cited is reduction of laboratory-proven infection in the former, rise in humoral antibody in the latter.  The vaccine remains experimental.

On the other hand, Du Y & al. report impaired immune response to the sporozoite vaccine in Systems Analysis of Immune Responses to Attenuated P. falciparum Malaria Sporozoite Vaccination Reveals Excessive Inflammatory Signatures Correlating with Impaired Immunity, PLoS Pathog, 2022 Feb 2; 18(2):E1010282. doi: 10.1371/Journal.Ppat.1010282.

Another approach to vaccine development is reported in Rider PJF & al., An Attenuated HSV-1-Derived Malaria Vaccine Expressing Liver-Stage Exported Proteins Induces Sterilizing Protection Against Infectious Sporozoite Challenge, Vaccines (Basel), 2022 Feb 16; 10(2):300. doi: 10.3390/ vaccines10020300. The authors “used the novel HSV-1-derived viral vaccine vector VC2 to express three different malaria parasite LS antigens. VC2 is safe and immunogenic in mice, guinea pigs, and non-human primates.” To produce a malaria vaccine, they selected the three malaria parasite proteins for “immunizations of mice with a pooled vaccine, composed of the three attenuated virus strains expressing each LS antigen, induced sterile protection against the intravenous challenge of Plasmodium yoelii 17X-NL salivary gland sporozoites. Our data suggest that this malaria vaccine may be effective in preventing malaria parasite infection using practical routes of immunization in humans.”

Wunderlich F & al. report on a mechanism by which Vaccination Accelerates Liver-Intrinsic Expression of Megakaryocyte-Related Genes in Response to Blood-Stage Malaria, Vaccines (Basel), 2022 Feb 14; 10(2):287. doi: 10.3390/vaccines10020287. Unfortunately the abstract does not mention which vaccine was used.

Abeywickrema M & Goodman AL argue that  COVID-19 Vaccine Results Might Inform Malaria Vaccine Strategies, Lancet Infect Dis, 2022 Feb 24; doi.org/10.1016/S1473-3099(22)00139-6.  Based on what we know of various vaccines against COVID-19, they raise the question whether the currently recommended RTS,S vaccine may be followed by an RS21 booster for greater efficacy.  Further, they also raise the possibility of increasing the time iterval between initial immunization and the booster.

Although not a report on vaccines, Kapulu MC & al., Controlled Human Malaria Infection (CHMI) Outcomes in Kenyan Adults Is Associated with Prior History of Malaria Exposure and Anti-Schizont Antibody Response, BMC Infect Dis, 2022 Jan 24; 22(1):86. doi: 10.1186/S12879-022-07044-8 is a report on the immunization level achieved in a study population that was deliberately infected using the “controlled human malaria infection (CHMI) model … To identify the in vivo outcomes that most closely reflected naturally acquired immunity, parameters based on qPCR measurements were compared with anti-schizont antibody levels and residence as proxy markers of naturally acquired immunity.” The conclusion supports this method to investigate development of immunity.

Likewise, Addy J & al., 10-Year Longitudinal Study of Malaria in Children: Insights into Acquisition and Maintenance of Naturally Acquired Immunity, Wellcome Open Res, 2022 Feb 4; 6:79. doi: 10.12688/ Wellcomeopenres.16562.3 asked how children infected by malaria acquire immunity.  “There was large variability in the accumulation of numbers of clinical malaria episodes experienced by the children, despite being of similar age and living in the same general location. One group of children from a particular sub-region of the cohort stopped accumulating clinical malaria episodes earlier than other children in the study. Despite lack of further clinical episodes of malaria, these children had higher asymptomatic parasite densities and higher antibody titres to a panel of P. falciparum blood-stage antigens.”

Vector control and protection from vectors

Sherrard-Smith E A & al., Optimising the Deployment of Vector Control Tools Against Malaria: A Data-Informed Modelling Study, Lancet Planet Health, 2022 Feb; 6(2):e100-e109. doi: 10.1016/S2542-5196(21)00296-5 reports on “published data from experimental hut trials conducted across Africa to characterise the entomological effect of pyrethroid-only ITNs versus ITNs combining a pyrethroid insecticide with the synergist piperonyl butoxide (PBO).” The conclusion is “that switching from pyrethroid-only to pyrethroid-PBO ITNs could averted up to twice as many cases, although the additional benefit is highly variable and depends on the setting conditions. We project that annual delivery of long-lasting, non-pyrethroid IRS would prevent substantially more cases over 3-years, while pyrethroid-PBO ITNs tend to be the most cost-effective intervention per case averted.”

Also on the subject of pyrethroid resistance, Hancock PA., Modelling Spatiotemporal Trends in The Frequency of Genetic Mutations Conferring Insecticide Target-Site Resistance in African Mosquito Malaria Vector Species, BMC Biol, 2022 Feb 15; 20(1):46. doi: 10.1186/S12915-022-01242-1.  They constructed a “model to interpret species-specific trends in the frequency of the most common resistance mutations, Vgsc-995S and Vgsc-995F, in three major malaria vector species Anopheles gambiae, An. coluzzii, and An. arabiensis over the period 2005-2017. The models are informed by 2418 observations of the frequency of each mutation in field sampled mosquitoes collected from 27 countries spanning western and eastern regions of Africa.” They claim that their “predictive maps show how spatiotemporal trends in insecticide target-site resistance mechanisms in African An. gambiae vary across individual vector species and geographic regions;” and recommend “[m]olecular surveillance of resistance mechanisms … to predict resistance phenotypes and track their spread.”

Still on the subject of enhancing the effectiveness of insecticide treated nets, Mbewe RB & al. “investigated the blood-feeding patterns of malaria vectors and whether LLINs containing pyrethroid and PBO led to a reduction of human blood feeding than those containing only pyrethroids.” Their report, Blood-Feeding Patterns of Anopheles Vectors of Human Malaria in Malawi: Implications for Malaria Transmission and Effectiveness of LLIN Interventions, Malaria J, 2022 Mar 3, vol 21 art 67. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04089-7, however, is more descriptive than analytic and yield little insight into the issue of pyrethroid resistance in mosquitoes.

Forty J & Keetile M, Patterns and Correlates of Ownership and Utilization of Insecticide-Treated Bed-Nets for Malaria Control Among Women of Reproductive Age (15-49 Years) in Malawi, J Biosoc Sci, 2022 Mar; 54(2):269-278.  Doi: 10.1017/S002193202100002x addresses the issue of whether bednets are used as recommended and conclude that is the study population “odds of ownership [and utilization] of ITNs were significantly low among women with no education …, those with primary education [only] … and poor women …  Furthermore, the odds of utilization of ITNs were significantly low among women living in households without a radio … and those who have not seen or heard a malaria message in the last 6 months…”

Bednets are useful only if used and cared for appropriately. Kumoji E’K & al., Ideational Factors Associated with Net Care Behaviour: A Multi-Country Analysis, Malaria J, 2022 Feb 17, vol 21 art 53. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04053-5 is a report on household data nationwide in Côte d’Ivoire, from the North and Far North regions of Cameroon, and from Port Loko and Bo districts in Sierra Leone, between 2018 and 2019. The dependent variable was respondents reporting that they fold or tie up their nets… Among respondents, 50.2% in Cameroon, 52.0% in Côte d’Ivoire and 75.6% in Sierra Leone reported folding or tying up their net when it was not in use. …Consistent use of nets was strongly correlated with net-care behaviour. Furthermore, five ideational variables were positively associated with the outcome behaviour in all three countries: positive attitude towards net care, perceived susceptibility for malaria, response-efficacy of ITNs, perceived self-efficacy for net use, and the perception that net use was a community norm.”

Taremwa IM, Ashaba S Kyarisiima R & al., Treatment-Seeking and Uptake of Malaria Prevention Strategies Among Pregnant Women and Caregivers of Children Under-Five Years During Covid-19 Pandemic in Rural Communities in South West Uganda: A Qualitative Study, BMC Public Health, 2022 Feb 21; 22(1):373, doi: 10.1186/S12889-022-12771-3 is “a qualitative case study … Home medication and the use of local herbs were a common practice. Some participants didn’t use any of the malaria prevention methods due to deliberate refusal, perceived negative effects of the ITNs, and family disparity.”

Investigation of barriers other than bed nets is the subject of Shenton FC & al., The Durability, Functionality and Acceptability of Novel Screened Doors and Windows After 4 Years of Use in a Gambian Village: A Cross-Sectional Survey, Malaria J, 2022 Feb 23, vol 21 art 64, https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04087-9. They conclude that “the screened doors and windows were in full-working order and undamaged after 4 years of use. The doors and windows were well liked, especially for their ability to reduce the entry of mosquitoes and for the security they afforded. Improvements to the lock design are needed before scale-up. Most householders hung curtains behind their doors for privacy. Installation of screening in buildings should be accompanied with recommendations that at night, when doors and windows are closed, curtains be lifted or drawn to one side—to improve ventilation and keep the house cool.”

The effort to skew the Anopheles population toward the non-vector males is the topic of Metchanun N & al., Modeling Impact and Cost-Effectiveness of Driving-Y Gene Drives for Malaria Elimination in the Democratic Republic of the Congo, Evol Appl, 2022 Jan 7; 15(1):132-148. doi: 10.1111/eva.13331. They state that “[s]ex-ratio-distorting gene drives, such as driving-Y, could play a role in an integrated elimination strategy if they can effectively suppress vector populations.” They predict that adding this modality to strategies already in effect, such as treated net use, “could eliminate malaria and were the most cost-effective intervention overall if the drive component was highly … at relatively low fertility cost, and associated cost of deployment below 7.17 $int per person per year.”

Wise IJ & Borry P, An Ethical Overview of the CRISPR-Based Elimination of Anopheles gambiae to Combat Malaria, J Bioeth Inq, 2022 Feb 17. doi: 10.1007/s11673-022-10172-0 is an article that presents three arguments in favor of continuing efforts to eliminate Anopheles gambiae, while recommending formal harm benefit analysis of taking these efforts to their ultimate conclusion.

“Insecticide resistance in Anopheles mosquitoes is seriously threatening the success of insecticide-based malaria vector control.” Wipf NC & al. “investigated the molecular mechanisms of insecticide resistance in three Anopheles coluzzii field populations from southern Côte d’Ivoire.” Their report, Multi-Insecticide Resistant Malaria Vectors in the Field Remain Susceptible to Malathion, Despite the Presence of Ace1 Point Mutations, PLoS Genet, 2022 Feb 10;18(2):E1009963. doi: 10.1371/ Journal.Pgen.1009963 states that “[a]ll three populations were resistant to bendiocarb, deltamethrin and DDT, but not or only very weakly resistant to malathion.”

Permethrin is a pyrethroid used the world over for insect control.  It is not without side effects if inhaled or consumed, but Boyce RM & al. report its use in babies 6 to 18 month of age in Permethrin-Treated Baby Wraps for the Prevention of Malaria: Results of a Randomized Controlled Pilot Study in Rural Uganda, Malaria J, 2022 Feb 23, vol 21 art 63, https://malariajournal.biomedcentral.com/articles/ 10.1186/s12936-022-04086-w.  They conclude that “[p]ermethrin-treated baby wraps were well-tolerated and broadly acceptable. Adverse events were infrequent and mild. These findings support future trials seeking to determine the efficacy of treated wraps to prevent P. falciparum malaria infection in young children as a complementary tool to existing household-based interventions.”

Chemoprophylaxis

Okedo-Alex EN & al., Community Malaria Knowledge, Experiences, Perceived Roles, and Acceptability of Community-Directed Distribution of Intermittent Preventive Therapy for Pregnancy in Rural Southeast Nigeria, J Parasitol Res, 2022 Jan 18; 2022:8418917, doi: 10.1155/2022/8418917 is “part of the baseline findings of a before-and-after study. Data was collected from 817 community members in Ebonyi State using interviewer-administered questionnaires and focus group discussions (FGDs). [It] assessed malaria experiences, knowledge, perceived roles in malaria prevention in pregnancy, and acceptability of community-directed distribution of intermittent preventive therapy (IPTp) for malaria in pregnancy in rural Southeast Nigeria.” Not surprisingly, “there was inadequate knowledge of malaria prevention in pregnancy notably intermittent preventive therapy. There was positive perception of roles in malaria prevention in pregnancy and high acceptability of community-directed distribution of IPTp.”

“Burkina Faso has one of the highest malaria burdens in sub-Saharan Africa despite the mass deployment of insecticide-treated nets (ITNs) and use of seasonal malaria chemoprevention (SMC) in children aged up to 5 years. Identification of risk factors for Plasmodium falciparum infection in rural Burkina Faso could help to identify and target malaria control measures.” Yaro JB & al. conducted a “cross-sectional survey of 1,199 children and adults was conducted during the peak malaria transmission season in the Cascades Region of south-west Burkina Faso in 2017.”  Their report, Risk of Plasmodium falciparum Infection in South-West Burkina Faso: Potential Impact of Expanding Eligibility for Seasonal Malaria Chemoprevention, Sci Rep, 2022 Jan 26; 12(1):1402. doi:10.1038/S41598-022-05056-7 found the vurden of illness very high in school age children as well.  Therefore they advocate extension of age related criteria for seasonal chemoprevention.

Diagnosis:

Several articles deal with Rapid Diagnostic Tests (RDTs).

Leonard CM & al., Investigation of Plasmodium falciparum pfhrp2 and pfhrp3 Gene Deletions and Performance of a Rapid Diagnostic Test for Identifying Asymptomatic Malaria Infection in Northern Ethiopia, 2015, Malaria J, 2022 Mar 4, vol 21 art 70, https://malariajournal.biomedcentral.com/ articles/10.1186/s12936-022-04097-7 aver that rapid diagnostic tests (RDTs) based on histidine-rich protein-2 (HRP2) may be misleading if the local malaria parasite lacks certain genes.  Their study in an area of low malaria prevalence seems to support this hypothesis, but needs further study.

Yimam Y & al. report on RDT in Comparison of Diagnostic Performance Between Conventional and Ultrasensitive Rapid Diagnostic Tests for Diagnosis of Malaria: A Systematic Review and Meta-Analysis, PLoS One, 2022 Feb 10; 17(2):e0263770. doi:10.1371/journal.pone.0263770.   Although the abstract does not specify how ultrasensitive RDT (us-RDT) is different from “conventional” RDT, their meta-analysis of 15 studies covering over 20,000 comparisons between the two tests concludes that The us-RDT test showed better performance than [RDT] test, and this characteristic is more evident in asymptomatic individuals and low transmission areas.”  All the same, even us-RDT was only 61% sensitive in the pooled data.

The premise of Nate Z & al., Recent Progress in Electrochemical Sensors for Detection and Quantification of Malaria, Anal Biochem, 2022 Apr 15;643:114592,  doi: 10.1016/j.ab.2022.114592 is that the sensitivity of RDT is inadequate.  Therefore they focus on other methods of detecting various biomarkers of Plasmodium parasites and conclude that electrochemical methods promise a good alternative.  The feasibility of deploying these in the field is not mentioned.

Onken & al., Malaria Prevalence and Performance of Diagnostic Tests Among Patients Hospitalized With Acute Undifferentiated Fever in Zanzibar, Malar J. 2022 Feb 19; 21(1):54, doi: 10.1186/s12936-022-04067-z “emphasizes that malaria was a frequent cause of febrile illness in hospitalized patients in Zanzibar in the years 2015-2016, particularly among school age children and young adults. We found evidence of autochthonous malaria transmission in Zanzibar. Compared to PCR, both RDT and microscopy had low sensitivity, and false negative results were associated with low parasitaemia.”

Agbana HB & al. compared several diagnostic methods and reported in Detecting Asymptomatic Carriage of Plasmodium falciparum In Southern Ghana: Utility of Molecular and Serological Diagnostic Tools, Malaria J, 2022 Feb19, vol 21 art 57, malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04078-w that HRP2 based RDT and microscopy were consistently the least sensitive for diagnosing asymptomatic individuals in two communities studied, one high and one low prevalence.

Baptista V & al., Review of Microdevices for Hemozoin-Based Malaria Detection, Biosensors (Basel), 2022 Feb 11; 12(2):110, doi: 10.3390/Bios12020110 also start from the premise that the sensitivity of currently used tests in the field is inadequate, especially in detecting low level parasitemia.  They discuss the use of hemozoin as a biomarker and advocate the development of “lab on a chip” to enable the development of field testing for the substance.

The focus of Marita E & al., Implementation of Community Case Management of Malaria in Malaria Endemic Counties of Western Kenya: Are Community Health Volunteers Up to the Task in Diagnosing Malaria?, Malaria J, 2022 Mar 5, vol 21 art 73, https://malariajournal.biomedcentral.com/ articles/ 10.1186/s12936-022-04094-w was not RDT, but its application by community health workers, compared to the performance of the same test by trained laboratory personnel.  The correlation was very strong.

“ Malaria-related deaths could be prevented if powerful diagnostic and reliable prognostic biomarkers were available to allow rapid prediction of the clinical severity allowing adequate treatment,” aver  Tornyigah B, & al in Specific Combinations of Inflammatory, Angiogenesis and Vascular Integrity Biomarkers Are Associated with Clinical Severity, Coma and Mortality in Beninese Children with Plasmodium falciparum Malaria, Diagnostics (Basel), 2022 Feb 18; 12(2):524, doi:10.3390/ diagnostics12020524.  Each of the six biomarker molecules they studied were higher in children who were comatose and five of them in those who ended up dying, than in others.  They state that these “might be potentially useful for the early prognostic of severe and fatal malaria, and to improve management of severe cases.”  However, there is no analysis whether any one may be preferable to others, or more feasible in regions where malaria is prevalent.

Treatment:

Ngwa Niba PT & al., Effectiveness and Safety of Artesunate-Amodiaquine [AS-AQ] Versus Artemether-Lumefantrine [AL] for Home-Based Treatment of Uncomplicated Plasmodium Falciparum Malaria Among Children 6-120 Months in Yaoundé, Cameroon: A Randomized Trial, BMC Infect Dis, 2022 Feb 21; 22(1):166, doi: 10.1186/S12879-022-07101-2 is a “two-arm, open-label, randomized, controlled trial comparing the equivalence of AS-AQ (experimental group) and AL (control group) … at two secondary hospitals in Yaoundé. … After the first dose, antimalarial drugs were given at home, rather than under direct observation by a study staff.” The results verified “that AS-AQ and AL are effective and safe for home management of malaria in Yaoundé.”

“The readiness of primary health facilities and health workers to deliver appropriate pre-referral care to children with complicated malaria in Kenya is inadequate” is the conclusion of Amboko B & al., Readiness of the Kenyan Public Health Sector to Provide Pre-Referral Care for Severe Paediatric Malaria, Trop Med Int Health, 2022 Jan 29. doi:10.1111/Tmi.13728. “A total of 1540 health workers from 1355 health facilities were interviewed. Injectable artesunate was available at 46%, injectable quinine at 7%, and artemether at 3% of the health facilities. None of the facilities had rectal artesunate suppositories in stock.” They state that “[f]urther investments are required to ensure (a) availability of nationally recommended pre-referral antimalarials; (b) appropriate training and supervision in their administration, and (c) monitoring of the entire referral process.”

Another study of health care workers was conducted by Machini B & al. They report in Cross-Sectional Study to Predict Subnational Levels of Health Workers’ Knowledge About Severe Malaria Treatment in Kenya, BMJ Open, 2022 Jan 5; 12(1):E058511, doi: 10.1136/Bmjopen-2021-058511 that they found a “third of the health workers had high knowledge levels on artesunate treatment policy; almost three-quarters had high knowledge levels on artesunate dosing and preparation. The likelihood of having high knowledge on severe malaria treatment policy was lower among nurses relative to clinicians … [and] health workers older than 30 years were 61% less likely to have high knowledge about dosing compared with younger health workers.” They deem this level of familiarity with treatment inadequate.

“Despite the well-known excellent tolerability of artemisinin-based combination therapy (ACT),” Nordmann T & al. state in Drug-Induced Hypersensitivity to Artemisinin-Based Therapies for Malaria, Trends Parasitol, 2022 Feb;38(2):136-146. doi: 10.1016/j.pt.2021.08.011 that “hypersensitivity to artemisinin derivatives remains a repeatedly documented adverse drug reaction of still unknown frequency. … artemisinin-induced hypersensitivity reaction[s] range from mild to life-threatening severity, and a significant number of cases may pass unnoticed… [The authors] discuss the medical importance of hypersensitivity to artemisinin derivatives and … review data on the presumed frequency and its potential underlying mechanisms… [They also] advocate to make alternative non-artemisinin-based drugs available for patients who do not tolerate artemisinin derivatives and to continue investing in the development of novel non-artemisinin-based combination regimens.”

A case report on another adverse effect of artemisinin-based therapy is Abohelva M & al., Delayed Auto-immune Haemolytic Anaemia After Artesunate Therapy for Severe Malaria, BMJ Case Rep, 2022 Jan 17; 15(1):e245845. doi: 10.1136/bcr-2021-245845.

Egwu CO & al., Impact of Drug Pressure Versus Limited Access to Drug in Malaria Control: The Dilemma, Medicines (Basel), 2022 Jan 4; 9(1):2. doi: 10.3390/medicines9010002 state that while “drug pressure” may hinder eradication of malaria by fostering the emergence of drug resistance in parasites, the lack of availability of drugs has the same inhibitory effect.  The abstract is silent on the relative importance of these two factors.

“The private sector plays a large role in malaria treatment provision in Nigeria. To improve access to, and affordability of, quality-assured artemisinin-based combination therapy (QA-ACT) within this sector, the Affordable Medicines Facility-Malaria began operations in 2010 and transitioned to a private sector co-payment mechanism (PSCM) until 2017.” Edwards HM & al. report in The Impact of the Private Sector Co-Payment Mechanism (PSCM) on the Private Market for ACT in Nigeria: Results of the 2018 Cross-Sectional Outlet and Household Market Surveys, Malaria J, 2022 Feb 14, vol 21 art 42, https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-04039-9 that based on an outlet survey of private pharmacies, Proprietary and Patent Medicine Vendors (PPMVs), and of households, the PSCM increased “not only the reach of subsidized QA brands, but also of non-subsidised brands,” which is of significant concern.

Birkholz L-M & al. state that “[p]reventing human-to-mosquito transmission of malaria parasites provides possible solutions to interrupt the malaria parasite life cycle for malaria elimination. The development of validated routine assays enabled the discovery of such transmission-blocking compounds.” Their paper, Transmission-Blocking Drugs for Malaria Elimination, Trends Parasitol, 2022 Feb 19; S1471-4922(22)00012-5, doi: 10.1016/J.Pt.2022.01.011 claims to be “an updated roadmap to the discovery and development of new antimalarials with transmission-blocking activity to guide drug discovery for malaria elimination.”

Saeheng T and Na-Bangchang K start their paper, Clinical Pharmacokinetics of Quinine and Its Relationship with Treatment Outcomes in Children, Pregnant Women, and Elderly Patients, with Uncomplicated and Complicated Malaria: A Systematic Review, Malaria J, 2022 Feb 10 vol 21, art 41. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04065-1, by stating that “[p]arenteral artesunate, followed by artemisinin-based combination therapy (ACT), is the recommended treatment for severe malaria, when available. Quinine is usually used if artesunate is not available, and is always used in combination with an additional agent, such as doxycycline. Quinine is also used, in combination with clindamycin, for uncomplicated Plasmodium falciparum infections in pregnant women during the first-trimester, as well as for chloroquine-resistant Plasmodium vivax infections … A recent systematic review (2020) has suggested a high risk of treatment failure in uncomplicated malaria patients (mostly second- and third-trimester pregnancies) after quinine monotherapy, while the efficacy of quinine-clindamycin combination was comparable with ACT.” Their meta-analysis of 28 published studies appears to support the latter finding.

Given the demonstrated continuing existence of vivax malaria in Sub-Saharan Africa, below are two articles related to its treatment.

“Malaria relapses are caused by Plasmodium vivax-induced latent liver stage hypnozoites, and relapses contribute significantly to the total disease burden.” Nain M & al. report in Effects of Host Genetic Polymorphisms on the Efficacy of the Radical Cure Malaria Drug Primaquine [PQ], Am J Trop Med Hyg, 2022 Jan 10; tpmd211115, doi:10.4269/ajtmh.21-1115 that “host glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with hemolysis after treatment with PQ. … Being a prodrug, PQ requires [multiple] host factors… for its metabolism and conversion to active form… It is vital to delineate the polymorphisms that determine the ultimate efficacy of PQ for formulating better malaria elimination strategies in countries with severe malaria burden. Thus population-based studies of these gene variants will provide new insights into the role of host genetics on PQ treatment outcomes.”

Somewhat in contrast with the above, Mwaiswelo RO & al. cite the WHO’s recommendation for “a single low dose (SLD) of primaquine (0.25 mg/kg) as P. falciparum gametocytocidal without the need for prior screening of G6PD status.” In their paper, Is It Time for Africa to Adopt Primaquine in the Era of Malaria Control and Elimination? Trop Med Health, 2022 Feb 25;50(1):17, doi: 10.1186/S41182-022-00408-5, they state that “[a]doption and implementation of SLD primaquine in Africa may … reduce malaria transmission, a pre-requisite for malaria elimination.” They found only 14 deaths attributed to PQ in their literature search among hundreds of thousands of use, and, none of which were alleged to be related to G6PD deficiency. They conclude that use of the drug as recommended by WHO is safe.

New drugs are being developed for malaria treatment.  The following articles deal with them:

Seo EB & al., Solidification of Self-Emulsifying Drug Delivery Systems as a Novel Approach to the Management of Uncomplicated Malaria, Pharmaceuticals (Basel), 2022 Jan 20; 15(2):120. doi: 10.3390/ph15020120 state that “existing and new anti-malarial drugs are hampered by significantly poor aqueous solubility and low permeability, resulting in low oral bioavailability and patient noncompliance. Lipid formulations are commonly used to increase solubility and efficacy and decrease toxicity. However, traditional SEDDSs are normally in liquid dosage forms, which are delivered orally to the site of absorption, and are hampered by poor stability. This paper discusses novel solidification techniques…”

SheilaNair A & al., Similarly Efficacious Anti-Malarial Drugs SJ733 and Pyronaridine Differ in Their Ability to Remove Circulating Parasites in Mice, Malaria J, 2202 Feb 16, vol 21 art 49. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04075-z finds that there are significant differences in which the two study drugs affect Plasmodium parasites in mice.  While they were both effective in reducing the parasite burden, these differences may impact on their usefulness.

Barber BE & al. report on a “novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum” in Safety, Pharmacokinetics, and Antimalarial Activity of the Novel Triaminopyrimidine ZY-19489: A Frist-in-Human Randomized, Placebo-Controlled, Double-Blind Single Ascending Dose Study, Pilot Food-Effect Study, and Volunteer-Infection Study, Lancet Infect Dis, 2022 Mar 2, doi.org/10-1016/S1473-3099(21)00679-4.  In their first human volunteer study, a clinical trial was conducted in healthy adults aged 18–55 years in Brisbane. Variable doses were given to small groups, after which they were infected with P. falciparum. Parasites were apparently cleared from the participants at all dose levels, but recrudesced at the lower dosages.  Side effects were frequent but mild, chiefly gastrointestinal.  A companion article, Daubenberger D & Burrows JN, Volunteer Infection Studies Accelerate the Clinical Development of Novel Drugs Against Malaria, Lancet Infect Dis, 2022 Mar 2, doi.org/10-1016/S1473-3099(21)00722-2 makes the argument inherent in the title.

Campaigns:

Omo-Imafidon E & al. explored promoting and limiting factors affecting the implementation of malaria policy and reported in Towards Improvement in Malaria Policy Implementation in Nigeria: A Qualitative Study on Factors Influencing the Translation of Malaria Policies to Practice, Trans R Soc Trop Med Hyg, 2022 Feb 3; Trac005. doi:10.1093/Trstmh/Trac005. Some of the variables increasing the implementation of malaria policies in Nigeria, according to respondents, were political will, access to funds from donors, and staff commitment. Insufficient planning, lack of commitment, poor finance, manpower shortages, and a lack of synergy between academics and policymakers, on the other hand, were recognized as important barriers to the malaria policy implementation process by respondents.

Nuwa A & al. took note of the resurgence of malaria in Uganda when support for indoor residual spraying was reduced in the mid-2010s and investigated whether new initiatives were effective in reducing the prevalence.  Their report is published as District-Led Malaria Surveillance and Response as an Effective Way to Manage Malaria Upsurges Following the Withdrawal of Indoor Residual Spraying: A Case Study From Nwoya District, Northern Uganda, Malaria J 2022 Feb 19 vol 21 art 55. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04066-0. Their conclusion is that “[m]alaria surveillance and response, with precisely targeted multipronged activities, when led and implemented by local district health authorities is an effective, efficient, and sustainable approach to prevent malaria upsurges and associated morbidity and mortality.” They cite data in support.

Amboko B & al., Factors Influencing Health Workers’ Compliance with Outpatient Malaria ‘Test and Treat’ Guidelines During the Plateauing Performance Phase in Kenya, 2014–2016, Malaria J, 2022 Mar 3, vol 21 art 68. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04093-x. This study examined the factors associated with high but suboptimal compliance levels at facilities with available malaria tests and drugs, because of the perception that campaigns against malaria were flagging in Kenya.  Thirty-one factors and compliance with malaria testing were analyzed. The complex results lead the authors to conclude that “Targeting of older and government health workers; dissemination of updated guidelines; and continuing with in-service training and supportive supervision with feedback is essential. Lastly, there is a need to improve health workers’ knowledge about malaria testing criteria considering their perceptions of endemicity.”

Wu L & al., Serological Evaluation of the Effectiveness of Reactive Focal Mass Drug Administration and Reactive Vector Control to Reduce Malaria Transmission in Zambezi Region, Namibia: Results from a Secondary Analysis of a Cluster Randomised Trial, EClinicalMedicine, 2022 Feb 14; 44:101272. doi: 10.1016/j.eclinm.2022.101272 is a statistical analysis on how best to measure campaign outcomes in

Touré M & al. report on success of a campaign in Mali in Trends In Malaria Epidemiological Factors Following the Implementation of Current Control Strategies in Dangassa, Mali, Malaria J, 2022 Feb 23, vol 21 Art 65. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04058-0.  Two new control strategies, universal treated bednet usage and seasonal malaria chemoprevention in children under age five resulted in marked decrease in malaria prevalence between 2015 and 2020.

Rwanda has achieved impressive reductions in malaria morbidity and mortality over the past two decades. Hakizimana D & al. investigated the effects the COVID-19 pandemic.  The Impact of Covid-19 on Malaria Services in Three High Endemic Districts in Rwanda: a Mixed-Method Study, Malaria J, 2022 Feb 14, vol 21 art 48. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04071-3 reports that while there was no change in the overall presentation rate for uncomplicated malaria and there was a monthly reduction in the proportion of severe malaria, healthcare workers and the population were fearful of malaria resurgence.

Epidemiology:

Bikundi EM & Coppieters Y, Prediction Ability of Vector Species, Environmental Characteristics and Socio-Economic Factors for Malaria Risk in Sub-Saharan African Countries, Int J Environ Health Res, 2022 Jan; 32(1):191-206.  doi: 10.1080/09603123.2020.1745763 is an analysis of the influence of Anopheles species in an area on malaria prevalence. “The lowest fever prevalence was found where Anopheles melas was dominant. Anopheles coluzzi and Anopheles gambiae were the dominant species where prevalence of malaria was high. Altitude, country and vector species were the best predictive factors. Anopheles arabiensis, An. coluzzi and An. gambiae were most common in urban areas.”

“Two species are responsible of the majority of the burden [of malaria], Plasmodium falciparum and Plasmodium vivax. For these two parasite species, the questions of their origin (how and when they appeared in humans), of their spread throughout the world, as well as how they have adapted to humans have long been of interest to the scientific community.” Rougeron V & al., A Population Genetic Perspective on the Origin, Spread and Adaptation of the Human Malaria Agents Plasmodium falciparum and Plasmodium vivax, FEMS Microbiol Rev, 2022 Feb 9; 46(1):fuab047, doi: 10.1093/femsre/fuab047 reviews the existing body of knowledge on these two species.

Two articles deal with malaria prevalence in Ethiopia: Amare A & al.,Dry-Season Transmission and Determinants of Plasmodium Infections in Jawi District, Northwest Ethiopia, Malaria J, 2022 Feb 14, vol 21 art 45. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04068-y and Abate A et al., Five-Year Trend of Malaria Prevalence in Mojo Town, Central Ethiopia: Shifting Burden of the Disease and Its Implication for Malaria Elimination: A Retrospective Study, Infect Drug Resist, 2022 Feb 11; 15:455-464. doi: 10.2147/IDR.S348203.  Of interest is that the latter study found 76% of cases to be caused by Plasmodium vivax.

According to Amoah LE & al., who studied samples collected from malaria patients throughout Ghana the overall frequency of P. falciparum, P. malariae and P. ovale detected by PCR was 74.9, 1.4 and 0.9%, respectively. … up to 98.7% (75/76) of P. malariae and 97.8% (45/46) of P. ovale infections detected by PCR were missed by microscopy. Their paper is Nationwide Molecular Surveillance of Three Plasmodium Species Harboured by Symptomatic Malaria Patients Living in Ghana, Parasit Vectors, 2022 Jan 28; 15(1):40, doi: 10.1186/S13071-022-05153-6.

Fofana B & al. studied a high-transmission setting in Mali. Risk factors including age, residence, and treatment regimen were compared among individuals experiencing eight or more clinical episodes of malaria (“high-incidence group”) and individuals experiencing up to three clinical episodes (“low-incidence group”). They report in Differential Incidence of Malaria in Neighboring Villages in a High-Transmission Setting of Southern Mali, Am J Trop Med Hyg, 2022 Feb 28; tpmd210788, doi: 10.4269/ajtmh.21-0788, that individuals in the high incidence group were significantly younger than individuals in the low-risk group and that those residing in the forested areas … had significantly greater odds of being in the high-incidence group compared with individuals residing in the semi-urban area.

In the DR Congo, Mitchell CL & al. did not find sufficient evidence on mining occupations influencing malaria rates, as reported in Impact of Extractive Industries on Malaria Prevalence in the Democratic Republic of the Congo: A Population-Based Cross-Sectional Study, Sci Rep, 2022 Feb 2; 12(1):1737, doi: 10.1038/S41598-022-05777-9.

Mtalimanja M & al. studied “the cost effectiveness of artesunate against quinine in patients under 14 years of age in Zambia” and report in Economic Evaluation of Severe Malaria in Children Under 14 Years in Zambia, Cost Eff Resour Alloc, 2022 Feb 5; 20(1):4, doi: 10.1186/S12962-022-00340-9, that “[t]he use of artesunate over quinine in the treatment of severe malaria in children under 14 years is a highly cost-effective strategy…”

Moukénet A & al. state that “[n]omadic populations in Chad are at increased risk of contracting malaria because of their lifestyle. Being highly mobile they are often excluded from disease control programmes, and access to preventive measures and treatment is more difficult.” Their report, Knowledge And Social Beliefs of Malaria and Prevention Strategies Among Itinerant Nomadic Arabs, Fulanis and Dagazada Groups in Chad: A Mixed Method Study, Malaria J, 2022 Feb 19, vol 21, art 56, https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04074-0, that “use of preventive interventions such as Seasonal Malaria Chemoprevention (SMC) for children and Intermittent Preventive Treatment (IPT) of malaria in pregnancy was very low. However, 42.3% of respondents reported owning at least one LLIN and 60% said they slept under an LLIN the night before the survey…”

Afai G, & al., Factors Associated with Knowledge About Malaria Prevention Among Women of Reproductive Age, Tete Province, Mozambique, 2019–2020, Malaria J, 2022 Mar 5, vol 21 art 76, https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04090-0 reports that among some 1900 women aged 15-49 years queried, fewer than half had what the authors call “complete malaria knowledge.” Education, income, fewer children, and being knowledgeable in Portuguese or the dominant local language of Cinyungwe were factors that influenced better knowledge.

The following papers are not strictly epidemiological in nature, but they deal with the historically known relative resistance to malaria among Africans who carry the mutant sickle cell (HbS) or HbC gene.

Gómez-Díaz E & Ranford-Cartwright L, Evolutionary Race: Malaria Evolves to Evade Sickle Cell Protection, Cell Host Microbe, 2022 Feb 9; 30(2):139-141, doi: 10.1016/J.Chom.2022.01.010, and Matuschewski K & Maier AG, Pas-De-Deux: African Plasmodium falciparum Adaptations to Sickle Hemoglobin, Trends Parasitol, 2022 Feb 9; S1471-4922(22)00010-1. doi: 10.1016/j.Pt.2022.01.009 both refer to Band G & al., Malaria Protection Due to Sickle Haemoglobin Depends on Parasite Genotype, Nature, 2022 Feb;602(7895):106-111, doi: 10.1038/S41586-021-04288-3, which was identified only by its title in last month’s report.  The latter authors found “a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome” in children with malaria.

Lopez-Perez M & al., Natural Acquired Immunity to Malaria Antigens Among Pregnant Women with Hemoglobin C Trait, Am J Trop Med Hyg, 2022 Jan 17;tpmd211039, doi: 10.4269/ajtmh.21-1039 reports that pregnant women heterozygous for HbC have reduced immune response to certain P. falciparum antigens than those with normal hemoglobin.  The abstract does not draw any clinical conclusions as to propensity for infection.