On April 12, the BBC website announced that the Republic of Ghana has approved the use of the R21 vaccine for use. On April 13, the University of Oxford released R21/Matrix-M™ malaria vaccine developed by University of Oxford receives regulatory clearance for use in Ghana, indicating a partnership with the Serum Institute of India, which, according to the BBC asserted that they are able to produce 100 million doses or more per year, including in a location within Ghana to be constructed. Logistical issues aside, the potential benefit of this new vaccine in comparison to the RTS,S vaccine is supposed to be great because preliminary studies indicated up to 80% efficacy in children after three doses and a booster.  The British Medical Journal published an editorial on the subject: Mahase E, Ghana Approves Oxford’s Malaria Vaccine for Children Aged 5 to 36 Months, BMJ, 2023 Apr 14; 381:p850, https://doi.org/10.1136/bmj.p850.  On April 17, Nigeria followed suit “provisionally”.

As of April 19, WHO has not released any information about a decision to endorse the use of the vaccine.  We have reported on articles pertaining to studies in Burkina Faso on this vaccine, including the following within the past 24 months: 

Datoo MS, Natama MH, Somé A & al., Efficacy of a Low-Dose Candidate Malaria Vaccine, R21 in Adjuvant Matrix-M, with Seasonal Administration to Children in Burkina Faso: A Randomised Controlled Trial, Lancet2021 May 15;397(10287):1809-1818. doi: 10.1016/S0140-6736(21)00943-0.

Moorthy V, Binka F, R21/Matrix-M: a second malaria vaccine? Lancet, 2021 May 15;397(10287):1782-1783. doi: 10.1016/S0140-6736(21)01065-5.

Datoo MS, Natama HM, Somé A & al., Efficacy and Immunogenicity of R-21/Matrix-M Vaccine Against Clinical Malaria after 2 Years’ Follow-Up in Children in Burkina Faso: A Phase 1/2b Randomised Controlled Trial,Lancet Inf Dis, 2022 Sep 7, doi: 10.1016/S1473-3099(22)0422-X.

Daubenberger C, Moncunill G, Next Generation of Malaria Subunit Vaccines to Reduce Disease Burden in African Children, Lancet Infect Dis, 2022 Sep 7, doi: 10.1016/S1473-3099(22)00523-0.

Abstracts of these as well as the entire U. of Oxford News Release are available to anyone.

On April 4, WHO published an 8-page pamphlet, Vector Control Products Targeting Outdoor Malaria Transmission.  It was “developed to indicate that WHO has identified vector control products targeting outdoor malaria transmission as an unmet public health need and to outline the preferred characteristics of such interventions. While keeping the scope of the PPC {preferred product characteristics} as broad as possible, it is primarily tailored to encourage new insecticidal/repellent products.” The pamphlet is available from the WHO website or from the author of these reviews.

On March 23, WHO announced the appointment of a new “Director of the Global Malaria Programme” effective April 8. “Dr Ngamije served as the Rwandan Minister of Health from February 2020 to November 2022. During this time, he led the development and execution of the Health Sector Strategic Plan as well as the development and implementation of the COVID-19 comprehensive response plan. https://www.who.int/news/item/23-03-2023-who-announces-new-director-of-the-global-malaria-programme

On March 29, WHO certified Azerbaijan and Tajikistan as malaria free. https://www.who.int/news/item/29-03-2023-who-certifies-azerbaijan-and-tajikistan-as-malaria-free

 

PEER REVIEWED PUBLICATIONS:

Prevention

Vaccines

Ironically timed in view of their government’s recent action with reference to the R21 vaccine, Adjei MR & al. report on the experience of Ghana with RTS,S. They conclude in Post Introduction Evaluation of the Malaria Vaccine Implementation Programme in Ghana, 2021, BMC Public Health. 2023 Mar 29; 23(1):586. https://doi.org/10.1186/s12889-023-15481-6 that the “vaccine has been piloted successfully in Ghana. Intensive advocacy; community engagement, and social mobilization; and regular onsite supportive supervision are critical enablers for successful introduction of new vaccines. Stakeholders are convinced of the feasibility of a nationwide scale up…” This despite the fact that while the vaccine was well accepted and administered correctly, only 44% of those queried “knew the number of doses needed for maximum protection.”

Reporting on publications pertaining to the various RTS,S vaccine formulations, Yihunie W & al., Systematic Review of Safety of RTS,S with AS01 and AS02 Adjuvant Systems Using Data from Randomized Controlled Trials in Infants, Children, and Adults, Clin Pharmacol. 2023 Mar 14; 15:21-32, https://doi.org/10.2147/cpaa.s400155conclude that these products are in effect safe.

Nnaji A & Ozdal MA “aimed to assess the perception and awareness of malaria vaccine policy implementation among health policy actors in Nigeria.” As reported in Perception and Awareness Towards Malaria Vaccine Policy Implementation in Nigeria by Health Policy Actors, Malar J, 2023 Mar 29, 22:111, https://doi.org/10.1186/s12936-023-04536-z, while awareness of vaccines’ role on prevention of disease, knowledge about malaria vaccines was not widespread. “As the number of years of work experience of the participants increased, the odds of being more likely to be aware of the malaria vaccine increased.”

In the Netherlands van der Boor SC & al. have developed a vaccine that utilizes the entire sporozoite of P. falciparum. Whole Sporozoite Immunization with Plasmodium falciparum Strain NF135 in a Randomized Trial, BMC Med.2023 Apr 7; 21(1):137, https://doi.org/10.1186/s12916-023-02788-9 describes the process by which volunteers were inoculated by P. falciparum 19 days after sporozoites were delivered by infected mosquito bites to volunteers who were on one of two prophylactic drug regimens.  Most volunteers eventually came down with malaria and had to be “rescued.” With these results on has to wonder whether this will be a fruitful avenue to pursue.

It is difficult to discern from the abstract of Quagliata M & al. Malaria Vaccines, Expert Opin Ther Pat. 2023 Mar 13, https://doi.org/10.1080/13543776.2023.2190884 what the thrust of the article is, whether it is a comprehensive review, or a description of the current status of the RTS,S vaccine.

Vector control and protection from vectors

The benefits of bed nets are highly dependent on their integrity over time. Hiruy HN & al. conducted a “three-year longitudinal study … to monitor attrition, physical integrity, and bio-efficacy and residual chemical concentration of LLINs in four regions in Ethiopia.” They report in Durability of Long-Lasting Insecticidal Nets (LLINs) in Ethiopia, Malar J, 2023 Mar 26, 22:109, https://doi.org/10.1186/s12936-023-04540-3 that of close to 3400 nets studied, only 12.9% were functionally surviving after 36 months. Close to half of the nets either lost their integrity or were repurposed in the interim.  Yet, while the median survival of the LLINs was 19 months, over 95% of the nets surviving 24 months “met the WHO criteria of bio-efficacy.”  

Fernández Montoya L & al. used questionnaires to conduct An Evaluation of LLIN Ownership, Access, and Use During the Magude Project in Southern Mozambique, PLoS One. 2023 Mar 27;18(3):e0282209, https://doi.org/10.1371/journal.pone.0282209 reveals inconsistent ownership of LLINs; “LLIN access never exceeded 76.3% and use varied seasonally between 40% and 76.4%. Also, 31% of households reported that they no longer owned bed nets more than a year after receiving them from campaigns..

Not many studies on malaria have been reported from Somalia. Aweis A & al.’s report, Long-Lasting Insecticidal Nets (LLINs) Use Among Household Members for Protection Against Mosquito Bite in Mogadishu Districts, PLoS Glob Public Health. 2023 Mar 16; 3(3):e0000724, https://doi.org/10.1371/ journal.pgph.0000724 is one.  Using questionnaires, they report that “[o]ut of 409 households only 155 (37.9%) owned LLINs. Out of 237 owned LLINs, 199 (84.0%) were used. Median household size being 6.0 (3.0), intra-household net accessibility was low, with one net (42.6%) frequent.”

Kebede W & al., Utilization of Insecticide-Treated Nets {ITNs} in Households for Under-5 Children and Associated Factors in East Mesekan District, Gurage Zone, Southern Ethiopia, Environ Health Insights. 2023 Mar 26; 17:11786302231164287, https://doi.org/10.1177/11786302231164287 is yet another report of underutilization. “In this study, 58.2% … of household participants used ITN for children under 5 years of age while sleeping the night before the survey.” The authors conclude that underutilization for children was “significantly associated with having a family size of less than 5, complaints of skin irritation, owning 1 or 2 ITNs, and having low and medium knowledge of its importance.”

Kouamé RMA & al., Widespread Occurrence of Copy Number Variants and Fixation of Pyrethroid Target Site Resistance in Anopheles gambiae (s.l.) from Southern Côte D’Ivoire, Curr Res Parasitol Vector Borne Dis. 2023 Mar 5; 3:100117, https://doi.org/10.1016/j.crpvbd.2023.100117 is a genetic analysis of various species of Anopheles as these are expressed in resistance to insecticides.

On March 14, WHO endorsed the use of ITNs impregnated by pyrethroids and chlorfenapyr in areas of mosquito resistance to pyrethroids. Vogel G, Next-Generation Bed Nets Gets Major Endorsement from World Health Organization, Science, 2023 Mar 15, https://doi.org/10.1126/science.adh8127 goes into some detail about the new product. “Chlorfenapyr was first introduced in the United States in 2001 for use on nonfood crops in greenhouses, but it is not allowed to be sprayed on fields because it can be toxic to birds and aquatic animals. Its use in bed nets, however, is considered environmentally safe because the treated nets hang indoors and have limited contact with the wider environment.” WHO Guidance on the Prioritization of Insecticide-Treated Nets in Situations where Resources Are Limited, https://media.malariaworld.org/9789240069428_eng_703989c08a.pdf is a related publication.

Perugini E & al. studied the effects of human activity on mosquito behavior and noted in The Interplay Between Malaria Vectors and Human Activity Accounts for High Residual Malaria Transmission in a Burkina Faso Village with Universal ITN Coverage, Parasit Vectors. 2023 Mar 15; 16(1):101. https://doi.org/10.1186/s13071-023-05710-7 that the peak of mosquito biting activity coincides with most humans’ sleep hours.

“Variation in mosquito body size and the ability to penetrate long-lasting insecticide-treated nets (LLINs) remains unknown.” Meza FC & al., The Ability of Anopheles funestus and A. arabiensis to Penetrate LLINs and Its Effect on Their Mortality, Wellcome Open Res. 2023 Apr 6; 7:265. https://doi.org/ 10.12688/wellcomeopenres.18242.3“evaluated the ability of Anopheles funestus and A. arabiensis to penetrate commercially available treated and untreated bednets and how this behaviour affects mosquito mortality… Three types of LLINs; DawaPlus 2.0, PermaNet 2.0, Olyset 2.0, and untreated (Safi Net) were tested.” The authors conclude that A. funestus and A. arabiensis mosquitoes are able “to penetrate the human-occupied treated and untreated bed nets. Despite this ability, mosquitoes that penetrated the bed net succumbed to death within two days.”

“The In2Care EaveTube is a house modification designed to block and kill malaria mosquitoes using an electrostatic netting treated with insecticide powder. A previous study demonstrated prolonged duration of effective action of insecticide-treated electrostatic netting …. As part of a cluster randomized controlled trial (CRT) of the EaveTube intervention in Côte d’Ivoire, [Ombouque WA & al.] investigated the residual efficacy of a pyrethroid insecticide deployed in EaveTubes under village conditions of use.” While mosquitoes were more readily killed by this method than by LLINs, the efficacy waned relatively rapidly, as reported in Exploring Alternative Insecticide Delivery Options in a “Lethal House Lure” for Malaria Vector Control, Sci Rep. 2023 Mar 24; 13(1):4820, https://doi.org/10.1038/s41598-023-31116-7

“Broflanilide is a new insecticide being developed for malaria vector control.” Govoetchan R & al. conducted “[d]ose-response WHO bottle. bioassays” on various strains of Anopheles mosquitoes known to be resistant to pyrethroids, DDT, dieldrin, and carbamates.  They report in Investigating Discriminating Concentrations for Monitoring Susceptibility to Broflanilide and Cross Resistance to Other Insecticide Classes in Anopheles gambiae sensu lato, Using the New WHO Bottle Bioassay Method, PLoS One. 2023 Mar 23; 18(3):e0276246. https://doi.org/10.1371/journal.pone.0276246 that “wild pyrethroid-resistant populations of An. gambiae s.l. from southern Benin were fully susceptible to the insecticide. Broflanilide also shows potential to be highly effective against An. gambiae s.l. vector populations that have developed resistance to other public health insecticides.”

In view of increasing vector resistance, Vigodny A & al., Digitally Managed Larviciding as a Cost-Effective Intervention for Urban Malaria: Operational Lessons from a Pilot in São Tomé and Príncipe Guided by the Zzapp System, Malar J, 2023 Apr 6, 22:114, https://doi.org/10.1186/s12936-023-04543-0 report on a very large larviciding project. “12,788 water bodies were located and treated a total of 128,864 times. The reduction impact on mosquito population and on malaria incidence was 74.90% and 52.5%, respectively. The overall cost per person protected (PPP) was US$ 0.86. The cost varied between areas: US$ 0.44 PPP in the urban area, and US$ 1.41 PPP in the rural area.”

The aim of Salomé G & al., Species Composition, Seasonal Abundance, and Biting Behavior of Malaria Vectors in Rural Conhane Village, Southern Mozambique, Int J Environ Res Public Health. 2023 Feb 17; 20(4):3597, https://doi.org/10.3390/ijerph20043597 is “to determine the species diversity and abundance, biting activity, and Plasmodium infectivity of Anopheles mosquitoes ….”  They identified eight species.  Whereas only two of the captured 1800 mosquitoes had malaria parasites in their bodies, the authors found significant outdoor biting activity in the early evening hours, which is a way around traditional preventive methods such as ITNs and indoor residual spraying. 

Sy O & al., Residual Malaria Transmission and the Role of Anopheles arabiensis and Anopheles melas in Central Senegal, J Med Entomol. 2023 Mar 18: tjad020, https://doi.org/10.1093/jme/tjad020 is a somewhat similar study from a region of Senegal with low infection rates.  In this setting, low residual malaria …is transmitted by An. arabiensis and An. melas. Consequently, both vectors will need to be targeted as part of malaria elimination efforts in this area of Senegal.

Chemoprophylaxis

Ampofo GD & Tagbor H, Community Delivery of Malaria Chemoprevention in Pregnancy, Lancet Glob Health. 2023 Apr; 11(4):e487-e488, https://doi.org/10.1016/s2214-109x(23)00126-2 is an unfortunate confirmation of a number of similar publications in reporting that “only 35% of pregnant women in malaria endemic regions receive the recommended three or more doses of IPTp.”  This contrasts with the fact that close to two-thirds of pregnant women attended pre-natal clinics at least four times.

It may appear at first blush that the relatively positive conclusions González R & al. reach in The Impact of Community Delivery of Intermittent Preventive Treatment of Malaria in Pregnancy on Its Coverage in Four Sub-Saharan African Countries (Democratic Republic of the Congo, Madagascar, Mozambique, and Nigeria): A Quasi-Experimental Multicentre Evaluation, Lancet Glob Health, 2023 Apr, 11(4):e566-e574, https://doi.org/10.1016/S2214-10i9X(23)00051-7 contrast with the above report in the same issue.  However, when the outcomes of “community delivery” as defined by González & al. are compared with those reported by Ampofo & Tagbor, the best outcome of the four countries (Madagascar) was still barely over 40%.  

The findings and conclusion of Bash CE &, McClintock HF, Antenatal Care and Adherence to Intermittent Preventive Treatment for Malaria During Pregnancy with Sulfadoxine-Pyrimethamine {IPTp-SP} in Gambia: An Examination of Demographic and Health Survey Data 2019-2020, Trans R Soc Trop Med Hyg. 2023 Apr 5: trad017, https://doi.org/10.1093/trstmh/trad017 are very similar to that of the Ampofo & Tagbor.  While more than 75% of women made at least four antenatal visits, only 47.3% received IPTp-SP three or more times.

Once again on the same subject, Ogba P & al., Review: Perceptions of Sulphadoxine-Pyrimethamine Use Among Pregnant Women in Sub-Saharan Africa: A Scoping Review, Malar World J 2023, 14:1, Ogba_2023-14_1.pdf decries the poor adherence to the WHO-recommended IPTp protocol.  They raise an interesting conclusion: some mothers report fear that SP will harm their children.

Kakuru A & Jagannathan P, Can We Reduce Malaria in Pregnancy and Improve Birth Outcomes, Lancet. 2023 Mar 10: S0140-6736(23)00101-0, https://doi.org/10.1016/s0140-6736(23)00101-0 is the article to which Henderson E, New Antimalarial Prevents Malaria More Effectively than Current Treatments but Does Not Improve Birth Outcomes, (reported last month) refers. This is a meta-analysis in that it reports results of other studies comparing the results with IPTp-SP to IPTp utilizing dihydroartemisinin-piperaquine. “In studies investigating alternative drugs for IPTp, dihydroartemisinin-piperaquine has shown promising results. Compared with IPTp with SP, IPTp with dihydroartemisinin-piperaquine was associated with a lower risk of clinical malaria, parasitaemia during pregnancy, and placental malaria at delivery. However, in the majority of these studies, IPTp with dihydroartemisinin-piperaquine was not associated with improved birth outcomes compared with IPTp with sulfadoxine–pyrimethamine, in part owing to these studies not being adequately powered to detect such differences…”

Madanitsa M & al., Effect of Monthly Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine with and Without Azithromycin Versus Monthly Sulfadoxine-Pyrimethamine on Adverse Pregnancy Outcomes in Africa: A Double-Blind Randomised, Partly Placebo-Controlled Trial, Lancet. 2023 Mar 10: S0140-6736(22)02535-1, https://doi.org/10.1016/s0140-6736(22)02535-1, published in the same Lancet issue as the above and comes to the same conclusion.  In addition, it also discounts any positive effect that azithromycin might have on the outcome, just as reported last month in the Lingani article (Effects of Maternal Antenatal Treatment with Two Doses of Azithromycin Added to Monthly Sulfadoxine-Pyrimethamine for the Prevention of Low Birth Weight in Burkina Faso: An Open-Label Randomized Controlled Trial, Malar J, 2023 Mar 17, 23:101), which was actually published a week later.   

Nigeria’s “National Malaria Elimination Programme undertook qualitative research in five states” shortly after the 2021 seasonal malaria chemoprevention (SMC) campaign to understand community attitudes to SMC. Ogbulafor N & al.,Facilitators and Barriers to Seasonal Malaria Chemoprevention (SMC) Uptake in Nigeria: A Qualitative Approach, Malar J, 2023 Apr 11, 21:120, https://doi.org/10.1186/ s12936-023-04547-w is a report from focus group discussion in five of Nigeria’s 36 states. “Caregivers preferred SMC delivered door-to-door to the fixed-point approach, because it allowed them to continue daily tasks, and allowed time for the [Community Drug Deliverers] to answer questions. Barriers to SMC uptake included perceived side-effects of SMC drugs, a lack of understanding of the purpose of SMC, … suspicions that medicines provided free may be unsafe or ineffective, and local shortages of drugs.”

The success of chemoprevention is dependent on many factors. The study of Ali AM & al, Interplay Among Malnutrition, Chemoprevention, and the Risk of Malaria in Young Ugandan Children: Longitudinal Pharmacodynamic and Growth Analysis, CPT Pharmacometrics Syst Pharmacol. 2023 Mar 14, https://doi.org/10.1002/psp4.12892 demonstrates convincingly that severe malnutrition of children has an inhibitory effect in this regard.  Children whose height was more than 2 standard deviation below the norm had a 17% higher incidence of chemoprevention failure than children at the norm.

“Utilization of malaria interventions is influenced by, among other things, the level of knowledge and attitude that the community has toward the infection as well as the available interventions.” Ngasala B & al., Malaria Knowledge, Attitude, and Practice Among Communities Involved in a Seasonal Malaria Chemoprevention Study in Nanyumbu and Masasi Districts, Tanzania, Front Public Health. 2023 Feb 15; 11:976354,  https://doi.org/10.3389/fpubh.2023.976354 “assessed malaria knowledge, attitudes, and practices on malaria infection and interventions in Masasi and Nanyumbu districts, Tanzania.”  The results stand out among similar studies, having demonstrated good knowledge and good utilization of preventive methods.

Other

Mass drug administration (MDA) is the subject of Deng C & al., Malaria Control by Mass Drug Administration with Artemisinin Plus Piperaquine on Grande Comore Island, Union of Comoros, Open Forum Infect Dis. 2023 Feb 14; 10(3):ofad076 https://doi.org/10.1093/ofid/ofad076.  The regimen was supplemented by ow dose piperaquine in the minority of districts.  With 80% or more of the population participating in the MDA, the authors report over 96% “effectiveness” of the process after only two administration series.

Foy BD & al., Repeat Ivermectin Mass Drug Administrations for Malaria Control II: Protocol for a Double-blind, Cluster-Randomized, Placebo-Controlled Trial for the Integrated Control of Malaria, JMIR Res Protoc. 2023 Mar 20; 12:e41197, https://doi.org/10.2196/41197 is a description of the study without any information as to its outcome.

Carrasco-Tenezaca M & al. used two experimental huts to determine the Effect of Passive and Active Ventilation on Malaria Mosquito House Entry and Human Comfort: An Experimental Study in Rural Gambia, J R Soc Interface. 2023 Apr; 20(201):20220794, https://doi.org/10.1098/rsif.2022.0794. They found that mosquito entry was greatly reduced by the utilization of ceiling fans at night, although constant use of the fans made the occupants of the fan-equipped hut uncomfortable because of the drop in temperature.

Asante KP & al. report that “anecdotal evidence suggests that smoke from [household air pollution] has a repellent effect on mosquitoes,” which led them to investigate the effect of improving the atmosphere by reducing smoke from cooking on maternal and infant malaria.  They conducted a controlled study and report in Association Between Malaria and Household Air Pollution Interventions in a Predominantly Rural Area of Ghana, Malar J, 2023 Mar 24, 22:106, https://doi.org/10.1186/s12936-022-04431-z that there was no significant difference in malaria incidence among pregnant women and infants between the study and control groups, suggesting that cookstove interventions do not lead to increased incidence of malaria.

How the publication by Ayala D & al. of The Genome Sequence of the Malaria Mosquito, Anopheles funestus, Giles, 1900, Wellcome Open Res. 2023 Mar 27; 7:287. https://doi.org/10.12688/ wellcomeopenres.18445.2 will improve the fight against malaria in the short run is unclear, but it may well play a role in drug design of the future.

Diagnosis

General diagnostics

The accuracy of Rapid Diagnostic Tests (RDTs) for falciparum malaria is dependent on the presence of histidine-rich protein (HRP), which will be missing if certain genes are missing in the parasite genome.  Ikegbunam M & al. studied the prevalence of these gene deletions and report in Low Prevalence of Plasmodium falciparum Histidine-Rich Protein 2 and 3 Gene Deletions-A Multiregional Study in Central and West Africa, Pathogens. 2023 Mar 14; 12(3):455. https://doi.org/10.3390/ pathogens12030455 that the deletions in the countries studied varied between 0 and 1.6%.  Therefore, they conclude that at this time RDTs are accurate in these regions.

Field diagnostics

Biruksew A & al., Diagnostic Performance of NxTek^™ Eliminate Malaria-Pf Test for the Detection of Plasmodium falciparum in School Children with Asymptomatic Malaria, Malar J, 2023 Mar 29, 22:112, https://doi.org/10.1186/s12936-023-04529-y concludes that the highly sensitive Rapid diagnostic Test (hsRDT) described in the title has higher sensitivity than microscopy or conventional RDT, but share that same high specificity and positive predictive value.

While P. falciparum is the dominant case of malaria in Africa, other Plasmodium species cannot be ignored because the disease they cause may relapse despite apparent cure.  Herman C & al., Non-Falciparum Malaria Infection and IgG Seroprevalence Among Children Under 15 Years in Nigeria, 2018, Nat Commun. 2023 Mar 13; 14(1):1360, https://doi.org/10.1038/s41467-023-37010-0 document the significant prevalence of antibodies to P. malariae in Nigerian children, overall 34.2% (actual infection rate with P. malariae was 6.6%).  Antibodies to P. ovale and P. vivaxwere less prevalent.

New diagnostic methods

Lai MY & al., Lateral Flow Recombinase Polymerase Amplification Assays for the Detection of Human Plasmodium Species, Am J Trop Med Hyg. 2023 Mar 3: tpmd220657, https://doi.org/10.4269/ajtmh.22-0657“highlights the development of two lateral flow recombinase polymerase amplification assays for the diagnosis of human malaria. The lateral flow cassettes contained test lines that captured biotin-, 6-carboxyfluorescein, digoxigenin-, cyanine 5-, and dinitrophenyl-labeled amplicons. The overall process can be completed in 30 minutes. Recombinase polymerase amplification coupled with lateral flow had a detection limit of 1 copy/µL for Plasmodium knowlesi, Plasmodium vivax, and Plasmodium falciparum. No cross-reactivity was observed among nonhuman malaria parasites…”

Other

Nkansah C & al., Serum Anti-Erythropoietin Antibodies Among Pregnant Women with Plasmodium falciparumMalaria and Anaemia: A Case-Control Study in Northern Ghana, PLoS One. 2023 Mar 29; 18(3):e0283427, https://doi.org/10.1371/journal.pone.0283427 does not report on malaria diagnosis, but may shed light on the cause of pronounced anemia in pregnant women with malaria.

Treatment

Treatment results

Chemwor GC & al. reports on three different combination regimens anchored on artesunates in Therapeutic Response to Artemisinin Combination Therapies Among Individuals with Plasmodium falciparum Single Infection Versus Mixed Plasmodium Species Infections: A Retrospective Post-Hoc Analysis in Kisumu County, Western Kenya, Int J Infect Dis, 2023 Apr 13; S1201-9712(23)00132-7, https://doi.org/10.1016/j.ijid.2023.04.008. In this study all regimens were effective whether there was mono-infection with P. falciparum, or if other species were also present. However, dihydroartemisinin-piperaquine regimen yielded the longest duration before a recurrent infection presented itself.

In contrast with Chemfor & al., Dinko B & al. state in Prevalence of Plasmodium falciparum Gametocytaemia in Asymptomatic School Children Before and After Treatment with Dihydroartemisinin-Piperaquine (DP),Parasite Epidemiol Control. 2023 Feb 17; 21:e00292, https://doi.org/10.1016/j.parepi.2023.e00292 that there was a consistent small percentage of children who continued to harbor microscopically diagnosable parasites after DP treatment.  Therefore, they suggest that DP is not suitable for mass drug administration.

“Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for this form of the disease mainly due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate.” Matshe WMR & al., A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria, Macromol Biosci. 2023 Mar 31: e2200518. https://doi.org/10.1002/mabi.202200518 states that the authors “conjugated the aqueous insoluble but very important antimalarial lumefantrine to a carrier polymer to create a new water-soluble chemical entity … suitable for intravenous administration in a clinically relevant formulation.

Three articles refer to the WHO recommendation against pre-referral rectal artesunate, issued in 2022 (World Health Organization. The Use of Rectal Artesunate as a Pre-Referral Treatment for Severe P. falciparum Malaria: Information Note. Geneva: World Health Organization; 2022.), which itself was the result of a multi-country study (BroadImpact Development & Business Consulting. Community Access to Rectal Artesunate for Malaria (CARAMAL) Project and Output 3 of the Supply Side Grant, 2021.https://unitaid.org/assets/CARAMAL_Evaluation_Final-Report_BroadImpact_May-2021.pdf.) 1. Watson JA, & al, The CARAMAL Study Could Not Assess the Effectiveness of Rectal Artesunate in Treating Suspected Severe Malaria, BMC Med. 2023 Mar 30; 21(1):118, https://doi.org/10.1186/s12916-023-02776-z and 2. Hetzel MW & al., Pre-Referral Rectal Artesunate Is No “Magic Bullet” in Weak Health Systems, BMC Med. 2023 Mar 30; 21(1):119, https://doi.org/10.1186/s12916-023-02777-y both decry the WHO recommendation, which was based on the demonstrated lack of consistent follow up for the children so treated.  These two articles build on others (reported in 2022 and earlier this year) that also espouse the view that instead of negating potentially life-saving treatment in resource poor areas, efforts should be made to ensure that practitioners administering the drug should emphasize the need for follow up and communities should be given the resources to guide potentially reluctant parents to facilities where definitive treatment can be completed. As reported in February, Peto TJ & al. (the same authors in different order as Watson above), WHO Should Accelerate, Not Stall, Rectal Artesunate Deployment for Pre-Referral Treatment of Severe Malaria, Trans R Soc Trop Med Hyg. 2023 Feb 1: trad002, doi: 10.1093/trstmh/trad002 assert: “The recent World Health Organization moratorium on rectal artesunate (RAS) for pre-referral treatment of severe childhood malaria is costing young lives. The decision was based on disappointing findings from a large observational study that provided RAS to community health workers with little training and supervision. This non-randomized, operational research has provided useful information to guide the implementation of RAS but is subject to bias and confounding and cannot be used to assess treatment effects. Parenteral artesunate reduces severe malaria mortality and a large body of evidence also shows RAS has lifesaving efficacy. There is now more than a decade of delay in conducting the necessary engagement and training required for successful deployment of RAS. Further delays will result in more preventable deaths.”  The controversy will probably continue for a while, witness the also recent Signorelli A, & al., Health Worker Compliance with Severe Malaria Treatment Guidelines in the Context of Implementing Pre-Referral Rectal Artesunate in the Democratic Republic Of The Congo, Nigeria, And Uganda: An Operational Study, PLoS Med. 2023 Feb 21; 20(2):e1004189, https://doi.org/10.1371/journal.pmed.1004189, which appears to support the WHO stance. 3. Oliff MS & al., The Five Continuum of Care Criteria That Should Accompany Rectal Artesunate Interventions: Lessons Learned from an Implementation Study in Malawi, Malar J, 2023 Mar 25, 22:108, https://doi.org/10.1186/s12936-023-04514-5 partly agrees with broth sets of authors and states that rectal artesunate should be administered only when authors’ five criteria for proper follow up are met.

Side effects and complications

None this month

Drug resistance

Afolabi OJ & al., Pfmdr 1 and Kelch 13 Genes Distribution Among Children That Are 5 Years and Below in Akure, Nigeria, J Parasit Dis. 2023 Mar; 47(1):59-67. https://doi.org/10.1007/s12639-022-01538-7 reports among other findings that multi-resistant P. falciparum genes were found more often in infected children with Blood Group B.

Niba PTN & al. searched the genetic evolution of P. falciparum in the capital city of Cameroun after the introduction of artemisinins. Evolution of Plasmodium falciparum Antimalarial Drug Resistance Markers Post-Adoption of Artemisinin-Based Combination Therapies in Yaounde, Cameroon, Int J Infect Dis. 2023 Apr 5: S1201-9712(23)00129-7, https://doi.org/10.1016/j.ijid.2023.03.050 reports that some genetic markers associated with resistance to previous antimalarials were waning in the mosquito specimens collected, while those that appear to cause pyrimethamine resistance appeared in numbers.

One of the factors predisposing to the development of drug resistance is the inappropriate use of antimalarials (just as it is with antibiotics). Nyeko R & al. report that there is inappropriate treatment of febrile children before referral to tertiary care institutions. The conclusion of their article, Anti-Malarial Drug Use, Appropriateness and Associated Factors Among Children Under-Five with Febrile Illnesses Presenting to a Tertiary Health Facility: A Cross Sectional Study, Malar J, 2023 Mar 21, 22:103, https://doi.org/10.1186/s12936-023-04534-1 reads as follows: “Inappropriate use of anti-malarials for childhood febrile illnesses is prevalent in the study setting, facilitated by the ease of over-the-counter access, empiric prescription and use of leftover anti-malarials. This calls for a need to address communities’ health-seeking behaviour and the health providers’ practice alike.”

Consistent with Neko R & al., Shelus V & al., Private Sector Antimalarial Sales a Decade After “Test and Treat”: A Cross-Sectional Study of Drug Shop Clients in Rural Uganda, Front Public Health, 2023 Mar 28; 11:1140405, https://doi.org/10.3389/fpubh.2023.1140405 reports on high prevalence of treatment of febrile children through “drug shops” without following the WHO’s “Test and Treat” protocol.

New drug research

Jameel E & al. report on basic research aimed attacking the malaria parasite in Identification of New Oxospiro Chromane Quinoline-Carboxylate Antimalarials that Arrest Parasite Growth at Ring Stage, J Biomol Struct Dyn. 2023 Mar 27: 1-22, https://doi.org/10.1080/07391102.2023.2188959.  They report that the compounds synthesized had in vitro activity against both P. falciparum and P. vivax.

Tiwari R & al., Synthesis and Antimalarial Activity of Amide and Ester Conjugates of Siderophores and Ozonides, Biometals. 2023 Apr; 36(2):315-320, https://doi.org/10.1007/s10534-022-00375-8 focuses on the treatment of cerebral malaria with bio metallic compounds.

Pandey SK & al., Drug Development Strategies for Malaria: With the Hope for New Antimalarial Drug Discovery-An Update, Adv Med. 2023 Mar 14; 2023:5060665, https://doi.org/10.1155/2023/5060665 is a somewhat general description of new drug research.  The authors state that their “review focuses on the history of antimalarial drug discovery and the advantages, loopholes, and opportunities associated with the common strategies being followed for antimalarial drug development.”

Likewise, Tripathi H & al., Malaria Therapeutics: Are We Close Enough? Parasit Vectors, 2023 Apr 14; 16(1):130, https://doi.org/10.1186/s13071-023-05755-8 is broadly focused: “This article concisely reviews basic malaria biology, the parasite’s life cycle, approved drugs, vaccine candidates, and available diagnostic approaches. It emphasizes new avenues of therapeutics for malaria.”

Increasing attention is being paid to drugs that prevent transmission of the parasite from infected individuals to the vectors. Carucci M & al., Safe Drugs with High Potential to Block Malaria Transmission Revealed by a Spleen-Mimetic Screening, Nat Commun. 2023 Apr 7; 14(1):1951, https://doi.org/10.1038/s41467-023-37359-2 focuses on three such compounds which are currently completing Phase I testing and are found to be safe.

Plant extracts and traditional treatments

An interesting theory is presented in Maciuk A & al., Future Antimalarials from Artemisia? A Rationale for Natural Product Mining Against Drug-Refractory Plasmodium Stages, Nat Prod Rep. 2023 Apr 6, https://doi.org/10.1039/d3np00001j, namely that the plants that form the basis of current Artemisinin Combination Therapy (ACT) may produce other compounds that, when extracted, may be potential antimalarials through mechanisms other than those of the artemisinins.

This month was particularly rich in articles that report on work with extracts of various plants that are (or not) currently used in folk medicine to treat malaria.  These include:

Essoh AP & al., Antimalarial and Cytotoxic Activity of Native Plants Used in Cabo Verde Traditional Medicine, Plants (Basel). 2023 Feb 20;12(4):963, https://doi.org/10.3390/plants12040963

Amang À & al., Antileishmanial and Antiplasmodial Activities of Secondary Metabolites from the Root of Antrocaryon klaineanum Pierre (Anacardiaceae), Molecules. 2023 Mar 17; 28(6):2730, https://doi.org/10.3390/molecules28062730

Evbuomwan IO & al., In Silico Modeling Revealed Phytomolecules Derived from Cymbopogon citratus (DC.) Leaf Extract as Promising Candidates for Malaria Therapy, J Biomol Struct Dyn. 2023 Mar 28: 1-18, https://doi.org/10.1080/07391102.2023.2192799

Girmaw F & Ashagrie G, Evaluation of the Anti-Malarial Activity of the Crude Root Extract and Solvent Fraction of Sesamum indicum (Fabaceae), J Exp Pharmacol. 2023 Mar 28; 15:163-175, https://doi.org/10.2147/jep.s407557

Guy-Armand GN & al., Antiplasmodial, Antioxidant and Cytotoxicity Activity of Ethanol and Aqueous Extracts of Khaya grandifoliola Stem Bark, J Trop Med. 2023 Mar 28; 2023:8062453, https://doi.org/10.1155/2023/8062453

Campaigns and Policies

Messenger LA & al. performed a meta-analysis of malaria prevention and control data published in 22 papers between 1989 and 2018. All papers referred to periods of humanitarian emergencies in the societies studied. They report in Vector Control for Malaria Prevention During Humanitarian Emergencies: A Systematic Review and Meta-Analysis, Lancet Glob Health, 2023 April, 11(4):e534-e545, https://doi.org/10.1016/S2214-109X(23)00044-X that “[i]nsecticide-treated nets significantly decreased Plasmodium falciparum incidence (… high certainty) and Plasmodium vivax incidence (… high certainty).”  Other interventions did not rise to this level of certainty of benefit. Boëte C, Vector Control and Malaria in Humanitarian Emergencies: The Limitations and the Needs, Lancet Glob Health, 2023 Apr, 11(4):e482-e483, https://doi.org/10.1016/S2214-109X(23)00129-4 is a commentary of the above report.  While this comment does not dispute Messenger & al.’s findings, it does point out that only 22 papers met the inclusion criteria of the authors, out of over 10,000 retrieved and that all reviewed papers dealt with “chronic” emergencies, not acute ones.

The effectiveness of lectures as a continuing medical education activity has been called in question.  Gebreyesus T, & al set out to determine whether this issue is also one in Sub-Sahara Africa.  Their paper, Qualitative Evaluation of the Africa Malaria Task Force Symposia Effectiveness on African Partner Nations’ Malaria Vector Management Capacity, Mil Med. 2023 Mar 20; 188(3-4):e725-e730,  https://doi.org/10.1093/milmed/usab345 appears to validate the effectiveness lf symposia at least in military medical settings.

James SL & al., point out that gene drive has not been pursued vigorously as a malaria preventive technology. Their paper, Regulatory And Policy Considerations For The Implementation Of Gene Drive-Modified Mosquitoes To Prevent Malaria Transmission, Transgenic Res. 2023 Mar 15, https://doi.org/10.1007/s11248-023-00335-z argues for regional cooperation in creating regulatory and ethical framework in which gene-drive-mosquitoes may be utilized in the service of eliminating malaria vectors from communities.

Nzalie RNT & al., User Fee Exemption and Malaria Treatment-Seeking for Children Under Five in a Cameroonian Health District: A Cross-Sectional Study, Malar J, 2023 Apr 13, 22:124, https://doi.org/ 10.1186/s12936-023-04509-2 concludes that despite user fee exemption, other factors such as educational and income levels of guardians affect malaria treatment-seeking time for children aged under five. Therefore, these factors should be considered when enacting policies aimed at increasing access of children to health facilities.

Epidemiology                                                        

Climate change, biodiversity and environment

The influence of temperature is reported to be the major climatic variable influencing the prevalence of malaria, according to Chouakeu NAK  & al., Malaria Transmission Pattern Across the Sahelian, Humid Savanna, Highland and Forest Eco-Epidemiological Settings in Cameroon, Malar J, 2023 Apr 7, 22:116, https://doi.org/10.1186/s12936-023-04544-z. “Nevertheless, other environmental and climatic factors causing transmission include vegetation, water bodies, slopes, elevation, rainfall, and relative humidity.”

Zayed A & al., Effects of Seasonal Conditions on Abundance of Malaria Vector Anopheles stephensiMosquitoes, Djibouti, 2018-2021, Emerg Infect Dis. 2023 Apr; 29(4):801-805. https://doi.org/10.3201/eid2904.220549 describes “the influence of seasonal meteorologic variations and rainfall events on Anopheles stephensi mosquito populations during a 40-month surveillance study at a US military base in Djibouti.”

“Using the Global Burden of Disease regions approach,” Ryan SJ & al., Mapping Current and Future Thermal Limits to Suitability for Malaria Transmission by the Invasive Mosquito Anopheles stephensi, Malar J, 2023 Mar 23, 22:104, https://doi.org/10.1186/s12936-023-04531-4 “revealed that heterogenous regional increases and decreases in risk did not mask the overall pattern of massive increases of PAR for malaria transmission suitability with An. stephensi presence. … poleward expansion for thermal suitability were seen for both P. falciparum and P. vivaxtransmission potential.”

Nyawanda BO & al. found that there was a resurgence of malaria in Western Kenya after 2016, despite high bed net use. The Relative Effect of Climate Variability on Malaria Incidence After Scale-Up of Interventions in Western Kenya: A Time-Series Analysis of Monthly Incidence Data from 2008 to 2019, Parasite Epidemiol Control. 2023 Mar 15; 21:e00297, https://doi.org/10.1016/j.parepi.2023.e00297 reports that “[i]ncrease in daytime land surface temperature was associated with a decline in malaria incidence …, while rainfall was associated with increased incidence …. Bed net use was associated with a decline in malaria incidence in children aged 6-59 months … but not in older age groups.” In summary, “[v]ariability in climatic factors showed a stronger effect on malaria incidence than bed net use.”

General epidemiology

Alemayehu A, Biology and Epidemiology of Plasmodium falciparum and Plasmodium vivax Gametocyte Carriage: Implication for Malaria Control and Elimination, Parasite Epidemiol Control. 2023 Mar 7; 21:e00295, https://doi.org/10.1016/j.parepi.2023.e00295 is an article that covers several subjects; from the point of view of epidemiology, the following is of note: “Female Anopheles mosquito orchestrates the transmission of malaria by taking gametocytes and introducing sporozoite while taking blood meals. Interrupting transmission is the major strategy for malaria elimination. The gametocyte stage is essential for the onward transmission of malaria… A considerable number of malaria patients carry gametocytes at a sub-microscopic level, thereby serving as a potential infectious reservoir of transmission. Factors involving the human host, Plasmodium parasite, and intervention parameters play a critical role in gametocyte biology and prevalence. The contribution of asymptomatic and sub-microscopic infections to malaria transmission is unknown. The clear impact of G-6-PD deficiency on malaria control and elimination remains unclear.”

Ge Y & al. report in How Socioeconomic Status Affected the Access to Health Facilities and Malaria Diagnosis in Children Under Five Years: Findings from 19 Sub-Saharan African Countries, Infect Dis Poverty. 2023 Apr 6; 12(1):29, https://doi.org/10.1186/s40249-023-01075-2 that “[s]ignificant socio-economic disparities existed both in the access to health facilities and laboratory diagnosis of malaria in children in sub-Saharan African countries … disparities were particularly evident in the private sector.”

Fondjo E & al. collected “139,322 Anopheles mosquitoes from 18 species (or 21 including identified sub-species) were collected across all sites. Out of the 18 species, 12 were malaria vectors.” In High Vector Diversity and Malaria Transmission Dynamics in Five Sentinel Sites in Cameroon, Malar J, 2023 Apr 13, 22:123, 10.1186/s12936-023-04552-z they “assess vector density, species composition, human biting rate (HBR), endophagic index, indoor resting density (IRD), parity, sporozoite infection rates, entomological inoculation rate (EIR), and Anopheles vectorial capacity.”

“The prevalence of severe childhood malaria increased by as much as 11.0%, with a disproportionate increase in mortality compared to the pre-pandemic level. Most children with severe malaria presented late with multiple features of severe malaria, probably contributing to the poor hospitalization outcomes (death) observed,” according to Ibrahim OR & al., Outcomes of Childhood Severe Malaria: A Comparative Study of Pre-COVID-19 and COVID-19 Periods, BMC Pediatr, 2023 Apr 15; 23(1):177, https://doi.org/10.1186/s12887-023-03985-4.

In South Africa, “mobile and migrant populations pose a substantial risk to importation of malaria parasites. It has been hypothesized that halting cross-border movement of mobile and migrant populations will decrease the importation of malaria…” Maharaj R & al. report in The Effect of the COVID-19 Lockdown on Malaria Transmission in South Africa, Malar J, 2023 Mar 24, 22:107, https://doi.org/10.1186/s12936-023-04542-1 that imported cases were indeed lower in the post-intervention period in all three provinces studied.

Mangusho C & al. found malaria diagnosed by RDT in 62 of 238 asymptomatic pregnant women (26.1%), as reported in High Prevalence of Malaria in Pregnancy Among Women Attending Antenatal Care at a Large Referral Hospital in Northwestern Uganda: A Cross-Sectional Study, PLoS One. 2023 Apr 5; 18(4):e0283755, https://doi.org/10.1371/journal.pone.0283755.

Reactive case detection (RACD) is the screening of household members and neighbors of index cases reported in passive surveillance. This strategy seeks asymptomatic infections and provides treatment to break transmission without testing or treating the entire population. Aidoo EK & al., Reactive Case Detection Strategy for Malaria Control and Elimination: A 12 Year Systematic Review and Meta-Analysis from 25 Malaria-Endemic Countries, Trop Med Infect Dis. 2023 Mar 18; 8(3):180, https://doi.org/10.3390/tropicalmed8030180 discusses and highlights RACD as a recommended strategy for the detection and elimination of asymptomatic malaria as it pertains in different countries.

It appears that mosquitoes demonstrate preference as to whom they will bite. Mbewe RB & al. report in Genotyping of Anopheles mosquito blood meals reveals nonrandom human host selection: implications for human-to-mosquito Plasmodium falciparum transmission, Malar J, 2023 Apr 7, 22:115, https://doi.org/10.1186/s12936-023-04541-2 that in a region of moderate-to-high malaria incidence in southeastern Malawi, “[c]hildren ≤ 5 years old were under-represented in mosquito blood meals while older males (31–75 years old) were over-represented. However, the largest number of malaria-infected blood meals was from school age children (6-15 years old).”

Namountougou M & al. demonstrate persistence of malaria transmission despite what they call “the intense use of vector control tools as LLINs and IRS by correlating mosquito biting time and human behavior.” Their article, Residual Malaria Transmission: Magnitude and Drivers of Persistent Plasmodium Infections Despite High Coverage of Control Interventions in Burkina Faso, West Africa, Acta Trop. 2023 Mar 28: 106913, https://doi.org/10.1016/j.actatropica.2023.106913 contains an analysis of the mosquito population as well as evaluation of vector control methods utilized.

Conditions in refugee camps pose special difficulties in malaria prevention and control. Semakula HM & al., Determinants of Malaria Infections Among Children in Refugee Settlements in Uganda During 2018-2019,Infect Dis Poverty. 2023 Apr 10; 12(1):31, https://doi.org/10.21203/rs.3.rs-2497041/v1 reports that “open water sources, poor hygiene, and lack of preventive measures … enhanced mosquito survival and infection.”

Vanhuysse S & al. created a “hazard map [that] was combined with a population density map to generate a gridded urban malaria exposure map at a spatial resolution of 100 m” in Dakar, Senegal.  “Urban malaria exposure was defined as the contact risk between adult Anopheles vectors … and urban population and accounted for socioeconomic vulnerability …. Larval habitat suitability was mapped … and validated with existing geolocated entomological data. Adult vector habitat suitability was … based on dispersal from suitable breeding site locations.” The article is Fine-Scale Mapping of Urban Malaria Exposure Under Data Scarcity: An Approach Centred on Vector Ecology, Malar J, 2023 Apr 3, 22:113, https://doi.org/10.1186/s12936-023-04527-0

Spatiotemporal studies

Getachew H & al., Asymptomatic and Submicroscopic Malaria Infections in Sugar Cane and Rice Development Areas of Ethiopia, Res Sq. 2023 Mar 21: rs.3.rs-2692688. https://doi.org/10.21203/rs.3.rs-2692688/v1

Khan A & al., Spatiotemporal Overlapping of Dengue, Chikungunya, and Malaria Infections in Children in Kenya, BMC Infect Dis. 2023 Mar 29; 23(1):183. https://doi.org/10.1186/s12879-023-08157-4

Bello IS & al., Malaria Among the Elderly in Five Communities of Osun East District, Southwest Nigeria: Prevalence and Association with Non-Communicable Diseases, SAGE Open Med. 2023 Mar 31; 11:20503121231164259, https://doi.org/10.1177/20503121231164259

Ofgeha GY, Spatial Analysis of Malaria Hotspots in Dilla Sub-Watershed: Western Ethiopia, PLoS One. 2023 Apr 6; 18(4):e0273271, https://doi.org/10.1371/journal.pone.0273271

Chouakeu, NAK & al., Malaria Transmission Pattern Across the Sahelian, Humid Savanna, Highland and Forest Eco-Epidemiological Settings in Cameroon, Malar J, 2023 Apr 7, 22:116, https://doi.org/10.1186/s12936-023-04544-z

Jeang B & al., Serological Markers of Exposure to Plasmodium falciparum and Plasmodium vivax Infection in Southwestern Ethiopia, Am J Trop Med Hyg. 2023 Apr 10: tpmd220645 , https://doi.org/10.4269/ajtmh.22-0645

CAVEAT (repeated in part from March 2023 report)

The British-American political/economic weekly, The Economist, included an article entitled “Doctored data” in its February 25^th edition.  The lengthy article explored the history of dealing with scientific fraud and came to the doleful conclusion that it is becoming more rampant.  Based on work done by scientific sleuths, they conclude that world-wide, the incidence of published articles with unreliable data (on a spectrum of erroneous, plagiarized and manipulated to simply invented) is as high as 2%.  They state that “…fakes had authors from more than 70 countries,” though China, Russia, Iran, Malaysia, and Egypt led as the sources of papers that had to be retracted after publication because their data were found unreliable.  This caveat is included in this report, because of the 400+ papers that have to be sorted or even the 40 or so reported every month are too overwhelming for me to analyze as to data integrity and frankly even if I had the time to do so, I do not possess the expertise.  While we have not reported on many papers that originated from the above countries, no other country, including the US and UK, is immune to this phenomenon. Therefore, it is highly likely that over the two years that these reports have been published, a few with unreliable data have been included.  This will probably continue to occur; so papers with conclusions that materially differ from previous known findings should be treated with caution until their conclusions are supported from elsewhere.