Two articles in Malaria World this week describing research in East Africa provide more evidence suggesting that the main factor correlated with malaria is poverty.

‘Household practices and infrastructure associated with high Plasmodium falciparum infection rates among children under five years old in Northern Uganda’ by Echodu et al found housing structures, particularly mud/clay walls and grass-thatched roofs, were significantly associated with higher malaria prevalence (p < 0.001). Children living in houses with cement walls and iron sheet roofs were much less likely to have malaria.

Naturally, the authors linked their findings to hypothesised mosquito transmission by stating that individuals living in houses with intact, plastered walls are less likely to contract malaria compared to those in homes with holes in the walls.

However, the second article, ‘A household randomized-control trial of insecticide-treated screening for malaria control in unimproved houses in Tanzania’  by Odufuwa et al casts doubt on this. In their research, which reminded me a lot of Grassi’s railway study, described in my translation of ‘Studies of a Zoologist about Malaria’, the researchers compared houses with holes fitted with screens to patch holes and those without.

 In Chalinze district, Tanzania, 421 households were randomized into two arms. In June-July 2021, one group of households’ houses was fitted with ITS (insecticide treated nets with deltamethrin and piperonyl butoxide) on eaves, windows, and wall holes, while the second group did not receive screening (see picture). After installation, consenting household members (aged ≥ 6 months) were tested for malaria infection using quantitative polymerase chain reaction after the long rainy season (June/July 2022, primary outcome) and the short rainy season (January/February 2022, secondary outcome).

The results were not significant either in occurrence of malaria (as measured with PCR) or even in the number of mosquitos trapped. The authors suggest this could be due to the study design, intervention insecticidal properties and residuality, and the high number of withdrawals of participants from the study. There was a slight reduction in detection of plasmodia using PCR in the improved houses that was significant for school aged children. However, these relatively insignificant benefits are likely due to the unblinded nature of the study.

So what is the real benefit of living in a better house on occurrence of malaria? It is another clue that clearly links the prevalence of malaria to poverty. Those who can afford a better house can also afford better food, more frequent cleaning and better water and sanitation. Until researchers properly consider these factors, there will not find the real causes and cures of the scourge of malaria.

Malaria vaccines is a hot research topic in Malaria World and is addressed this week in two highlighted news articles and three research papers.

One research paper is a review ‘Malaria Vaccines: Current Achievements and Path Forward’ by Chen et al. It summarises the current establishment views describing the two approved vaccines, RTS, S/AS01(Mosquirix by GlaxoSmithKline) and R21/Matrix-M (developed by Oxford University and the Serum Institute of India). It also introduces 13 other vaccines in development that are described as either Pre-erythrocytic stage, Blood stage or Sexual stage.

One of these, the Pre-erythrocytic PfSPZ vaccine is the subject of one of the news articles, ‘Sanaria reports positive initial safety results for groundbreaking PfSPZ-LARC2 malaria vaccine’. No details are included though the press release says physician-scientists at Groupe de Recherche Action en Santé (GRAS) in Burkina Faso have successfully completed initial safety evaluations in 30 adult Burkinabés as the first phase of a clinical trial of Sanaria® PfSPZ-LARC2 Vaccine, which is designed to prevent infection with Plasmodium falciparum malaria. The initial data of the 30 adults confirmed the vaccine was safe, fully attenuated, and caused no malaria infections. It does not say if a control was used or if there were any side effects.

One scientific paper is an animal study (‘Epitope specificity of antibody-mediated protection induced in mice by the malaria vaccine RTS,S/AS01’ by Flores-Garcia et al) and I will not consider it as it does not address real world efficacy.

The other two articles are not very positive of the effect of vaccines at combating malaria. One is a podcast, The Johns Hopkins Malaria Minute, ‘Why malaria vaccines may work better in some places than others (with Lemu Golassa)’. Professor Lemu Golassa, Head of Medical Parasitology at Addis Ababa University in Ethiopia stated that the RTS, S/AS01 and R21/Matrix-M are unsuitable for combatting he strains of Plasmodium falciparum circulating in Ethiopia.

The research paper ‘Efficacy of RTS,S/AS01E only seen in baseline parasitemic and not baseline aparasitemic Plasmodium falciparum-exposed, drug-treated Kenyan adults’ by Copeland et al found that the RTS,S/AS01 did not prevent malaria in Kenyan adults who did not have the parasite prior to vaccination. There was a modest benefit in preventing malaria in those already infected. However, the control groups in this study received intramuscular injection with a rabies vaccine (Abhayrab®, Human Biologicals Institute, Andra Pradesh, India). This questionable practice was addressed in my first blog post ‘R21 Vaccine is less toxic and ineffective than a Rabies Vaccine’.

Indeed, in this study for the subjects with negative PCRs for malaria parasites, while not statistically significant (-24%, 95% CI; -97 to 22.4; p=0.373) the unadjusted estimated vaccine efficacy is lower for Mosquirix® than for Abhayrab®. The Bill and Melinda Gates Foundation funded study concludes that a vaccine comprising only the CS (circumsporozoite) protein is unlikely to be sufficient to accelerate Pf malaria elimination due to modest efficacy in preventing infection, including in adults. It calls for more research on multi-antigen/multi-stage vaccine approaches that include a CS-component, as well as a one or more blood-stage and/or sexual-stage (transmission-blocking) antigens.

There are a few articles this week in Malaria World discussing accuracy of tests. There are two types of tests is common use. The first is old fashioned microscopy that is considered the ‘gold standard’. A drop of blood is smeared on an microscope slide and it is inspected visually for plasmodia. This method requires a basic laboratory and a skilled trained operator.

The second method is RTD (rapid diagnostic tests). mRDTs (m for malaria) detect the presence of histidine rich proteins released from parasitized red blood cells of a drop of blood. Their use does not require a laboratory or as much training. They have been widely used for routine malaria diagnosis in many rural areas of sub-Saharan Africa.

It is a similar situation to that which applied during the COVID ‘pandemic’. Lateral flow RTDs could be used by anyone and allowed increased testing when compared to PCR (polymerase chain reaction) that was considered the ‘gold standard’. PCR is occasionally used for malaria detection but probably has many false positives (See ‘PCR Detects More Asymptomatic Malaria Cases than RDT’).

The lead article in Malaria World is ‘Researchers question reliability of Abbott’s rapid malaria tests’ by Offord in Science. WHO is concerned that 11 “affected” lots from two Abbott RDTs—Pf/Pv and Pf/Pan—that were associated with “faint lines and false negative results” in reports from “multiple research groups.” They are concerned that the tests do not detect cases especially in Asia. False negatives may be less likely in countries where malaria transmission and parasite densities are higher, as in parts of Africa, says Nick White, a malaria researcher at MORU who is co-authoring an academic paper describing SMRU’s findings.

The second paper of interest on this topic in Malaria World this week is scientific study called ‘Point-of-Care Evaluation of Malaria Rapid Diagnostic Test (mRDT) for Detection of Plasmodium falciparum Among Children Under 5 Years of Age Attending Panyadoli Health Center III in Kiryandongo Refugee Settlement, Mid-Western Uganda’ by Acan et al. The cross-sectional study was conducted among refugee children under 5 years old from February to April 2023. All eligible refugee children aged ≤5 years with suspected malaria symptoms, such as anorexia, vomiting, or abdominal discomfort, with or without diarrhoea, or with a body temperature above 37.4°C or a history of fever within the past 24–48h were included.

380 blood specimens were obtained using the finger prick method and examined for malaria parasites using mRDT (Carestart by Apacor – pictured) and microscopy. A structured questionnaire was used to collect sociodemographic characteristics of the respondents. Data were analyzed using descriptive statistics, while Kappa value was used to provide insights into the agreement between the two diagnostic methods.

The prevalence of malaria using mRDT and microscopy was 12.8% (95% CI: 8.0%–17.8%) and 12.2% (95% CI: 7.4%–17.4%), respectively. mRTD detects a few more cases on average than the ‘gold standard’. But are they mostly the same cases? Cohen’s Kappa Statistic is used to measure the level of agreement between two raters or judges who each classify items into mutually exclusive categories. The concludes that the strong agreement between mRDT and microscopy (Kappa=0.75) further confirms the effectiveness of mRDT as a diagnostic tool. This is considered substantial agreement (0.61-0.80) but not near perfect agreement (0.81-0.99). There is not perfect overlap of the two methods.

In Malaria World this week there is an article ‘Exploring the prevalence and association between nutritional status and asymptomatic malaria in Rwanda among under-5 children: a cross-sectional analysis’ by Uwimana et al describes the association between malaria and malnutrition.  

Data from three Demographic and Health Surveys (DHS) conducted in Rwanda in 2010, 2014–15, and 2019–20 were used in the study, including children aged 6 to 59 months and confirmed malaria diagnoses via blood smear. Asymptomatic malaria was found to be present in 1.3% of the population. The results indicate that malaria was more frequent in children with stunting. Underweight children were also found to have an increased prevalence of malaria. Children from the richest families were found to be protected from malaria in all 3 DHS.

In Malaria World this week there is another paper highlighting the effect of socio-economic inequalities in malaria prevalence, ‘Socio-economic inequalities in malaria prevalence among under-five children in Ghana between 2016 and 2019: a decomposition analysis’ by Edusei et al. In their analysis of results from 2019 Ghana Malaria Indicator Surveys (GMIS) of under-five children the concentration index (Concentration Index = − 0.224; Standard Error = 0.059; p-value = 0.000) was statistically significant and negative, indicating higher malaria prevalence among children from lower socio-economic backgrounds.

The study found socioeconomic status related inequalities in malaria prevalence to the disadvantage of poorer under-five children, highlighting the significant role played by socioeconomic status, maternal education, regional disparities, and rural residency.

Other articles on interest in Malaria World this week include a discussion of Bill Gates announcement that he plans to wind up the Gates Foundation and a discussion of the 1922 Zionist launch of sustainable malaria control and an examination of the education which enabled that control.

In Malaria World this week there is a review ‘Global trends and burdens of neglected tropical diseases and malaria from 1990 to 2021: a systematic analysis of the Global Burden of Disease Study 2021’ by Chen et al. Its introduction has an interesting un-cited statement ‘Malaria, commonly referred to as the “disease of poverty”’. The paper itself which is a review of trends over the 31 year period has data that shows that the incidence, prevalence, deaths and DALY (disability adjusted life years) have decreased over the timeframe.

But most interestingly it had a figure that shows that the effect on DALY (disability adjusted life years) for neglected tropical diseases and malaria is strongly dependent on SDI (sociodemographic index). These data strongly support the statement above.

A search of the internet provides more evidence. Even the UN for World Malaria Day in 2023 have published a web article entitled ‘Malaria: a disease of poverty’. Gallup and Sachs (Jeffrey) wrote ‘The Intolerable Burden of Malaria: A New Look at the Numbers: Supplement to Volume 64(1) of the American Journal of Tropical Medicine and Hygiene’ the first line of which is ‘Malaria and poverty are intimately connected’. These articles do maintain the mosquito connection, but state that the reasons for the connection with poverty are unclear. Mosquitos do not differentiate between rich and poor. So perhaps malaria has other causes?

An article in Malaria World this week, ‘Lessons from failure to success on malaria elimination in the Huai River Basin in China’ by Liu et al has interesting data of the rates of malaria from Yongcheng City and Guoyang County, Huai River Basin, China (1955-2023). What is very notable is how dramatically incidence declined from very high peaks around 1960 during the Great Chinese Famine (1959-1961) and 1970 during the cultural revolution (1966-1976) to practically no malaria 1983-2023, apart from a small increase from 2003-2008 (see figure).

The Cultural Revolution was characterized by violence and chaos across Chinese society. Estimates of the death toll vary widely, typically ranging from 1–2 million, including a massacre in Guangxi that included acts of cannibalism, as well as massacres in Beijing, Inner Mongolia, Guangdong, Yunnan, and Hunan.

The Great Chinese Famine was a famine that occurred between 1959 and 1961 as a result of policies of the Mao’s Great Leap Forward. It is widely regarded as the deadliest famine and one of the greatest man-made disasters in human history, with an estimated death toll due to starvation that ranges in the tens of millions (15 to 55 million). The Tibetan government in exile claimed that many Tibetans died from famines in 1961–1964 and 1968–1973 as a result of forced collectivization.

This particular ‘elephant in the room’ linking malaria incidence to famine is ignored by the authors who concentrate their discussion on the slight increase from practically zero to ~600 cases per 100,000 (0.6%) in Guoyang County in 2006. In 1970 there were 18,000/100,000 cases (18%) in Guoyang County in and 33,000/100,000 (33%) in Yongcheng City. This slight increase 2003-2008 was blamed on merger or closure of malaria control facilities, loss of medical professionals, low capacity for detection, diagnosis, prevention, and management of malaria cases, and underestimating the transmission potential of Anopheles sinensis. The Chinese authorities reacted to these deficiencies following typical Health Authority malaria control methods and consider that these reversed the decline. Increases of malaria budgets are considered particularly important.

As usual the linkage of malaria to malnutrition was ignored.

Malaria World this week includes a reference to a protocol of a very interesting literature review to be carried out. ‘Integrated malaria vector control strategies and their effectiveness in sub-Saharan Africa: a systematic review protocol for interventional studies’ by Kombate et al will systematically retrieve published and grey literature from electronic databases and clinical trial registries. A meta-analysis will be conducted based on studies that have reported a high level of evidence.

The study will look for interventions that integrate malaria-specific vector control approaches. This implies a combination of two or more of the following strategies:

• ITNs (insecticide treated nets)
• Installation of screens on windows
• Ventilation openings and open roof eaves to prevent mosquitos from entering homes
• Closing windows and doors at sunset to reduce mosquito entry into homes
• IRS (indoor residual spraying)
• Environmental management and source reduction
• LSM (larval source management)
• Topical and spatial mosquito repellents
• Mosquito coils
• Insecticide sprays

The control data will be provided by studies with a comparator or control group using single-intervention strategies or no intervention.

The target outcomes are

• Malaria incidence: measured as the number of new cases of malaria diagnosed in a specific population over a given period of time.
• Malaria prevalence: measured as the proportion of surveyed children and pregnant women who are infected with malaria at a specific point in time at the community level.

The analysis will include papers published in English and French from 01 January 2004 and 01 May 2024. It will include cluster-randomised controlled trials (RCTS), cluster-randomised studies using a stepped-wedge design, cluster-randomised cross-over studies, cohort studies (prospective or retrospective), non-randomised cross-over studies, controlled before and after studies, programmatic evaluations, cross-sectional studies, case–control studies, interrupted time series, and case series.

The analysis will use the accepted methods for similar meta-analyses which are fully described in the protocol.

I look forward to the resulting paper when the study is complete. I previously discussed a Cochrane review that examined the effect of indoor residual spraying and found no convincing evidence of its effectiveness. It will be interesting to see what this study focusing on multiple vector control methods finds. If malaria is spread by mosquitos reducing their number and the number of bites should reduce incidence and prevalence?

‘Relationship between unimproved household sanitation facilities and malaria infection among under‑five children in Nigeria: insights from Malaria Indicator Survey 2021’, by Asifat et al, in this weeks Malaria World has interesting insights on factors associated with malaria. They found that the type of toilet facility, unimproved versus improved was strongly associated with occurrence of malaria, measured with RDT (rapid diagnostic tests) on children under five years, (3.766 odds ratio). However, this was not significantly associated with malaria (1.297, 95% Confidence interval 0.898–1.875) after adjusting for socioeconomic and demographic factors.

Improved sanitation means flush toilets and unimproved includes pit latrines without slabs, open defecation, and other forms. There is a strong association with occurrence of malaria, but correlation does not indicate causation. Because as rightly pointed out by the authors, unimproved sanitation is associated with poverty, rural residence, and less maternal education. Poor children with less educated mothers living in rural locations are more likely to have malaria and to only have unimproved sanitation facilities. Other factors that were found to be associated with occurrence of malaria were accommodation with unimproved wall materials and roof materials. These factors are also associated with poverty.

One factor that surprised me was that the drinking water source was not significantly associated with occurrence of malaria. Drinking water sources were classified according to the WHO/UNICEF Joint Monitoring Programme (JMP) framework: 4.5% safely managed water (piped into dwelling), 64.0% basic water (protected wells, boreholes, public taps), 24.4% unimproved water (unprotected wells, tanker trucks), and 7.1% surface water (rivers, lakes, canals). Surface water compared to safely managed water has 3.183 times more malaria. However, both are small numbers in the sample and are also associated with wealth. Most subjects have basic water or unimproved water, the quality of which is unknown without testing.

So, what is the factors that increase susceptibility to malaria? It is most likely related to poverty. There is no discussion of nutrition in this paper. The quality of nutrition is likely associated with wealth and the education level of the mother. It is a factor that merits more attention.

Several weeks ago I addressed the issue of asymptomatic malaria and had also addressed it a year ago. I am not convinced that asymptomatic malaria is an illness. Most malaria researchers with their parasite model will argue that they are ‘cases’. However, I would love to see how many cases a method such as that described in Malaria World this week would find in a ‘malaria free’ country. But don’t expect that type of control experiment any time soon.

What surprised me most about ‘Asymptomatic malaria reservoirs are the last challenge in the elimination in Cambodia’ by Doum et al was how low the case numbers were. And they used PCR (polymerase chain reaction) as the detection technique. We remember that PCR was used extensively during the COVID19 pandemic and was criticised because, if a large number of cycles were used, it had a high false positive level. Many of the ‘cases’ detected were asymptomatic.

The paper summary states that all qPCR-diagnosed cases were asymptomatic. Malaria cross-sectional surveys were conducted in high-risk populations (forest dwellers, forest goers and forest rangers) at three different time (T0, T1, T2) from October 2022 to February 2023, overlapping the rainy, malaria transmission season and into the dry season. In Mondulkiri, the prevalence of Plasmodium falciparum was 0.63% at T0, increasing to 0.81% at T1, and decreasing to 0.18% at T2. Plasmodium vivax decreased from 4.80% at T0 to 1.97% at T1 and 1.65% at T2. In Kampong Speu, overall prevalence was 7.06% at T0, declining to 5.19% at T1 and 4.59% at T2. Plasmodium falciparum prevalence was 0.30% at T0, decreasing to 0.09% at T1 and rising slightly to 0.10% at T2. The forest goers showed a prevalence increase to 1.95% at T1 and decrease to 1.46% by T2, while forest dwellers decreased to 3.25% at T1 and further to 3.13% at T2.

Just like with COVID RDTs (rapid diagnostic tests) were less likely to be positive. Passively reported malaria cases showed 1.09% of cases in Mondulkiri and 0.21% of cases in Kampong Speu were rapid diagnostic test (RDT) positive.

This study was carried out on high-risk populations and all cases were asymptomatic. RDTs had 1% positivity or less. With PCR higher numbers were detected but all were still <10%. It would seem to me that a case could be made that malaria has now been eliminated from Cambodia, if this is as bad as it gets. I repeat it would be interesting to see how many positive cases there would be in a similar study in a malaria free country.