Malaria Public Health Status: Global Context and Update on Gulf Cooperation Council Countries

1. Global Status of Malaria: Public Health Post-COVID-19

Malaria in humans is caused by species of the Plasmodium genus, with the most devastating and virulent species being P. falciparum, a unicellular protozoan parasite capable of intracellular existence. Over the 2000-2019 period, the global malaria death toll declined from 864,000 to 576,000 deaths (World Malaria Report 2023, World Health Organization, WHO). However, this trend was reversed in 2020, with 631,000 deaths recorded worldwide (a 10% increase compared to the number of deaths recorded in 2019), before levelling at around 610,000 deaths over the 2021-2022 period (World Malaria Report 2023, WHO). There were 63,000 deaths reported due to disruptions to essential malaria services during the COVID-19 pandemic (2019-2021) (World Malaria Report 2022, WHO). While there have been reviews on the status of malaria in the Eastern Mediterranean Region (EMR; Figure 1a and 1b) based primarily on data prior to the pandemic (Al-Awadhi et al. 2021; Iqbal et al., 2021), this review represents a significant post-COVID-19 update on the status of malaria in this region, with a particular focus on the Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Qatar, Oman, Saudi Arabia, and the United Arab Emirates, UAE). Clinical data has been retrieved from publicly available databases for the GCC countries, and systematically collated (Table 1) and critically analyzed, thereby providing the most up-to-date snapshot of malaria in these countries pre- and post-COVID-19. Hence, in this review we assess the current world-wide status of malaria in terms of public health, prevention and treatment, before providing an Arabian regional perspective, with a critical evaluation of the malaria situation in the GCC countries.

In the EMR as defined by WHO (Figures 1a and 1b), annual cases of malaria decreased during 2000-2015, from 6.9 million to 4.3 million, before steadily increasing, reaching 8.3 million in 2022, a 92% increase (World Malaria Report 2023, WHO). Mortality due to malaria in the EMR also decreased from 13,600 to 7,500 deaths during 2000-2014, but then increased during 2014-2022 to reach 15,900 deaths, a more than 100% increase. Interestingly, publicly available data retrieved from Our World in Data (“Malaria” by Max Roser and Hannah Ritchie, for the period 2000-2021; ourworldindata.org/malaria; Figure 1a and 1b), representing estimates of malaria deaths by the Institute of Health Metrics and Evaluation (IHME), were found to be slightly different to the WHO data. While the IHME data show the same overall trends in mortality as the WHO data, the number of deaths were somewhat higher (Figures 1a and 1b). While a number of countries in the EMR appear to be free of indigenous malaria, there is still the threat of imported malaria (Al-Awadhi et al., 2021). In the Arabian Peninsula, most of the GCC countries have been declared free of indigenous malaria by the WHO (Bahrain, Kuwait, Qatar, and the UAE; World Malaria Report 2022, WHO); however, imported malaria accounts for a significant number of deaths in this region, and malaria is still endemic in two GCC countries (Saudi Arabia and Oman) and its neighbors (Yemen) (Al-Awadhi et al., 2021) (Figure 1c).

There are a number of factors that are threatening malaria control measures, including but not limited to: antimalarial drug resistance (Balikagala et al., 2021); false negative diagnostic test results due to pfhrp2/3 gene deletions (Feleke et al., 2021); insecticide resistance in mosquitoes to widely used insecticides (pyrethroids, organochlorines, organophosphates and carbamates) (Riveron et al., 2018; Hancock et al., 2020; Venkatesan, 2024); and the emergence of various highly invasive mosquito species, in particular Anopheles stephensi (Ahmed et al., 2021). The potential synergistic negative impact of the emergence of insecticide resistance in invasive species of mosquitoes is of grave concern. Insecticide resistance is acquired mainly through target resistance (e.g. mutant voltage-gated sodium channels, VGSCs, with reduces binding to pyrethroids), metabolic resistance (e.g. increase in detoxification enzymes such as cytochrome P450 monooxygenases, esterases, carboxylesterases and glutathione S-transferases), and penetration resistance (e.g. increase in structural protein involved in cuticle thickness) (Barnes et al., 2017; Riveron et al., 2017; Kouamo et al., 2021). Also of major concern are the emerging signs of antimalarial drug resistance in P. falciparum in Africa and South-East Asia, particularly to first-line drug treatment (artemisinin resistance, which manifests as delayed parasite clearance) and other drugs (antifolates, naphthoquinones, antibiotics like clindamycin and doxycycline and 4-aminoquinolines) (Balikagala et al., 2021). Furthermore, there are only a few novel targets for the development of new antimalarial drugs (Shibeshi et al., 2020), highlighting the need for the identification of further drug targets for antimalarial drug discovery. Elucidation of the structural properties of the protein-protein interactions required for the survival and pathology of the parasite in humans is critical to the continuous development of novel antimalarial drugs.

Similar to antimalarial drug development, advancement in effective malaria vaccine development has also been challenged by the pleiotropic nature of the parasite. Despite such hurdles, in 2021, the first malaria vaccine to be approved and licensed for widespread use was released (RTS,S/AS01; Mosquirix™; Laurens, 2020; Beeson et al., 2022). Furthermore, very recently a second malaria vaccine, R21/Matrix-M™ (R21/MM), was recommended for release (Siddiqui et al., 2023). While these vaccines hold much promise, they are designed for children, and hence further research and development is needed to produce malaria vaccines with broader reach at the population level. These malaria vaccines are critically evaluated later in the section on “Antimalarial drugs and vaccines”.

Given the recent increase in case and mortality rates, and the emerging threats to the control, elimination and ultimately eradication of malaria in regions of the globe with high burden, there is a dire need for a globally integrated approach to this infectious disease (Venkatesan, 2024). Despite the negative impact of COVID-19 on the public health status of malaria, the pandemic has shown what can be done when a disease is viewed as a global threat. Indeed, there is an urgent need for a universal effort in applying more strategic approaches towards the eradication of malaria. In the following sections we evaluate the global status of malaria in terms of prevention and treatment, before focusing on the GCC countries.

2. Malaria Prevention

Since mosquitoes act as vectors, one of the key preventative methods to control the spread of malaria is to reduce the vector population. Several approaches are used to control the malaria vector population, including drainage of swamps, application of pesticides and use of surface coverings (such as oil) to kill mosquito larvae present in standing water bodies. Indoor residual sprays (IRS) and long-lasting insecticidal nets (LLINs) are still the primary approaches to malaria prevention (Corrêa et al., 2019). Despite its effectiveness as a malaria control tool, the use of dichlorodiphenyltrichloroethane (DDT) is controversial because of the persistence of the chemical in the environment (Bouwman et al., 2011). The main insecticides used to control malaria vectors include pyrethroids, organochlorines, carbamates, and organophosphates (Killeen et al., 2017). Of these, pyrethroids pose the least public health concerns as they are bio-degradable (Casida et al., 1975; Cycoń and Piotrowska-Seget, 2016). However, as discussed in the previous section, the consistent use of insecticides leads to resistance to the chemicals by the mosquito vector. The recommended approach to mitigate against mounting insecticide resistance is to make use of IRS or combining IRS with LLINs (West et al., 2014). An alternative approach proposed to prevent insecticide resistance is to mix the active ingredients, and this has been reported to be effective when applied to mosquito bed nets (Pennetier et al., 2008). An additional advantage of this approach is that the active ingredients interact synergistically when applied in combination, such that low doses are highly effective (Pennetier et al., 2008).

Preventative approaches to malaria also involve a combination of vaccines and chemo-preventive approaches, none of which are effective in isolation. Several chemoprevention approaches for malaria have been stipulated in global guidelines, amongst them: intermittent preventive treatments during pregnancy (IPTp), and for infants (IPTi); seasonal malaria chemo-prevention (SMC); and for emergency situations, mass drug administration (MDA) (Plowe, 2022). Effective chemo-preventive approaches are associated not only with reduced disease burden, but also with a reduced incidence of drug resistance.

3. Antimalarial Drugs and Vaccines

Resistance has emerged in P. falciparum to artemisinin (and its derivatives), the globally recommended first-line therapy for malaria. Artemisinin and its derivatives (e.g., artesunate, artemether and arteether), synthesized by the plant Artemisia annua, are able to rapidly clear the parasite by inhibiting protein synthesis. Different research groups have reported that mutations in the P. falciparum Kelch13-encoding gene result in reduced levels of the essential protein PfKelch13, leading to artemisinin resistance (Siddiqui et al., 2021; Paloque et al., 2022). Mutation in PfKelch13 enables the early ring stage of the parasite to avoid going through cell cycle arrest and continue their intra-erythrocytic development when artemisinin is no longer available at effective concentrations (Mok et al., 2015; Mok et al., 2021). Resistance has been shown to develop in six Southeast Asian countries including Cambodia, Myanmar, Thailand, Vietnam, Laos, and southern China (Yunnan, and Guangxi) (Balikagala et al., 2021), and it poses a serious threat to other global regions. This emerging drug resistance has put a spotlight on the fact that there are only a few validated antimalarial drug targets (Shibeshi et al., 2020). One approach to overcoming resistance to artemisinin and other antimalarials has been combination drug therapy using complementary or synergistic drugs that act on distinct targets. Indeed, global guidelines have been released and implemented, involving the use of combinations of antimalarial drugs with distinct targets and mechanisms of action (WHO Guidelines for Malaria, 2022). However, this approach has had mixed success, highlighting that for significant improvement towards treatments where drug resistance is minimized, new antimalarials for combination drug therapies should ideally be derived from novel chemical scaffolds that have novel modes of action (Luo et al., 2023). Furthermore, while there are a number of promising candidate compounds feeding into next-generation antimalarial treatments, many target only the asexual, erythrocytic stage of the parasite’s life cycle. Thus, one logical approach is to identify novel chemotypes targeting the other parasitic stages or multiple stages, a topic that has been extensively reviewed (Luo et al., 2023). Broadly, contemporary approaches involve identification of a protein that is required for growth or survival of the parasite, followed by identification of a chemical series that inhibits the target. A key to antimalarial drug discovery is the subsequent medicinal chemistry efforts, which are designed to enhance binding to the parasite protein while sparing the closest human orthologs. To illustrate this concept, the malarial heat shock proteins (HSPs) are a case in point. The HSPs are a family of molecular chaperones whose expression is upregulated under stress (e.g. heat, low oxygen levels, pH variations, and nutrient deprivation), and which function to prevent the accumulation of toxic levels of misfolded and aggregated proteins under such conditions (Jee, 2016; Edkins and Boshoff, 2021). The major families of HSPs, including HSP10, HSP40, HSP60, HSP70, HSP90, and HSP100, are highly conserved from prokaryotes to eukaryotes, forming an intricate network critical for ensuring protein homeostasis (proteostasis). Consistent with this role, most HSPs have been found to be essential for the growth, survival, viability, and differentiation at all stages of the life cycle of kinetoplastid and apicomplexan parasites, including the malaria parasite (Shonhai et al., 2011; Zhang et al., 2018). Many HSPs are also essential for the pathogenesis and virulence of the malaria parasite (Blatch, 2022). These observations have led to the suggestion that the P. falciparum HSPs (PfHSPs), especially PfHSP40 (Daniyan et al., 2016; Daniyan and Blatch, 2017; Dutta et al., 2021a; Almaazmi et al., 2022), PfHSP70 (Przyborski et al., 2015; Batinovic et al., 2017; Zininga et al., 2017a; Zininga et al., 2017b; Chen et al., 2018; Day et al., 2019; Cortés et al., 2020; Barth et al., 2022; Mrozek et al., 2022), PfHSP90 (Banumathy et al., 2003; Bayih et al., 2016; Wang et al., 2016; Posfai et al., 2018; Shahinas et al., 2013; Seraphim et al., 2019; Stofberg et al., 2021) and their complexes (Botha et al., 2011; Cockburn et al., 2011; Cockburn et al., 2014; Dutta et al., 2021b; Almaazmi et al., 2023; Singh et al., 2023), could be prospective antimalarial drug targets. Unlike many other targets that have been explored, inhibition of these proteins could have broad effects on parasite survival at multiple stages, forming a potentially important addition to the antimalarial armamentarium.

In the preceding paragraphs, we outlined progress towards developing HSPs and their complexes as new targets for antimalarial drug discovery. Ideally, optimized versions of these single-agent compounds might be combined with both emerging and existing drugs. Combination therapies have become a promising tool for reducing burdens on the path to elimination (Luo et al., 2023). Mass drug administration (MDA) is the contemporaneous delivery of a full course of antimalarial medicine at a population level, regardless of whether individuals are infected with malaria or not, before or during high malaria transmission seasons (Eisele, 2019; WHO Guidelines for Malaria, 2022). According to the WHO, MDA use is recommended in settings approaching elimination, where vector control and monitoring are effective, treatment is accessible, and re-infection is minimal (WHO Guidelines for Malaria, 2022). For example, programmatic MDA (pMDA) campaigns with dihydroartemisinin-piperaquine (DHAP) were conducted in the Southern Province of Zambia as a malaria elimination tool (Fraser et al., 2020). Interrupted time-series results with comparison groups, indicated that two rounds of pMDA with DHAP over one year with moderate coverage, resulted in significant short-term reduction of malaria transmission in low transmission areas, but not eradication (Fraser et al., 2020). In recent years, MDA intervention using mosquitocidal drugs has been used in Gambia, combined with antimalarial treatments with ivermectin and DHAP, in an area of moderate malaria, where there is high coverage of insecticide-treated nets and indoor residual spraying. The implementation of MDA was found to be both safe and well-tolerated where there was a high coverage of standard control interventions, resulting in significant reductions in malaria prevalence, and to possibly promote malaria elimination where there was high coverage of vector control interventions (Dabira et al., 2022).

What is the status of antimalarial vaccines, and their role in antimalarial MDA? The first malaria vaccine to be released, RTS,S/AS01, is recommended for young children (five to six months old, with a booster at two years old) living in moderate-to-high malaria transmission locations (RTS,S Clinical Trials Partnership, 2015; Beeson et al., 2022). RTS,S/AS01 is a genetically engineered fusion protein-based vaccine (also referred to as a subunit vaccine) which targets the pre-erythrocytic stage of the P. falciparum life cycle. The fusion protein consists of the central tandem repeat region (R) and C-terminal T-cell epitopes (T) of the P. falciparum circumsporozoite protein, PfCSP, fused to the S antigen of the hepatitis B virus (S). This fusion protein (RTS) and the hepatitis B surface antigen, HBsAg, (S) are co-produced in a yeast (Saccharomyces cerevisiae) expression system, and formulated with the adjuvant AS01 (Zavala, 2022). RTS,S/AS01 clinical trials in malaria-endemic African countries reported only a modest decrease in malaria cases for test versus control groups (clinical efficacy), with ~55% efficacy in young children (5–17 months), and ~31–26% efficacy in infants (6–12-weeks) (Beeson et al., 2022; Zavala, 2022). Nevertheless, this vaccine appears to be safe, readily delivered, and already making a notable positive impact on protection from malaria among young children at the community level (Beeson et al., 2022). Indeed, the vaccine is reported to have already reached approximately 2 million children in three countries in Africa (Ghana, Kenya and Malawi). However, despite the promising potential of RTS,S/AS01, it does not meet the WHO threshold clinical efficacy (75%), and it offers only modest, short-lived and strain-specific protection (RTS,S Clinical Trials Partnership, 2015; Neafsey et al., 2015; Laurens, 2020). The recently approved second malaria vaccine, R21/Matrix-M™ (R21/MM), offers greater clinical efficacy, having exceeded the WHO efficacy threshold. R21/MM is also a subunit-based vaccine targeting the pre-erythrocytic stage of the parasite lifecycle, and designed for the prevention of malaria in young children (Datoo et al., 2021). This vaccine comprises R21, a PfCSP central tandem repeat region fused to the N-terminus of the HBsAg, co-produced with HBsAg in a yeast (Hansenula polymorpha) expression system, and formulated in the adjuvant Matrix-M (MM). R21/MM clinical trials in malaria-endemic African countries have demonstrated 74% (low dose) and 77% (high dose) efficacy in young children (5 and 17 months) (Datoo et al., 2022; Siddiqui et al., 2023). While there are now two malaria vaccines for young children, one released and licenced (RTS,S/AS01), and one approved for release (R21/MM), there is still currently no malaria vaccine available for older children, adolescents or adults at risk of malaria. Mass drug administration is proposed to interrupt transmission permanently if combined with mass vaccination (Tun et al., 2017). For example, the RTS,S/AS01 vaccine was shown to be safe and immunogenic for healthy adult Thai volunteers without adverse effects when administered in combination with DP and primaquine (Von Seidlein et al., 2020). The results of these interventions support the combined use of multiple antimalarial drugs in concert with malaria vaccines to accelerate the elimination of malaria. However, further large-scale intervention-research studies are necessary to improve the application of vaccine-drug strategies, as well as innovative approaches to next generation vaccines to produce malaria vaccines with greater reach across the life span.

4. Malaria in the GCC Countries

The History of Malaria in the Region

The GCC countries are all located in the Arabian Peninsula (Figure 1c), and for more than 30 years they have shared several common characteristics such as a dry hot climate, high income generated from an oil-based economy leading to rapid development, and modern healthcare and infrastructure (Al-Awadhi et al., 2021). In addition, these countries have large and dynamic expatriate populations feeding into their workforce. In most of the GCC countries, the expatriate population outnumber its citizens (Iqbal et al., 2021). The majority of the expatriates are from malaria-endemic developing countries within Africa (e.g. Ethiopia, Nigeria and Sudan; Table 1) and south/southeast Asia (e.g. Afghanistan, Bangladesh, India, Nepal, Pakistan, Philippines and Sri Lanka; Table 1) (Al-Awadhi et al., 2021; Iqbal et al., 2021). On an annual basis, the GCC countries welcome millions of new expatriates and expatriates returning from visits to their home countries, thereby increasing the risk of imported malaria entering the region (Iqbal et al., 2021). Since the 1950s, the GCC countries have increased their investments into malarial control leading to the interruption of local malaria transmission. This successfully eliminated malaria (malaria free status) in all the GCC countries, apart from Oman and Saudi Arabia (Al-Rumhi et al., 2020; Table 1). Oman still suffers from periodic outbreaks of malaria, while in Saudi Arabia, isolated clusters of indigenous malaria prevail. Hence, the GCC countries have shifted policy toward a malaria-free Arabian Peninsula, with an emphasis on approaches that prevent reintroduction of malaria (Regional Malaria Action Plan 2016-2020: Towards a Malaria-Free Region, WHO). None of the GCC countries is among the 25 high malaria burden countries, and since 2010 there have been zero, or close to zero, annually reported malarial deaths in this region (Our World in Data, IHME, 2022; World Malaria Report 2022, WHO; Figure 1b).

Malaria Status by Country

Bahrain: According to the WHO, Bahrain was declared malaria-free in 2012 (Table 1). However, the Bahrain Ministry of Health reported the national eradication of malaria in 1979 (Al-Awadhi et al., 2021). There have been limited research reports dedicated to the status of malaria in Bahrain (Ismaeel et al., 2004); however, a number of articles reviewing malaria epidemiology in the Eastern Mediterranean Region have included Bahrain (Al-Awadhi et al., 2021; Iqbal et al., 2021). Furthermore, since the year 2000, the Bahrain Ministry of Health has published health statistics, which include epidemiological data on malaria cases (Table 1). The previous reports indicated malaria cases of 1,572 for the 1992-2001 period (Ismaeel et al., 2004), and 133 in 2017 (Iqbal et al., 2021). Over the 2018-2020 period, the trend of declining malaria cases has continued with only 15 cases reported in 2020 (Table 1). As reported previously, all malaria cases appear to be imported among expatriates originating mostly from Pakistan and India, with the predominant causative agent being P. vivax. The last time Bahrain nationals presented with malaria was 2018 (6 out of a total of 53 malaria cases; Table 1); however, these are most likely citizens returning from travel in malaria endemic countries.

Kuwait: The WHO declared Kuwait as malaria-free in 1979 (Table 1). Ever since malaria was declared to be eradicated from Kuwait in 1963, no indigenous cases have been reported. However, several studies reported that despite precautions, imported malaria cases have been identified among expatriate families travelling from regions on the Indian subcontinent, Southeast Asia, and Africa where malaria is endemic (Iqbal et al., 2000; Iqbal et al., 2003; Iqbal et al., 2020; Sher and Latif, 2023). Nevertheless, the number of malaria cases has steadily decreased from 1,400 (in 1993) to less than 200 (in 2019) due to a highly effective malaria control program managed by the Ministry of Health, Kuwait (Sher and Latif, 2023; Table 1). While the majority of early reports (1985 to 2000) of malaria cases were single infections with P. falciparum and P. vivax, recent studies have revealed that the majority of current malaria cases in Kuwait were caused by mixed infections of both P. falciparum and P. vivax parasites, and that nearly all these mixed-infection cases were among travelers from India, the largest expatriate group in Kuwait (Iqbal et al., 2020; Sher and Latif 2023).

Oman: Oman is still officially considered a malaria endemic country, and while malaria has been a major public health issue since the 1960s, national eradication programs have considerably reduced the number of indigenous cases, which are now approaching zero on an ongoing basis in recent years (Table 1). In 1975, a malaria training program was initiated (Snow et al, 2013). This program had multiple key objectives and measures to reduce malarial cases in Oman, such as the establishment of malaria training centers, identification of vector sources and vector control using larvivorous fish, Aphanius dispar, and continuous tracking of larval control and the widespread use of larvicides. Furthermore, during the 1973-1979 period, in specific high endemic areas, weekly chloroquine prophylaxis treatment was offered to school children. Despite these measures, Oman remained endemic with the number of malaria cases escalating to almost 33,000 in 1990 (Hassan et al., 2017). In 1991, the Omani Ministry of Health launched the National Malaria Eradication Programme (NMEP), with the aim of reducing parasite incidence to 1/10,000 population by the year 2000, by robust vector control, and early identification, management and curing of active cases (Simon et al., 2017). Over the 1994-2004 period, indigenous cases decreased from 4415 to zero, with no local transmission reported between 2004 and 2006 (Simon et al., 2017; Al Mukhaini et al., 2023). However, since 2007, due to the continuous existence of the vector, local transmission has been reported in small outbreaks (Simon et al., 2017; Al Mukhaini et al., 2023). In 2016, malaria control efforts were further increased in Oman, by enhancing malaria surveillance as a fundamental approach for better monitoring and assessment of the effectiveness of interventions (Global Technical Strategy for Malaria 2016-2030, 2021 update, WHO). Analysis of publicly available malaria infection data for the 2018-2022 period (Table 1), revealed that the annual number of imported malaria cases was significant but steadily dropping, while the number of indigenous malaria cases was virtually zero for the last three years (Table1). Interestingly, the predominant malaria species has significantly changed over the years, somewhat mirroring the changes in the origin of imported cases. In the 1988-1999 period, the majority of malaria cases were due to infection by P. falciparum, and was attributed to imported cases from East Africa. Over the 2000-2017 period, there was a shift to predominantly P. vivax cases due to an increasing imported workforce from India (Al Mukhaini et al., 2023). However, since 2018 P. falciparum cases have again predominated, most likely due to an influx of immigrants from East Africa (Al Mukhaini et al., 2023). In 2022, a total of 259 cases were recorded (with only one indigenous case), mostly resulting from infection by P. vivax (52.5%), followed by P. falciparum (42.5%) (Table 1).

Qatar: In 1970, Qatar eliminated malaria transmission, with the WHO declaring it malaria-free in 2012 (Table 1). A number of studies (Al-Kuwari et al., 2009; Farag et al., 2018; Al-Rumhi et al., 2020) and recent reviews of the malaria situation in Qatar (Al-Awadhi et al 2021; Iqbal et al., 2021), have reported that all malaria cases have been travel-related, largely due to expatriates who have visited their home countries which are malaria-endemic, but also Qatari nationals who have visited malaria-endemic countries. The two predominant malaria vectors in Qatar were An. stephensi and An. multicolor which were eliminated by malaria elimination programs and intense vector control (Al-Kuwari et al., 2009). A study employing molecular diagnostic techniques reported that between 2013 to 2016, most cases of imported malaria were due to P. vivax, while P. falciparum and mixed P. falciparum/P. vivax infections occurred far less frequently (Al-Rumhi et al., 2020). P. vivax infections originated in the Indian subcontinent, whereas P. falciparum infections primarily originated from Africa. The study also demonstrated a high genetic variability of P. falciparum strains and the incidence of mutations in the PfKelch13-encoding gene, and other genes linked to drug resistance in malaria parasites. Scientists fear that there is a risk of the re-establishment of drug-resistant malaria in Qatar and other GCC nations due to the increasing introduction of multi-drug resistant P. falciparum (Al-Rumhi et al., 2020).

Saudi Arabia: Saudi Arabia is still officially classified as endemic for malaria. In 1998, Saudi Arabia faced a major malaria outbreak, but due to intensive federal malaria control programs, the number of reported indigenous malaria cases sharply declined (Shibl et al., 2012; Coleman et al., 2014; El Hassan et al., 2015). Over the past two decades, extensive measures have been introduced to reduce indigenous malaria. Analysis of publicly available data for the 2018-2022 period (Table 1) revealed that while the number of imported malaria cases per annum was significant, the number of indigenous malaria cases has been relatively low (Table1). Indeed, by 2021, Saudi Arabia achieved its inaugural year of reporting zero indigenous malaria cases, which was maintained through 2022 (Table 1). The majority of reported indigenous malaria cases appear to originate from endemic countries bordering Saudi Arabia, which were not part of the GCC (El Hassan et al., 2015; Alshahrani et al., 2016; Al Zahrani et al., 2018; Alshahrani et al., 2019). A study conducted in south-western Saudi Arabia, reported that the vast majority of cases were due to P. falciparum (98%), with very few cases caused by mixed P. falciparum/P. vivax infection (1.85%), and no detection of P. vivax cases (Bin Dajem, 2015). Another study investigated the type of malaria parasite in western Saudi Arabia (the Makkah region), where millions of immigrants annually visit to perform the Islamic pilgrimage, Haj, and reported that 95% of malaria cases were among non-Saudi nationals. Most of the malaria cases were caused by P. falciparum (67%) and P. vivax (32%), with the majority (62%) of cases originating from immigrants traveling from India, Pakistan and Nigeria (Memish et al., 2014). Antimalarial drug resistance alleles have been reported in Saudi Arabia, especially mutations associated with chloroquine resistance and anti-folate drug resistance, suggesting that improvements were needed in future antimalarial drug regimens (Soliman et al., 2018; Dafalla et al., 2020; Madkhali et al., 2020).

United Arab Emirates (UAE): Since 2007, the UAE has been declared by the WHO as malaria-free (Table 1). However, imported malaria cases have been reported annually among working expatriates or returning travelers from endemic countries (Al-Awadhi et al., 2021; Table 1). A study performed in a Dubai hospital between 2008 and 2010, reported 629 malaria cases, where most of the patients (90.1%) were from Pakistan or India, 7% were from sub-Saharan Africa and none of the reported cases were Emirati citizens. The study showed that most of the cases (78%) were caused by P. vivax followed by P. falciparum and only 2% of infections were caused by mixed P. vivax/P. falciparum (Nilles et al., 2014; Al-Awadhi et al., 2021). The UAE Ministry of Health and Prevention has implemented national strategies to maintain a malaria-free status, including early malaria detection and treatment of imported cases, workforce training in malaria prevention and control, and enhanced vector control. These measures appear to be effective, as publicly available data for a five-year period (2018-2022; Table 1), indicated that the number of imported malaria cases has been steadily decreasing year-on-year, while the number of indigenous malaria cases has been zero for the entire period (Table1). Interestingly, the majority of imported malaria cases are reported from the Emirates of Abu Dhabi and Dubai (Table S1), which is perhaps not surprising given that they are major cities, channeling millions of travelers into the UAE every year through their international airports. Strategic preventative measures could be implemented, such as compulsory pre-screening of travelers on route to the UAE prior to departure from malaria endemic countries. National strategies such as these, informed by tried and tested COVID-19 infection control procedures, could potentially result in a substantial reduction in future imported malaria cases.

Impact of Mosquito Vector Insecticide Resistance in the Region

Over the last two decades, insecticide resistance in the highly invasive malaria vector, Anopheles stephensi, has spread widely across most endemic countries, posing a substantial threat to successfully control of malaria (Riveron et al., 2018; World Malaria Report 2023, WHO). This is of major concern to the GCC countries, given they are under constant risk of the re-introduction of Anopheles species (including species previously undetected in the region), particularly from neighbouring countries with compromised malaria vector control measures (Al-Eryani et al., 2023). The WHO have released two “Vector Alerts” (WHO Vector Alerts, 2019 and 2022), highlighting the threat of the spread of An. stephensi into regions where it has not previously been detected, notably countries in the Horn of Africa and Yemen (Malaria Threats Map, Global Malaria Programme, World Health Organization, WHO 2024; apps.who.int/malaria/maps/threats/; accessed 20 March 2024; Figure 2). The presence of An. stephensi was not reported in Yemen until 2021, although it may have been resident but not detected (Al-Eryani et al., 2023). Furthermore, the vector was found to be resistance to multiple insecticides (pyrethroids, organochlorines, organophosphates and carbamates) (Figure 2). Yemen has recently become the centre of increasingly acute conflict and upheaval, resulting in the displacement of segments of the population into make-shift urban dwellings, which has inadvertently created conditions favourable to the spread of the malaria vector (Allan et al., 2023). This has seriously compromised the capacity of Yemen to control the spread of malaria, and hence its proximity to the GCC countries poses a major threat to the spread and re-establishment of malaria in this largely malaria-free region. In particularly, the threat of the spread of insecticide resistant and invasive mosquito species across the Horn of Africa and through Yemen to the GCC countries, requires that stricter cross-border vector surveillance and control measures are established in the Arabian Peninsula.

Impact of Climate Change on Malaria Cases in the Region

The Arabian Peninsula is highly vulnerable to the negative impacts of climate change, particularly the adverse effects on the control of infectious diseases (Waha et al., 2017). The spread of malaria relies on a strong ecosystem between humans, the environment and infected mosquitoes, and the degree of malaria distribution and seasonal activity are highly sensitive to climactic factors (Costello et al., 2009). Given that mosquitoes are poikilothermic, variation in temperature, humidity and rainfall can significantly affect mosquito prevalence, successful development of the malaria parasite within the vector, and malaria transmission (Carrington et al., 2013; Shapiro et al., 2017; Mordecai et al., 2019). From a risk framework perspective, there is a high likelihood that climate change will cause an increase in malaria infections not only in endemic areas, but also current malaria-free regions. Modelling of potential future world-wide climate change scenarios indicate conditions in tropical highlands could favor the spread of malaria, socioeconomic factors not-withstanding (Caminade et al., 2014). In the next 10 years, GCC countries are predicted to suffer from extreme heat waves (Salimi and Al-Ghamdi, 2020), and severe water constraints (Bayram and Öztürk, 2021). There are data gaps regarding climate dynamics and disease populations across the GCC, reflecting an under-representation in global health forecast research for this region (Rawson et al., 2023), and highlighting the urgent need for such public health research in the near future.

5. Conclusion

While global malaria cases and deaths fell significantly during the 2000-2015 period, progress has since slowed, particularly in the EMR, which has experienced an overall increase in malaria cases and deaths. The emergence of widespread resistance in P. falciparum to first-line treatment drugs, such as artemisinin, has highlighted the need for new antimalarial drugs, and smarter approaches, including better combination therapies and mass drug administration. Furthermore, the threat of the spread of insecticide resistant and invasive mosquitoes from endemic to non-endemic regions, requires that stricter cross-border vector surveillance and control measures are established. The recent successes of the first malaria vaccine (RTS,S/AS01), and the approval of a second (R21/MM), have renewed the promise of widely applicable vaccines, which provide long-term protection, and are affordable and accessible in malaria endemic areas. In the Arabian Peninsula, while most of the GCC countries have been declared free of indigenous malaria (Bahrain, Kuwait, Qatar, and the United Arab Emirates), malaria is still endemic in two GCC countries (Saudi Arabia and Oman) and their neighbors (Yemen). The GCC region is poised in the near future to move towards malaria-free status for all member states. Preventative measures have proven highly successful in population-level control of malaria, while the targeted treatment of malaria infected patients will continue to be an important approach for preventing deaths. However, evolving environmental conditions such as climate change with increasing average temperatures, increased insecticide resistance and invasiveness of the mosquito vector, and increased resistance of the malaria parasite to first-line treatment drugs, mean that malaria should still be considered a major threat to public health in the GCC region. Therefore, further strengthening of current malaria-control frameworks, with well-developed prevention, surveillance, monitoring, diagnosis and treatment regimes, will be required before the entire GCC region can achieve malaria-free status. A region is only as safe as its “weakest link”, and hence, as the world learnt from the COVID-19 pandemic, borderless, collective intent leads to robust solutions to public health threats.