In 2020, over 200 million clinical cases of malaria and more than 600,000 malaria deaths were reported, with the vast majority occurring in sub-Saharan Africa (1). Importantly, malaria, which is the leading cause of death in young children, also poses great danger to pregnant mothers (2). The emergence of the Coronavirus disease 2019 (COVID-19) pandemic and related transmission control measures, such as social distancing and travel restrictions, disrupted and complicated the implementation of previously ongoing malaria control and intervention strategies (3). Importantly, malariology experts have highlighted the need to develop more tools and strategies towards achieving malaria elimination and eventual eradication (4). It is anticipated that a highly effective malaria vaccine might further reduce the global burden of malaria. Although RTS,S, the recently approved circumsporozoite protein (CSP)-based malaria vaccine has low efficacy, it has renewed hope for the development and deployment of effective malaria vaccines (5).

Although the number of COVID-19 cases in Africa has been lower than predicted, its effect on other tropical diseases such as malaria, which pose significant burdens to a significant portion of African population cannot be underestimated (1, 3). Nevertheless, the fast-tracked vaccine discovery efforts against severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) highlighted new opportunities for malaria vaccine development and deployment in malaria holoendemic regions of Africa.

Currently, several strategies are being used to develop vaccines against various parasite developmental stages. Indeed, in the last 10 years, there has been an exponential growth in the number of studies aiming to develop such vaccines [as reviewed (6)]but these have been hampered by several challenges, some of which can be overcome using strategies that have been used to rapidly develop vaccines against COVID-19 (7). We believe that such a vaccine will alleviate the current malaria related problems in Africa that are now compounded by the emergence of the SARS-CoV-2 virus.

Plasmodium falciparum, the main causative agent of malaria, has a complex life cycle alternating between human and anopheles mosquitoes. Current malaria vaccine candidates generally target pre-erythrocytic, erythrocytic and sexual stage parasites. Some of the antigens under consideration are shown in Figure 1 (6). Vaccines targeting the pre-erythrocytic stage prevent infection progression to symptomatic malaria (6). Phase III vaccine trials of the CSP-based RTS,S showed that it modestly reduced clinical malaria episodes (by approximately 36%) in young African children and by about 26% among infants who received four vaccine doses with statistically significant efficacy against severe malaria in young children (8). Pilot rollout of the RTS,S vaccine is now underway in Malawi, Ghana, and Kenya to assess protective benefits and safety during routine use in real-life settings (9). The WHO has recently approved the widespread deployment of the RTS,S vaccine (5). In addition, a phase 2b trial involving CSP-based R21 in Matrix-M adjuvant was observed to be safe and very immunogenic with a protective efficacy of more than 74% in children aged 5–17 months drawn from a highly seasonal malaria transmission setting of Burkina Faso (10). Phase 3 trials in different malaria transmission settings are now required. PfCelTOS, a micronemal secreted-protein, is the only non-CSP based recombinant protein be evaluated in a clinical trial (Clinicaltrials.gov NCT02174978).

Erythrocytic or blood-stage vaccines are aimed at inducing high antibody levels targeting specific parasite antigens in order to inhibit erythrocyte invasion by merozoites, thereby controlling parasite replication in the host. Vaccine antigens like Reticulocyte-binding Protein Homolog 5 (PfRh5) and PfRh5-interacting protein (PfRipr) are very promising, with clear functional activity ( Table 1 ) (12, 21). PfRh5 binds to basigin and forms an essential stable merozoite invasion complex with PfRipr and Cysteine-Rich Protective Antigen (PfCyRPA) (12). The three proteins elicit invasion-inhibitory antibodies in experimental animals and naturally acquired antibodies in humans correlate with protection from clinical malaria (12, 21, 22). Other blood-stage antigens in the clinical development phase include MSP3, Glutamic-acid-rich protein (PfGARP) and Schizont Egress Antigen 1 (PfSEA-1). A randomized phase 2 study involving children in Burkina Faso, Gabon, Ghana, and Uganda found that although the GMZ vaccine, a fusion of MSP3 and GLURP, exhibited good tolerability, immunogenicity, and some protection from malaria infection, its efficacy was low (23). However, because other studies have shown that MSP3 is effective, improved formulation or the use of alternative adjuvants that may enhance the GMZ vaccine’s immunogenicity and the duration of protection should be explored (24, 25). PfGARP is expressed on the exofacial surface of erythrocytes infected in the early–late trophozoite stage. Anti-PfGARP activates programmed cell death of parasites via caspase-like proteases and fragmentation of parasite DNA (13). PfSEA-1 is expressed in schizont-infected erythrocytes and anti-PfSEA-1 antibodies block parasite egress from RBCs (14). Other promising vaccine antigens include Serine rich antigen 5 (SERA 5) (18) and Plasmodium-encoded Macrophage Inhibitory Factor (PMIF) (19).

On the other hand, transmission blocking vaccines (TBVs) present an excellent path to stopping population transmission although with no direct benefits to the vaccinee (26–28). TBVs are based on the principle that when antibodies against a specific antigen expressed in the sexual stages of the malaria parasite (gametocyte, gamete, zygote and ookinete) are taken up along with gametocytes during a blood meal, they can reduce the number of oocysts in mosquito vectors (26). Potential TBV target antigens include Pfs230, Pfs48/45, Pf25, and Pfs28, which are expressed on the surface of gametocytes, gametes, zygotes, and ookinete (20, 28, 29). The advantages of TBVs are summarized elsewhere and their advancement has progressed to clinical trials (26–28, 30). While these efforts have mainly focused on antigens like Pfs25, Pfs230, and Pfs48/45, which were identified in the pre-genome era, new antigen discovery approaches promise to change this (28).

In addition, whole organism vaccines, such as the radiation-attenuated P. falciparum sporozoite (PfSPZ) vaccine have also been pursued. For instance, the vaccine was confirmed to be safe, well tolerated, and showed significant protection against P. falciparum infection in Malian adults in a randomized, double-blind phase 1 trial (31). The PfSPZ vaccine could also induce a strain-transcending protection against homologous and heterologous parasites in American adult (35–45 years) volunteers enrolled in a controlled human malaria infection (32). Similar observations were reported in a multi-arm, double-blind, randomized, placebo-controlled trial involving 336 Kenyan infants (5–12 months) albeit with no significant protective efficacy (33). Nonetheless, the sourcing of sporozoites that require mosquito colonies, and the need for aseptic cryopreserved delivery of sporozoites remains a major problem (34). On the other hand, because the in vitro culturing of the blood stage parasites is well-established and would allow easy vaccine manufacturing, efforts are currently ongoing to develop and evaluate genetically or chemically attenuated whole-parasite blood-stage vaccines (35, 36).

The COVID-19 vaccine discovery and development landscape developed at an unprecedented scale. The relatively short duration (10 months) between publication of the first SARS-CoV-2 sequences to phase 3 trials was remarkable when compared with the typical vaccine development timeline of 3–9 years (37, 38). The COVID-19 vaccine pipeline is made of a broad range of technology platforms, including traditional and novel approaches (39). Although most of these technologies, including a mRNA and nanotechnologies, had been developed over the previous decade, the development of COVID-19 vaccines indicate that leveraging such approaches along with other genomic era technologies to identify effective vaccine candidate molecules can accelerate the development of vaccines against other tropical diseases, including malaria (40). The mRNA-based platforms are highly flexible and quick, while retaining the capacity to induce robust immune responses against specific targets. This has renewed the hope of quickly developing effective vaccines against malaria, a topic we discuss below. Leveraging the strategies and gains made during COVID-19 vaccine development will significantly accelerate the development of such promising mRNA malaria vaccines.

Strategies like the use of viral vectors, nanotechnology-based vaccines, and machine learning designed vaccines may offer effective alternatives or supplement mRNA vaccines. Viral vectors are modified, harmless viruses capable of infecting human cells and expressing an antigen of interest (67), triggering robust immune responses (68). Their advantages over conventional modes of vaccine delivery include; a) capacity for large inserts, which allows delivery of any antigen of choice, b) ability to deliver antigens with high fidelity as they are delivered as genetic instructions, and c) generation of potent immune reactions without need for adjuvants by mimicking normal infection (68, 69). Despite concerns about their recombination risk and unknown virulence (68, 69), viral vector vaccines have been developed for infections like Ebola (70) and COVID-19 (71). Although animal models and human trials (6, 72) indicate that viral vector vaccines may be efficacious against malaria, none are in clinical use. However, given that R21, a virus-like particle malaria vaccine that meets the ≥75% efficacy threshold recommended by the WHO has concluded phase 2b trial, viral vector vaccines may develop into effective alternatives to mRNA vaccines (10). In addition, during the COVID-19 pandemic, machine learning (ML) and artificial intelligence (AI) have been widely used (73), including in guiding the development of universal vaccines (74), designing multi-epitope vaccines (75), and predicting the best sites for trials and those likely to benefit from vaccines (76, 77). These applications highlight the potential value of ML and AI during the development and deployment of malaria mRNA vaccines (78, 79). Similarly, nanotechnology facilitates targeted vaccine delivery, stability, slow release, and immunogenicity (78, 79). The high efficacy of the COVID-19 mRNA vaccines is attributable to the lipid nanoparticles (LNPs) used to shield the mRNA from degradation by ribonucleases (80). This technology has the potential to significantly benefit the development of mRNA/nanotechnology-based malaria vaccines. Indeed, using spontaneous nanoliposome antigen particularization (SNAP), conjugated malaria antigens have been stably presented in uniformly-oriented display without covalent modification or disruption of antigen conformations (81). Immunizing mice and rabbits with SNAP carrying Pfs25 (a malaria transmission-blocking vaccine candidate) was well tolerated and triggered a robust antibody response with minimal local reactogenicity (81). Importantly, multiplexing up to four antigens triggered strong and balanced antibody production (81), highlighting the potential of nanotechnology in the development of multi-antigen/multi-stage particulate vaccines.

Current data suggest that developing of a malaria vaccine leveraging COVID-19 pipelines is a rational approach for strengthening global health. The preclinical trials of the pre-erythrocytic PfCSP and PMIF mRNA vaccine candidates have showed that it may be possible to achieve malaria protection, making this approach worth pursuing. Expanding these platforms to other vaccine targets deserve further investigation.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

BNK is an EDCTP Fellow under EDCTP2 programme supported by the European Union grant number TMA2020CDF-3203-EndPAMAL. FK is also an EDCTP Fellow supported by grant number TMA2019CDF-2736-IRMiP. JG is supported by the African Academy of Sciences and the Royal Society FLAIR grant number FLR\R1\201314. The funding sources had no role in study design, collection, analysis, interpretation of data, and publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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