Malaria is one of the oldest diseases that people suffer and die from. Despite previous and ongoing efforts to control and reduce mortality and morbidity from this disease, the WHO estimated that 229 million people are infected and 409,000 people have died from it. As recently as 2019, 274,000 of them were children under the age of 5.

One of the “holy grails” of malaria control (and possible eradication) was the development of a malaria vaccine …

One of the “holy grails” of malaria control (and possible eradication) has been the development of a malaria vaccine that can protect people from at least the most severe symptoms of malaria, such as cerebral malaria, severe anemia, and shortness of breath. Malaria vaccine development began as early as 1910, and many researchers and doctors spent their lives developing an effective malaria vaccine.

Unfortunately that is Plasmodium Parasite, which is responsible for causing malaria, is not as easy a target for vaccine development as many other pathogens, such as SARS-cov-2, which caused the COVID-19 pandemic. First, it’s a unicellular eukaryotic protozoon, much more complicated than a simple virus, with more than 5000 genes. Second, it is known for its ability to suppress and modulate the immune response and actively creates variants of surface proteins that defy the antibody response. After all, it has a complex life cycle of five different stages or forms in the human blood and liver, some inside and some outside of the red blood cells (erythrocytes). Therefore, it is difficult to develop a vaccine that will target all different forms of the pathogen. If we want to prevent the infection of liver cells as soon as the pathogen enters the body, we have to target the sporozoite stage, which is the anopheles Mosquito vectors inject into us with their saliva.

In the past, vaccination with dead or attenuated forms of the pathogen has been attempted with limited success. An additional challenge is infection with Plasmodium only triggers partial immunity, not a sterilizing immune response. The acquired immunity is short-lived and protection can be lost within a year.

Schematic representation of the erythrocyte stage of the malaria parasite. Photo credit: Enomoto et al., PLoS One 2012 10.1371 / journal.pone.0039499

Despite these challenges, vaccine development has been promoted by several pharmaceutical companies, research groups, nonprofits, and public institutions to demonstrate the importance of this endeavor. The WHO published an updated Malaria Vaccine Technologies Roadmap in 2013 calling for the development of multiple vaccine candidates to achieve 75% vaccine effectiveness. There are currently 27 different vaccine candidates in various stages of vaccine development, and we’ve already covered some of them here at Bugbitten.

There are currently 27 different vaccine candidates at different stages of vaccine development …

The vaccine RTS, S / AS01 (Mosquirix), developed by GlaxoSmithKline in collaboration with the Malaria Vaccine Initiative and many others, has advanced the fastest in clinical trials. It is a recombinant protein-based vaccine that contains antigens from the repeat and T-cell epitope of the circumsporozoite protein (CSP) of Plasmodium fused with the hepatitis B surface antigen (HBsAg) that self-transforms into virus-like particles (VLPs ) together) in yeast. It is important that RST, S / AS01 contains only 20% of the fusion protein residues (larger molecules), while 80% of the HBsAg is expressed as monomers, which limits how much CSP gets onto the surface of the virus-like particle. This could explain why, after very promising results in Phase II studies, subsequent Phase III studies showed only moderate protection against infections with vaccine effectiveness of 36.3% in children aged 5 to 17 months. In addition, there were possible safety signals triggered by an increased incidence of meningitis, cerebral malaria, and increased female mortality in the malaria vaccine group. While the European Medicines Agency (EMA) has given a positive scientific opinion, the RTS vaccine S / AS01 has not yet been pre-qualified for use by the WHO. Instead, a malaria vaccine implementation program was launched in 2019 to further study the risks and benefits of this vaccine.

A recently unparsed study by researchers from Oxford University, the London School of Hygiene and Tropical Medicine, the pharmaceutical company Novavax, the Serum Institute of India and the Institute de Recherche en Sciences de la Sante in Burkina Faso on the promising results of a phase -II study with an alternative vaccine report. The new vaccine R21 is very similar to RTS S / AS01 in that it still contains the central repeat and the C-terminus of the circumsporozoite protein (CSP) fused to the N-terminal end of HBsAg. In contrast to RTS, S / AS01, however, it does not contain the HBsAg in monomer form, but only as fusion protein units, which provides more surface for the CSP on the virus-like particle, which leads to a more specific immune response. Additionally, R21 is mixed with another saponin-based adjuvant called Matrix-M, made by Novavax. The vaccines used in the study were made at the Serum Institute of India, the world’s largest vaccine manufacturer. The study was conducted in Burkina Faso on 450 children aged 5 to 17 months in 2019-2020 with three doses of primary vaccination followed by a booster shot 12 months after their third dose. There were three groups in this double-blind, randomized clinical trial, with two groups receiving the vaccine containing 25 and 50 µg of the adjuvant and a control group receiving a rabies shot. Participants were followed up for 12 months and assessed for malaria infection and adverse events.

These proportions resulted in 71% and 75% vaccine …

After 6 months, only 43 and 38 out of 146 participants in the vaccine groups reported malaria infection, while 104 out of 147 children in the control group reported malaria infection. After 12 months, only 7, 1, and 1 additional cases were reported in each group. These proportions resulted in vaccine efficacy of 71% and 75% in the two different dose adjuvant groups, in line with the recommendations of the Malaria Vaccine Technology Roadmap. The safety profile of the vaccine was excellent. Only seven serious adverse events were reported, all of which were considered unrelated to vaccination. Both groups of vaccinated children developed large antibody titers which fell over the following 12 months. It is important that the antibody levels were increased by the fourth vaccination to values ‚Äč‚Äčthat were similar to those after the third vaccination, which was not the case with the RTS, S / AS01 vaccine.

These exciting results give hope that we finally have a highly effective and safe malaria vaccine that could save the lives of countless children in Africa and elsewhere. The authors note that given the lower dose of the vaccine compared to RTS, S / AS01 and the reduced complexity of the Matrix-M adjuvant compared to AS01, the new R21 vaccine would also be cheaper and easier to manufacture on a large scale adjuvant.

However, there is still a lot to be done …

Much remains to be done, however. The location of this current study in Burkina Faso is characterized by a seasonal malaria transmission over 6 months a year, which explains the small number of additional malaria cases even in the control group in the second half of the follow-up period, which makes the assessment of effectiveness beyond 6 months. The authors will follow the participants for another year and report on the effectiveness during the next malaria season. At the same time, phase III studies with this vaccine are just starting at five African locations with different malaria transmission and seasonality. We will look forward to seeing the results of these trials and hopefully confirm these results. Maybe we can finally crack the holy grail of malaria vaccine development and maybe have a chance to get rid of one of our oldest scourges once and for all.

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