New R21 vaccine offers hope to save children from malaria in Africa, but more needs to be done

Malaria is one of the oldest diseases humans suffer and die. Despite past and ongoing efforts to control and reduce mortality and morbidity from this disease, 229 million people were estimated by WHO infected, and 409,000 people died in 2019 alone. 274,000 of them were children under 5 years old.

One of the “holy grails” of the fight against malaria (and its potential eradication) was the development of a malaria vaccine …

One of the “holy grails” of the fight against malaria (and its potential eradication) has been the development of a malaria vaccine capable of protecting people from at least the most severe symptoms of malaria, such as cerebral malaria, severe anemia and respiratory distress. Development of malaria vaccines has started from 1910and many researchers and doctors have spent their lives trying to develop an effective malaria vaccine.

Unfortunately the Plasmodium The parasite that causes malaria is not as easy a target for vaccine development as many other pathogens, such as SARS-cov-2 that caused the COVID-19 pandemic. First, it is a eukaryotic unicellular protozoan, much more complicated than a simple virus, with more than 5,000 genes. Second, it is well known for its ability to suppress and modulate the immune response and actively generate variants of surface proteins that escape the antibody response. Finally, it has a complex life cycle, with five different stages or forms in human blood and liver, some inside and others outside of red blood cells (erythrocytes). Therefore, it is difficult to develop a vaccine that can target all the different forms of the pathogen. If we want to prevent infection of liver cells the very moment the pathogen enters the body, we need to target the sporozoite stage that the Anopheles vector mosquitoes inject us with their saliva.

Vaccination using dead or attenuated forms of the pathogen has been attempted in the past, with limited success. An additional challenge is that infection with Plasmodium elicits only partial immunity, not a sterilizing immune response. Acquired immunity is short-lived and protection may be lost in a year.

Diagram centered on the erythrocyte stage of the malaria parasite. Credit: Enomoto et al, PLoS One 2012 10.1371 / journal.pone.0039499

Despite these challenges, vaccine development has been pursued by several pharmaceutical companies, research groups, non-profit organizations and public entities, demonstrating the importance of this endeavor. WHO has released an update Malaria vaccine technology roadmap in 2013, which called for the development of several candidate vaccines, with the aim of achieving a vaccine efficacy of 75%. There are 27 different vaccine candidates currently in different stages of vaccine development, and we’ve already reported on some of them here at Bugbitten.

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

The one that has progressed the fastest in clinical trials is the RTS, S / AS01 (Mosquirix) vaccine, developed by GlaxoSmithKline, in collaboration with the Malaria Vaccine Initiative and many others. It is a recombinant protein vaccine, containing repeated epitope antigens and Plasmodium circumsporozoite protein (CSP) T lymphocytes, fused to hepatitis B surface antigen (HBsAg ), which self-assemble into virus-like particles (VLPs). ) in yeast. Mostly, RST, S / AS01 contains only 20% fusion protein fragments (larger molecules), while 80% of HBsAg are expressed as monomers, which limits the amount of CSP on the surface of the virus-like particle. This could explain why, after very promising results in phase II trials, subsequent phase III trials demonstrated only modest protection against infection, with a vaccine efficacy of 36.3% in children aged 5 to 17 months. In addition, it was possible safety signs increased due to increased incidence of meningitis, cerebral malaria and increased female mortality in the group vaccinated against malaria. While the European Medicines Agency (EMA) provided a positive scientific opinion, the RTS, S / AS01 vaccine has not yet been prequalified for use by WHO. Instead, in 2019, a Malaria vaccine implementation program was initiated to further investigate the risks and benefits of this vaccine.

Now a recent study not yet peer reviewed by researchers from the University of Oxford, the London School of Hygiene and Tropical Medicine, the pharmaceutical company Novavax, the Serum Institute of India and the Institute for Research in Health Sciences in Burkina Faso, report the promising results of a Phase II trial with an alternative vaccine. The new vaccine, R21, is very similar to RTS, S / AS01, in that it always contains the central repeat and the C-terminus of the circumsporozoite protein (CSP) fused to the N-terminus of HBsAg. However, unlike RTS, S / AS01, it does not contain HBsAg as a monomer, only as fusion protein fragments, providing more surface area for CSP on the virus-like particle, which allows a more specific immune response. In addition, R21 is mixed with a different saponin-based adjuvant called Matrix-M, produced by Novavax. The vaccines used in the trial were produced in Serum Institute of India, the world’s largest vaccine producer. The trial 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 12 months after their third dose. There were three groups in this randomized, double-blind clinical trial, with two groups receiving the vaccine with 25 and 50 µgrams of the adjuvant, and a control group receiving rabies vaccine. Participants were followed 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 of 146 participants in the vaccination groups reported malaria infection, while 104 of 147 children in the control group reported malaria infection. After 12 months, there were only 7, 1, and 1 additional cases reported in each group, respectively. These proportions resulted in vaccine efficacy of 71% and 75% in the groups with the two different doses of adjuvants, meeting the recommendations of the Malaria Vaccine Technology Roadmap. The safety profile of the vaccine was excellent, with only seven serious adverse events reported, all considered unrelated to vaccination. Both groups of vaccinated children developed significant antibody titers, which fell over the next 12 months. Importantly, antibody levels were increased by the fourth vaccination to levels similar to those after the third vaccination, which was not the case for the RTS vaccine, S / AS01.

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

However, there is still work to be done …

However, there is still work to be done. The location of this ongoing trial in Burkina Faso is characterized by seasonal transmission of malaria for 6 months of the year, explaining the low number of additional cases of malaria, even in the control group, in the second half of the period. follow-up, which complicates the estimation of efficacy beyond 6 months. The authors will continue to follow participants for an additional year and report on effectiveness in the next malaria control season. At the same time, phase III trials of this vaccine in five African sites of malaria transmission and different seasonality are only just beginning. We look forward to seeing the results of these trials, hopefully confirming these results. Maybe we can finally break through the holy grail of malaria vaccine development, and maybe have a chance. Discard one of our oldest plagues once and for all.

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