Zev van Zanten
Over the next two years, nearly 18 million more live-saving doses of RTS,S/AS01 – the first-ever malaria vaccine – will be distributed throughout Africa. While the issues that have plagued the roll-out so far are likely to continue, the widespread release of this vaccine (and the continual development of new vaccines) are still humanity’s best weapon in the fight to end malaria.
Malaria and Our History With It:
Malaria has long plagued humanity, with cases (or at least what we assume are cases based on symptoms) reported as far back as 2700 BCE. Caused by a mosquito-transmitted parasite (something humanity didn’t realize until the late 1800s), malaria is a serious and sometimes fatal disease that presents with symptoms including high fevers, chills, and flu-like symptoms. It also ravaged much of the known world, with cases occurring everywhere from southern Europe to Eastern China, killing tens of millions in the process.
Today, malaria still plagues over 100 countries and territories, and about half of the world’s population is at risk of contracting it, with the portions of Africa south of the Sahara and large swathes of Oceania being most affected due to their climate. Despite all of our efforts and modern medicine advances, malaria still kills around 2.7 million people a year, with most deaths happening in Africa and most of the victims being children under five. The sheer number of deaths is due in part to a lack of affordable and easily accessible treatments for Malaria in the Global South.
Humanity has long sought to understand malaria to fight and prevent it, which would allow them to save countless lives in the process. An early misconception of the disease’s etiology was that malaria was caused by “bad air” and miasmas rising from swamps – though after the discovery of bacteria and the development of germ theory, research went in a newer, more productive direction. This led to the discovery of parasites as the cause, mosquitos as the vector, and several new treatments. Simultaneously, researchers unlocked the secret of quinine and were able to distill it from cinchona bark (which has long been used as a treatment without an understanding of how it worked), greatly improving humanity’s access to this life-saving treatment.
At first, knowledge of malaria’s causes was used to exterminate malaria by cutting off the source of transmission: mosquitoes. Nation after nation engaged in large-scale extermination campaigns, deploying massive amounts of Dichlorodiphenyltrichloroethane (DDT) and other pesticides and often working to drain or destroy potential swamp breeding sites. While these efforts greatly reduced malaria’s range, natural immunities meant that spraying was often never fully successful in eradicating malaria-carrying mosquitoes, and the pesticides resulted in massive damage to nature captured by works such as “Silent Spring.” Because of this, people sought out new venues to exterminate malaria, namely vaccines that would let us prevent infection instead of putting us in an unwinnable battle with mosquitoes.
Developing A Vaccine:
Developing a malaria vaccine proved to be incredibly difficult, requiring nearly 60 years of intensive medical research primarily targeted at the most deadly and dangerous strain of malaria. This was due in large part to the difficulty of dealing with P. falciparum (the parasite that causes the aforementioned strain), which has an incredibly complex biology, life cycle and, genome, and because of the lack of natural immunity (outside of sickle cell anemia carriers) and how malaria evades the human immune system. Additionally, parasites as a whole are incredibly difficult to develop vaccines against due to the challenges of cultivating parasites in vitro, which has also led to a lack of other well-developed vaccines for parasite-caused diseases in humans.
To overcome these barriers, researchers gathered as many antigens as they could in hopes of finding a protein to target or some other attribute of malaria that they could target with a vaccine, a method that had historically proven successful in creating vaccines. Unfortunately, malaria proved to be too complex for this, forcing scientists to seek out new ways of creating immunity.
Sporozoites (a spore-like stage of the malaria life cycle) quickly became a focus, as vaccines focusing on this would allow the immune system to attack at the very beginning of infection, keeping malaria from spreading throughout the body. Circumsporozoite protein (CSP) – a major component of the sporozoite surface – was viewed as a particularly promising way of attacking the sporozoites.
The work that led to RTS,S/AS01 started in 1984 during a collaboration between Walter Reed Army Institute of Research and pharmaceutical company GSK, both of whom were trying to create malaria vaccines using attenuated sporozoites. Pre-clinical studies soon revealed that CSP inoculation could create antibodies that resisted malaria infection during the sporozoite stage, leading to efforts being refocused on this area. While there were initial hurdles in identifying and synthesizing the correct CSP antigen due to difficulties in producing an antigen of CSP’s size with existing technology, scientists were able to produce a working CSP and, with it, an effective malaria vaccine in 1987.
RTS,S/AS01 would then go through additional refinements and enhancements to maximize effectiveness, thanks in large part to funding from groups such as the Bill and Melinda Gates Foundation. The vaccine soon showed that it was well worth the investment, with a Phase 3 clinical efficacy and clinical trial conducted between 2009 and 2014 across seven countries showing incredible results. After inoculation, cases of malaria and severe malaria were reduced by 1 in 4 and 1 in 3, and a subsequent long-term impact study showed that the vaccine effects persisted to some extent with no long-term negative effects.
With the evidence of its success clear, RTS,S/AS01 was prequalified for use by WHO in July of 2022. With a vaccine discovered, the next step was to deploy it on a far larger scale than ever before.
Deploying the Vaccine:
While the vaccine had already been delivered on a smaller scale with help from the Malaria Vaccine Implementation Programme, manufacturing 18 million doses and deploying them en masse throughout Africa would require more money, more manufacturing, and more focus on logistics. Thankfully, Gavi, the Vaccine Alliance, WHO, UNICEF, and other organizations were both willing and able to continue to fund vaccine efforts and to lend logistic support.
Unfortunately, the inadequate supply of RTS,S/AS01 (though efforts are underway to increase supply) has forced nations and NGOs to make tough decisions about how much to distribute and to where it will be distributed. Under the current WHO framework, the ultimate priority is giving the vaccine to the nations with the greatest need, as defined by the burden of the disease in children and the risk of death. But even with questions regarding how many vaccines different nations will get somewhat settled, the storage requirements of RTS,S/AS01 will likely make deploying the vaccines to more remote locales either improbable or highly expensive.
Future Developments:
While we await to see hopefully positive effects of the large-scale rollout of RTS,S/AS01, new vaccines are already either in development or undergoing trials and will hopefully prove to be even more effective than RTS,S/AS01. Two of the most promising of these vaccines are the Oxford-developed R21 Vaccine and BNT165b1, a potential mRNA-based vaccine from BioNTech. R21 mixes the malaria parasite-specific R21 antigen developed by Oxford with a compound designed by Novavas to make the immune response even more effective. BNT165b1, on the other hand, hopes to use the same mRNA technique used to create the Pfizer-BioNTech Covid-19 vaccine to target Malaria.
Another potential venture with vaccine development for malaria is to target the other parasite strains. There are a total of five malaria-causing parasite strains that can affect humans, and while none are as dangerous as P. falciparum, they are still debilitating. There are also always new treatments for malaria in development that, while not capable of preventing malaria, will greatly improve the lives of the people with malaria. But no matter what direction the research takes, it will take us even closer to exterminating malaria, making life better in the process.
References:
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