By Hannah Scheucher
With the whole world intently watching the roll out of COVID-19 vaccines, another development in the field of vaccines is striking headlines. The WHO set a target for production of a vaccine against malaria with 75% efficacy (the % reduction of disease in vaccinated groups compared to those who are unvaccinated) – and for the first time, clinical trials have shown that this target has been met.
Malaria is caused by the Plasmodium parasite and is transmitted by female Anopheles mosquitoes (World Health Organization, 2021). The WHO estimates that in 2019 there were 229 million cases of malaria, of which roughly 410,000 were fatal (World Health Organization, 2021). Children under the age of 5 are the most vulnerable and highly affected, making up 70% of patients, with other vulnerable groups including pregnant women and people infected with HIV/AIDS.
Malaria primarily causes fever, headache and chills which are common symptoms, sometimes making diagnosis difficult. Left untreated, infection can result in serious, often fatal illness (WHO, 2016). All Plasmodium species are first injected into the bloodstream by the female Anopheles mosquitoes during a blood meal. The injected sporozoite (a motile, spore-like stage of the malaria life-cycle) infects hepatocyte cells and develops to the merozoite form of malaria. These merozoites enter the blood-stage in which they infect erythrocyte cells and multiply asexually. Red blood cells rupture, releasing merozoites into the bloodstream to allow further erythrocyte invasion and some merozoites develop into gametocytes. Mosquitos ingest these when biting an affected individual. Finally, ingested gametocytes replicate in the midgut and travel to the salivary glands to infect the next human (Crompton, Pierce and Miller, 2010; Centre for Disease Control and Prevention, 2020). The destruction and depletion of erythrocytes is the main cause for symptoms and pathologies such as anaemia, associated organ dysfunction among others (WHO, 2016).
Currently, the best efforts to combat malaria include “vector control”- preventing mosquitoes from transmitting the parasite by blocking their access to humans. Long-lasting insecticidal nets and indoor spraying of insecticides, as well as advances in diagnostic testing abilities, have caused the malaria death rate to fall by roughly 60% since 2000 (WHO, 2016). Pharmacological treatment has also been developed, with artemisinin-based combination therapy used to cure malaria (WHO, no date). Its use has contributed to the decrease in fatalities but nevertheless, case numbers remain high.
Resistance to these methods of disease control has developed over the last few decades, aggravating occurrences and severity of malaria outbreaks (WHO, no date). Resistance to anti-malarial drugs such as artemisinin-based combination therapy is becoming more frequent. Increased travel has allowed resistant variants to invade new areas (Bloland, 2001). Adaptation of mosquito species carrying the parasite to evade vector control are also now a concern. These insects can undergo either physiological or behavioural changes to avoid eradication, and present a significant challenge to vector control (Sokhna, Ndiath and Rogier, 2013). Physiological adaptation in these malaria-spreading insects can lead to metabolic resistance via genetic mutation, allowing immunity against insecticides (Gnanguenon et al., 2015). Behavioural changes permit evasion of the insecticide entirely. For example, a mosquito may go from staying in houses after a blood meal, thereby exposing themselves to insecticides, to leaving the house, circumventing the threat (Sokhna, Ndiath and Rogier, 2013).
With the emergence of the genome-editing technology CRISPR-Cas9, scientists are investigating the use of gene drives to eliminate certain mosquito populations (Hammond et al., 2016). Gene drives are the application of technologies such as CRISPR-Cas9, to induce the biased inheritance of a gene (Champer, Buchman and Akbari, 2016). In the context of malaria prevention, this may be a recessive gene inducing sterility in female Anopheles species. However, ethical and safety concerns are limiting their implication.
As malaria has been a long-standing burden on public health, one would think that a vaccine would already be available. This is not the case and there are multiple reasons for this; Funding for vaccine development remains scarce. Compared to HIV/AIDS vaccine developments, efforts to prevent malaria receive less than 25% of funds (Crompton, Pierce and Miller, 2010). Additionally, the parasite itself is hard to target. It expresses many proteins involved in avoiding immune destruction (Gardner et al., 2002), as well as proteins with a range of antigenicity (and so the immune system has difficulty recognising the parasite) (Florens et al., 2002), and runs through different life cycles each with its own set of antigens (Moorthy, Good and Hill, 2004). Thus, with over 5300 antigens expressed in the most clinically important malaria species P. falciparum, no key targets have been identified to date that confer strong, long-lasting immune responses.
Natural immunity towards specific strains can occur in adults in areas highly plagued by the parasite (Moorthy, Good and Hill, 2004). This immunity is short-lived and does not prevent infection but rather disease outbreak. Researchers are trying to understand the underlying processes conferring natural immunity in order to exploit them for vaccine development (Crompton, Pierce and Miller, 2010). However, efforts are also being made to inhibit infection completely, conferring types of immunity that are not seen naturally.
Three main types of vaccines are currently being developed, each targeting a different life cycle of the parasite. Blood stage vaccines work, in principle, by simulating natural immunity (Crompton, Pierce and Miller, 2010). Previous experiments have strongly implicated antibodies in the natural immune response (Cohen, McGregor and Carrington, 1961). However, as it is currently unknown what antigens the antibodies specify to and the mechanisms by which they exert their anti-malarial effects, none of the developed blood-stage vaccines to date have shown efficiency in early-stage clinical trials (Crompton, Pierce and Miller, 2010). Due to genetic diversity, many therapeutic targets may also be polymorphic and therefore able to evade destruction upon selective pressure.
Other means of protection from malaria could involve blood-stage vaccines targeting the invasion of erythrocytes. The issue with this approach is that the proteins involved in the process are poorly understood, and the receptors known to be involved have multiple functionally redundant copies within the genome. A vaccine would need to induce a response against many of these to be effective (Crompton, Pierce and Miller, 2010).
Other vaccine options are transmission-blocking vaccines, designed to induce a response against antigens on gametocytes and zygotes. Some antigens expressed in these stages are not polymorphic and are therefore promising targets. The aim of this type of vaccine would be to prevent the transmission of the disease rather than protect the individual from falling ill. However, many vaccines are required to reduce overall transmission and there are concerns about prioritising this vaccination approach if no resistance is conferred to the individual. A combination of pre-erythrocytic or erythrocytic and transmission-blocking vaccines could have the capacity to overcome this issue (Crompton, Pierce and Miller, 2010).
Pre-erythrocytic vaccines act to prevent sporozoites from invading liver cells. Natural immunity exists only for blood-stages, therefore, it was initially assumed that this stage would be hard to target. In 1967, a paper describing immunity in rodents towards partially inactivated sporozoites illustrated that it was indeed possible (Nussenzweig et al., 1967). Nearly a decade later, it was found that a particular key sporozoite protein alone, the circumsporozoite protein, could induce immunisation (Nussenzweig and Nussenzweig, 1985). This paved the way for the RTS,S vaccine; this includes a fusion protein made up of the circumsporozoite protein together with a hepatitis B specific surface antigen. This fusion protein aggregates with free wild-type hepatitis B specific surface antigen (Moorthy, Good and Hill, 2004) which allows the formation of a viral particle carrying the parasitic antigen (Casares, Brumeanu and Richie, 2010). RTS,S was one of the first vaccines to show promising results, with clinical trials presenting efficacy of roughly 55% (Roxby, 2021). Recently, a new vaccine, R21/MM, was striking headlines, with promises of 77% efficacy – topping the WHO’S target of 75% (Datoo et al., 2021). R21/MM uses the same fusion protein as RTS,S but does not include free hepatitis B specific surface antigen, meaning that more circumsporozoite epitopes are free for immune system recognition thus inducing stronger and longer lasting immunity. Additionally, the new vaccine has shown to be better tolerated as compared to its predecessor.
R21/MM is being met with a lot of enthusiasm from the field. The potential for saving lives is huge, particularly because its production is also simple and cheap, facilitating large scale vaccination programmes. Cautious optimism must be taken, however, and research into the underlying mechanism of this dangerous parasite must continue to find new ways to induce long-lasting immunity.
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