RNA Therapeutics: The World’s First mRNA Malaria Vaccine

Malaria represents one of the greatest unmet clinical needs in the world. In the last decade, research has been ongoing to develop effective preventative methods and effective treatment to reduce the risk of severe illness, which typically occurs in children. With only one malaria vaccine on the market, the industry is beginning to shift its approach towards the mRNA platform as a potential vaccine, which could be safer and more effective in the long-term. 

Introduction 

Malaria is a life threatening disease caused by the transmission of a parasite via infected female mosquitos. Despite the disease being preventable and curable, there were an estimated 229 million cases of malaria worldwide in 2019. According to WHO, the WHO African Region carries a disproportionately high proportion and accounts for 94% of the global malaria cases and deaths in 2019. 

In the majority of cases, malaria is transmitted through female Anopheles mosquitoes who typically targets prey between dusk and dawn. These mosquitoes are known as vector species as they are the vehicle through which the parasite is transmitted. While there are approximately 400 different species of Anopheles Mosquitoes, around 30 are malaria vectors of significant importance. 

Significant progress has been made in the prevention of malaria over the last decade, with the total funding for malaria control and elimination reaching an estimated US $3 billion in 2019. Prevention techniques have been the main way to prevent and reduce malaria transmission and primarily comprise insecticide-treated mosquito nets and antimalarial drugs.

Insecticide-treated mosquito nets have proven to significantly reduce the risk of malaria transmission, especially so in the African population. According to WHO, in 2019, an estimated 46% of all people at risk of malaria in Africa were protected by an insecticide-treated net, compared to 2% in 2000.

Despite these interventions, malaria continues to pose a significant risk across the globe and represents an unmet clinical problem with a relatively high number of cases. The rise of antimalaria drug resistance is a recurring problem that continues to emerge in high risk regions, posing a problem for the prevention of the disease which can be fatal in young children. 

The development of a vaccine for malaria has been a key focus for the last five years, in order to significantly reduce the transmission of malaria and life-threatening complications. While the insecticide nets provide some protection against the mosquitos, these nets are not always available to access and also do not protect against severe disease. Furthermore, compared to antimalarial drugs, a malaria vaccine would offer more long-term protection.

Current progress

RTS,S/AS01 vaccine

To date, the only malaria vaccine on the market is GSK’s Mosquirix, also known as RTS,S/AS01 vaccine. The RTS,S/AS01 vaccine acts against the most deadly and prevalent malaria parasite in Africa – P. falciparum. 

In comparison with other vaccines, the RTS,S demonstrates a higher level of immunity with a booster dose than the primary vaccination. The studies are ongoing for this vaccine but show significant promise. A recent clinical trial by Oxford University’s Jenner Institute showed that its experimental RTS,S/AS01 malaria shot “could be around 77% effective against the disease”.

Currently, the RTS,S/AS01E malaria vaccine is the most advanced so far, having demonstrated promising results in the latest phase 3 clinical trials – specifically, a significant reduction in malaria (and life-threatening malaria) in young african children. The vaccine was tested in a phase 3 clinical trial of a three-dose immunisation schedule, with a fourth dose 18 months after the primary vaccination. According to a recent publication, the booster dose partly restored the waning vaccine efficacy which has been seen in infants rather than children.   

In a recent publication, it has been highlighted that WHO has recognised the potential of the RTS,S/AS01 vaccine for public health and “acknowledged the need for further evaluation before individual countries consider adopting its use in routine vaccination schedules”. 

Whole Sporozoite Vaccines (WSV)

Another promising malaria vaccine candidate include the whole sporozoites – sporozoites are a defined as a “a motile spore-like stage in the life cycle of some parasitic sporozoans (e.g. the malaria organism), that is typically the infective agent introduced into a host”.

Experimental malaria vaccines using whole sporozoites have shown to produce an increased range of immunogens in comparison with subunit vaccines across at least two life cycle stages of the parasite. Immunogens simply refers to a specific type of antigen which elicits an immune response. 

One of the desired properties of these vaccines has been that WSVs can elicit immunity without causing the clinical symptoms of malaria. However, there remain a number of challenges for this vaccine including the manufacturing of large quantities of sporozoites for vaccine commercialisation. In addition, a recent WSV failed to provide sufficient protection in pre-exposed individuals. 

Therefore, it has been suggested that improved dosing strategies or perhaps an alternative vaccine approach is needed for populations in malarious regions. 

BioNTech mRNA vaccines

Despite the success of RTS,S vaccines so far, a number of limitations including sterile efficacy and duration of protection, have seen the industry look for alternative approaches for malarial vaccination.  

The recent success with mRNA-based COVID-19 vaccines has highlighted the advantages of mRNA-based platforms for vaccinations. The greater specificity of targeting, scalable manufacturing and eliciting of a strong immune response has opened the door for utilising these for malarial vaccines. 

BioNTech aims to develop the world’s first mRNA-based vaccine by the end of 2022, following the launch of it’s ‘Malaria Project’.  The development of a safe, effective mRNA vaccine is one of two objectives for the malaria project. While this vaccine will still rely on P. falciparum’s circumsporozoite protein to generate an immune response, this approach will use mRNA to synthesise the protein to trigger an immune response (like the COVID-19 mRNA vaccine). The vaccine will also utilise a lipid nanoparticle as a vector for the mRNA material. 

The second objective of the malaria project is the development of “sustainable vaccine production and supply solutions on the African continent”. 

A recent preclinical study has already demonstrated sterilising immunity against malaria. Evaluation of PfCSP (circumsporozoite protein) mRNA as a malaria vaccine found that the candidate was found to be well expressed in a number of preclinical models including mammalian cells, immunogenic in mice, and protective in both homologous and heterologous transgenic rodent models.

A quote from the lead author in a recent article supported the potential of mRNA-based malarial vaccines, highlighting that “while more work remains before clinical testing, these results are an encouraging sign that an effective, mRNA-based malaria vaccine is achievable.”

The success of the mRNA-based COVID-19 vaccine and the significant investment in RNA research supports the viability of developing a safe and effective vaccine for malaria with long-term protection for those most at risk. The advancement of an mRNA-based malarial vaccine is dependent on further preclinical studies and hopefully, future human clinical trials.

Charlotte Di Salvo, Former Editor & Chief Medical Writer
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