Mosquirix (RTS,S)

A Novel Vaccine for the Prevention of Plasmodium falciparum Malaria

Kyle J Wilby BSP ACPR, PharmD; Tim TY Lau PharmD ACPR FCSHP; Samuel E Gilchrist MSc (Pharm), PhD; Mary HH Ensom PharmD FASHP FCCP FCSHP FCAHS

Disclosures

The Annals of Pharmacotherapy. 2012;46(3):384-393. 

In This Article

Pharmacology and Biopharmaceutics

The Ideal Malaria Vaccine

The ideal malaria vaccine would provide immunity against the parasite upon entry into the body and before infection of the liver, minimizing development of clinical disease and preventing hepatocellular damage.[3] However, this initial stage of entry in the parasite life cycle is short-lived (~30 minutes), and consequently, immune responses are not rapid enough to prevent infection. Targeting the posthepatic stage would be a more viable option, but would not avert infection of the liver and subsequent hepatocyte damage. Considering these limitations, a feasible alternative would be to target the parasite during both pre-hepatic and hepatic stages to prevent clinical disease.

Antigen

Identification of an antigen capable of eliciting effective immune response is fundamental for vaccine efficacy, especially when the parasite itself is not highly immunogenic. In malaria vaccine studies, the parasitic circum-sporozoite (CS) protein is the most dominant surface antigen of the initial pre-erythrocytic phase and is expressed on sporozoites during invasion of hepatocytes[7] (Figure 1). The CS protein is involved in the binding process of sporozoite to liver cells and capable of inducing immune responses during both pre-hepatic and hepatic stages. Each Plasmodium species (eg, P. falciparum) expresses a variant of the CS protein. By targeting the CS protein, clinical disease could conceivably be prevented and hepatocyte damage minimized.[3]

Unfortunately, early vaccine studies using P. falciparum CS protein as antigen showed discouraging results due to low efficacy and immunogenicity. However, when combined with hepatitis B surface antigen (HBsAg) as a matrix carrier, the combination successfully induced CS antibody production in mice. When HBsAg is present at sufficient concentrations, viral particles spontaneously assemble without DNA, resulting in a noninfectious immunogenic construct. Coadministration enables activation of the immune system and increases antibody response to the CS protein. The CS protein has since been further modified to include the entire C-terminal region of the protein containing specific T-cell epitopes, which are required for inducing T-cell responses and maximizing antigenicity. This forms the basis for the RTS,S vaccine, which consists of 25% fusion protein RTS and 75% wild-type HBsAg (S) antigen, and is effective only against P. falciparum disease.[3]

Adjuvant

Adjuvants are used in vaccine technology to enhance activation of immune response and provide antigen stabilization by overcoming tolerance mechanisms to stimulate production of antibodies against a selected antigen. These adjuvants are critical for augmenting immunogenicity of RTS,S, as the CS protein alone does not result in sustained immune responses.[3]

GSK has developed proprietary adjuvant systems (AS) for use with RTS,S. Two major systems studied are AS02 and AS01. AS02 is a squalene-in-water emulsion containing monophosphoril lipid A and saponin from the bark of Quillaja saponaria, which is thought to envelop components of the vaccine through hydrophobic interactions. In contrast, the AS01 formulation replaces the oil-in-water emulsion components with liposomes, but contains the same amounts of monophosphoril lipid A and Quillaja saponaria as in AS02.

A Phase 2 trial in Ghanaian children compared immune responses between AS02D and AS01E.[8] Despite similar safety profiles, AS01E appeared to have greater immunogenicity when compared to AS02D. Consequently, AS01 was selected as the adjuvant system for Phase 3 trials.[9]

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