The challenges of a circumsporozoite protein-based malaria vaccine

ABSTRACT

Introduction

A safe and effective vaccine will likely be necessary for the control or eradication of malaria which kills 400,000 annually. Our most advanced vaccine candidate to date is RTS,S which is based on the Plasmodium falciparum circumsporozoite protein (PfCSP) of the malaria parasite. However, protection by RTS,S is incomplete and short-lived.

Areas covered

Here we summarize results from recent clinical trials of RTS,S and critically evaluate recent studies that aim to understand the correlates of protective immunity and why vaccine-induced protection is short-lived. In particular, recent systems serology studies have highlighted a key role for the necessity of inducing functional antibodies. In-depth analyses of immune responses to CSP in both mouse models and vaccinated humans have also highlighted difficulties in generating the maintaining high-quality antibody responses. Finally, in recent years biophysical and structural studies of antibody binding to PfCSP have led to a better understanding of how highly potent antibodies can block infection, which can inform vaccine design.

Expert Opinion

We highlight how both structure-guided vaccine design and a better understanding of the immune response to PfCSP can inform a second generation of PfCSP-based vaccines stimulating a broader range of protective targets within PfCSP.

KEYWORDS:

• Malaria vaccine
• circumsporozoite protein
• RTS,S
• Bcells
• antibodies
• Tcells
• structure-guided vaccine design

Acknowledgments

Work in the Cockburn laboratory is supported by the National Health and Medical Research Council (Australia) GNT 1158404.

Declaration of interest

I. A. Cockburn receives funding from the National Health and Medical Research Council (Australia) in the form of funding provided to the Cockburn Laboratory. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that their laboratory is working to develop T-cell vaccines for malaria with NIH support; that they have filed patents through the University of Washington based on some of this work; lastly that they have founding equity in a vaccine company (Sound Vaccines). All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

DC and IAC drafted and revised the manuscript.

Article highlights

• Natural exposure to parasites does not induce sterile protective immunity, but immunization with RAS can do so, a key target of protective immunity induced by SPZ is CSP.

• CSP consists of N and C terminal domains which are believed to be important for recognition and invasion of hepatocytes. These domains are separated by a repeating domain. Cleavage at the junction between the N terminal domain and the repeat exposes the C terminal domain facilitating binding to hepatocytes.

• The repeat domain is the target of protective antibodies but has also been proposed to be an immunological ‘decoy’ that induces strong immune responses at the expense of other potentially more protective responses to other domains of PfCSP and other antigens.

• The most advanced vaccine candidate for malaria is RTS,S that is based on a truncated PfCSP molecule containing the immunodominant repeat region which is the target of antibodies and the C terminal domain which contains T-cell epitopes.

• In Phase III clinical trials in malaria-endemic areas RTS,S confers ~50% efficacy against severe disease for < 1year.

• Both anti-PfCSP antibody amount and quality are important for protection. In particular antibodies that fix complement, bind Fc-gamma 3 receptors and interact with cellular components of the innate immune responses are important for protection.

• Recent studies have aimed to improve PfCSP-based vaccines through structure-based-vaccine design. These studies have highlighted a potentially important role for antibodies that target CSP at or close to the junction between the N-terminal domain and the repeat domain.

• PfCSP may not induce efficient germinal center B cell responses limiting the potency of individual antibodies

• Antibody feedback can restrict the rise in repeat specific titers by booster doses, but allows subdominant B cells targeting other epitopes to expand

• Improved PfCSP-based vaccines will need an improvement in the quality and longevity of the antibody responses they generate.

Additional information

Funding

This paper was not funded.