Polymorphism in liver-stage malaria vaccine candidate proteins: immune evasion and implications for vaccine design

ABSTRACT

The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver-stage infections. The parasite also uses ‘surgical strike’ strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes.

KEYWORDS:

• Malaria
• pre-erythrocytic
• antigen
• polymorphism
• cross-reactivity
• immune evasion
• vaccine
• antagonism
• immune interference

Financial & competing interests disclosure

M Plebanski is a National Health and Medical Research Council (NHMRC) Senior Fellow. M Plebanski is also a Director of PX Biosolutions Pty Ltd. K Wilson is recipient of an Australian Postgraduate Award (APA) scholarship. 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.

Key issues

• Malaria vaccines targeting the pre-erythrocytic stage of malaria infection aim to prevent progression to the clinically active blood stage of infection

• Malaria parasites can affect vaccine efficacy by promoting immunosuppression through mechanisms including induction of immunosuppressive cytokines, impaired DC function, and altered Treg homeostasis

• Polymorphism is another mechanism the malaria parasite has evolved to evade immunity

• Naturally occurring polymorphic variants of a T cell epitope region are called APLs

• Even single amino acid changes in APLs can lead to loss of binding to MHC, lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes

• Pre-erythrocytic malaria vaccine candidate antigens such as CS protein and TRAP are polymorphic, posing a potential challenge for vaccine design

• Natural variants of CS protein employ APL antagonism to provide a survival advantage to the parasite in individuals infected with more than one parasite strain

• The effect of natural polymorphism on T cell immunity to pre-erythrocytic antigens other than CS protein has not been investigated.

• Vaccines have nontargeted effects on susceptibility to other infections, possibly via the induction of cross-reactive T cells against non-vaccine pathogens, but it is not known whether malaria vaccines induce non-vaccine-related T cell responses

• Animal models provide a system for studying cross-reactivity and antagonism of variant epitopes in diverse antigen candidates in order to find strategies to overcome immune evasion when designing vaccines that target highly polymorphic regions