Impact of pre-existing MSP142-allele specific immunity on potency of an erythrocytic Plasmodium falciparum vaccine

Abstract

BackgroundMSP1 is the major surface protein on merozoites and a prime candidate for a blood stage malaria vaccine. Preclinical and seroepidemiological studies have implicated antibodies to MSP1 in protection against blood stage parasitaemia and/or reduced parasite densities, respectively. Malaria endemic areas have multiple strains of Plasmodium falciparum circulating at any given time, giving rise to complex immune responses, an issue which is generally not addressed in clinical trials conducted in non-endemic areas. A lack of understanding of the effect of pre-existing immunity to heterologous parasite strains may significantly contribute to vaccine failure in the field. The purpose of this study was to model the effect of pre-existing immunity to MSP142 on the immunogenicity of blood-stage malaria vaccines based on alternative MSP1 alleles.MethodsInbred and outbred mice were immunized with various recombinant P. falciparum MSP142 proteins that represent the two major alleles of MSP142, MAD20 (3D7) and Wellcome (K1, FVO). Humoral immune responses were analysed by ELISA and LuminexTM, and functional activity of induced MSP142-specific antibodies was assessed by growth inhibition assays. T-cell responses were characterized using ex vivo ELISpot assays.ResultsAnalysis of the immune responses induced by various immunization regimens demonstrated a strong allele-specific response at the T cell level in both inbred and outbred mice. The success of heterologous regimens depended on the degree of homology of the N-terminal p33 portion of the MSP142, likely due to the fact that most T cell epitopes reside in this part of the molecule. Analysis of humoral immune responses revealed a marked cross-reactivity between the alleles. Functional analyses showed that some of the heterologous regimens induced antibodies with improved growth inhibitory activities.ConclusionThe development of a more broadly efficacious MSP1 based vaccine may be hindered by clonally imprinted p33 responses mainly restricted at the T cell level. In this study, the homology of the p33 sequence between the clonally imprinted response and the vaccine allele determines the magnitude of vaccine induced responses.

High levels of IgG3 anti ICB2-5 in Plasmodium vivax-infected individuals who did not develop symptoms

“…Association between IgG3 antibodies and clinical protection from malaria was previously reported for P. falciparum antigens, such as MSP1 42 , MSP1 19 , AMA-1, MSP2 and MSP3 [ 22 , 23 , 40 - 44 ]. Similarly, IgG3 immune response to P. falciparum MSP1 (N-terminus) was associated with prolonged periods without malarial infection [ 45 ].…”

Adjuvants in the Driver’s Seat: How Magnitude, Type, Fine Specificity and Longevity of Immune Responses Are Driven by Distinct Classes of Immune Potentiators

“…A number of vaccines which work well in industrialized countries (or which were successfully tested in healthy volunteers from developed countries) failed when given to populations in developing countries [ 211 ]. Numerous reasons have been identified, including pre-existing immunity to other strains of the same pathogen in the case of a malaria vaccine [ 212 ], and poor nutritional status, or co-infections with pathogens such as intestinal worms which bias immune responses towards a Th2-profile. The finding that several of these factors can be overcome by a strong vaccine such as the licensed measles vaccine suggests that vaccines for these recipients may simply need to be reformulated with sufficiently strong immune stimulators to provide the same benefit [ 213 ].…”

Enhanced acquired antibodies to a chimeric Plasmodium falciparum antigen; UB05‐09 is associated with protective immunity against malaria

“…Natural immunity against malaria is mediated in part by antibodies directed against the blood stage parasite, as demonstrated by passive transfer experiments of immunoglobulins . There are likely many target antigens that mediate protective immunity; however, their identification is obscured by the presence of malaria‐specific antibodies that do not necessarily correlate with immune protection.…”