Protection Induced by Plasmodium falciparum MSP142 Is Strain-Specific, Antigen and Adjuvant Dependent, and Correlates with Antibody Responses

Abstract

Vaccination with Plasmodium falciparum MSP142/complete Freund's adjuvant (FA) followed by MSP142/incomplete FA is the only known regimen that protects Aotus nancymaae monkeys against infection by erythrocytic stage malaria parasites. The role of adjuvant is not defined; however complete FA cannot be used in humans. In rodent models, immunity is strain-specific. We vaccinated Aotus monkeys with the FVO or 3D7 alleles of MSP142 expressed in Escherichia coli or with the FVO allele expressed in baculovirus (bv) combined with complete and incomplete FA, Montanide ISA-720 (ISA-720) or AS02A. Challenge with FVO strain P. falciparum showed that suppression of cumulative day 11 parasitemia was strain-specific and could be induced by E. coli expressed MSP142 in combination with FA or ISA-720 but not with AS02A. The coli42-FVO antigen induced a stronger protective effect than the bv42-FVO antigen, and FA induced a stronger protective effect than ISA-720. ELISA antibody (Ab) responses at day of challenge (DOC) were strain-specific and correlated inversely with c-day 11 parasitemia (r = −0.843). ELISA Ab levels at DOC meeting a titer of at least 115,000 ELISA Ab units identified the vaccinees not requiring treatment (noTx) with a true positive rate of 83.3% and false positive rate of 14.3 %. Correlation between functional growth inhibitory Ab levels (GIA) and cumulative day 11 parasitemia was weaker (r = −0.511), and was not as predictive for a response of noTx. The lowest false positive rate for GIA was 30% when requiring a true positive rate of 83.3%. These inhibition results along with those showing that antigen/FA combinations induced a stronger protective immunity than antigen/ISA-720 or antigen/AS02 combinations are consistent with protection as ascribed to MSP1-specific cytophilic antibodies. Development of an effective MSP142 vaccine against erythrocytic stage P. falciparum infection will depend not only on antigen quality, but also upon the selection of an optimal adjuvant component.

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

“…These two Ags have been associated with protective immunity in naturally exposed individuals (5-7), as well as proving efficacious in preclinical vaccine studies of mice (8)(9)(10) and nonhuman primates (11)(12)(13)(14). Although protective blood-stage immunity has been widely associated with Ab responses, a growing body of evidence in both animal and human studies supports a contributing role for cellular immunity (15,16).…”

“…Importantly, Abs against MSP1 and AMA1 have been shown to elicit vaccine strain-specific efficacy in nonhuman primate studies (12,14), as well as most recently in humans in the case of a monovalent 3D7 strain AMA1 protein/adjuvant vaccine tested in Malian children (27). Attempts to address this issue of antigenic polymorphism have involved the development of multivalent vaccine formulations containing multiple allelic variants of the MSP1 or AMA1 target Ag (28)(29)(30) or artificial diversity covering consensus sequences (31).…”

Allele Specificity of Gamma Interferon Responses to the Carboxyl-Terminal Region of Plasmodium falciparum Merozoite Surface Protein 1 by Kenyan Adults with Naturally Acquired Immunity to Malaria

“…The 19-kDa fragment of MSP1 contains the major B-cell epitopes (18), the recognition of which is enhanced by T-helper epitopes in the 33-kDa fragment (1). Antibodies to MSP1 19 that interfere with RBC invasion by merozoites are one of several possible mechanisms by which naturally acquired immunity and experimental MSP1 vaccines may mediate protection against blood stage infection (27,34). Studies of primates and mice immunized with MSP1 and more limited observations of residents of areas in which P. falciparum is endemic who have naturally acquired immunity and malaria-naïve human volunteers vaccinated with MSP1 42 suggest that T-cell responses to MSP1 are driven primarily by epitopes within the shed MSP1 33 fragment and that gamma interferon (IFN-␥) is important for optimal protective immunity (20,23,44,46).…”

Immunogenicity of the Merozoite Surface Protein-1 (Msp-1) of Human Plasmodium Sp.

“…A significantly lower parasitemic level was detected in the rhesus monkeys immunized with E. coli-expressed P. vivax MSP-1 42 compared to the negative control group upon a challenge with P. cynomolgi, a P. vivax-closely related Plasmodium sp., blood stage parasites (49,50). On the other hand, A. nancymai vaccinated with E. coli-expressed P. falciparum MSP-1 42 was highly protected during a lethal P. falciparum challenge (51)(52)(53), and the protective effect was stronger than the baculovirus-expressed P. falciparum MSP-1 42 (54). Moreover, specific antibodies and antigenspecific T-cell responses with the production of IFN-γ were also detected in M. mulatta which were immunized with DNA plasmid encoding P. falciparum MSP-1 42 (55).…”