Growth-inhibitory antibodies are not necessary for protective immunity to malaria infection

Autor: Lina Wang, Ross L. Coppel, Magdalena Plebanski, Casilda G Black, E. Elsa Herdiana Murhandarwati, Harini D De Silva, Charles Wai Chung Ma
Rok vydání: 2009
Předmět:
Zdroj: Infection and immunity. 78(2)
ISSN: 1098-5522
Popis: Infection of humans by Plasmodium falciparum is the cause of severe morbidity and mortality, leading to millions of deaths annually, predominantly in children under 5 years of age. Invasion of red blood cells by asexual-stage parasites is the stage of infection associated with clinical signs and symptoms. Much effort has been directed to the development of a subunit vaccine against asexual blood stages. However, progress has been slow and is hampered by the large number of candidate antigens and alternative modalities of immunization, the complexities of antigen combinations, and the high cost of clinical trials involving good manufacturing practices recombinant protein. There is considerable uncertainty as to how to prioritize the large number of new candidate vaccine molecules revealed by genomic, transcriptomic, and proteomic studies (5). Attention has focused on properties such as location and accessibility to antibodies, efficacy in model systems, sero-epidemiological correlates in clinically immune humans, and coding sequence conservation. Production of antibodies capable of inhibiting parasite growth in vitro by sera raised in experimental animals appears to be a desirable property, but it is not clear whether this should be a prerequisite for selection as a vaccine candidate (27, 36). In particular, there are limited data as to whether this ability correlates closely with protection in model systems. We set out to examine this important relationship in a well-regarded host-parasite system using one of the leading subunit vaccine candidates. Merozoite surface protein 1 (MSP1) is one of the proteins involved in red blood cell invasion by the parasite, and the 19-kDa C-terminal fragment of this protein (MSP119) is a leading vaccine candidate. Studies in rodent and nonhuman primate models have shown that passive transfer with anti-MSP119 antibodies or immunization with recombinant MSP119 can provide significant protection against lethal challenge (9, 21, 25, 37). Antibodies to MSP119, either affinity purified from immune human sera or monoclonal or polyclonal experimental sera, are capable of inhibiting parasite growth in vitro (3, 12, 32). In field studies, naturally acquired anti-MSP119 antibodies have been shown to be associated with protection from P. falciparum infection (1, 13, 33). However, the correlation between MSP119-specific antibodies and in vivo protection remains unclear. For example, high levels of anti-MSP119 antibodies passively transferred to mice or monkeys were not invariably associated with protection against parasite infection (15, 17), and a lack of correlation between MSP119-specific antibodies in immune humans and their clinical immunity has been reported in several field settings (11, 34). In addition, antibodies directed against MSP119 have been shown to have variable effects on parasite growth, ranging from inhibition to enhancement (16, 28). These findings point out the limitations of using conventional antibody-based detection methods, such as an enzyme-linked immunosorbent assay (ELISA), for the evaluation of the immune status of a subject induced either by natural exposure or by vaccination. In an attempt to elucidate the relationship between specific antibody levels and functional capacity, O'Donnell et al. used an allelic replacement approach to generate a P. falciparum parasite line that expresses the MSP119 region from the distantly related rodent malaria species Plasmodium chabaudi (30). By comparing the growth rate of this transgenic parasite line with that of a matched transgenic line that expresses the endogenous P. falciparum MSP119, the fraction of inhibitory activity attributable to MSP119-specific antibodies can be determined. Using this assay, O'Donnell et al. reported that MSP119-specific antibodies are a major component of the total inhibitory response in the serum samples from long-term residents living in areas where malaria is endemic in Papua New Guinea (29). Further analysis of a longitudinal cohort of Kenyans indicated that the presence of growth-inhibitory antibodies to MSP119 correlated with the presence of clinical immunity to malaria (19). However, there is uncertainty about whether this can serve as an accurate correlate of protection (6). The availability of this transgenic parasite line also provides a potential tool to measure MSP119-specific inhibitory antibodies induced by immunization with P. chabaudi MSP119 and assess their possible correlation with the protective status of the immunized mice. However, P. chabaudi is not widely used as a model in MSP119-based vaccine trials, as control of P. chabaudi infection can be achieved by T-cell-dependent mechanisms (22, 24). P. yoelii is considered a superior model, because immunity to this rodent malaria species is predominantly antibody mediated, similar to P. falciparum infection (7, 17, 18, 24, 35). In the present study, we used allelic replacement to generate a P. falciparum parasite line that expresses the MSP119 region from P. yoelii. This new transgenic line allows us to address the relationship between induction of antibodies capable of inhibiting parasite invasion and protective efficacy in a well-studied and tractable experimental model.
Databáze: OpenAIRE
Externí odkaz: