Comparison of Biological Activity of Human Anti-Apical Membrane Antigen-1 Antibodies Induced by Natural Infection and Vaccination

Malaria Vaccine Development Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
The Journal of Immunology (Impact Factor: 4.92). 01/2009; 181(12):8776-83. DOI: 10.4049/jimmunol.181.12.8776
Source: PubMed


Vaccines represent a significant potential means of decreasing global morbidity and mortality due to malaria. Clinical trials in the United States with Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) showed that the vaccine induced biologically active Abs judged by an in vitro parasite growth inhibition assay (GIA). However, the same vaccine in Malian adults did not increase biological activity, although it elevated ELISA titers. Because GIA has been used to evaluate the biological activity of Abs induced by blood stage malarial vaccine candidates, we explored this discrepancy in this study. We affinity purified AMA1-specific Abs from both U.S. vaccinees and nonvaccinated individuals living in a malaria-endemic area of Mali and performed ELISA and GIA. Both AMA1-specifc Abs induced by vaccination (U.S.) and by natural infection (Mali) have comparable biological activity in GIA when the ELISA titer is normalized. However, a fraction of Malians' IgG that did not bind to AMA1 protein (Mali-non-AMA1 IgG) reduced the biological activity of the AMA1 Abs from U.S. vaccinees; in contrast, U.S.-non-AMA1 IgGs did not show a reduction of the biological activity. Further investigation revealed that the reduction was due to malaria-specific IgGs in the Mali-non-AMA1 IgGs. The fact that both U.S.- and Mali-AMA1-specific Abs showed comparable biological activity supports further development of AMA1-based vaccines. However, the reduction of biological activity of AMA1-specific Ab by other malaria-specific IgGs likely explains the limited effect on growth-inhibitory activity of Abs induced by AMA1 vaccination in Malian adults and may complicate efforts to develop a blood stage malaria vaccine.

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    • "In the case of the AMA1 vaccinated group, GIA was associated with anti-AMA1 ELISA titer both pre- and post-CHMI consistent with the notion that the measurable activity was due to these antibodies as opposed to de novo responses against other blood-stage parasite antigens. A previous AMA1 vaccine study in Mali suggested that malaria-specific non-AMA1 IgGs can interfere with GIA mediated by AMA1-specific IgGs [51]. In our case however, there was no obvious induction of de novo antibodies against other antigens during the CHMI that interfered with AMA1-associated GIA. "
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    ABSTRACT: The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite - MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors - ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses.
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    • "Such antibodies would be expected to result in invasion/growth inhibition of blood stage Plasmodium falciparum (Pf) parasite in vitro, as measured by a growth inhibition assay (GIA). This assay quantifies antibodymediated activity against blood stage parasites by measuring parasite growth in the presence of malaria exposed plasma in comparison with non-malaria exposed control plasma and thought to be mediated primarily by IgG (Crompton et al., 2010; Miura et al., 2008). GIA has been used in vaccine studies (Darko et al., 2005; Singh et al., 2003, 2006; Dicko et al., 2007; Thera et al., 2006; Withers et al., 2006) and found in persons with naturally acquired malaria immunity (Bolad et al., 2003; Dent et al., 2008; Perraut et al., 2005). "
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    • "Efforts are underway to develop AMA-1 vaccines that induce allele-cross-reactive responses to overcome this limitation (Remarque et al., 2008; Dutta et al., 2010). However, the success of any AMA-1 based malaria vaccines is also impeded by the fact that sera from malariaendemic areas appear to contain antibodies capable of blocking the activity of AMA-1 specific antibodies (Miura et al., 2008). "

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