Abstract
A low proportion of P. vivax-exposed individuals acquire protective strain-transcending neutralizing IgG antibodies that are able to block the interaction between the Duffy binding protein II (DBPII) and its erythrocyte-specific invasion receptor. In a recent study, a novel surface-engineered DBPII-based vaccine termed DEKnull-2, whose antibody response target conserved DBPII epitopes, was able to induce broadly binding-inhibitory IgG antibodies (BIAbs) that inhibit P. vivax reticulocyte invasion. Toward the development of DEKnull-2 as an effective P. vivax blood-stage vaccine, we investigate the relationship between naturally acquired DBPII-specific IgM response and the profile of IgG antibodies/BIAbs activity over time. A nine-year follow-up study was carried-out among long-term P. vivax-exposed Amazonian individuals and included six cross-sectional surveys at periods of high and low malaria transmission. DBPII immune responses associated with either strain-specific (Sal1, natural DBPII variant circulating in the study area) or conserved epitopes (DEKnull-2) were monitored by conventional serology (ELISA-detected IgM and IgG antibodies), with IgG BIAbs activity evaluated by functional assays (in vitro inhibition of DBPII-erythrocyte binding). The results showed a tendency of IgM antibodies toward Sal1-specific response; the profile of Sal1 over DEKnull-2 was not associated with acute malaria and sustained throughout the observation period. The low malaria incidence in two consecutive years allowed us to demonstrate that variant-specific IgG (but not IgM) antibodies waned over time, which resulted in IgG skewed to the DEKnull-2 response. A persistent DBPII-specific IgM response was not associated with the presence (or absence) of broadly neutralizing IgG antibody response. The current study demonstrates that long-term exposure to low and unstable levels of P. vivax transmission led to a sustained DBPII-specific IgM response against variant-specific epitopes, while sustained IgG responses are skewed to conserved epitopes. Further studies should investigate on the role of a stable and persistent IgM antibody response in the immune response mediated by DBPII.
Highlights
Plasmodium vivax is characterized by dormant liver stage hypnozoite-parasites responsible for high frequency of relapses [1], which imposes a challenge for the current policies of malaria control and elimination
In an Amazonian community exposed to low levels intermittent malaria transmission, we sought to investigate the relationship between anti-Duffy binding protein II (DBPII) IgM and IgG antibody responses reactive with strain-specific (Sal1) or strain-transcending (DEKnull-2) immune responses [22]
The majority of high IgM responses (RI> 3) were no longer detected in the low transmission period, the results suggest that individuals in P. vivax-endemic Amazonian communities were able to sustain their DBPII-specific IgM antibody responses
Summary
Plasmodium vivax is characterized by dormant liver stage hypnozoite-parasites responsible for high frequency of relapses [1], which imposes a challenge for the current policies of malaria control and elimination. Naturally acquired DBPII antibodies tend to be biased towards strain-specific responses [11,12,13], our project identified the epitope targets of protective neutralizing IgG antibody response to overlap conserved residues essential for receptor binding and DBP dimerization [12, 14,15,16,17,18,19]. A low proportion of P. vivax-exposed individuals acquire protective strain-transcending neutralizing IgG antibodies that are able to block the interaction between the Duffy binding protein II (DBPII) and its erythrocyte-specific invasion receptor. A novel surface-engineered DBPII-based vaccine termed DEKnull-2, whose antibody response target conserved DBPII epitopes, was able to induce broadly binding-inhibitory IgG antibodies (BIAbs) that inhibit P. vivax reticulocyte invasion. Toward the development of DEKnull-2 as an effective P. vivax blood-stage vaccine, we investigate the relationship between naturally acquired DBPII-specific IgM response and the profile of IgG antibodies/BIAbs activity over time
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