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Scientific session 41

Source: TropIKA

Title of the session: Scientific session 41

Date: 6 November, 2009

Agenda item: Scientific session

Session theme: Immunology: Antibodies

Meeting room: Lenana

Chair(s):

• Daniel Dodoo, Accra
• Marita Troye-Blomberg, Stockholm

Presenters:

• Odile Puijalon, Insttut Pasteur – Paris
• George Warimwe, Kenya Medical Research Institute/Welcome Trust Research Programme
• James Tuju, Kenya Medical Research Institute/Welcome Trust Research Programme
• Eduard Rovira-Vallbona, Barcelona Centre for International Health Research
• Nnaemeka Iriemenam, Stockholm University
• Kwadwo Kusi, Biomedical Primate Research Centre (BPRC)
• Evelina Angov, US Military Malaria Vaccine Program
• Cleopatra Mugyenyi, Kenya Medical Research Institute/Welcome Trust Collaborative Programme
• Diana Quelhas, Manhica Health Research Centre
• Moses Otiende, Walter Reed Project/United States Army Medical Research Unit

TropIKA rapporteur: Dr. Tom Were

Major topics:

• Plasmodium falciparum var gene expression
• effect of IPTi-SP on acquisition of immunity to malaria
• antibody responses to AMA1 and PfEMP1 Var DBLα domains

Keywords:

• Antibodies
• IPTi-SP
• PfEMP1 DBLα
• AMA1
• seroprevalence

Scope: Nearly all the presentations focused on antibody responses to malaria in children

REPORT ON ORIGINAL SESSION

Overview

Immunological studies on candidate vaccine antigens are important in understanding immunity in African children. Antibody responses form an integral part of immunity to malaria. Several studies across Africa are focusing on elucidating antibody responses in terms of the epitopes and quality of the responses to a number of candidate blood stage antigens. These include AMA1, MSP1 and PfEMP1. The studies have focused on identifying domains and alleles in these antigens that mediate protective immunity in children. Studies in the Sudan, Senegal, Kenya and Mozambique indicate that antibody responses particularly IgG and IgM including IgG isotypes are important in mediating protection against clinical malaria in African children.

CONTEXT AND ISSUE

The evaluation of antibody responses to blood stage malaria antigens in African children in Sudan, Kenya, Senegal, and Mozambique among other countries is being undertaken. These immune-epidemiological and molecular studies will provide information on the role of PfEMP1, MSP1 and AMA1 domains in acquisition of immunity to malaria and their possible incorporation in candidate malaria vaccines.

Key facts and figures

The blood stage of the parasite is responsible for clinical manifestations of malaria. Several antigens expressed at the blood stage are being evaluated for correlation with immunity. These include MSP1, AMA1 and PfEMP1 among others. The PfEMP1 is important in mediating resetting and adherence which are associated with severe malaria. This antigen is composed of several domains. The DBLα domain is associated with protection but the seroreactivity is not clearly characterized in endemic populations of Africa.

Initiatives on the ground; experience/s derived

The methodologies ranged from seroepidemiological studies, molecular analyses of gene expression and flow cytometry studies for antibody against variant surface antigens; growth inhibition for parasite growth and immunizations using rabbits and mice.

Research Findings

Acquisition of antibody against VarO, a Plasmodium falciparum rosette-forming variant, in a Senegalese holoendemic rural setting: a high age-dependent seroprevalence (>70%) of antibodies against PfEMP1 VarO recombinant domains (NTS-DBL1α1 >>DBL2bC2 >>CIDRγ) exists in individuals from Senegal. Antibodies to VarO are associated with protection by reducing rate of clinical malaria.

Humoral immunity in Mozambican children with severe and uncomplicated malaria: Children with severe malaria have lower IgG levels to PfEMP1 DBLα, and lower IgM levels to MSP1, AMA1 and DBLα.

Antibody responses to a panel of Plasmodium falciparum malaria blood-stage antigens in relation to clinical outcome in Sudan: antibody responses to the panel of blood stage antigens showed that IgG1 and IgG3 are higher in individuals with uncomplicated malaria compared to severe malaria. Age was associated with increasing antibody levels with IgG1 dominating in children <5 years and IgG3 in children >5 years.

Heterologous prime-boost immunizations with different allele of MSP1 as strategy to overcome allele-specific immunity: an experimental Balb/C mice model has been developed to evaluate T and B cell responses induced by homologous or heterologous boosting by PfMSP142 major alleles (3D7, FVO, Camp/FUP). Heterologous boosting increased specific antibody production that inhibit parasite growth in vitro and induces both Th1 and Th2 responses.

Humoral immune response to mixed PfAMA1 alleles; multivalent PfAMA1 vaccines induce broad specificity: competition ELISA with affinity-purified cross-reactive antibodies of two different alleles showed that >80% of these antibodies were shared with other alleles. These antibodies with broad specificity are able to inhibit parasite growth in vitro.

Antibodies to an invasion-inhibitory epitope on Plasmodium falciparum Apical Membrane Antigen 1 are associated with protection from clinical disease: antibodies to AMA1 invasion non-inhibitory epitope 2C5 (52.0%) and inhibitory 1F9 epitope (20.7%) are present in the Kilifi population. Although antibodies to the inhibitory epitope are low in the population, they are associated with protection against malaria but this is lost after adjusting for age. Antibodies to the 1F9 epitope are also associated with growth inhibitory activity.

Plasmodium falciparum var gene expression is modified by host immunity: Expression of DBLα sequence tags with cys2 var genes is positively associated with severe malaria and is negatively associated with host age. The Cys2 var genes are associated with >15% protection against severe malaria and impaired consciousness.

Are antibody responses to PfEMP1 reflected by antibody responses to DBLα-tags? 50 PfEMP1 DBLα tags from field isolates and dominant were analysed for recognition by sera from children from Kilifi. The analyses showed no IgG boosting to homogenous sera but heterogeneous in some individuals, while IgM boosting was transient.

Lessons learned

There exist subgroups of PfEMP1 DBLα sequence tags in the Kilifi population based on expression cysteine residues (2,3,4 or more). The 2 cysteine (cys2) var genes are the most prevalent and are associated with impaired consciousness and severe malarial anemia. There is a higher seroprevalence to PfEMP1 domains in the Senegalese and Kenyan populations.

Issues raised, obstacles, difficulties

In the measurement of antibody responses to PfEMP1 antigens, it was not known whether antibodies from mother affected the results.

Future plans

Most of the studies were preliminary and additional analyses and experiments were still on-going.

FINDINGS AND CONCLUSIONS

From formal presentations

Public health Implications

IPTi-SP does not affect the acquisition of immunity in children and therefore its use is justified.

Knowledge gap created

Cellular responses to the PfEMP1domains need to be investigated.

From open discussions/debates

The lack of antibody responses in the Mozambique study may be due to masking of VSA antigens on the RBC.

Identified conclusions

Children with severe malaria have lower IgG levels to DBLα domain of PfEMP1 is in immunity to severe malaria.

Recommendations

• Determine cellular responses to PfEMP1 domains in terms of cytokines and cellular phenotype.

Personal observations from rapporteur

Very important presentations on PfEMP1 and acquisition of immunity.

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