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Infection and Immunity, April 2003, p. 2296, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2296.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Specificity and Cross-Reactivity of Plasmodium falciparum Variant Surface Antigen-Specific Antibody Responses


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In their recent study, Chattopadhyay et al. (5) reported the acquisition of agglutinating antibodies that cross-react with variant surface antigens (VSA) expressed by genotypically distinct parasite isolates following single episodes of monoclonal Plasmodium falciparum malaria in adults living in an area of low transmission intensity in India. This is in contrast to previous studies from areas of intense parasite transmission in Africa showing that VSA antibodies have a high degree of specificity for the VSA expressed by the infecting isolate (4, 9, 12) and that VSA-specific antibodies predominantly recognize variant-specific rather than cross-reactive epitopes (10). However, the study agrees well with data from Sudan, where it was found that individuals acquired antibodies to VSA expressed by heterologous parasite isolates after a single disease episode (7, 8). As in the study from India, the effect was quite marked, since a single or a few monoclonal malaria attacks can induce production of immunoglobulin G (IgG) that is reactive with VSA expressed by 15 to 20% of heterologous parasite isolates (T. G. Theander et al., unpublished data).

What then is the basis of the relative cross-reactivity of VSA-specific IgG in India and Sudan compared to the variant-specific responses observed in the Gambia, Ghana, and Kenya? David Roberts (13) suggests that the PfEMP1 repertoire of Indian parasites may be more restricted than in tropical Africa, but the above-mentioned data from Sudan are at variance with such a hypothesis. Furthermore, VSA-specific plasma antibodies are generally able to recognize parasites from distant geographical regions well (1, 6; M. A. Nielsen et al., unpublished data).

Instead, we propose that the specificity-cross-reactivity balance is determined by transmission intensity through its impact on acquisition of protective immunity. We and others have shown that antibody recognition of VSA varies markedly between different parasite isolates (2, 3, 11). Thus, some VSA are recognized at high titers by most parasite-exposed individuals, whereas other VSA are only poorly recognized by a minority of people. Importantly, the former type of VSA tend to be expressed by parasites infecting young children with little protective immunity and tend to cause severe disease, whereas the opposite is true for parasites expressing the latter type (2, 3, 11). It thus appears that parasites expressing common VSA are at a selective advantage in nonimmune patients but that the balance is gradually tipping in favor of rare VSA with the acquisition of protective immunity. This hypothesis would explain the long-standing but unresolved observation that immunity to severe disease develops much more rapidly than immunity to parasitemia per se. If—as seems likely—the common VSA are more conserved (and cross-reactive) among isolates than are rare VSA, the differences between the above-mentioned data from India and Sudan on the one hand and the Gambia, Ghana, and Kenya on the other probably reflect differences in seasonality and intensity of malaria transmission—and hence the immune status of patients—more than anything else. Studies such as those by Chattopadhyay et al. (5) emphasize the continued need for field-based immunology studies in a wide variety of epidemiological settings.


   FOOTNOTES
 
Ed. Note: The authors of the published article declined to respond.


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1. Aguiar, J. C., G. R. Albrecht, P. Cegielski, B. M. Greenwood, J. B. Jensen, G. Lallinger, A. Martinez, I. A. McGregor, J. N. Minjas, J. Neequaye, M. E. Patarroyo, J. A. Sherwood, and R. J. Howard. 1992. Agglutination of Plasmodium falciparum-infected erythrocytes from East and West African isolates by human sera from distant geographic regions. Am. J. Trop. Med. Hyg. 47:621-632.
2. Bull, P. C., M. Kortok, O. Kai, F. Ndungu, A. Ross, B. S. Lowe, C. I. Newbold, and K. Marsh. 2000. Plasmodium falciparum-infected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age. J. Infect. Dis. 182:252-259.[CrossRef][Medline]
3. Bull, P. C., B. S. Lowe, M. Kortok, and K. Marsh. 1999. Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variants. Infect. Immun. 67:733-739.[Abstract/Free Full Text]
4. Bull, P. C., B. S. Lowe, M. Kortok, C. S. Molyneux, C. I. Newbold, and K. Marsh. 1998. Parasite antigens on the infected red cell are targets for naturally acquired immunity to malaria. Nat. Med. 4:358-360.[CrossRef][Medline]
5. Chattopadhyay, R., A. Sharma, V. K. Srivastava, S. S. Pati, S. K. Sharma, B. S. Das, and C. E. Chitnis. 2003. Plasmodium falciparum infection elicits both variant-specific and cross-reactive antibodies against parasite surface antigen variants. Infect. Immun. 71:597-604.[Abstract/Free Full Text]
6. Fried, M., F. Nosten, A. Brockman, B. T. Brabin, and P. E. Duffy. 1998. Maternal antibodies block malaria. Nature 395:851-852.[CrossRef][Medline]
7. Giha, H. A., T. Staalsoe, D. Dodoo, I. M. Elhassan, C. Roper, G. M. Satti, D. E. Arnot, T. G. Theander, and L. Hviid. 1999. Nine-year longitudinal study of antibodies to variant antigens on the surface of Plasmodium falciparum-infected erythrocytes. Infect. Immun. 67:4092-4098.[Abstract/Free Full Text]
8. Giha, H. A., T. Staalsoe, D. Dodoo, I. M. Elhassan, C. Roper, G. M. H. Satti, D. E. Arnot, L. Hviid, and T. G. Theander. 1999. Overlapping antigenic repertoires of variant antigens expressed on the surface of erythrocytes infected by Plasmodium falciparum. Parasitology 119:7-17.
9. Marsh, K., and R. J. Howard. 1986. Antigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinants. Science 231:150-153.[Abstract/Free Full Text]
10. Newbold, C. I., R. Pinches, D. J. Roberts, and K. Marsh. 1992. Plasmodium falciparum: the human agglutinating antibody response to the infected red cell surface is predominantly variant specific. Exp. Parasitol. 75:281-292.[CrossRef][Medline]
11. Nielsen, M. A., T. Staalsoe, J. A. L. Kurtzhals, B. Q. Goka, D. Dodoo, M. Alifrangis, T. G. Theander, B. D. Akanmori, and L. Hviid. 2002. Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and non-severe malaria and is modified by acquired immunity. J. Immunol. 168:3444-3450.[Abstract/Free Full Text]
12. Ofori, M. F., D. Dodoo, T. Staalsoe, J. A. L. Kurtzhals, K. Koram, T. G. Theander, B. D. Akanmori, and L. Hviid. 2002. Malaria-induced acquisition of antibodies to Plasmodium falciparum variant surface antigens. Infect. Immun. 70:2982-2988.[Abstract/Free Full Text]
13. Roberts, D. J. 2003. Understanding naturally acquired immunity to Plasmodium falciparum malaria. Infect. Immun. 71:589-590.
Lars Hviid*
Trine Staalsoe
Morten A. Nielsen
Thor G. Theander
Centre for Medical Parasitology
Department of Infectious Diseases
Copenhagen University Hospital (Rigshospitalet)
University of Copenhagen
Copenhagen, Denmark

* Phone: 45 35 45 76 44
Fax: 45 35 45 79 57
E-mail: lhcmp{at}rh.dk

Infection and Immunity, April 2003, p. 2296, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2296.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.




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