Research

Molecular dissection of the human antibody response to the structural repeat epitope of Plasmodium falciparum sporozoite from a protected donor

Jonathan A Chappel¹ , William O Rogers^2,3 , Stephen L Hoffman^2,4 and Angray S Kang^1,5

¹Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

²Malaria Program, Naval Medical Research Center, Silver Spring, MD 20910-7500, USA

³Present address: Naval Medical Research Unit #3, Ghana Det, c/o Department of State, 2020 Accra Place, Washington, DC 20521-2020, USA

⁴Present address: Sanaria Inc, 12115 Parklawn Drive Suite L, Rockville, MD 20852, USA

⁵Present address: Avanir Pharmaceuticals Inc, 11388 Sorrento Valley Road, San Diego, CA 92121, USA

author email corresponding author email

Malaria Journal 2004, 3:28doi:10.1186/1475-2875-3-28

Published:	29 July 2004

Abstract

Background

The circumsporozoite surface protein is the primary target of human antibodies against Plasmodium falciparum sporozoites, these antibodies are predominantly directed to the major repetitive epitope (Asn-Pro-Asn-Ala)_n, (NPNA)_n. In individuals immunized by the bites of irradiated Anopheles mosquitoes carrying P. falciparum sporozoites in their salivary glands, the anti-repeat response dominates and is thought by many to play a role in protective immunity.

Methods

The antibody repertoire from a protected individual immunized by the bites of irradiated P. falciparum infected Anopheles stephensi was recapitulated in a phage display library. Following affinity based selection against (NPNA)₃ antibody fragments that recognized the PfCSP repeat epitope were rescued.

Results

Analysis of selected antibody fragments implied the response was restricted to a single antibody fragment consisting of V_H3 and V_κI families for heavy and light chain respectively with moderate affinity for the ligand.

Conclusion

The dissection of the protective antibody response against the repeat epitope revealed that the response was apparently restricted to a single V_H/V_L pairing (PfNPNA-1). The affinity for the ligand was in the μM range. If anti-repeat antibodies are involved in the protective immunity elicited by exposure to radiation attenuated P. falciparum sporozoites, then high circulating levels of antibodies against the repeat region may be more important than intrinsic high affinity for protection. The ability to attain and sustain high levels of anti-(NPNA)_n will be one of the key determinants of efficacy for a vaccine that relies upon anti-PfCSP repeat antibodies as the primary mechanism of protective immunity against P. falciparum.