Background Malaria vaccines based on the 19-kDa region of merozoite surface protein 1 (MSP-119) derived from the 3D7 strain of Plasmodium falciparum are being tested in clinical trials in Africa. Knowledge of the distribution and natural dynamics of vaccine antigen polymorphisms in populations in which malaria vaccines will be tested will guide vaccine design and permit distinction between natural fluctuations in genetic diversity and vaccine-induced selection. Methods and Findings Using pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-119 were genotyped from 1,363 malaria infections experienced by 100 children who participated in a prospective cohort study in Mali from 1999 to 2001. The frequencies of 14 MSP-119 haplotypes were compared over the course of the malaria transmission season for all three years, in three age groups, and in consecutive infections within individuals. While the frequency of individual MSP-119 haplotypes fluctuated, haplotypes corresponding to FVO and FUP strains of P. falciparum (MSP-119 haplotypes QKSNGL and EKSNGL, respectively) were most prevalent during three consecutive years and in all age groups with overall prevalences of 46% (95% confidence interval [CI] 44%–49%) and 36% (95% CI 34%–39%), respectively. The 3D7 haplotype had a lower overall prevalence of 16% (95% CI 14%–18%). Multiplicity of infection based on MSP-119 was higher at the beginning of the transmission season and in the oldest individuals (aged ≥11 y). Three MSP-119 haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-119 polymorphisms in consecutive infections implicate three polymorphisms (at positions 1691, 1700, and 1701) as being particularly important in determining allele specificity of anti-MSP-119 immunity. Conclusions Parasites with MSP-119 haplotypes different from that of the leading vaccine strain were consistently the most prevalent at a vaccine trial site. If immunity elicited by an MSP-1-based vaccine is allele-specific, a vaccine based on either the FVO or FUP strain might have better initial efficacy at this site. This study, to our knowledge the largest of its kind to date, provides molecular information needed to interpret population responses to MSP-1-based vaccines and suggests that certain MSP-119 polymorphisms may be relevant to cross-protective immunity.
References
[1]
Greenwood B, Mutabingwa T (2002) Malaria in 2002. Nature 415: 670–672.
[2]
McKenzie FE, Baird JK, Beier JC, Lal AA, Bossert WH (2002) A biologic basis for integrated malaria control. Am J Trop Med Hyg 67: 571–577.
[3]
Dagan R, Givon-Lavi N, Zamir O, Fraser D (2003) Effect of a nonavalent conjugate vaccine on carriage of antibiotic-resistant in day-care centers. Pediatr Infect Dis J 22: 532–540.
[4]
Obaro SK, Adegbola RA, Banya WA, Greenwood BM (1996) Carriage of pneumococci after pneumococcal vaccination. Lancet 348: 271–272.
[5]
Beall B, McEllistrem MC, Gertz RE Jr., Wedel S, Boxrud DJ, et al. (2006) Pre- and postvaccination clonal compositions of invasive pneumococcal serotypes for isolates collected in the United States in 1999, 2001, and 2002. J Clin Microbiol 44: 999–1017.
[6]
Gonzalez BE, Hulten KG, Lamberth L, Kaplan SL, Mason EO Jr. (2006) Streptococcus pneumoniae serogroups 15 and 33: An increasing cause of pneumococcal infections in children in the United States after the introduction of the pneumococcal 7-valent conjugate vaccine. Pediatr Infect Dis J 25: 301–305.
[7]
Gerdil C (2003) The annual production cycle for influenza vaccine. Vaccine 21: 1776–1779.
[8]
Lal RB, Chakrabarti S, Yang C (2005) Impact of genetic diversity of HIV-1 on diagnosis, antiretroviral therapy & vaccine development. Indian J Med Res 121: 287–314.
[9]
Blackman MJ, Heidrich HG, Donachie S, McBride JS, Holder AA (1990) A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion- inhibiting antibodies. J Exp Med 172: 379–382.
[10]
Holder AA, Blackman MJ, Burghaus PA, Chappel JA, Ling IT, et al. (1992) A malaria merozoite surface protein (MSP1)-structure, processing and function. Mem Inst Oswaldo Cruz 87: 37–42.
[11]
Nwuba RI, Sodeinde O, Anumudu CI, Omosun YO, Odaibo AB, et al. (2002) The human immune response to includes both antibodies that inhibit merozoite surface protein 1 secondary processing and blocking antibodies. Infect Immun 70: 5328–5331.
[12]
Patino JAG, Holder AA, McBride JS, Blackman MJ (1997) Antibodies that inhibit malaria Merozoite Surface Protein-1 processing and erythrocyte invasion are blocked by naturally acquired human antibodies. J Exp Med 186: 1689–1699.
[13]
Branch OH, Udhayakumar V, Hightower AW, Oloo AJ, Hawley WA, et al. (1998) A longitudinal investigation of IgG and IgM antibody responses to the merozoite surface protein-1 19-kiloDalton domain of in pregnant women and infants: Associations with febrile illness, parasitemia, and anemia. Am J Trop Med Hyg 58: 211–219.
[14]
Branch OH, Oloo AJ, Nahlen BL, Kaslow D, Lal AA (2000) Anti-merozoite surface protein-1 19-kDa IgG in mother-infant pairs naturally exposed to : Subclass analysis with age, exposure to asexual parasitemia, and protection against malaria. V. The Asembo Bay Cohort Project. J Infect Dis 181: 1746–1752.
[15]
Egan AF, Morris J, Barnish G, Allen S, Greenwood BM, et al. (1996) Clinical immunity to malaria is associated with serum antibodies to the 19-kDa C-terminal fragment of the merozoite surface antigen, PfMSP-1. J Infect Dis 173: 765–769.
[16]
Riley EM, Allen SJ, Wheeler JG, Blackman MJ, Bennett S, et al. (1992) Naturally acquired cellular and humoral immune responses to the major merozoite surface antigen (PfMSP1) of are associated with reduced malaria morbidity. Parasite Immunol 14: 321–337.
[17]
John CC, O'Donnell RA, Sumba PO, Moormann AM, Koning-Ward TF, et al. (2004) Evidence that invasion-inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein-1 (MSP-1 19) can play a protective role against blood-stage infection in individuals in a malaria endemic area of Africa. J Immunol 173: 666–672.
[18]
Okech BA, Corran PH, Todd J, Joynson-Hicks A, Uthaipibull C, et al. (2004) Fine specificity of serum antibodies to merozoite surface protein, PfMSP-1(19), predicts protection from malaria infection and high-density parasitemia. Infect Immun 72: 1557–1567.
[19]
Da Silveira LA, Ribeiro WL, Kirchgatter K, Wunderlich G, Matsuoka H, et al. (2001) Sequence diversity and linkage disequilibrium within the merozoite surface protein-1 (MSP-1) locus of : A longitudinal study in Brazil. J Eukaryot Microbiol 48: 433–439.
[20]
Ferreira MU, Ribeiro WL, Tonon AP, Kawamoto F, Rich SM (2003) Sequence diversity and evolution of the malaria vaccine candidate merozoite surface protein-1 (MSP-1) of . Gene 304: 65–75.
[21]
Miller LH, Roberts T, Shahabuddin M, McCutchan TF (1993) Analysis of sequence diversity in the merozoite surface protein-1 (MSP-1). Mol Biochem Parasitol 59: 1–14.
[22]
Qari SH, Shi YP, Goldman IF, Nahlen BL, Tibayrenc M, Lal AA (1998) Predicted and observed alleles of merozoite surface protein-1 (MSP-1), a potential malaria vaccine antigen. Mol Biochem Parasitol 92: 241–252.
[23]
Sakihama N, Kimura M, Hirayama K, Kanda T, Na-Bangchang K, et al. (1999) Allelic recombination and linkage disequilibrium within Msp-1 of , the malignant human malaria parasite. Gene 230: 47–54.
[24]
Egan AF, Chappel JA, Burghaus PA, Morris JS, McBride JS, et al. (1995) Serum antibodies from malaria-exposed people recognize conserved epitopes formed by the two epidermal growth factor motifs of MSP1(19), the carboxy-terminal fragment of the major merozoite surface protein of . Infect Immun 63: 456–466.
[25]
Shi YP, Sayed U, Qari SH, Roberts JM, Udhayakumar V, et al. (1996) Natural immune response to the C-terminal 19-kilodalton domain of merozoite surface protein 1. Infect Immun 64: 2716–2723.
[26]
Diallo TO, Spiegel A, Diouf A, Perraut R, Kaslow DC, et al. (2001) Short report: IgG1/IgG3 antibody responses to various analogs of recombinant ypfmsp119—A study in immune adults living in areas of transmission. Am J Trop Med Hyg 64: 204–206.
[27]
Udhayakumar V, Anyona D, Kariuki S, Shi YP, Bloland PB, et al. (1995) Identification of T and B cell epitopes recognized by humans in the C-terminal 42-kDa domain of the merozoite surface protein (MSP)-1. J Immunol 154: 6022–6030.
[28]
Ockenhouse CF, Angov E, Kester KE, Diggs C, Soisson L, et al. (2006) Phase I safety and immunogenicity trial of FMP1/AS02A, a MSP-1 asexual blood stage vaccine. Vaccine 24: 3009–3017.
[29]
Stoute JA, Gombe J, Withers MR, Siangla J, McKinney D, et al. (2007) Phase 1 randomized double-blind safety and immunogenicity trial of malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya. Vaccine 25: 176–184.
[30]
Thera MA, Doumbo OK, Coulibaly D, Diallo DA, Sagara I, et al. (2006) Safety and allele-specific immunogenicity of a malaria vaccine in Malian adults: Results of a phase I randomized trial. PLoS Clin Trials 1: e34. doi:10.1371/journal.pctr.0010034.
[31]
Angov E, Aufiero BM, Turgeon AM, Van Handenhove M, Ockenhouse CF, et al. (2003) Development and pre-clinical analysis of a merozoite surface protein-1(42) malaria vaccine. Mol Biochem Parasitol 128: 195–204.
[32]
Alloueche A, Milligan P, Conway DJ, Pinder M, Bojang K, et al. (2003) Protective efficacy of the RTS,S/AS02 malaria vaccine is not strain specific. Am J Trop Med Hyg 68: 97–101.
[33]
Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, et al. (2004) Efficacy of the RTS,S/AS02A vaccine against infection and disease in young African children: Randomised controlled trial. Lancet 364: 1411–1420.
[34]
Genton B, Betuela I, Felger I, Al-Yaman F, Anders RF, et al. (2002) A recombinant blood-stage malaria vaccine reduces density and exerts selective pressure on parasite populations in a phase 1–2b trial in Papua New Guinea. J Infect Dis 185: 820–827.
[35]
Enosse S, Dobano C, Quelhas D, Aponte JJ, Lievens M, et al. (2006) RTS,S/AS02A malaria vaccine does not induce parasite CSP T cell epitope selection and reduces multiplicity of infection. PLoS Clin Trials 1: e5.. doi:10.1371/journal.pctr.0010005.
[36]
Coulibaly D, Diallo DA, Thera MA, Dicko A, Guindo AB, et al. (2002) Impact of preseason treatment on incidence of falciparum malaria and parasite density at a site for testing malaria vaccines in Bandiagara, Mali. Am J Trop Med Hyg 67: 604–610.
[37]
Lyke KE, Dicko A, Kone A, Coulibaly D, Guindo A, et al. (2004) Incidence of severe malaria as a primary endpoint for vaccine efficacy trials in Bandiagara, Mali. Vaccine 22: 3169–3174.
[38]
Takala SL, Smith DL, Stine OC, Coulibaly D, Thera MA, et al. (2006) A high-throughput method for quantifying alleles and haplotypes of the malaria vaccine candidate merozoite surface protein-1 19kDa. Malar J 5: 31.
[39]
Drakeley CJ, Corran PH, Coleman PG, Tongren JE, McDonald SL, et al. (2005) Estimating medium- and long-term trends in malaria transmission by using serological markers of malaria exposure. Proc Natl Acad Sci U S A 102: 5108–5113.
[40]
Conway DJ, Cavanagh DR, Tanabe K, Roper C, Mikes ZS, et al. (2000) A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat Med 6: 689–692.
[41]
Hughes AL (1992) Positive selection and interallelic recombination at the merozoite surface antigen-1 (MSA-1) locus of . Mol Biol Evol 9: 381–393.
[42]
Tanabe K, Sakihama N, Nakamura Y, Kaneko O, Kimura M, et al. (2000) Selection and genetic drift of polymorphisms within the merozoite surface protein-1 gene of . Gene 241: 325–331.
[43]
Branch OH, Takala S, Kariuki S, Nahlen BL, Kolczak M, et al. (2001) genotypes, low complexity of infection, and resistance to subsequent malaria in participants in the Asembo Bay Cohort Project. Infect Immun 69: 7783–7792.
[44]
Konate L, Zwetyenga J, Rogier C, Bischoff E, Fontenille D, et al. (1999) Variation of msp1 block 2 and msp2 allele prevalence and of infection complexity in two neighbouring Senegalese villages with different transmission conditions. Trans R Soc Trop Med Hyg 93: 21–28.
[45]
Beck HP, Felger I, Huber W, Steiger S, Smith T, et al. (1997) Analysis of multiple infections in Tanzanian children during the phase III trial of the malaria vaccine SPf66. J Infect Dis 175: 921–926.
[46]
Haywood M, Conway DJ, Weiss H, Metzger W, D'Alessandro U, et al. (1999) Reduction in the mean number of genotypes in Gambian children immunized with the malaria vaccine SPf66. Trans R Soc Trop Med Hyg 93(Suppl 1): 6568.
