A Challenge for the Development of Malaria Vaccines: Polymorphic Target Antigens
| العنوان: | A Challenge for the Development of Malaria Vaccines: Polymorphic Target Antigens |
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| المؤلفون: | Christopher V. Plowe, Abdoulaye Djimde, Abdoulaye K. Kone, Mahamadou A. Thera, Karim Traore, Dapa A. Diallo, Paul S. Sehdev, Amed Ouattara, Ogobara K. Doumbo, Kirsten E. Lyke, Alassane Dicko, Ando B. Guindo, Shannon L. Takala, David L. Smith, Drissa Coulibaly |
| المصدر: | PLoS Medicine PLoS Medicine, Vol 4, Iss 3, p e93 (2007) |
| بيانات النشر: | Public Library of Science, 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Immunology and allergy, 030231 tropical medicine, Immunology, Plasmodium falciparum, Public Health and Epidemiology, Antigens, Protozoan, Asymptomatic, Microbiology, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Malaria Vaccines, medicine, Genetics, Animals, Humans, Amino Acid Sequence, Malaria, Falciparum, Allele frequency, Molecular Biology, 030304 developmental biology, 0303 health sciences, Evolutionary Biology, Polymorphism, Genetic, biology, Molecular epidemiology, Malaria vaccine, Health Policy, Haplotype, General Medicine, biology.organism_classification, medicine.disease, Virology, 3. Good health, Malaria, Infectious Diseases, Haplotypes, Drug Design, Medicine, medicine.symptom, Cohort study, Research Article |
| الوصف: | 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. Christopher Plowe and colleagues surveyed local malaria parasites for genetic diversity in MSP-1, a candidate vaccine antigen. These data are needed to interpret population responses to MSP-1-based vaccines during trials planned at this site. Editors' Summary Background. Malaria, a tropical parasitic disease, kills about one million people—mainly children—every year. Most of these deaths are caused by Plasmodium falciparum, which is transmitted to humans through the bites of infected mosquitoes. These insects inject a form of the parasite known as sporozoites into people that replicates inside liver cells without causing symptoms. Four to five days later, merozoites (another form of the parasite) are released from the liver cells and invade red blood cells. Here, they replicate 10-fold before bursting out and infecting other red blood cells. This massive increase in parasite burden causes malaria's flu-like symptoms. If untreated, it also causes anemia (a red blood cell deficit) and damages the brain and other organs where parasitized red blood cells sequester. Malaria can be treated with antimalarial drugs and partly prevented by reducing the chances of being bitten by an infected mosquito. In addition, researchers are developing vaccines designed to reduce the global burden of malaria. These contain individual malaria antigens (proteins from the parasite that stimulate an immune response) that should, when injected into people, prime the immune system so that it can rapidly control malaria infections. Why Was This Study Done? The development of an effective malaria vaccine is not easy, in part because people can be simultaneously infected with several parasite strains. These often carry different variants (alleles) of the genes encoding antigens, which means that the actual parasite proteins might differ from the ones used for vaccination. If this is the case, the immune response generated by the vaccine might be less effective or even ineffective. An ideal vaccine would therefore stimulate an immune response that recognizes all these strain-specific antigens. However, little is known about their distribution in parasite populations in malarial regions, or about how this distribution changes over time (its dynamics). This information is needed to aid vaccine design and development. In this study, the researchers have investigated the distribution and dynamics of genetic variants of a merozoite antigen called MSP-119, which is included in a vaccine currently being tested in Mali, West Africa. Although most of the MSP-119 sequence is conserved, it contains six strain-specific polymorphisms (genetic variations); the candidate vaccine contains MSP-119 from the 3D7 strain of P. falciparum. What Did the Researchers Do and Find? The researchers used rapid DNA sequencing (pyrosequencing) to examine the MSP-119 sequence in more than 1,300 malaria infections in 100 Malian children. They compared the frequencies of 14 MSP-119 haplotypes (sets of polymorphisms at the six variant sites) over three years, in three age groups, and in consecutive infections within individuals. They found that the frequency of individual MSP-119 haplotypes fluctuated in their study population but that those found in P. falciparum FVO and FUP strains were always the commonest, each being present in about 40% of the infections. By contrast, the P. falciparum 3D7 MSP-119 haplotype was present in only 16% of the infections. They also found that mixed infections were more common at the start of each malaria season and in older individuals. In addition, individuals who were infected repeatedly by parasites from different strains (with different MSP-119 variants) seemed to get sick with malaria more often than those infected multiple times by the same strain. The differences might, therefore, be important in determining the specificity of the immune response to MSP-119. What Do These Findings Mean? These findings indicate that most parasites that cause malaria at the Malian test site for the malaria vaccine that contains 3D7-specific MSP-119 have a different form of MSP-119. Although early results from field trials suggest that the 3D7-derived vaccine provides some protection against the more common FVO and FUP strains, the immunity stimulated by the vaccine might be mainly allele specific. If this turns out to be the case, these results suggest that a FVO- or FUP-derived vaccine might be more effective in Mali than the 3D7-derived vaccine, though not necessarily elsewhere. More generally, these results show the importance of determining the genetics of pathogen populations before starting vaccine trials. Without this information, a vaccine's ability to prevent infections with specific parasite strains cannot be determined accurately and potentially useful vaccines might be abandoned if they are tested in inappropriate populations. Importantly, baseline information of this sort will also allow vaccine developers to detect any vaccine-induced changes in the pathogen population that might affect the long-term efficacy of their vaccines. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040093Test. A related PLoS Medicine Perspective by Colin Sutherland discusses variation in malaria antigens as a challenge in vaccine development The malaria program of the University of Maryland Center for Vaccine Development performs research on many aspects of malaria Information on malaria and the development of vaccines is available from the Malaria Vaccine Initiative The World Health Organization provides links to general information on malaria plus some specific information on malaria vaccine development MedlinePlus encyclopedia has entries on malaria and on vaccination US Centers for Disease Control and Prevention provides information for patients and professionals on malaria US National Institute of Allergy and Infectious Diseases has information on malaria, including research into vaccines |
| اللغة: | English |
| تدمد: | 1549-1676 1549-1277 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa8ffc9eb7669f14fc9171a36164e83aTest http://europepmc.org/articles/PMC1820605Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fa8ffc9eb7669f14fc9171a36164e83a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15491676 15491277 |
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