Structural and antigenic polymorphism of the 35- to 48-kilodalton merozoite surface antigen (MSA-2) of the malaria parasite Plasmodium falciparum.

Abstract

Merozoite surface antigen MSA-2 of the human parasite Plasmodiumfalciparum is being considered for the development of a malaria vaccine. The antigen is polymorphic, and specific monoclonal antibodies differentiate five serological variants of MSA-2 among 25 parasite isolates. The variants are grouped into two major serogroups, A and B. Genes encoding two different variants from serogroup A have been sequenced, and their DNA together with deduced amino acid sequences were compared with sequences encoded by other alleles. The comparison shows that the serological classification reflects differences in DNA sequences and deduced primary structure of MSA-2 variants and serogroups. Thus, the overall homologies of DNA and amino acid sequences are over 95% among variants in the same serogroup. In contrast, similarities between the group A variants and a group B variant are only 70 and 64% for DNA and amino acid sequences, respectively. We propose that the MSA-2 protein is encoded by two highly divergent groups of alleles, with limited additional polymorphism displayed within each group.

The Origin of Antigenic Diversity in Plasmodium falciparum

“…But it has been shown that, despite the abundant intragenic recombination within Csp CR, there is an apparent absence of recombination between 5Ј and 3Ј NR, suggesting that the duplication and deletion of RATs occur by mitotic processes such as SSM 25 . SSM has also been implicated 28 as the cause of repeat variation in Msp2. However, it is interesting to note that among Ͼ100 field isolates from which Msp2 has been sequenced and entered in GenBank, only six have hybrid 3D7/Camp-FC27 sequences, despite the strong bias towards sequencing isolates with unusual serotyping results.…”

“…For example, A1 alleles possess four amino acid motifs, whereas a repeating eight amino acid motif occurs in A3. Fenton et al have shown that the allelic subclasses within the 3D7/Camp family are derived from a common ancestral nucleotide sequence and that the diversity arises from duplication and deletion of repeat subunits 28 .…”

“…Fenton et al 28 proposed a model to explain the origin of repeat diversity within the 3D7/Camp family of alleles. The 3D7/Camp family was divided into distinct allelic subclasses, which included types A1 and A3, distinguished by amino acid repeats of different lengths.…”

“…The methods described in Ref. 28 have been used to determine whether PrMsp2 provides insight into the ancestry of the FC27 and 3D7/Camp families. Figure 2a shows the amino acid sequence alignment of two P. falciparum MSP-2 proteins with the PrMSP2.…”

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

“…7,8,[20][21][22] Including all the parasite's genetic variants (thousands) involved in invasion, thereby trying to saturate the immunologic system for preventing a single parasite's escape from the immune response would be an impossible task, even more so when these genetic variants are found very close to functionally relevant amino acid sequences (such as those binding to host cells), thus biasing the immune system toward responding against functionally irrelevant regions.…”