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Summary and Overall Impression:

Overall, this paper presents an in-depth structural analysis of potential SNPs that may cause issues in vaccines targeting the RIPR protein. The authors perform deep amplicon sequencing and successfully identify 15 novel SNPs, in addition to 11 previously described SNPs, that could be implicated in potential parasite vaccine evasion. Readers would benefit from clearer wording when describing the distribution of novel SNPs identified. The authors then use structural modeling to elucidate the effects of stabilizing and destabilizing mutations on the formation of the complex needed to facilitate parasite entry into red blood cells. The authors present a strong argument on how the mutations affect RIPR stability, but do not provide the same level of detail for mutations that affect the RIPR/CyRPA interaction stability. From this work, the authors conclude that the identified SNPS would not significantly impact vaccines targeting the RIPR region, providing promise for the ongoing effort for malaria control strategies. This is an over impactful paper with implications for future malaria vaccine development. Revisions to address clarity of methods and writing style would greatly improve the impact of this work. 

Major issues: 

1. The authors do not clearly differentiate between RIPR/CyRPA interaction stability vs RIPR stability

   1. The authors present a strong argument on how the mutations affect RIPR stability. However, they do not provide the same level of detail for mutations that affect the RIPR/CyRPA interaction stability. It is unclear as to what conclusion is drawn. It would be helpful to elaborate on the mechanistic impact that RIPR/CyRPA interaction stability would have on the ability of the parasite to invade red blood cells, similar to how the effect of RIPR stability was presented.

Minor issues: 

1. Stylistic writing improvements could be made to improve clarity, especially with the results section, introducing the identified SNPs.

   1. This sentence is not clear: “All SNPs were only identified in a single sample, with the exception of D454G, which was identified in two samples. Of the samples with SNPs, 41/64 (64.1%) had one SNP, 16/64 (25%) had two SNPs, and 7/64 (10.9%) had three SNPs.” Please clarify whether this sentence refers to whether there were many repeat SNPs or if most of the SNPs were unique to each sample.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they did not use generative AI to come up with new ideas for their review.