Plasmodium falciparum is the causative agent of malaria, one of the deadliest infectious diseases in the world, which causes an estimated 263 million cases and 600,000 deaths annually in 2024. Considerable efforts have been made towards malaria elimination over the past few decades but since 2016 progress has stalled in reducing global morbidity and mortality. The implementation of malaria vaccines shows incredible promise with the World Health Organization (WHO) approving two sub-unit vaccines, RTS,S/AS01 and R21/Matrix-M, for use in pediatric populations in high transmission environments. These landmark recommendations represent a major milestone in the development and implementation of novel tools to combat malaria, but obstacles remain in the struggle to achieve robust, longitudinal efficacy in endemic regions. A major challenge in developing better vaccines is overcoming allele-specific efficacy, the process by which vaccines are only highly efficacious against parasites which are sufficiently immunologically similar to the reference used in the vaccine. To interrogate the phenomena of allele-specific efficacy the Silva lab applied whole-genome sieve analysis (SAWG) to samples collected during two clinical malaria vaccine trials using whole-sporozoite vaccination regiments and identified 16 candidate targets of vaccine-induced protective immunity suspected of being susceptible to vaccine evasion through allele-specific vaccine efficacy. This dissertation continues this work by down-selecting these 16 candidates and characterizing the effect of the implicated single nucleotide polymorphisms (SNPs), or target sites, and indels on the immunogenicity of these target loci. We found that target sites disproportionately occurred within nonsynonymous sites but did not occur disproportionately within predicted CD8+ T-cell epitopes, even though cell-mediated immunity is suspected to drive vaccine-induced immunity from whole sporozoite vaccinations. Leveraging publicly available data, I conducted a global assessment of nucleotide and protein diversity in 2053 samples from 17 countries, and conducted tests of neutrality to identify trends in population genomic parameters which are reflective of established antigens. These analyses led to the identification and characterization of two novel potential antigenic targets, PF3D7_1324300 and PF3D7_1361800, along with an established antigen, thrombospondin-related anonymous protein (Pftrap), PF3D7_1335900. This work also characterized the potential for these putative targets to be used as future vaccine candidate. Lastly, we reconstructed de novo the five down-selected loci based on the whole genome sequencing reads generated from the clinical trial parasite isolates. This allowed me to investigate the effects of SNPs and insertions and deletions on the immunogenicity of these targets. We investigated the effect of these changes on the predicted CD8+ T-cell epitopes and B-cell epitopes, the sequence-dependent means by which immunogenicity may be disrupted, but also how these changes may cause off target effects which modify the tertiary structure of the targets and disrupt immunogenicity through a mechanism that is independent of the epitope sequence. I observed tertiary structural changes which, though not significant across the length of the investigated target locus, may have meaningful impact on the binding of immune effector cells at key epitopes and allow immune evasion. These findings suggest that whole-genome sieve analysis is a viable tool in the identification of novel vaccine candidates and that current vaccine formulations must consider the immense genetic diversity of Plasmodium falciparum in order to overcome allele-specific vaccine efficacy and create malaria vaccines with robust efficacy in high disease transmission environments. This work also applied novel predictive in-silico tools to characterize the effects of indels on the immunogenicity of a known vaccine candidate antigen, providing novel insight into the impacts of indels on immunogenicity, a critically understudied aspect of protein diversity.