If this test is positive at any time, the patient will be discontinued from the study. 4.4 Study assessments Signed, IRB-approved informed consent must be obtained from patients prior to any pretreatment assessments. 4.4.1 Pretreatment assessments All patients must have a Complete Blood Count (CBC) and Comprehensive Metabolic Panel (CMP) within two months of trial initiation and, for female patients, a urine pregnancy test (upon consent to study), for screening and immediately prior to any vaccine inoculations or DTH. If the pregnancy test is positive, the patient will be excluded from the study. Women who have had a hysterectomy, bilateral oophorectomy, tubal ligation, documented absence of menses for two years, or FSH hormonal laboratory results that verify menopause, will not be required to have pregnancy testing. For patients who have a complete metastatic evaluation (CBC, LFTs, CXR, chest and abdomen CT, bone scan, and PET scan) available, all studies will be screened, but these studies are not required for enrollment. Results of cardiac evaluation with MUGA or ECHO will also be screened. Disease-free status will be assured by the patients’ primary treating/referring physician. Overall health screen will be assessed utilizing the ECOG performance status grading system (Appendix F). To ensure eligibility, each patient will be HLA-typed as described in Section 4.4.5). They will be asked for 6-8 cc of blood for HLA-A2/A3/A24/A26 screening. Analysis will be performed at a CLIA certified laboratory at MD Anderson. 27 Protocol: 2014-0443 Version 2.1 Version Date: 11 April 2016 All patients regardless of randomization may be assessed for baseline immunologic responses prior to the first inoculation. Specimen handling, processing, and assays are described in Sections 4.4.4 and 4.4.6. All patients will be tested for pre-inoculation DTH reaction against nelipepimut-S as described in Section 4.4.8. Reactions will be read 48-72 hours after placement of the peptide. 4.4.2 Assessments during treatment All patients will have cardiac assessment performed according to standard practice (approximately every 3 months) as dictated by their treating oncologist. Either MUGA or ECHO is acceptable but should be consistently used for any given patient. Results of cardiac testing will be reviewed by the research nurses or study coordinators and any abnormal results will be reviewed by the study investigators. Per standard practice, all patients will have CBC and CMP monitoring approximately every 3 months during the primary series and approximately every 6 months during the booster phase. Any laboratory evaluations or imaging studies ordered by the treating oncologist as part of standard practice will be reviewed by the research nurses or study coordinators and any abnormal results will be reviewed by the study investigators. For both the PVS and the booster inoculations, the patient will be monitored for 30 minutes after the inoculation with vital signs taken as needed. Patients will either return to their study site or be contacted by phone for questioning regarding any systemic and local toxicity during the initial 48-72 hours after inoculation. If they return to their study site, the local reaction at the inoculation sites will be examined and measured. For patients that do not return to the study site, a tool will be given and instructions provided to measure the local reaction. The NCI CTCAE version 4.03 graded toxicity scale (Appendix C) will be utilized to assess local and systemic toxicity. Blood samples will be obtained from all patients, regardless of randomization, to determine induction of peptide-specific immune responses as described in Sections 4.4.4 and 4.4.6. 4.4.3 Follow-up assessments The clinical endpoint of recurrence will be determined by patients’ own physicians at the individual study sites during routine follow-up. This will include 28 Protocol: 2014-0443 Version 2.1 Version Date: 11 April 2016 physical examination every 3-6 months for all patients and yearly mammogram for patients undergoing breast conserving therapy (per ASCO guidelines). 48 Additional laboratory and radiographic surveillance will be performed as indicated and directed by the patients treating physicians. The determination of recurrence will be per standard practice by the treating physicians and communicated to the study investigators on a routine basis. Documentation of the recurrence will be obtained. Whenever possible, pathologic confirmation of recurrence will be obtained. However, a patient will also be considered to have a recurrence if highly suggested on radiographic evaluation and oncologic treatment for the recurrence is initiated by the treating physician. Documentation of the latter will be obtained. For the purposes of this trial, the invasive DFS will be calculated from the date of initiation of trastuzumab maintenance therapy until date of last follow-up or recurrence. If records are not available, patients, or their referring physicians, will be contacted to discern their disease status and every effort will be made to obtain documentation. All enrolled patients, regardless of randomization, will be followed for clinical recurrence for up to three years from the date of initiation of trastuzumab maintenance therapy. 4.4.4 Blood collection and processing Multiple blood draws will be required for this trial. All blood tubes will be labeled only with the patients’ unique study number. Approximately 6-8 cc will be drawn for HLA-typing and approximately 70cc for each Immunologic assessment (pre DTH #1 and #2, prior to each booster and 1 month ± 1 week after each booster and at study completion 36 months after initiation of trastuzumab maintenance therapy). Thus a total of approximately 800cc of blood will be drawn over the three year course of the study. De-identified patient blood samples showing only the unique study ID number will be sent from study sites via overnight delivery to the laboratory of the Principal Investigator, Dr. Elizabeth Mittendorf, at MD Anderson where immunologic response assays (Section 4.6) will be performed. At no point will MD Anderson personnel have access to patient identifiers. Blood not used to perform the dextramer assay (Section 4.6) will be frozen and stored in the laboratory of Dr. Elizabeth Mittendorf under the unique protocol number and identifier for up to five years for additional immunologic studies related to this protocol (for example, to repeat assays or perform new immunologic assays that do not exist at present but may become available) as needed and then destroyed. No genetic testing will be performed on this material.