Stories to Prevent Cancer: A Pilot Study Using Cancer Survivor Narratives to Increase Human Papillomavirus Vaccine Intentions.

INTRODUCTION: Human papillomavirus (HPV) vaccination rates are lower than other recommended adolescent vaccines. Cancer survivor narratives are used to promote cancer prevention and control, but little is known about their impact on adolescent HPV vaccination. OBJECTIVE: This pilot study explored the feasibility and effects of a video education intervention using a cancer survivor narrative to improve parents' attitudes toward and intentions to get the HPV vaccine. METHODS: This study utilized a one-group design; participants completed a pre-intervention survey, watched the video before attending their sons' wellness visits, and completed a post-intervention survey within one week of their appointment. Using the narrative persuasion framework, we developed a 4-minute video of a local HPV-related cancer survivor to promote the HPV vaccine as cancer prevention. We recruited 37 participants between June and October 2020. Participants were parents of males ages 9-17 who had not yet initiated HPV vaccination. RESULTS: After the video, more parents agreed that HPV vaccination is safe (pre: 66% vs. post: 82%; P = .045) and that their child's chances of getting HPV-related cancer in the future are high (pre: 24% vs. post: 46%; P = .014). Overall, 91% of parents felt the cancer survivor story helped them understand the risks of HPV cancers, and 52% said the story influenced their decision to start HPV vaccination for their child. CONCLUSIONS: Our findings suggest that cancer survivor narratives influence parents' vaccine opinions and understanding of their child's risk of HPV infection, leading to increased parental intent to get the HPV vaccine for their adolescent males.

Geometric parameters that affect the behavior of logic-gated CAR T cells.

Clinical applications of CAR-T cells are limited by the scarcity of tumor-specific targets and are often afflicted with the same on-target/off-tumor toxicities that plague other cancer treatments. A new promising strategy to enforce tumor selectivity is the use of logic-gated, two-receptor systems. One well-described application is termed Tmod™, which originally utilized a blocking inhibitory receptor directed towards HLA-I target antigens to create a protective NOT gate. Here we show that the function of Tmod blockers targeting non-HLA-I antigens is dependent on the height of the blocker antigen and is generally compatible with small, membrane-proximal targets. We compensate for this apparent limitation by incorporating modular hinge units to artificially extend or retract the ligand-binding domains relative to the effector cell surface, thereby modulating Tmod activator and blocker function. By accounting for structural differences between activator and blocker targets, we developed a set of simple geometric parameters for Tmod receptor design that enables targeting of blocker antigens beyond HLA-I, thereby broadening the applications of logic-gated cell therapies.

How Does a Junior Faculty Development Program Affect Burnout? A Mixed Methods Assessment.

OBJECTIVES: Burnout is common among junior faculty. Professional development has been proposed as a method to improve engagement and reduce burnout among academic physicians. The Penn State College of Medicine Junior Faculty Development Program (JFDP) is a well-established, interdisciplinary program. However, an increase in burnout was noted among participants during the program. The authors sought to quantify the change in burnout seen among JFDP participants across 3 cohorts, and to explore sources of well-being and burnout among participants. METHODS: Through a sequential explanatory mixed methods approach, participants in the 2018/19, 2019/20, and 2020/21 cohorts took a survey assessing burnout (Copenhagen Burnout Inventory), quality of life (QoL), job satisfaction, and work-home conflict at the start and end of the course. Descriptive statistics were generated as well as Pearson χ2 test/Fisher exact test for categorical variables and Wilcoxon rank sum tests for continuous variables for group comparisons. To better understand the outcome, past participants were invited to interviews regarding their experience of burnout during the course. Inductive thematic analysis (kappa = 0.86) was used to derive themes. RESULTS: Start- and end-of-course surveys were completed by 84 and 75 participants, respectively (response rates: 95.5% and 85.2%). Burnout associated with patient/learner/client/colleague increased (P = .005) and QoL decreased (P = .02) at the end compared with the start. Nonsignificant trends toward worsening in other burnout categories, work-home conflict, and job satisfaction were also observed. Nineteen interviews yielded themes related to risks and protective factors for burnout including competing demands, benefits of networking, professional growth, and challenges related to diverse faculty roles. CONCLUSION: Junior Faculty Development Program participants demonstrated worsening of burnout and QoL during the program while benefiting from opportunities including skill building and networking. The impact of Junior Faculty Development Programs on the well-being of participants should be considered as an element of their design, evaluation, and refinement over time.

Assessment of a Recognition Program in an Academic Family Medicine Department.

BACKGROUND AND OBJECTIVES: Burnout is prevalent among clinicians and faculty. We sought to understand the impact of a recognition program designed to reduce burnout and affect engagement and job satisfaction in a large academic family medicine department. METHODS: A recognition program was created in which three clinicians and faculty from the department were randomly selected each month to be recognized ("awardees"). Each awardee was asked to honor a person who had supported them (a "hidden hero" [HH]). Clinicians and faculty not recognized or selected as an HH were considered "bystanders." Interviews were completed with 12 awardees, 12 HHs, and 12 bystanders for a total of 36 interviews. We used content analysis to qualitatively evaluate the program. RESULTS: Assessment of the "We Are" Recognition Program resulted in the categories of impact (subcategories: process positives, process negatives, and fairness of program) and HHs (subcategories: teamwork and awareness of the program). We conducted interviews on a rolling basis and made iterative changes to the program based on feedback. CONCLUSIONS: This recognition program helped create a sense of value for clinicians and faculty in a large, geographically dispersed department. It represents a model that would be easy to replicate, requires no special training or significant financial investment, and can be implemented in a virtual format.

Toward generalizable prediction of antibody thermostability using machine learning on sequence and structure features.

Over the last three decades, the appeal for monoclonal antibodies (mAbs) as therapeutics has been steadily increasing as evident with FDA's recent landmark approval of the 100th mAb. Unlike mAbs that bind to single targets, multispecific biologics (msAbs) have garnered particular interest owing to the advantage of engaging distinct targets. One important modular component of msAbs is the single-chain variable fragment (scFv). Despite the exquisite specificity and affinity of these scFv modules, their relatively poor thermostability often hampers their development as a potential therapeutic drug. In recent years, engineering antibody sequences to enhance their stability by mutations has gained considerable momentum. As experimental methods for antibody engineering are time-intensive, laborious and expensive, computational methods serve as a fast and inexpensive alternative to conventional routes. In this work, we show two machine learning approaches - one with pre-trained language models (PTLM) capturing functional effects of sequence variation, and second, a supervised convolutional neural network (CNN) trained with Rosetta energetic features - to better classify thermostable scFv variants from sequence. Both of these models are trained over temperature-specific data (TS50 measurements) derived from multiple libraries of scFv sequences. On out-of-distribution (refers to the fact that the out-of-distribution sequnes are blind to the algorithm) sequences, we show that a sufficiently simple CNN model performs better than general pre-trained language models trained on diverse protein sequences (average Spearman correlation coefficient, ρ, of 0.4 as opposed to 0.15). On the other hand, an antibody-specific language model performs comparatively better than the CNN model on the same task (ρ= 0.52). Further, we demonstrate that for an independent mAb with available thermal melting temperatures for 20 experimentally characterized thermostable mutations, these models trained on TS50 data could identify 18 residue positions and 5 identical amino-acid mutations showing remarkable generalizability. Our results suggest that such models can be broadly applicable for improving the biological characteristics of antibodies. Further, transferring such models for alternative physicochemical properties of scFvs can have potential applications in optimizing large-scale production and delivery of mAbs or bsAbs.

HLA-A∗02-gated safety switch for cancer therapy has exquisite specificity for its allelic target antigen.

Innovative cell-based therapies are important new weapons in the fight against difficult-to-treat cancers. One promising strategy involves cell therapies equipped with multiple receptors to integrate signals from more than one antigen. We developed a specific embodiment of this approach called Tmod, a two-receptor system that combines activating and inhibitory inputs to distinguish between tumor and normal cells. The selectivity of Tmod is enforced by the inhibitory receptor (blocker) that recognizes an antigen, such as an HLA allele, whose expression is absent from tumors because of loss of heterozygosity. Although unwanted cross-reactivity of the blocker likely reduces efficacy rather than safety, it is important to verify the blocker's specificity. We have tested an A∗02-directed blocker derived from the PA2.1 mouse antibody as a safety mechanism paired with a mesothelin-specific activating CAR in our Tmod construct. We solved the crystal structure of humanized PA2.1 Fab in complex with HLA-A∗02 to determine its binding epitope, which was used to bioinformatically select specific class I HLA alleles to test the blocker's functional specificity in vitro. We found that this A∗02-directed blocker is highly specific for its cognate antigen, with only one cross-reactive allele (A∗69) capable of triggering comparable function.

Effects of Early COVID-19 Restrictions on Resident Well-being and Burnout.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic has contributed to burnout among residents, a population already at increased risk for heightened stress and work-related fatigue. Residency programs were also forced to alter schedules and educational objectives. We assessed how social distancing restrictions (specifically self-isolation) enacted early in the COVID-19 pandemic affected family medicine (FM) resident well-being and burnout. Our FM department created a 2-week reserve rotation as a response to the need to socially distance and protect the residents. We explored how the reserve rotations impacted their experiences. METHODS: A purposive sample of FM residents were recruited in May and June of 2020. Qualitative interviews explored well-being and burnout, changes in education and provision of patient care, and overall adaptation to the pandemic. We employed interpretative phenomenology to analyze the interviews. RESULTS: We interviewed six out of 24 residents before saturation was reached. Qualitative analysis revealed themes related to positive and negative consequences of the pandemic, including uncertainty/fear of the unknown, schedule/life changes, communication, and adapting to a new routine. CONCLUSIONS: The COVID-19 pandemic placed an additional burden on residents, a group already at increased risk for burnout. While uncertainty and disruptions in work and home life were significant stressors, this cohort demonstrated adaptability and resilience that was facilitated by peer support and effective communication. These factors, along with the reserve rotation with decreased clinical responsibilities, led to an improved sense of well-being and decreased feelings of burnout.

Integrating Quality Improvement and Community Engagement Education: Curricular Evaluation of Resident Population Health Training.

BACKGROUND AND OBJECTIVES: The Accreditation Council for Graduate Medical Education requires all residents be trained in population health, but the most effective training strategies to impact care of patients and populations are not well established. The purpose of this study is to assess resident self-efficacy and expected application of population management skills through iterative experiential, longitudinal, team-based training in the office and community settings. METHODS: Using a prospective longitudinal curricular evaluation, we surveyed residents at a single institution from 2014-2020, evaluating self-efficacy in population health skills as well as perceived impact on patient care and future practice. We collected surveys before and after participating in a 3-year, longitudinal, team-based, experiential population health curriculum that integrates clinic-based quality improvement and community engagement projects. RESULTS: Fifty-nine of 68 residents (87%) responded to the presurvey, and 42/56 (75%) responded to the postsurvey. We observed significant increases in resident self-efficacy in all population health skills. All respondents reported finding common population health skills that were applicable in both office and community settings; 81% reported care of their continuity clinic patients changed because of taking part in the curriculum. Finally, 94% of respondents reported the intention to use population health skills and incorporate quality improvement (75%) and community engagement (100%) in future practice. CONCLUSIONS: Teaching population health management skills in both office and community settings allows residents to integrate and apply these skills across settings and may enhance their use in patient care and future practice.

Challenges in Effective Faculty and Provider Recognition to Enhance Engagement.

BACKGROUND AND OBJECTIVES: Burnout is associated with reduction in patient care time and leaving academic medicine, and is prevalent among faculty, residents, and advanced practice providers. Recognition may positively impact workplace well-being and reduce attrition. The objective of this study was to understand needs and preferences regarding recognition among faculty and providers in a large academic department. METHODS: A survey including quantitative and qualitative elements was sent to faculty and providers to identify whether additional recognition was needed and, if so, to seek potential opportunities to improve recognition, with mixed-methods assessment of results. RESULTS: Fifty-two participants completed the survey (35.9% response rate; 53.8% female, 59.6% faculty); 26.9% reported performing duties at work that are not being recognized, and 19.2% reported seriously considering leaving the institution because they did not feel appreciated. Females were more likely to want tangible goods as a source of recognition (P=.008). While providers preferred to have recommendations for recognition made by office staff (P=.007), associate professors did not (P=.005). Qualitative responses to the survey also revealed concerns regarding favoritism and risk of feeling unappreciated if a recognition system is perceived as unfair. CONCLUSIONS: This survey demonstrated a deficit of recognition and a lack of consensus regarding how or when faculty and providers should be recognized. There were concerns regarding fairness of recognition. Efforts to enhance recognition should avoid assumptions about faculty and provider preferences, and should be attuned to fairness and inclusion.

Protocol for high-throughput cloning, expression, purification, and evaluation of bispecific antibodies.

Bispecific antibodies are a powerful new class of therapeutics, but their development often requires enormous amounts of time and resources. Here, we describe a high-throughput protocol for cloning, expressing, purifying, and evaluating bispecific antibodies. This protocol enables the rapid screening of large panels of bispecific molecules to identify top candidates for further development. For complete details on the use and execution of this protocol, please refer to Estes et al. (2021).

Mindfulness-Based Stress Reduction Live Online During the COVID-19 Pandemic: A Mixed Methods Feasibility Study.

Objectives: To assess the feasibility, acceptability, and effects of Mindfulness Based Stress Reduction (MBSR) live online during the COVID-19 shutdown. Design: Mixed-methods study using a sequential explanatory design. Settings/location: Cohorts 1-4 took place in-person and Cohorts 5-6 took place over Zoom following the onset of the COVID-19 pandemic. Subjects: Participants were paying members of the general public enrolled in one of six live MBSR courses. Interventions: All MBSR courses followed the standard 8-week MBSR curriculum, led by experienced instructors. Outcome measures: Feasibility measured via class attendance, acceptability measured via the adapted Treatment Satisfaction Survey, and MBSR course effects measured by a focus group with Cohort 5, and the following assessments completed by all cohorts: Perceived Stress Scale-10, Generalized Anxiety Disorder-7, Patient Health Questionnaire-9 and the 36-item Short Form Survey. Results: 73 adults participated in six live MBSR courses (48 in the four in-person courses; 25 in the two online courses). Most of the participants identified as white, non-Hispanic, middle-aged females, with annual household income >$100,000. Course completion, defined as at least 6/8 classes attended, did not differ between in-person and online cohorts (84.1% versus 67.6%, respectively, p = 0.327). Participants in Cohort 5 who completed the course (n = 10) rated it as very important and useful for stress coping, and reported high likelihood of continuing their mindfulness practice (all ratings: between 8 and 10 on a 1-10 Likert scale), with open-ended responses corroborating their numerical ratings. Focus group (n = 6) responses indicated that online MBSR was positively received, reduced perceived loss of control, and improved quality of life and morale during the pandemic. Conclusions: Delivering MBSR live online can be feasible and acceptable for the general public, and is potentially beneficial, including during the social upheaval of the COVID-19 pandemic. Online delivery could help expand access to MBSR and address health inequities.

Next generation Fc scaffold for multispecific antibodies.

Bispecific antibodies (Bispecifics) demonstrate exceptional clinical potential to address some of the most complex diseases. However, Bispecific production in a single cell often requires the correct pairing of multiple polypeptide chains for desired assembly. This is a considerable hurdle that hinders the development of many immunoglobulin G (IgG)-like bispecific formats. Our approach focuses on the rational engineering of charged residues to facilitate the chain pairing of distinct heavy chains (HC). Here, we deploy structure-guided protein design to engineer charge pair mutations (CPMs) placed in the CH3-CH3' interface of the fragment crystallizable (Fc) region of an antibody (Ab) to correctly steer heavy chain pairing. When used in combination with our stable effector functionless 2 (SEFL2.2) technology, we observed high pairing efficiency without significant losses in expression yields. Furthermore, we investigate the relationship between CPMs and the sequence diversity in the parental antibodies, proposing a rational strategy to deploy these engineering technologies.

Enhancing the Prefusion Conformational Stability of SARS-CoV-2 Spike Protein Through Structure-Guided Design.

The worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented and the impact on public health and the global economy continues to be devastating. Although early therapies such as prophylactic antibodies and vaccines show great promise, there are concerns about the long-term efficacy and universal applicability of these therapies as the virus continues to mutate. Thus, protein-based immunogens that can quickly respond to viral changes remain of continued interest. The Spike protein, the main immunogen of this virus, displays a highly dynamic trimeric structure that presents a challenge for therapeutic development. Here, guided by the structure of the Spike trimer, we rationally design new Spike constructs that show a uniquely high stability profile while simultaneously remaining locked into the immunogen-desirable prefusion state. Furthermore, our approach emphasizes the relationship between the highly conserved S2 region and structurally dynamic Receptor Binding Domains (RBD) to enable vaccine development as well as the generation of antibodies able to resist viral mutation.

Rational selection of building blocks for the assembly of bispecific antibodies.

Bispecific antibodies, engineered to recognize two targets simultaneously, demonstrate exceptional clinical potential for the therapeutic intervention of complex diseases. However, these molecules are often composed of multiple polypeptide chains of differing sequences. To meet industrial scale productivity, enforcing the correct quaternary assembly of these chains is critical. Here, we describe Chain Selectivity Assessment (CSA), a high-throughput method to rationally select parental monoclonal antibodies (mAbs) to make bispecific antibodies requiring correct heavy/light chain pairing. By deploying CSA, we have successfully identified mAbs that exhibit a native preference toward cognate chain pairing that enables the production of hetero-IgGs without additional engineering. Furthermore, CSA also identified rare light chains (LCs) that permit positive binding of the non-cognate arm in the common LC hetero-IgGs, also without engineering. This rational selection of parental mAbs with favorable developability characteristics is critical to the successful development of bispecific molecules with optimal manufacturability properties.

TRPM3 expression and control of glutamate release from primary vagal afferent neurons.

Vagal afferent fibers contact neurons in the nucleus of the solitary tract (NTS) and release glutamate via three distinct release pathways: synchronous, asynchronous, and spontaneous. The presence of TRPV1 in vagal afferents is predictive of activity-dependent asynchronous glutamate release along with temperature-sensitive spontaneous vesicle fusion. However, pharmacological blockade or genetic deletion of TRPV1 does not eliminate the asynchronous profile and only attenuates the temperature-dependent spontaneous release at high temperatures (>40°C), indicating additional temperature-sensitive calcium conductance(s) contributing to these release pathways. The transient receptor potential cation channel melastatin subtype 3 (TRPM3) is a calcium-selective channel that functions as a thermosensor (30-37°C) in somatic primary afferent neurons. We predict that TRPM3 is expressed in vagal afferent neurons and contributes to asynchronous and spontaneous glutamate release pathways. We investigated these hypotheses via measurements on cultured nodose neurons and in brainstem slice preparations containing vagal afferent to NTS synaptic contacts. We found histological and genetic evidence that TRPM3 is highly expressed in vagal afferent neurons. The TRPM3-selective agonist, pregnenolone sulfate, rapidly and reversibly activated the majority (∼70%) of nodose neurons; most of which also contained TRPV1. We confirmed the role of TRPM3 with pharmacological blockade and genetic deletion. In the brain, TRPM3 signaling strongly controlled both basal and temperature-driven spontaneous glutamate release. Surprisingly, genetic deletion of TRPM3 did not alter synchronous or asynchronous glutamate release. These results provide convergent evidence that vagal afferents express functional TRPM3 that serves as an additional temperature-sensitive calcium conductance involved in controlling spontaneous glutamate release onto neurons in the NTS.NEW & NOTEWORTHY Vagal afferent signaling coordinates autonomic reflex function and informs associated behaviors. Thermosensitive transient receptor potential (TRP) channels detect temperature and nociceptive stimuli in somatosensory afferent neurons, however their role in vagal signaling remains less well understood. We report that the TRPM3 ion channel provides a major thermosensitive point of control over vagal signaling and synaptic transmission. We conclude that TRPM3 translates physiological changes in temperature to neurophysiological outputs and can serve as a cellular integrator in vagal afferent signaling.

Mock Trial as a Learning Tool in a Family Medicine Residency.

BACKGROUND AND OBJECTIVES: Mock trials have been used to teach medical learners about malpractice litigation, ethics, legal concepts, and evidence-based practice. Although 5.2% of family physicians are sued for malpractice annually, there is no formal requirement nor curriculum for educating our residents about malpractice, and mock trial has not been reported as an education modality in a family medicine residency. We developed a mock trial experience to educate family medicine residents about malpractice litigation and evaluated the resident experience over 3 years. METHODS: This is a retrospective, single-site study evaluating resident experience in our mock trials. We assessed perceived value using a 5-point Likert scale; and we assessed knowledge with free-text answers to both open and closed questions. We used descriptive statistics to describe data. RESULTS: Residents found the mock trial effective and engaging, giving the experience an overall evaluation of 4.9/5±0.3; 86.4% identified the importance of documentation as a learning outcome; 72.7% of residents identified negligence as necessary to justify a lawsuit, but they demonstrated limited mastery of the four elements of negligence, with 45.5% correctly listing harm, 40.9% causation, 13.6% breach of duty, and 0% duty owed. CONCLUSIONS: Mock trial is an enjoyable and effective tool to engage residents and provide a general understanding of malpractice litigation. It is less effective in conveying nuanced details of negligence. It may also be effective in teaching practice management techniques.

Feasibility of Nonanonymous Burnout Surveys in a Large Academic Department.

BACKGROUND AND OBJECTIVES: Burnout is prevalent among clinicians and entails negative personal, professional, and organizational consequences. Assessments of burnout are typically anonymous to facilitate psychological safety. This limits the capacity of leadership to help struggling providers and reduces the level of demographic detail. Nonanonymous, confidential assessments may facilitate outreach to individuals or targeted interventions for at-risk populations. METHODS: We administered the Maslach Burnout Inventory to physician faculty and advanced practice providers in an academic department of family medicine. We identified a wellness officer within the department who served as an honest broker to keep nonanonymous survey responses confidential. Respondents had the option of taking the survey anonymously or confidentially. Anonymous respondents were allowed to withhold demographic information to ensure anonymity. RESULTS: Sixty-seven of 109 providers responded (61% response rate), with 46 (69%) doing so confidentially. Burnout rates were similar between groups: 48% among confidential respondents, and 43% among anonymous respondents (P=.71). Subscales of the MBI also showed no significant differences. Because a large proportion of anonymous respondents withheld demographic data, no demographic trends could be identified among them. Younger confidential respondents were more likely to exhibit depersonalization (P=.01). CONCLUSIONS: Most participants chose to respond confidentially. There was no significant difference in the level of burnout between confidential and anonymous respondents. Our findings refute the conventional wisdom that clinicians require anonymity to respond to burnout surveys. This finding has the potential to open a new line of inquiry regarding burnout, its drivers and potential solutions.

Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD.

Structure Based Prediction of Neoantigen Immunogenicity.

The development of immunological therapies that incorporate peptide antigens presented to T cells by MHC proteins is a long sought-after goal, particularly for cancer, where mutated neoantigens are being explored as personalized cancer vaccines. Although neoantigens can be identified through sequencing, bioinformatics and mass spectrometry, identifying those which are immunogenic and able to promote tumor rejection remains a significant challenge. Here we examined the potential of high-resolution structural modeling followed by energetic scoring of structural features for predicting neoantigen immunogenicity. After developing a strategy to rapidly and accurately model nonameric peptides bound to the common class I MHC protein HLA-A2, we trained a neural network on structural features that influence T cell receptor (TCR) and peptide binding energies. The resulting structurally-parameterized neural network outperformed methods that do not incorporate explicit structural or energetic properties in predicting CD8+ T cell responses of HLA-A2 presented nonameric peptides, while also providing insight into the underlying structural and biophysical mechanisms governing immunogenicity. Our proof-of-concept study demonstrates the potential for structure-based immunogenicity predictions in the development of personalized peptide-based vaccines.