ENG: Biomedical Engineering: Scholarly Papers

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Spatial frequency domain imaging for monitoring immune-mediated chemotherapy treatment response and resistance in a murine breast cancer model
(Springer Science and Business Media LLC, 2022-04-07) Tank, Anup; Vergato, Cameron; Waxman, David J.; Roblyer, Darren
Spatial Frequency Domain Imaging (SFDI) can provide longitudinal, label-free, and widefield hemodynamic and scattering measurements of murine tumors in vivo. Our previous work has shown that the reduced scattering coefficient (μ's) at 800 nm, as well as the wavelength dependence of scattering, both have prognostic value in tracking apoptosis and proliferation during treatment with anti-cancer therapies. However, there is limited work in validating these optical biomarkers in clinically relevant tumor models that manifest specific treatment resistance mechanisms that mimic the clinical setting. It was recently demonstrated that metronomic dosing of cyclophosphamide induces a strong anti-tumor immune response and tumor volume reduction in the E0771 murine breast cancer model. This immune activation mechanism can be blocked with an IFNAR-1 antibody, leading to treatment resistance. Here we present a longitudinal study utilizing SFDI to monitor this paired responsive-resistant model for up to 30 days of drug treatment. Mice receiving the immune modulatory metronomic cyclophosphamide schedule had a significant increase in tumor optical scattering compared to mice receiving cyclophosphamide in combination with the IFNAR-1 antibody (9% increase vs 10% decrease on day 5 of treatment, p < 0.001). The magnitude of these differences increased throughout the duration of treatment. Additionally, scattering changes on day 4 of treatment could discriminate responsive versus resistant tumors with an accuracy of 78%, while tumor volume had an accuracy of only 52%. These results validate optical scattering as a promising prognostic biomarker that can discriminate between treatment responsive and resistant tumor models.
Mechanical response of cardiac microtissues to acute localized injury
(American Physiological Society, 2022-10-01) Das, Shoshana L.; Sutherland, Bryan P.; Lejeune, Emma; Eyckmans, Jeroen; Chen, Christopher S.
After a myocardial infarction (MI), the heart undergoes changes including local remodeling that can lead to regional abnormalities in mechanical and electrical properties, ultimately increasing the risk of arrhythmias and heart failure. Although these responses have been successfully recapitulated in animal models of MI, local changes in tissue and cell-level mechanics caused by MI remain difficult to study in vivo. Here, we developed an in vitro cardiac microtissue (CMT) injury system that through acute focal injury recapitulates aspects of the regional responses seen following an MI. With a pulsed laser, cell death was induced in the center of the microtissue causing a loss of calcium signaling and a complete loss of contractile function in the injured region and resulting in a 39% reduction in the CMT's overall force production. After 7 days, the injured area remained void of cardiomyocytes (CMs) and showed increased expression of vimentin and fibronectin, two markers for fibrotic remodeling. Interestingly, although the injured region showed minimal recovery, calcium amplitudes in uninjured regions returned to levels comparable with control. Furthermore, overall force production returned to preinjury levels despite the lack of contractile function in the injured region. Instead, uninjured regions exhibited elevated contractile function, compensating for the loss of function in the injured region, drawing parallels to changes in tissue-level mechanics seen in vivo. Overall, this work presents a new in vitro model to study cardiac tissue remodeling and electromechanical changes after injury.NEW & NOTEWORTHY We report an in vitro cardiac injury model that uses a high-powered laser to induce regional cell death and a focal fibrotic response within a human-engineered cardiac microtissue. The model captures the effects of acute injury on tissue response, remodeling, and electromechanical recovery in both the damaged region and surrounding healthy tissue, modeling similar changes to contractile function observed in vivo following myocardial infarction.
Comparison of BinaxNOW and SARS-CoV-2 qRT-PCR detection of the omicron variant from matched anterior nares swabs
(American Society for Microbiology, 2022-12-21) Landaverde, Lena; Turcinovic, Jacquelyn; Doucette-Stamm, Lynn; Gonzales, Kevin; Platt, Judy; Connor, John H.; Klapperich, Catherine
The COVID-19 pandemic has increased use of rapid diagnostic tests (RDTs). In winter 2021 to 2022, the Omicron variant surge made it apparent that although RDTs are less sensitive than quantitative reverse transcription-PCR (qRT-PCR), the accessibility, ease of use, and rapid readouts made them a sought after and often sold-out item at local suppliers. Here, we sought to qualify the Abbott BinaxNOW RDT for use in our university testing program as a method to rule in positive or rule out negative individuals quickly at our priority qRT-PCR testing site. To perform this qualification study, we collected additional swabs from individuals attending this site. All swabs were tested using BinaxNOW. Initially as part of a feasibility study, test period 1 (n = 110) samples were stored cold before testing. In test period 2 (n = 209), samples were tested immediately. Combined, 102/319 samples tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive via qRT-PCR. All sequenced samples were Omicron (n = 92). We calculated 53.9% sensitivity, 100% specificity, a 100% positive predictive value, and an 82.2% negative predictive value for BinaxNOW (n = 319). Sensitivity would be improved (75.3%) by changing the qRT-PCR positivity threshold from a threshold cycle (CT) value of 40 to a CT value of 30. The receiver operating characteristic (ROC) curve shows that for qRT-PCR-positive CT values of between 24 and 40, the BinaxNOW test is of limited value diagnostically. Results suggest BinaxNOW could be used in our setting to confirm SARS-CoV-2 infection in individuals with substantial viral load, but a significant fraction of infected individuals would be missed if we used RDTs exclusively to rule out infection. IMPORTANCE Our results suggest BinaxNOW can rule in SARS-CoV-2 infection but would miss infections if RDTs were exclusively used.
Tendon explants maintain greater matrix synthesis in response to stress deprivation
(2022-02-04) Aggouras, Anthony; Connizzo, Brianne
Senescence contributes to death resistance of aged tenocytes in a model of secondary joint damage
(2023-02-10) Stowe, Emma; Connizzo, Brianne
Earlier proteoglycan turnover promotes higher efficiency matrix remodeling in MRL/MpJ tendons
(Wiley, 2023-02-10) Aggouras, Anthony; Connizzo, Brianne
While most mammalian tissue regeneration is limited, the Murphy Roths Large (MRL/MpJ) mouse has been identified to regenerate several tissues, including tendon. Recent studies have indicated that this regenerative response is innate to the tendon tissue and not reliant on a systemic inflammatory response. Therefore, we hypothesized that MRL/MpJ mice may also exhibit a more robust homeostatic regulation of tendon structure in response to mechanical loading. To assess this, MRL/MpJ and C57BL/6J Flexor digitorum longus tendon explants were subjected to stress-deprived conditions in vitro for up to 14 days. Explant tendon health (metabolism, biosynthesis, and composition), matrix metalloproteinase activity, gene expression, and tendon biomechanics were assessed periodically. We found a more robust response to a loss of mechanical stimulus in the MRL/MpJ tendon explants, exhibiting an increase in collagen production and MMP activity consistent with previous in vivo studies. This greater collagen turnover was preceded by an early expression of small leucine rich proteoglycans and proteoglycan-degrading MMP-3, promoting efficient regulation and organization of newly synthesized collagen and allowing for more efficient overall turnover in MRL/MpJ tendons. Therefore, mechanisms of MRL/MpJ matrix homeostasis may be fundamentally different from that of B6 tendons and may indicate better recovery from mechanical microdamage in MRL/MpJ tendons. We demonstrate here the utility of the MRL/MpJ model in elucidating mechanisms of efficient matrix turnover and its potential to shed light on new targets for more effective treatments for degenerative matrix changes brought about by injury, disease, or aging. This article is protected by copyright. All rights reserved.
Differential effect of acute compressive injury on young and aged tendons
(2023-02-10) Mlawer, Samuel; Connizzo, Brianne
Inner hair cell stereocilia displacement in response to focal stimulation of the basilar membrane in the ex vivo gerbil cochlea
(Elsevier BV, 2021-12) Zosuls, Aleksandrs; Rupprecht, Laura C.; Mountain, David C.
The inner hair cells in the mammalian cochlea transduce mechanical signals to electrical signals that provide input to the auditory nerve. The spatial-temporal displacement of the inner hair cell stereocilia (IHCsc) relative to basilar membrane (BM) displacement is central to characterizing the transduction process. This study specifically focuses on measuring displacement of the stereocilia hair bundles in the radial dimensions where they are most sensitive. To simplify the mechanical response of the cochlear partition, a mechanical probe was used to drive the BM. Optical imaging was used to measure radial displacement of the inner hair cell stereocilia local to the probe in ex vivo gerbil cochleae. The mechanical probe displaced the BM in the transverse direction using sinusoidal stimuli with frequencies ranging from 10 Hz to 42.5 kHz. IHCsc displacement measurements were made in the radial dimension as a function of their longitudinal location along the length of the BM. The results were used to quantify the frequency response, longitudinal space coupling, traveling wave velocity, and wavelength of the radial displacement of the stereocilia. The measurements were centered at two best frequency locations along the BM: Proximal to the round window (first turn), and in the second turn. At both locations, frequency tuning was seen that was consistent with published place maps. At both locations, traveling waves were observed simultaneously propagating basal and apical from the probe. The velocity of the traveling waves at the center frequency (CF) of the location was higher in the first turn than in the second. As the stimulus frequency increased and approached CF for a location, the traveling wavelength decreased. Differential motion of the BM and IHCsc was observed in the second turn as the stimulus frequency increased toward CF. The longitudinal coupling measured in this study was longer than observed in previous studies. In summary the results suggest that the shape of the wave patterns present on the BM are not sufficient to characterize the displacement of the IHCsc.
Hippocampal cells segregate positive and negative engrams
(Springer Science and Business Media LLC, 2022-09-26) Shpokayte, Monika; McKissick, Olivia; Guan, Xiaonan; Yuan, Bingbing; Rahsepar, Bahar; Fernandez, Fernando R.; Ruesch, Evan; Grella, Stephanie L.; White, John A.; Liu, X. Shawn; Ramirez, Steve
The hippocampus is involved in processing a variety of mnemonic computations specifically the spatiotemporal components and emotional dimensions of contextual memory. Recent studies have demonstrated cellular heterogeneity along the hippocampal axis. The ventral hippocampus has been shown to be important in the processing of emotion and valence. Here, we combine transgenic and all-virus based activity-dependent tagging strategies to visualize multiple valence-specific engrams in the vHPC and demonstrate two partially segregated cell populations and projections that respond to appetitive and aversive experiences. Next, using RNA sequencing and DNA methylation sequencing approaches, we find that vHPC appetitive and aversive engram cells display different transcriptional programs and DNA methylation landscapes compared to a neutral engram population. Additionally, optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive appetitive or aversive behavior in real-time place preference, stimulation of tagged vHPC terminals projecting to the amygdala and nucleus accumbens (NAc), but not the prefrontal cortex (PFC), showed the capacity drive preference and avoidance. These terminals also were able to change their capacity to drive behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally segregated populations of cells processing appetitive and aversive memory engrams.
Low concentration DNA extraction and recovery using a silica solid phase
(PUBLIC LIBRARY SCIENCE, 2017-05-05) Katevatis, Constantinos; Fan, Andy; Klapperich, Catherine M.
DNA extraction from clinical samples is commonly achieved with a silica solid phase extraction column in the presence of a chaotrope. Versions of these protocols have been adapted for point of care (POC) diagnostic devices in miniaturized platforms, but commercial kits require a high amount of input DNA. Thus, when the input clinical sample contains less than 1 μg of total DNA, the target-specific DNA recovery from most of these protocols is low without supplementing the sample with exogenous carrier DNA. In fact, many clinical samples used in the development of POC diagnostics often exhibit target DNA concentrations as low as 3 ng/mL. With the broader goal of improving the yield and efficiency of nucleic acid-based POC devices for dilute samples, we investigated both DNA adsorption and recovery from silica particles by using 1 pg– 1 μg of DNA with a set of adsorption and elution buffers ranging in pH and chaotropic presence. In terms of adsorption, we found that low pH and the presence of chaotropic guanidinium thiocyanate (GuSCN) enhanced DNA-silica adsorption. When eluting with a standard low-salt, high-pH buffer, > 70% of DNA was unrecoverable, except when DNA was initially adsorbed with 5 M GuSCN at pH 5.2. Unrecovered DNA was either not initially adsorbed or irreversibly bound on the silica surface. Recovery was improved when eluting with 95°C formamide and 1 M NaOH, which suggested that DNA-silica-chaotrope interactions are dominated by hydrophobic interactions and hydrogen bonding. While heated formamide and NaOH are non-ideal elution buffers for practical POC devices, the salient results are important for engineering a set of optimized reagents that could maximize nucleic acid recovery from a microfluidic DNA-silica-chaotrope system.
Method for the elucidation of LAMP products captured on lateral flow strips in a point of care test for HPV 16
(2020-09) Landaverde, Lena; Wong, Winnie; Hernandez, Gabriela; Fan, Andy; Klapperich, Catherine
Loop-mediated amplification (LAMP) is an isothermal amplification technique favored in diagnostics and point-of-care work due to its high sensitivity and ability to run in isothermal conditions. In addition, a visual readout by lateral flow strips (LFS) can be used in conjunction with LAMP, making the assay accessible at the point-of-care. However, the amplicons resulting from a LAMP reaction varied in length and shape, making them undiscernible on a double-stranded DNA intercalating dye stained gel. Standard characterization techniques also do not identify which amplicons specifically bind to the LFS, which generate the visual readout. We aimed to standardize our characterization of LAMP products during assay development by using fluorescein amidite (FAM) and biotin-tagged loop forward and backward primers during assay development. A pvuII restriction enzyme digest is applied to the LAMP products. FAM-tagged bands are directly correlated with the LFS visual readout. We applied this assay development workflow for an HPV 16 assay using both plasmid DNA and clinical samples to demonstrate proof of concept for generalized assay development work.
Ultrasensitive CRISPR-based diagnostic for field-applicable detection of Plasmodium species in symptomatic and asymptomatic malaria
(2020-10-13) Lee, Rose A.; Puig, Helena De; Nguyen, Peter Q.; Angenent-Mari, Nicolaas M.; Donghia, Nina M.; McGee, James P.; Dvorin, Jeffrey D.; Klapperich, Catherine M.; Pollock, Nira R.; Collins, James J.
Asymptomatic carriers of Plasmodium parasites hamper malaria control and eradication. Achieving malaria eradication requires ultrasensitive diagnostics for low parasite density infections (<100 parasites per microliter blood) that work in resource-limited settings (RLS). Sensitive point-of-care diagnostics are also lacking for nonfalciparum malaria, which is characterized by lower density infections and may require additional therapy for radical cure. Molecular methods, such as PCR, have high sensitivity and specificity, but remain high-complexity technologies impractical for RLS. Here we describe a CRISPR-based diagnostic for ultrasensitive detection and differentiation of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae, using the nucleic acid detection platform SHERLOCK (specific high-sensitivity enzymatic reporter unlocking). We present a streamlined, field-applicable, diagnostic comprised of a 10-min SHERLOCK parasite rapid extraction protocol, followed by SHERLOCK for 60 min for Plasmodium species-specific detection via fluorescent or lateral flow strip readout. We optimized one-pot, lyophilized, isothermal assays with a simplified sample preparation method independent of nucleic acid extraction, and showed that these assays are capable of detection below two parasites per microliter blood, a limit of detection suggested by the World Health Organization. Our P. falciparum and P. vivax assays exhibited 100% sensitivity and specificity on clinical samples (5 P. falciparum and 10 P. vivax samples). This work establishes a field-applicable diagnostic for ultrasensitive detection of asymptomatic carriers as well as a rapid point-of-care clinical diagnostic for nonfalciparum malaria species and low parasite density P. falciparum infections.
Development and clinical validation of Iso-IMRS: a novel diagnostic assay for P. falciparum malaria
(2021-02-02) Kolluri, Nikunja; Kamath, Shwetha; Lally, Patrick; Zanna, Mina; Galagan, James; Gitaka, Jesse; Kamita, Moses; Cabodi, Mario; Lolabattu, Srinivasa Raju; Klapperich, Catherine M.
In many countries targeting malaria elimination, persistent malaria infections can have parasite loads significantly below the lower limit of detection (LLOD) of standard diagnostic techniques, making them difficult to identify and treat. The most sensitive diagnostic methods involve amplification and detection of Plasmodium DNA by polymerase chain reaction (PCR), which requires expensive thermal cycling equipment and is difficult to deploy in resource-limited settings. Isothermal DNA amplification assays have been developed, but they require complex primer design, resulting in high nonspecific amplification, and show a decrease in sensitivity than PCR methods. Here, we have used a computational approach to design a novel isothermal amplification assay with a simple primer design to amplify P. falciparum DNA with analytical sensitivity comparable to PCR. We have identified short DNA sequences repeated throughout the parasite genome to be used as primers for DNA amplification and demonstrated that these primers can be used, without modification, to isothermally amplify P. falciparum parasite DNA via strand displacement amplification. Our novel assay shows a LLOD of ∼1 parasite/μL within a 30 min amplification time. The assay was demonstrated with clinical samples using patient blood and saliva. We further characterized the assay using direct amplicon next-generation sequencing and modified the assay to work with a visual readout. The technique developed here achieves similar analytical sensitivity to current gold standard PCR assays requiring a fraction of time and resources for PCR. This highly sensitive isothermal assay can be more easily adapted to field settings, making it a potentially useful tool for malaria elimination.
Amplicon residues in research laboratories masquerade as COVID-19 in surveillance tests
(2021-05-24) Davidi, Dan; Fitzgerald, Susan; Glaspell, Hannah L.; Jalbert, Samantha; Klapperich, Catherine M.; Landaverde, Lena; Maheras, Stylianos; Mattoon, Stephanie E.; Britto, Vanessa M.; Nguyen, Giang T.; Platt, Judy T.; Kuhfeldt, Kayla; Landsberg, Hannah; Stuopis, Cecilia W.; Turse, Joshua E.; Hamer, Davidson H.; Springer, Michael
Asymptomatic surveillance testing together with COVID-19-related research can lead to positive SARS-CoV-2 tests resulting not from true infections, but non-infectious, non-hazardous by-products of research (amplicons). Amplicons can be widespread and persistent in lab environments and can be difficult to distinguish for true infections. We discuss prevention and mitigation strategies.
Electrochemical strategy for low-cost viral detection
(2021-06-23) Zamani, Marjon; Robson, James M.; Fan, Andy; Bono, Michael S.; Furst, Ariel L.; Klapperich, Catherine M.
Sexually transmitted infections, including the human immunodeficiency virus (HIV) and the human papillomavirus (HPV), disproportionally impact those in low-resource settings. Early diagnosis is essential for managing HIV. Similarly, HPV causes nearly all cases of cervical cancer, the majority (90%) of which occur in low-resource settings. Importantly, infection with HPV is six times more likely to progress to cervical cancer in women who are HIV-positive. An inexpensive, adaptable point-of-care test for viral infections would make screening for these viruses more accessible to a broader set of the population. Here, we report a novel, cost-effective electrochemical platform using gold leaf electrodes to detect clinically relevant viral loads. We have combined this platform with loop-mediated isothermal amplification and a CRISPR-based recognition assay to detect HPV. Lower limits of detection were demonstrated down to 104 total copies of input nucleic acids, which is a clinically relevant viral load for HPV DNA. Further, proof-of-concept experiments with cervical swab samples, extracted using standard extraction protocols, demonstrated that the strategy is extendable to complex human samples. This adaptable technology could be applied to detect any viral infection rapidly and cost-effectively.
AIM: a network model of attention in auditory cortex
(Public Library of Science (PLoS), 2021) Chou, Kenny F.; Sen, Kamal
Generation of a purified iPSC-derived smooth muscle-like population for cell sheet engineering
(2019-09-10) Kwong, George; Marquez, Hector A.; Yang, Chian; Wong, Joyce Y.; Kotton, Darrell N.
Induced pluripotent stem cells (iPSCs) provide a potential source for the derivation of smooth muscle cells (SMCs); however, current approaches are limited by the production of heterogeneous cell types and a paucity of tools or markers for tracking and purifying candidate SMCs. Here, we develop murine and human iPSC lines carrying fluorochrome reporters (Acta2hrGFP and ACTA2eGFP, respectively) that identify Acta2+/ACTA2+ cells as they emerge in vitro in real time during iPSC-directed differentiation. We find that Acta2hrGFP+ and ACTA2eGFP+ cells can be sorted to purity and are enriched in markers characteristic of an immature or synthetic SMC. We characterize the resulting GFP+ populations through global transcriptomic profiling and functional studies, including the capacity to form engineered cell sheets. We conclude that these reporter lines allow for generation of sortable, live iPSC-derived Acta2+/ACTA2+ cells highly enriched in smooth muscle lineages for basic developmental studies, tissue engineering, or future clinical regenerative applications.
Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein
(2021) Van Egeren, Debra; Novokhodko, Alexander; Stoddard, Madison; Tran, Uyen; Zetter, Bruce; Rogers, Michael; Pentelute, Bradley L.; Carlson, Jonathan M.; Hixon, Mark; Joseph-McCarthy, Diane; Chakravarty, Arijit
The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities.
Controlling long-term SARS-CoV-2 infections can slow viral evolution and reduce the risk of treatment failure.
(2021-11-19) Van Egeren, Debra; Novokhodko, Alexander; Stoddard, Madison; Tran, Uyen; Zetter, Bruce; Rogers, Michael S.; Joseph-McCarthy, Diane; Chakravarty, Arijit
The rapid emergence and expansion of novel SARS-CoV-2 variants threatens our ability to achieve herd immunity for COVID-19. These novel SARS-CoV-2 variants often harbor multiple point mutations, conferring one or more evolutionarily advantageous traits, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we used a stochastic evolutionary modeling framework to explore the emergence of fitter variants of SARS-CoV-2 during long-term infections. We found that increased viral load and infection duration favor emergence of such variants. While the overall probability of emergence and subsequent transmission from any given infection is low, on a population level these events occur fairly frequently. Targeting these low-probability stochastic events that lead to the establishment of novel advantageous viral variants might allow us to slow the rate at which they emerge in the patient population, and prevent them from spreading deterministically due to natural selection. Our work thus suggests practical ways to achieve control of long-term SARS-CoV-2 infections, which will be critical for slowing the rate of viral evolution.
Rapid relaxation of pandemic restrictions after vaccine rollout favors growth of SARS-CoV-2 variants: a model-based analysis
(2021) Van Egeren, Debra; Stoddard, Madison; Novokhodko, Alexander; Rogers, Michael S.; Joseph-McCarthy, Diane; Zetter, Bruce; Chakravarty, Arijit
The development and deployment of several SARS-CoV-2 vaccines in a little over a year is an unprecedented achievement of modern medicine. The high levels of efficacy against transmission for some of these vaccines makes it feasible to use them to suppress SARS-CoV-2 altogether in regions with high vaccine acceptance. However, viral variants with reduced susceptibility to vaccinal and natural immunity threaten the utility of vaccines, particularly in scenarios where a return to pre-pandemic conditions occurs before the suppression of SARS-CoV-2 transmission. In this work we model the situation in the United States in May-June 2021, to demonstrate how pre-existing variants of SARS-CoV-2 may cause a rebound wave of COVID-19 in a matter of months under a certain set of conditions. A high burden of morbidity (and likely mortality) remains possible, even if the vaccines are partially effective against new variants and widely accepted. Our modeling suggests that variants that are already present within the population may be capable of quickly defeating the vaccines as a public health intervention, a serious potential limitation for strategies that emphasize rapid reopening before achieving control of SARS-CoV-2.

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