Biomedical Interventions Research Articles

Advances in Triboelectric Nanogenerators for Self‐Powered Regenerative Medicine

AbstractOver the last decade, in pursuit to provide suitable alternatives for power supplies of medical devices in regenerative medicine, extensive research on nanogenerators has been developed. Such devices can overcome current commercial battery challenges, including intense heat‐on‐body complications due to the electrical current during therapeutic usage, leading to protein denaturation, cell structure destruction, and even cell necrosis. In addition, these traditional batteries contain a bulky and heavy structure that prevents them from providing sustainable on body biomedical therapeutic intervention. Furthermore, advantages such as wide‐range biocompatible and biodegradable materials, lightweight, and sufficient stretchability for device construction can minimize the side effects of implantable devices, including inflammation or toxicity, as well as eliminate secondary surgery to replace or remove batteries. Triboelectric nanogenerators (TENGs) are associated with harvesting mechanical energy in various forms, among which human body motions can serve as a renewable power source for healthcare systems. This review is written to emphasize the importance of TENG's applications in regenerative medicine and modulation purposes, particularly for the nervous system. Some crucial parameters for implantable consideration are discussed. In the concluding remarks, features for clinical utilization including output efficiency, encapsulation, stability, and miniaturization are suggested as challenges and prospects.

COVID-19-Related Stressors, Sex Behaviors, and HIV Status Neutral Care Among Black Men Who Have Sex With Men and Transgender Women in Chicago, USA.

Background:COVID-19 has disproportionately impacted vulnerable populations, including Black men who have sex with men (BMSM) and transgender women (BTW). We investigated associations of COVID-19 stressors and sex behaviors with pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) among BMSM and BTW.Methods:As part of the Neighborhoods and Networks (N2) study, we conducted virtual interviews during peak COVID-19 infectivity in Chicago among BMSM and BTW (April–July 2020). Survey questions included multilevel COVID-19 stressors, sex behaviors, and current PrEP/ART use and access. Poisson regressions were used to examining relationships between COVID-19 stressors, sex behaviors, and PrEP/ART use/access.Results:Among 222 participants, 31.8% of participants not living with HIV reported current PrEP use and 91.8% of participants living with HIV reported ART use during the pandemic. Most (83.3% and 78.2%, respectively) reported similar or easier PrEP and ART access during the pandemic. Physical stress reaction to COVID-19 [adjusted prevalence ratio [aPR] = 2.1; confidence interval (CI): 1.3 to 3.5] and being in close proximity with someone diagnosed with COVID-19 (aPR = 1.7; CI: 1.1 to 2.8) were associated with current PrEP use. Intimate partner violence (aPR = 2.7; CI: 1.0 to 7.2) and losing health insurance (aPR = 3.5; CI: 1.1 to 10.7) were associated with harder ART access. Travel-related financial burden was associated with harder access in PrEP (aPR = 3.2; CI: 1.0 to 10.1) and ART (aPR = 6.2; CI: 1.6 to 24.3).Conclusions:Multiple COVID-19 stressors were found to interfere with PrEP and ART use and access among BMSM and BTW. Contextually relevant strategies (eg, promoting telehealth and decreasing transportation burden) to address COVID-19 stressors and their sequelae should be considered to minimize disruption in HIV biomedical interventions.

Beyond the new normal: Assessing the feasibility of vaccine-based suppression of SARS-CoV-2.

As the COVID-19 pandemic drags into its second year, there is hope on the horizon, in the form of SARS-CoV-2 vaccines which promise disease suppression and a return to pre-pandemic normalcy. In this study we critically examine the basis for that hope, using an epidemiological modeling framework to establish the link between vaccine characteristics and effectiveness in bringing an end to this unprecedented public health crisis. Our findings suggest that a return to pre-pandemic social and economic conditions without fully suppressing SARS-CoV-2 will lead to extensive viral spread, resulting in a high disease burden even in the presence of vaccines that reduce risk of infection and mortality. Our modeling points to the feasibility of complete SARS-CoV-2 suppression with high population-level compliance and vaccines that are highly effective at reducing SARS-CoV-2 infection. Notably, vaccine-mediated reduction of transmission is critical for viral suppression, and in order for partially-effective vaccines to play a positive role in SARS-CoV-2 suppression, complementary biomedical interventions and public health measures must be deployed simultaneously.

A self-powered implantable and bioresorbable electrostimulation device for biofeedback bone fracture healing

Electrostimulation has been recognized as a promising nonpharmacological treatment in orthopedics to promote bone fracture healing. However, clinical applications have been largely limited by the complexity of equipment operation and stimulation implementation. Here, we present a self-powered implantable and bioresorbable bone fracture electrostimulation device, which consists of a triboelectric nanogenerator for electricity generation and a pair of dressing electrodes for applying electrostimulations directly toward the fracture. The device can be attached to irregular tissue surfaces and provide biphasic electric pulses in response to nearby body movements. We demonstrated the operation of this device on rats and achieved effective bone fracture healing in as short as 6 wk versus the controls for more than 10 wk to reach the same healing result. The optimized electrical field could activate relevant growth factors to regulate bone microenvironment for promoting bone formation and bone remodeling to accelerate bone regeneration and maturation, with statistically significant 27% and 83% improvement over the control groups in mineral density and flexural strength, respectively. This work provided an effective implantable fracture therapy device that is self-responsive, battery free, and requires no surgical removal after fulfilling the biomedical intervention.

Perception of preconception care among women attending antenatal care clinic in a tertiary health care hospital in south east, Nigeria

Preconception care is the provision of biomedical, behavioral and social health interventions to women and couples before conception occurs. This study aimed to assess women’s knowledge, practice, perceived views and ideas and associated factors in preconception care amongst women attending antenatal care at Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra state, Nigeria. A facility based cross-sectional study conducted among 150 randomly selected reproductive age group women who attended antenatal clinic from September 9 to September 26, 2020.The data were collected using self-administered and interviewer-administered questionnaires. The data were analyzed using Statistical Package for Social Sciences version 20.0. The study revealed 31.3% overall knowledge of preconception care. The knowledge level on preconception care was significantly associated with occupation, level of education, residence, number of pregnancies and past obstetrics complications. Age has no association with the level of knowledge. Only about one-fifth of the participants have good knowledge of the importance of folic acid use prior to and during pregnancy (17.3%), 32% had wrong knowledge and the rest had no knowledge (50.7%). Majority of the participants (87.7%) had prospective views concerning preconception care encouraging every woman to partake in it. In this finding, the level of women’s knowledge on preconception care was very low. Having a high level of education, living in urban area and having an obstetrics history were associated with good knowledge. The finding also showed positive views on the uptake and practice preconception care. This finding suggests that there is a need to give more emphasis on educating women on preconception care with the sole aim of achieving a sound maternal and child health.

Cytotoxicity of MXene-based nanomaterials for biomedical applications: A mini review

MXene based nanomaterial is an uprising two-dimensional material gaining tremendous scientific attentions due to its versatile properties for the applications in electronic devices, power generation, sensors, drug delivery, and biomedicine. However, the cytotoxic effects of MXene still remained a huge concern. Therefore, stringent analysis of biocompatibility of MXene is an essential requirement before introduction to human physiological system. Several in vitro and in vivo toxicological studies have been reported to investigate the interactions between MXenes with living organisms such as microbes, mammalian cells and animal models. The biological response and cytotoxicity reported were dependent on the physicochemical properties of MXene. The biocompatibility and cytotoxicity of MXene were dependent on size, dose, and surface coating. This review demystifies the in vitro and in vivo biocompatibility studies associated with MXene. Various methods proposed to mitigate the cytotoxicity of MXene for in vivo applications were revealed. The machine learning methods were developed to predict the cytotoxicity of experimentally synthesized MXene compounds. Finally, we also discussed the current research gaps of applying MXenes in biomedical interventions.

Magnetic Nanoparticles in Biology and Medicine: Past, Present, and Future Trends.

The use of magnetism in medicine has changed dramatically since its first application by the ancient Greeks in 624 BC. Now, by leveraging magnetic nanoparticles, investigators have developed a range of modern applications that use external magnetic fields to manipulate biological systems. Drug delivery systems that incorporate these particles can target therapeutics to specific tissues without the need for biological or chemical cues. Once precisely located within an organism, magnetic nanoparticles can be heated by oscillating magnetic fields, which results in localized inductive heating that can be used for thermal ablation or more subtle cellular manipulation. Biological imaging can also be improved using magnetic nanoparticles as contrast agents; several types of iron oxide nanoparticles are US Food and Drug Administration (FDA)-approved for use in magnetic resonance imaging (MRI) as contrast agents that can improve image resolution and information content. New imaging modalities, such as magnetic particle imaging (MPI), directly detect magnetic nanoparticles within organisms, allowing for background-free imaging of magnetic particle transport and collection. “Lab-on-a-chip” technology benefits from the increased control that magnetic nanoparticles provide over separation, leading to improved cellular separation. Magnetic separation is also becoming important in next-generation immunoassays, in which particles are used to both increase sensitivity and enable multiple analyte detection. More recently, the ability to manipulate material motion with external fields has been applied in magnetically actuated soft robotics that are designed for biomedical interventions. In this review article, the origins of these various areas are introduced, followed by a discussion of current clinical applications, as well as emerging trends in the study and application of these materials.

The case for biotechnological exceptionalism

Do biomedical interventions raise special moral concerns? A rising number of prominent authors claim that at least in the case of biomedical enhancement they do not. Treating biomedical enhancements different from non-biomedical ones, they claim, amounts to unjustified biomedical exceptionalism. This article vindicates the familiar thesis that biomedical enhancement raises specific concerns. Taking a close look at the argumentative strategy against biomedical exceptionalism and provides counterexamples showing that the biomedical mode of interventions raises concerns not relevant otherwise. In particular, biomedical interventions throughout raise concerns of informed consent, which only rarely turn up in comparable non-biomedical interventions.

Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions

In 2017, facing lack of progress and failures encountered in targeted drug development for Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders, the ISCTM with the ECNP created the ASD Working Group charged to identify barriers to progress and recommending research strategies for the field to gain traction. Working Group international academic, regulatory and industry representatives held multiple in-person meetings, teleconferences, and subgroup communications to gather a wide range of perspectives on lessons learned from extant studies, current challenges, and paths for fundamental advances in ASD therapeutics. This overview delineates the barriers identified, and outlines major goals for next generation biomedical intervention development in ASD. Current challenges for ASD research are many: heterogeneity, lack of validated biomarkers, need for improved endpoints, prioritizing molecular targets, comorbidities, and more. The Working Group emphasized cautious but unwavering optimism for therapeutic progress for ASD core features given advances in the basic neuroscience of ASD and related disorders. Leveraging genetic data, intermediate phenotypes, digital phenotyping, big database discovery, refined endpoints, and earlier intervention, the prospects for breakthrough treatments are substantial. Recommendations include new priorities for expanded research funding to overcome challenges in translational clinical ASD therapeutic research.

Slight reduction in SARS-CoV-2 exposure viral load due to masking results in a significant reduction in transmission with widespread implementation

Masks are a vital tool for limiting SARS-CoV-2 spread in the population. Here we utilize a mathematical model to assess the impact of masking on transmission within individual transmission pairs and at the population level. Our model quantitatively links mask efficacy to reductions in viral load and subsequent transmission risk. Our results reinforce that the use of masks by both a potential transmitter and exposed person substantially reduces the probability of successful transmission, even if masks only lower exposure viral load by ~ 50%. Slight increases in mask adherence and/or efficacy above current levels would reduce the effective reproductive number (Re) substantially below 1, particularly if implemented comprehensively in potential super-spreader environments. Our model predicts that moderately efficacious masks will also lower exposure viral load tenfold among people who get infected despite masking, potentially limiting infection severity. Because peak viral load tends to occur pre-symptomatically, we also identify that antiviral therapy targeting symptomatic individuals is unlikely to impact transmission risk. Instead, antiviral therapy would only lower Re if dosed as post-exposure prophylaxis and if given to ~ 50% of newly infected people within 3 days of an exposure. These results highlight the primacy of masking relative to other biomedical interventions under consideration for limiting the extent of the COVID-19 pandemic prior to widespread implementation of a vaccine. To confirm this prediction, we used a regression model of King County, Washington data and simulated the counterfactual scenario without mask wearing to estimate that in the absence of additional interventions, mask wearing decreased Re from 1.3–1.5 to ~ 1.0 between June and September 2020.

Intervening for HIV prevention and mental health: a review of global literature.

IntroductionNumerous effective HIV prevention options exist, including behaviour change interventions, condom promotion and biomedical interventions, like voluntary medical male circumcision and pre‐exposure prophylaxis. However, populations at risk of HIV also face overlapping vulnerabilities to common mental disorders and severe mental illness. Mental health status can affect engagement in HIV risk behaviours and HIV prevention programmes. We conducted a narrative review of the literature on HIV prevention among key populations and other groups vulnerable to HIV infection to understand the relationship between mental health conditions and HIV prevention outcomes and summarize existing evidence on integrated approaches to HIV prevention and mental healthcare.MethodsWe searched five databases for studies published from January 2015 to August 2020, focused on HIV prevention and mental health conditions among key populations and individuals with serious mental illness. Studies were included if they evaluated an HIV prevention intervention or assessed correlates of HIV risk reduction and included assessment of mental health conditions or a mental health intervention.Results and discussionWe identified 50 studies meeting our inclusion criteria, of which 26 were randomized controlled trials or other experimental designs of an HIV prevention intervention with or without a mental health component. Behaviour change interventions were the most common HIV prevention approach. A majority of studies recruited men who have sex with men and adolescents. Two studies provided distinct approaches to integrated HIV prevention and mental health service delivery. Overall, a majority of included studies showed that symptoms of mental disorder or distress are associated with HIV prevention outcomes (e.g. increased risky sexual behaviour, poor engagement in HIV prevention behaviours). In addition, several studies conducted among groups at high risk of poor mental health found that integrating a mental health component into a behaviour change intervention or linking mental health services to combination prevention activities significantly reduced risk behaviour and mental distress and improved access to mental healthcare.ConclusionsEvidence suggests that mental health conditions are associated with poorer HIV prevention outcomes, and tailored integrated approaches are urgently needed to address overlapping vulnerabilities among key populations and other individuals at risk.

Paradigm Shifting From Bio-Medical to Bio-Psycho-Social and Role of Medical Social Work

The health miseries emerged after the horrific incident of Second World War challenged the bio-medical model dominating the healthcare perceptions during the 19th century. The healthcare interventions in post war years have had to change toward a new idea, the social perspective of health. In 1977, Engel introduced a new approach “bio-psycho-social” (BPS) which emphasized that merely bio-medical intervention by ignoring the psycho-social determinants cannot be helpful in achieving absolute recovery. Although this paradigm shift in healthcare was widely acknowledged but the application of the approach is limited. In the context, the role of Medical Social Work, a profession focused on the reduction of the psycho-social and environmental determinants of health for absolute recovery, is considerable. This review study concludes that the interventions of Social work profession with its unique attributes such as breadth, holistic care and believe in absolute rehabilitation, can make the health system more responsive. Keywords: Healthcare, determinants, Medical Social Work, Social, Psychological

Experiencia de un programa de profilaxis preexposición en una unidad de virus de la inmunodeficiencia humana hospitalaria. Descripción del perfil basal del usuario e identificación de oportunidades de mejora

IntroductionPre-Exposure Prophylaxis (PrEP) is a biomedical intervention to prevent HIV infection in seronegative people at high risk of becoming infected. This strategy was endorsed in October 2019 by the Spanish Ministry of Health. ObjectiveTo present the PrEP initial experience in the HIV Unit of the Hospital Clínic of Barcelona, paying special attention to the analysis of the vulnerability factors in the cohort. Materials and methodsRetrospective, descriptive study. The epidemiological, sociodemographic, and clinical characteristics of the users included in the program during the first year are analyzed, paying particular attention to Infections, risky practices, and substance use. Results190 individuals were included, 177 men and 12 trans women with a mean age of 35 years (8 SD). 70% had higher education, and half had Spanish nationality. An average of 10 couples per trimester and 60% reported unprotected anal sex. 31% had at least one positive PCR for STIs, with N. gonorrhoeae being the most prevalent microorganism (51%) and the rectal sample the most affected (21%). 63% reported chemsex use, 19% polydrug use, and 8% “slamming”. Half expressed concern about consumption and/or sexual practices and 25% the need for help. ConclusionsThe PrEP user profile attended in our Hospital Unit justifies the creation of multidisciplinary teams that allow us to provide holistic attention to the sexual life of these people.

Associations in preventive sexual health service utilization and pre-exposure prophylaxis (PrEP) interest among young Black women in the United States, 2018

ABSTRACT Despite declines in HIV prevalence among all U.S. women, HIV remains a serious concern for Black women. PrEP is an effective biomedical intervention and has high acceptability among Black women. Therefore, offering PrEP, in addition to screening and testing for STI/HIV consistently, can reduce HIV risk among this population. We examine the associations of preventive sexual health service utilization (PSHSU) and PrEP interest among young Black women (YBW) (N = 209) in the United States in 2018. YBW, ages 18–25, completed a self-administered questionnaire, assessing sexual risk and prevention behaviors, HIV/STI testing, and PrEP interest. More than half of YBW were aware of PrEP and its benefits. YBW, who received an HIV test within the past three to six months, had higher odds of PrEP interest. The proportion of YBW who reported being interested in PrEP did not differ by PSHSU. Active contraceptive use was associated with PrEP interest. The results suggest YBW engage in preventive sexual health services, including HIV/STI testing, reproductive health, and sexual health behavioral counseling. Additional efforts should be made to normalize PrEP education for heterosexual, cisgender women at student health centers on college and university campuses, and other venues outside of traditional HIV/STI testing facilities.

If we build it, they will come: Caregiver decision to use an accessible outpatient psychiatric service for children and adolescents in Nigeria

ObjectiveIf child and adolescent psychiatric (CAP) services were accessible in lower-middle-income countries (LMIC) such as Nigeria, what individual and socio-cultural factors would influence caregivers’ willingness to use these services when they are needed? MethodsTo address this question, we conducted structured interviews with a stratified random sampling of 442 adult caregivers of children aged 5 to 19-years who lived within 10 km of an established CAP outpatient service in Ibadan, Nigeria. ResultsBased on structural equation modeling, our cross-sectional findings indicated that caregivers were generally willing to use the accessible outpatient CAP service for a narrow range of overtly disruptive and developmentally atypical child behavior. However, their decisions were not influenced by their recognition of child and adolescent mental health (CAMH) conditions, competing life stressors, caregiver wellness, nor stigma as we had initially hypothesized. Rather caregivers pragmatically considered a range of approaches to address CAMH concerns. Post-hoc hypotheses confirmed that caregivers’ beliefs about etiology and treatment effectiveness for CAMH conditions shaped their help-seeking decisions and stigmatization of CAP services. Specifically, caregivers who attributed CAMH conditions to physical causes regarded biomedical interventions as the most effective treatment while spiritual interventions were deemed to be the least effective. ConclusionsTaken together our results suggested that caregivers were receptive and willing to use outpatient psychiatric services for their children. However, their beliefs about the etiology and treatment effectiveness of CAMH conditions shaped how they intended to engage the services. These findings underscored the importance of scaling up a broader spectrum of accessible complementary CAMH intervention and prevention services in Nigeria that extend beyond indigenous or biomedical models. In doing so caregivers will come.

What is pain: Are cognitive and social features core components?

Pain is a universal experience, but it has been challenging to adequately define. The revised definition of pain recently published by the International Association for the Study of Pain addressed important shortcomings of the previous version; however, it remains narrow in its focus on sensory and emotional features of pain, failing to capture the substantial roles of cognitive and social core components of the experience and their importance to advances in pain management. This paper reviews evidence and theoretical models for the significant role social and cognitive factors play in pain experience and we argue that without explicit recognition of these core components in the definition, significant nuances are lost at a cost to understanding and clinical management of pain. A focus on sensory and emotional features perpetuates biomedical interventions and research, whereas recognition of cognitive and social features supports a multidimensional model of pain, advances in interdisciplinary care, and the benefits of cognitive behavioral therapy and self‐management interventions. We also explore the six Key Notes that accompany the new definition of pain, discuss their application to the understanding of pain in childhood, and, in doing so, further explore social and cognitive implications. Considerations are also described for assessment and treatment of pain in pediatric populations.

A cross-case analysis of developing program sustainability and institutionalization in early stages of a multisite biomedical student diversity initiative

BackgroundGrant funding often drives innovative programming in efforts to enhance diversity in biomedical fields, yet strategies for sustainability of grant-funded biomedical intervention are not well understood. Additionally, as funding agencies shift toward supporting institutional change to biomedical training, less is known about the extent to which sustainability strategies can support long-term institutionalization of the original goals of the grant-funded initiative. The purpose of this study is twofold: to identify strategies used by grant-funded programs for promoting sustainability, and to examine the interrelations between the concepts of sustainability and institutionalization during early stages of grant-funded biomedical career training efforts.MethodsWe employed a multiple case study design and cross-case analysis using interviews of program administrators and participants from 10 undergraduate institutions that received Building Infrastructure Leading to Diversity (BUILD) awards funded by the National Institutes of Health (NIH).ResultsBUILD sites engaged in the following strategies to develop program sustainability: 1) scaling and adapting to expand programmatic impact, 2) identifying additional funding and cost-cutting measures, 3) developing and maintaining infrastructure and structural operations, 4) leveraging relationships and with intra-and inter-institutional partners, and 5) and addressing hiring, policies, and reward systems at the institution. Senior administrative support supported program sustainability and early institutionalization, although we also identified situations where participants felt that they were on track for sustainable changes without administrative support or institutional change. Of the strategies identified, those that involve organizational and infrastructural changes contribute to early stages of institutionalization.ConclusionsThis study contributes to literature on organizational change by providing evidence of distinctions and interrelations between program sustainability efforts and institutionalization of change efforts in that some sustainability strategies can overlap with strategies to move toward institutionalization. The findings indicate the importance of program administrators developing early sustainability plans that also lead to institutionalization, as well as an opportunity for funding agencies to develop technical assistance on sustainability, organizational change, and institutionalization as a resource to support program administrators’ efforts toward making lasting, structural change on their campuses.

Interventions on Food Security and Water Uses for Improving Nutritional Status of Pregnant Women and Children Younger Than Five Years in Low-Middle Income Countries: A Systematic Review.

Malnutrition is a global health issue concerning children and pregnant women in low- and middle-income countries (LMICs). The aim of this review was to assess the health-impact outcomes of interventions addressing food security, water quality and hygiene in order to address the improvement of the nutritional status in children below five years and pregnant women in LMICs. Using PRISMA procedures, a systematic review was conducted by searching in biomedical databases clinical trials and interventions for children and pregnant women. Full articles were screened (nf = 252) and critically appraised. The review included 27 randomized and non-randomized trials and interventions. Based on the analysis, three agents concerning nutritional status were identified. First, exclusive breastfeeding and complementary feeding were fundamental elements in preventing malnutrition. Second, provision of sanitation facilities and the promotion of hygienic practices were also essential to prevent infections spread and the consequent deterioration of nutritional status. Finally, seasonality was also seen to be a relevant factor to consider while planning and implementing interventions in the populations under study. In spite of the efforts conducted over last decades, the improvement in food insecurity rates has remained insufficient. Therefore, the development of global health programs is fundamental to guide future actions.

In Silico Assessment of SARS-CoV-2 Mutations with Relevancy to Prophylactic and Monoclonal-Based Treatment Strategies

Abstract The ongoing pandemic caused by SARS-CoV-2 has inflicted significant disease burden worldwide. Several vaccines are now in use that are based on the virus’s highly immunogenic spike “S” protein, which mediates infection of host cells. However, since the emergence of the reference strain in 2019, the virus has underdone >40,000 nucleotide mutations, many of which have resulted in deletions or amino acid substitutions in the S protein. Most mutations appear to be random, while others deviate from expected outcomes. Indeed, some non-random mutations appear to confer resistance to either innate or adaptive immune functions while other enhance transmissibility. Although the consequences of these mutations are largely unknown, there is concern for the ability of select mutations to detract from the protection conferred by prophylaxis strategies and interventional therapies. We have therefore selected >50 whole genome-length mutant strain from 3 relatively closed populations to compare against widely circulating strains of concern and the reference strain so that we could assess differences in mutation events within the context of distinct population immunogenetics. For each strain we have biochemically characterized potentially critical mutations, assessed the randomness of each mutation, and assessed key mutations occurring in the S, M, E and N proteins for their ability to influence innate or adaptive immune recognition using bioinformatic platforms. The results of this study further our understanding for how these mutations influence population-based immunity to the virus, including biomedical interventions, as well as help explain the selection pressures and external events that are driving this genetic diversification.

Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein.

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.