Potential impact of annual vaccination with reformulated COVID-19 vaccines: Lessons from the US COVID-19 scenario modeling hub.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Here, we present projections of COVID-19 hospitalizations and deaths in the United States for the next 2 years under 2 plausible assumptions about immune escape (20% per year and 50% per year) and 3 possible CDC recommendations for the use of annually reformulated vaccines (no recommendation, vaccination for those aged 65 years and over, vaccination for all eligible age groups based on FDA approval). METHODS AND FINDINGS: The COVID-19 Scenario Modeling Hub solicited projections of COVID-19 hospitalization and deaths between April 15, 2023 and April 15, 2025 under 6 scenarios representing the intersection of considered levels of immune escape and vaccination. Annually reformulated vaccines are assumed to be 65% effective against symptomatic infection with strains circulating on June 15 of each year and to become available on September 1. Age- and state-specific coverage in recommended groups was assumed to match that seen for the first (fall 2021) COVID-19 booster. State and national projections from 8 modeling teams were ensembled to produce projections for each scenario and expected reductions in disease outcomes due to vaccination over the projection period. From April 15, 2023 to April 15, 2025, COVID-19 is projected to cause annual epidemics peaking November to January. In the most pessimistic scenario (high immune escape, no vaccination recommendation), we project 2.1 million (90% projection interval (PI) [1,438,000, 4,270,000]) hospitalizations and 209,000 (90% PI [139,000, 461,000]) deaths, exceeding pre-pandemic mortality of influenza and pneumonia. In high immune escape scenarios, vaccination of those aged 65+ results in 230,000 (95% confidence interval (CI) [104,000, 355,000]) fewer hospitalizations and 33,000 (95% CI [12,000, 54,000]) fewer deaths, while vaccination of all eligible individuals results in 431,000 (95% CI: 264,000-598,000) fewer hospitalizations and 49,000 (95% CI [29,000, 69,000]) fewer deaths. CONCLUSIONS: COVID-19 is projected to be a significant public health threat over the coming 2 years. Broad vaccination has the potential to substantially reduce the burden of this disease, saving tens of thousands of lives each year.

Effects of energy-restricted diets with or without nuts on weight, body composition and glycaemic control in adults: a scoping review.

Energy-restricted (ER) diets promote weight loss and improve body composition and glycaemic control. Nut consumption also improves these parameters. However, less is known about the combined benefit of these two strategies. This scoping review implemented a systematic search of Medline, Embase and Scopus to identify randomised controlled trials evaluating the effect of ER diets with or without nuts on body mass, body composition and glycaemic control in adults. After reviewing titles and abstracts, twenty-nine full-text articles were screened, resulting in seven studies reported in eight papers that met the inclusion criteria. Energy restriction was achieved by prescribing a set energy target or reducing intake by 1000-4200 kJ from daily energy requirements. Interventions ranged from 4 to 52 weeks in duration and contained 42-84 g/d of almonds, peanuts, pistachios or walnuts. While all studies reported that energy restriction resulted in significant weight loss, the addition of nuts to ER diets demonstrated significantly greater weight loss in only approximately half of the included studies (4/7 studies). There was limited evidence to support additional benefits from nuts for body composition measures or glycaemic control. Although improvements in weight loss and glycaemia were not consistent when nuts were included in ER diets, no study revealed an adverse effect of nut consumption on health outcomes. Future studies could explore the effect of consuming different types and amounts of nuts, combined with various levels of energy restriction on weight, body composition and glycaemic control.

Primary Targeted Muscle Reinnervation in Above-Knee Amputations in Patients with Unsalvageable Limbs from Limb-Threatening Ischemia or Infection.

BACKGROUND: Amputees frequently suffer from chronic pain in both their residual limbs (RLP) and phantom limbs (PLP) following their amputation. Targeted muscle reinnervation (TMR) is a nerve transfer technique that has been demonstrated to improve pain secondarily and at time of amputation. The goal of this study is to report on the efficacy of primary TMR at time of above-knee level amputations in the setting of limb-threatening ischemia or infection. METHODS: This is a retrospective review of a single-surgeon experience with TMR in patients undergoing through- or above-knee level amputations from January 2018 to June 2021. Patient charts were reviewed for the comorbidities in the Charlson Comorbidity Index. Postoperative notes were assayed for presence and absence of RLP and PLP, overall pain severity, chronic narcotic use, ambulatory status, and complications. A control group of patients undergoing lower limb amputation who did not receive TMR from January 2014 to December 2017 was used for comparison. RESULTS: Forty-one patients with through- or above-knee level amputations and primary TMR were included in this study. The tibial and common peroneal nerves were transferred in all cases to motor branches to the gastrocnemius, semimembranosus, semitendinosus, and biceps femoris. Fifty-eight patients with through- or above-knee level amputations without TMR were included for comparison. The TMR group had significantly less overall pain (41.5 vs. 67.2%, p = 0.01), RLP (26.8 vs. 44.8%, p = 0.04), and PLP (19.5 vs. 43.1%, p = 0.02). There were no significant differences in complication rates. CONCLUSION: TMR can safely and effectively be performed at time of a through- and above-knee level amputation and improves pain outcomes.

To Mesh or Not to Mesh: What Is the Ideal Meshing Ratio for Split Thickness Skin Grafting of the Lower Extremity?

Split-thickness skin grafts can provide effective autologous wound closure in patients with dysvascular comorbidities. Meshing the graft allows for reduced donor site morbidity and expanded coverage. This study directly compares outcomes across varying meshing ratios used to treat chronic lower extremity wounds. Patients who received split-thickness skin grafts to their lower extremity for chronic ulcers from December 2014 to December 2019 at a single center were retrospectively reviewed. Patients were stratified by meshing ratios: nonmeshed (including pie crusting), 1.5:1, and 3:1. The primary outcome was clinical "healing" as determined by surgeon discretion at 30 days, 60 days, and the latest follow-up. Secondary outcomes included postoperative complications, graft loss, ulcer recurrence, progression to amputation, and mortality. A total of 321 patients were identified. Wound sizes and location differed significantly, with 3:1 meshing applied to the largest wounds (187.8 ± 157.6 cm2; 1.5:1 meshed, 110.4 ± 103.9 cm2; nonmeshed 38.7 ± 55.5 cm2; p < .0001) mostly of the lower leg (n = 18, 75%; 1.5:1 meshed, n = 23, 43.4%; nonmeshed n = 62, 25.7%; p < .0001). Meshed grafts displayed a significantly higher proportion of healing at 30 and 60 days, but no differences persisted by the final follow-up (16.5 ± 20.5 months). Longitudinally, nonmeshed STSG was associated with most graft loss (46, 19.1%; p = .011) and ulcer recurrence (44, 18.3%; p = .011). Of the 3 meshing ratios, 3:1 exhibited the lowest rates of complications. Our results suggest that 3:1 meshing is a safe option for coverage of large lower extremity wounds to minimize donor site morbidity.

Postoperative Glycemic Response in High-Risk Type II Diabetics Receiving Below-Knee Amputation: Does Intraoperative Dexamethasone Make an Impact?

Despite known risks of hyperglycemia on postoperative complications, the influence of intraoperative dexamethasone on blood glucose has yet to be evaluated within the diabetic limb salvage population. This study aimed to assess the effect of intraoperative dexamethasone on postoperative blood glucose in diabetic patients undergoing atraumatic major lower extremity amputations. A single-center retrospective review of diabetic patients undergoing below-knee amputation between January 2017 and December 2022 was performed. Blood glucose levels for the 5 days before and after amputation were recorded and compared with the primary endpoints of postoperative hyperglycemia (>200 mg/dL) and glucose variability (>200 mg/dL). Cohorts were divided by patients who did and did not receive intraoperative administration of dexamethasone. Three hundred eighty-one were screened for eligibility with 180 patients included. Of these, 50 patients received dexamethasone intraoperatively (38.5%). Average pre- and postoperative blood glucose, rate of pre- and postoperative hyperglycemia, perioperative glucose variability, and postoperative dehiscence and infection were comparable between cohorts. On multivariate analysis, intraoperative administration of dexamethasone was not associated with postoperative hyperglycemia (p = .104) or perioperative blood glucose variability > 200 mg/dL (p = .334). Perioperative blood glucose variability > 200 mg/dL was associated with higher odds of surgical site infection (SSI) (odds ratio 5.12, p = .003). Administration of intravenous dexamethasone to diabetic patients undergoing below-knee amputation is not associated with postoperative hyperglycemia or complications. This study confirms previous findings that high glucose is a predictor of SSI. Concerted effort by a multidisciplinary team to attain tight glycemic control is critical to optimizing healing.

Eggs and Cardiovascular Disease Risk: An Update of Recent Evidence.

PURPOSE OF REVIEW: This review summarizes recent evidence published since a previous review in 2018 on the association between egg consumption and risk of cardiovascular disease (CVD) mortality, CVD incidence, and CVD risk factors. RECENT FINDINGS: No recent randomized controlled trials were identified. Evidence from observational studies is mixed, with studies reporting either an increased risk or no association of highest egg consumption with CVD mortality, and a similar spread of increased risk, decreased risk, or no association between egg intake and total CVD incidence. Most studies reported a reduced risk or no association between egg consumption and CVD risk factors. Included studies reported low and high egg intake as between 0 and 1.9 eggs/week and 2 and ≥14 eggs/week, respectively. Ethnicity may influence the risk of CVD with egg consumption, likely due to differences in how eggs are consumed in the diet rather than eggs themselves. Recent findings are inconsistent regarding the possible relationship between egg consumption and CVD mortality and morbidity. Dietary guidance should focus on improving the overall quality of the diet to promote cardiovascular health.

Acute feeding with almonds compared to a carbohydrate-based snack improves appetite-regulating hormones with no effect on self-reported appetite sensations: a randomised controlled trial.

PURPOSE: Early satiety has been identified as one of the mechanisms that may explain the beneficial effects of nuts for reducing obesity. This study compared postprandial changes in appetite-regulating hormones and self-reported appetite ratings after consuming almonds (AL, 15% of energy requirement) or an isocaloric carbohydrate-rich snack bar (SB). METHODS: This is a sub-analysis of baseline assessments of a larger parallel-arm randomised controlled trial in overweight and obese (Body Mass Index 27.5-34.9 kg/m2) adults (25-65 years). After an overnight fast, 140 participants consumed a randomly allocated snack (AL [n = 68] or SB [n = 72]). Appetite-regulating hormones and self-reported appetite sensations, measured using visual analogue scales, were assessed immediately before snack food consumption, and at 30, 60, 90 and 120 min following snack consumption. A sub-set of participants (AL, n = 49; SB, n = 48) then consumed a meal challenge buffet ad libitum to assess subsequent energy intake. An additional appetite rating assessment was administered post buffet at 150 min. RESULTS: Postprandial C-peptide area under the curve (AUC) response was 47% smaller with AL compared to SB (p < 0.001). Glucose-dependent insulinotropic polypeptide, glucagon and pancreatic polypeptide AUC responses were larger with AL compared to SB (18%, p = 0.005; 39% p < 0.001; 45% p < 0.001 respectively). Cholecystokinin, ghrelin, glucagon-like peptide-1, leptin and polypeptide YY AUCs were not different between groups. Self-reported appetite ratings and energy intake following the buffet did not differ between groups. CONCLUSION: More favourable appetite-regulating hormone responses to AL did not translate into better self-reported appetite or reduced short-term energy consumption. Future studies should investigate implications for longer term appetite regulation. ANZCTR REFERENCE NUMBER: ACTRN12618001861246 2018.

The risk of drug resistance during long-acting antimicrobial therapy.

The emergence of drug resistance during antimicrobial therapy is a major global health problem, especially for chronic infections like human immunodeficiency virus, hepatitis B and C, and tuberculosis. Sub-optimal adherence to long-term treatment is an important contributor to resistance risk. New long-acting drugs are being developed for weekly, monthly or less frequent dosing to improve adherence, but may lead to long-term exposure to intermediate drug levels. In this study, we analyse the effect of dosing frequency on the risk of resistance evolving during time-varying drug levels. We find that long-acting therapies can increase, decrease or have little effect on resistance, depending on the source (pre-existing or de novo) and degree of resistance, and rates of drug absorption and clearance. Long-acting therapies with rapid drug absorption, slow clearance and strong wild-type inhibition tend to reduce resistance caused by partially resistant strains in the early stages of treatment even if they do not improve adherence. However, if subpopulations of microbes persist and can reactivate during sub-optimal treatment, longer-acting therapies may substantially increase the resistance risk. Our results show that drug kinetics affect selection for resistance in a complicated manner, and that pathogen-specific models are needed to evaluate the benefits of new long-acting therapies.

Dynamics of COVID-19 under social distancing measures are driven by transmission network structure.

In the absence of pharmaceutical interventions, social distancing is being used worldwide to curb the spread of COVID-19. The impact of these measures has been inconsistent, with some regions rapidly nearing disease elimination and others seeing delayed peaks or nearly flat epidemic curves. Here we build a stochastic epidemic model to examine the effects of COVID-19 clinical progression and transmission network structure on the outcomes of social distancing interventions. Our simulations show that long delays between the adoption of control measures and observed declines in cases, hospitalizations, and deaths occur in many scenarios. We find that the strength of within-household transmission is a critical determinant of success, governing the timing and size of the epidemic peak, the rate of decline, individual risks of infection, and the success of partial relaxation measures. The structure of residual external connections, driven by workforce participation and essential businesses, interacts to determine outcomes. We suggest limited conditions under which the formation of household "bubbles" can be safe. These findings can improve future predictions of the timescale and efficacy of interventions needed to control second waves of COVID-19 as well as other similar outbreaks, and highlight the need for better quantification and control of household transmission.

Minimal changes in telomere length after a 12-week dietary intervention with almonds in mid-age to older, overweight and obese Australians: results of a randomised clinical trial.

Diet is a modifiable risk factor for chronic disease and a potential modulator of telomere length (TL). The study aim was to investigate associations between diet quality and TL in Australian adults after a 12-week dietary intervention with an almond-enriched diet (AED). Participants (overweight/obese, 50-80 years) were randomised to an AED (n 62) or isoenergetic nut-free diet (NFD, n 62) for 12 weeks. Diet quality was assessed using a Dietary Guideline Index (DGI), applied to weighed food records, that consists of ten components reflecting adequacy, variety and quality of core food components and discretionary choices within the diet. TL was measured by quantitative PCR in samples of lymphocytes, neutrophils, and whole blood. There were no significant associations between DGI scores and TL at baseline. Diet quality improved with AED and decreased with NFD after 12 weeks (change from baseline AED + 9·8 %, NFD - 14·3 %; P < 0·001). TL increased in neutrophils (+9·6 bp, P = 0·009) and decreased in whole blood, to a trivial extent (-12·1 bp, P = 0·001), and was unchanged in lymphocytes. Changes did not differ between intervention groups. There were no significant relationships between changes in diet quality scores and changes in lymphocyte, neutrophil or whole blood TL. The inclusion of almonds in the diet improved diet quality scores but had no impact on TL mid-age to older Australian adults. Future studies should investigate the impact of more substantial dietary changes over longer periods of time.

Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys.

The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy. Here we show that therapeutic vaccination with Ad26/MVA (recombinant adenovirus serotype 26 (Ad26) prime, modified vaccinia Ankara (MVA) boost) and stimulation of TLR7 (Toll-like receptor 7) improves virologic control and delays viral rebound following discontinuation of antiretroviral therapy in SIV-infected rhesus monkeys that began antiretroviral therapy during acute infection. Therapeutic vaccination with Ad26/MVA resulted in a marked increase in the magnitude and breadth of SIV-specific cellular immune responses in virologically suppressed, SIV-infected monkeys. TLR7 agonist administration led to innate immune stimulation and cellular immune activation. The combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in lymph nodes and peripheral blood, and improved virologic control and delayed viral rebound following discontinuation of antiretroviral therapy. The breadth of cellular immune responses correlated inversely with set point viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination combined with innate immune stimulation as a strategy aimed at a functional cure for HIV-1 infection.

Dynamics of bed bug infestations and control under disclosure policies.

Bed bugs have reemerged in the United States and worldwide over recent decades, presenting a major challenge to both public health practitioners and housing authorities. A number of municipalities have proposed or initiated policies to stem the bed bug epidemic, but little guidance is available to evaluate them. One contentious policy is disclosure, whereby landlords are obligated to notify potential tenants of current or prior bed bug infestations. Aimed to protect tenants from leasing an infested rental unit, disclosure also creates a kind of quarantine, partially and temporarily removing infested units from the market. Here, we develop a mathematical model for the spread of bed bugs in a generalized rental market, calibrate it to parameters of bed bug dispersion and housing turnover, and use it to evaluate the costs and benefits of disclosure policies to landlords. We find disclosure to be an effective control policy to curb infestation prevalence. Over the short term (within 5 years), disclosure policies result in modest increases in cost to landlords, while over the long term, reductions of infestation prevalence lead, on average, to savings. These results are insensitive to different assumptions regarding the prevalence of infestation, rate of introduction of bed bugs from other municipalities, and the strength of the quarantine effect created by disclosure. Beyond its application to bed bugs, our model offers a framework to evaluate policies to curtail the spread of household pests and is appropriate for systems in which spillover effects result in highly nonlinear cost-benefit relationships.

Insight into treatment of HIV infection from viral dynamics models.

The odds of living a long and healthy life with HIV infection have dramatically improved with the advent of combination antiretroviral therapy. Along with the early development and clinical trials of these drugs, and new field of research emerged called viral dynamics, which uses mathematical models to interpret and predict the time-course of viral levels during infection and how they are altered by treatment. In this review, we summarize the contributions that virus dynamics models have made to understanding the pathophysiology of infection and to designing effective therapies. This includes studies of the multiphasic decay of viral load when antiretroviral therapy is given, the evolution of drug resistance, the long-term persistence latently infected cells, and the rebound of viremia when drugs are stopped. We additionally discuss new work applying viral dynamics models to new classes of investigational treatment for HIV, including latency-reversing agents and immunotherapy.

Cutaneous toxicities occurring during palbociclib (CDK4/6 inhibitor) and endocrine therapy in patients with advanced breast cancer: a single-centre experience.

PURPOSE: Treatment with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with letrozole or fulvestrant endocrine therapies. However, limited information exists on its cutaneous adverse effects (AE). Hence, we conducted a retrospective cohort study to investigate the prevalence and management of cutaneous AE during palbociclib and endocrine therapy. METHOD: We included 324 adult patients with advanced breast cancer who received palbociclib between March 2016 and August 2020 within a tertiary comprehensive cancer centre. Patient demographics, details of previous and concurrent treatments, as well as treatment-related cutaneous AE were recorded from electronic records. RESULTS: The incidence of treatment-related cutaneous AE was 14.2% (46 from a total of 324 patients). The most frequent cutaneous reactions included maculopapular rash (41%), asteatosis (37%), pruritus and urticaria (20%), and bullous dermatitis reactions (9%). We identified two patients with treatment-induced subacute cutaneous lupus erythematosus, one case of bullous pemphigoid, and a single erythema multiforme. Patients received an average of 9 cycles of treatment, completing an average of 6 cycles before developing cutaneous AE, which persisted for a median of 43 days. Only 15% (n = 7) of affected patients required temporary suspension, and 4% (n = 2) required discontinuation. The majority were managed with potent topical steroids, with oral corticosteroids being required in 3 patients, and one patient required hydroxychloroquine. CONCLUSION: Our study describes both the spectrum of cutaneous AE of palbociclib and endocrine therapy, and approaches to management. Prompt management may limit the negative impact on patients, facilitating beneficial continuation of palbociclib and endocrine therapy.

Population structure across scales facilitates coexistence and spatial heterogeneity of antibiotic-resistant infections.

Antibiotic-resistant infections are a growing threat to human health, but basic features of the eco-evolutionary dynamics remain unexplained. Most prominently, there is no clear mechanism for the long-term coexistence of both drug-sensitive and resistant strains at intermediate levels, a ubiquitous pattern seen in surveillance data. Here we show that accounting for structured or spatially-heterogeneous host populations and variability in antibiotic consumption can lead to persistent coexistence over a wide range of treatment coverages, drug efficacies, costs of resistance, and mixing patterns. Moreover, this mechanism can explain other puzzling spatiotemporal features of drug-resistance epidemiology that have received less attention, such as large differences in the prevalence of resistance between geographical regions with similar antibiotic consumption or that neighbor one another. We find that the same amount of antibiotic use can lead to very different levels of resistance depending on how treatment is distributed in a transmission network. We also identify parameter regimes in which population structure alone cannot support coexistence, suggesting the need for other mechanisms to explain the epidemiology of antibiotic resistance. Our analysis identifies key features of host population structure that can be used to assess resistance risk and highlights the need to include spatial or demographic heterogeneity in models to guide resistance management.

Cancer patient experience of telephone clinics implemented in light of COVID-19.

INTRODUCTION: Due to the pandemic of COVID-19 a number of National Health Service (NHS) Trusts in the UK adopted telephone consultations for patients who were shielding. As the pandemic continues to affect these services an evaluation was conducted to determine whether telephone consultations implemented during the pandemic should be maintained long term. The objective was to evaluate this new service and to understand patient experience. METHODS: This study was conducted via a telephone survey. Staff working in the Macmillan centres across the Trust called patients to survey them about their experience of telephone consultations. Data were collected 23/06/20 - 17/07/20. A mix of eight open and closed questions were asked. Data were collected on an Excel spreadsheet and patient identifiable information was anonymised. RESULTS: 55 patients accepted to participate in this study. Out of 55, 39 patients rated the phone consultation they had as either 4 or 5 out of 5. When asked if they would like to continue with phone clinics 33 said they would. The majority of consultations were conducted by doctors (43/55). Patients commented they had received great support from their healthcare professionals and they felt that phone consultations were safer in the current climate. Three of the patients felt the calls were rushed and others found it difficult to discuss pain management, sides effects and post-surgery issues. CONCLUSIONS: This evaluation provides a brief snapshot of the experience cancer patients are having with phone clinics. A re-evaluation will take place once video consultations are implemented.

Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane.

The latent reservoir for HIV-1 in resting CD4+ T cells is a major barrier to cure. Several lines of evidence suggest that the latent reservoir is maintained through cellular proliferation. Analysis of this proliferative process is complicated by the fact that most infected cells carry defective proviruses. Additional complications are that stimuli that drive T cell proliferation can also induce virus production from latently infected cells and productively infected cells have a short in vivo half-life. In this ex vivo study, we show that latently infected cells containing replication-competent HIV-1 can proliferate in response to T cell receptor agonists or cytokines that are known to induce homeostatic proliferation and that this can occur without virus production. Some cells that have proliferated in response to these stimuli can survive for 7 d while retaining the ability to produce virus. This finding supports the hypothesis that both antigen-driven and cytokine-induced proliferation may contribute to the stability of the latent reservoir. Sequencing of replication-competent proviruses isolated from patients at different time points confirmed the presence of expanded clones and demonstrated that while some clones harboring replication-competent virus persist longitudinally on a scale of years, others wax and wane. A similar pattern is observed in longitudinal sampling of residual viremia in patients. The observed patterns are not consistent with a continuous, cell-autonomous, proliferative process related to the HIV-1 integration site. The fact that the latent reservoir can be maintained, in part, by cellular proliferation without viral reactivation poses challenges to cure.

Controlled Human Infection With Bordetella pertussis Induces Asymptomatic, Immunizing Colonization.

BACKGROUND: Bordetella pertussis is among the leading causes of vaccine-preventable deaths and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infections might be a target of future vaccine strategies, but has not been demonstrated. Our objective was to demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define the microbiological and immunological features of presymptomatic infection. METHODS: Healthy subjects aged 18-45 years with an antipertussis toxin immunoglobin G (IgG) concentration of <20 international units/ml were inoculated intranasally with nonattenuated, wild-type Bordetella pertussis strain B1917. Safety, colonization, and shedding were monitored over 17 days in an inpatient facility. Colonization was assessed by culture and quantitative polymerase chain reaction. Azithromycin was administered from Day 14. The inoculum dose was escalated, aiming to colonize at least 70% of participants. Immunological responses were measured. RESULTS: There were 34 participants challenged, in groups of 4 or 5. The dose was gradually escalated from 103 colony-forming units (0% colonized) to 105 colony-forming units (80% colonized). Minor symptoms were reported in a minority of participants. Azithromycin eradicated colonization in 48 hours in 88% of colonized individuals. Antipertussis toxin IgG seroconversion occurred in 9 out of 19 colonized participants and in none of the participants who were not colonized. Nasal wash was a more sensitive method to detect colonization than pernasal swabs. No shedding of Bordetella pertussis was detected in systematically collected environmental samples. CONCLUSIONS: Bordetella pertussis colonization can be deliberately induced and leads to a systemic immune response without causing pertussis symptoms. CLINICAL TRIALS REGISTRATION: NCT03751514.

Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys.

The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

High-Resolution Sequencing of Viral Populations during Early Simian Immunodeficiency Virus Infection Reveals Evolutionary Strategies for Rapid Escape from Emerging Env-Specific Antibody Responses.

Primate lentiviruses, including the human and simian immunodeficiency viruses (HIV and SIV), produce infections marked by persistent, ongoing viral replication. This occurs despite the presence of virus-specific adaptive immune responses, including antibodies targeting the viral envelope glycoprotein (Env), and evolution of antibody-escape variants is a well-documented feature of lentiviral infection. Here, we examined the evolutionary dynamics of the SIV env gene during early infection (≤29 weeks postinfection) in a cohort of four SIVmac251-infected rhesus macaques. We tracked env evolution during acute and early infection using frequent sampling and ultradeep sequencing of viral populations, capturing a transmission bottleneck and the subsequent reestablishment of Env diversity. A majority of changes in the gp120 subunit mapped to two short clusters, one in the first variable region (V1) and one in V4, while most changes in the gp41 subunit appeared in the cytoplasmic domain. Variation in V1 was dominated by short duplications and deletions of repetitive sequence, while variation in V4 was marked by short in-frame deletions and closely overlapping substitutions. The most common substitutions in both patches did not alter viral replicative fitness when tested using a highly sensitive, deep-sequencing-based competition assay. Our results, together with the observation that very similar or identical patterns of sequence evolution also occur in different macaque species infected with related but divergent strains of SIV, suggest that resistance to early, strain-specific anti-Env antibodies is the result of temporally and mutationally predictable pathways of escape that occur during the early stages of infection.IMPORTANCE The envelope glycoprotein (Env) of primate lentiviruses mediates entry by binding to host cell receptors followed by fusion of the viral membrane with the cell membrane. The exposure of Env complexes on the surface of the virion results in targeting by antibodies, leading to selection for virus escape mutations. We used the SIV/rhesus macaque model to track in vivo evolution of variation in Env during acute/early infection in animals with and without antibody responses to Env, uncovering remarkable variation in animals with antibody responses within weeks of infection. Using a deep-sequencing-based fitness assay, we found substitutions associated with antibody escape had little to no effect on inherent replicative capacity. The ability to readily propagate advantageous changes that incur little to no replicative fitness costs may be a mechanism to maintain continuous replication under constant immune selection, allowing the virus to persist for months to years in the infected host.