High Risk For Serious Disease Research Articles

1348. Identification of GB-0669, a Novel S-2 Targeted Spike Monoclonal Antibody in Development for SARS-CoV-2 Prophylaxis

Abstract Background The clinical benefit of anti-spike mAbs for prophylaxis and treatment of SARS-CoV-2 is now well established (Baum 2020, Loo 2022, Westendorf 2022, Jones 2021, Kreuzberger 2021, Cathcart 2021, Hirsch 2022, Shi 2020); However, the evolution of SARS CoV-2 due to immune pressure has compromised the utility of all previously approved mAbs which target the variable, immune dominant receptor binding domain of the Spike protein. Despite the success of vaccination protecting the general population, the immunocompromised and elderly remain at high risk of serious disease and mortality from SARS CoV-2 infection. Therefore, there is a need to develop mAbs that remain active across current and emergent SARS CoV-2 variants for such populations. Methods The Generate Platform uses machine learning (ML) models to generate therapeutics with desirable properties. We used this platform to explore the amino acid sequence landscape compatible with the binding conformation and breadth of neutralization for mAbs targeting the conserved S-2 stem helix of Spike. While S-2 directed antibodies can broadly neutralize diverse coronaviruses, they are generally limited by potency. We employed an iterative computation- experimentation loop to design antibodies that bind to the S-2 stem helix, optimizing for potency, breadth and developability. Results The Generate Platform was employed to identify S-2 targeted Spike antibodies with high potency and breadth of neutralization resulting in GB-0669. GB-0669 exhibits sub-nM neutralization against all SARS-CoV-2 variants and Omicron sublineages including the highly immune evasive strain XBB. GB-0669 also displays sub-nM neutralization against sarbecoviruses associated with previous epidemics (SARS-CoV-1) and those of pandemic potential (WIV1, bat SARS-like coronavirus). The GB 0669 epitope was mapped by co-crystallization and is consistent with the observed breadth; all key interactions are >99% conserved with no evidence of immune escape. Conclusion GB-0669, a novel mAB targeting the conserved S-2 region of Spike, is hypothesized to be effective for prophylaxis of COVID-19 across all Omicron sublineages and future variants as well as CoVs with pandemic potential. Disclosures Francesco Borriello, MD PhD, Generate Biomedicines: Employee Gevorg Grigoryan, PhD, Generate Biomedicines: Chief Technology Officer|Generate Biomedicines: Ownership Interest|Generate Biomedicines: Stocks/Bonds Daria Hazuda, PhD, Generate Biomedicines: Employee|Generate Biomedicines: Stocks/Bonds|Merck and Co: Employee|Merck and Co: Stocks/Bonds Nathan H. Joh, PhD, Generate Biomedicines: Employee at Generate Biomedicines

COVID-19 mortality prediction using ensemble learning and grey wolf optimization.

COVID-19 is now often moderate and self-recovering, but in a significant proportion of individuals, it is severe and deadly. Determining whether individuals are at high risk for serious disease or death is crucial for making appropriate treatment decisions. We propose a computational method to estimate the mortality risk for patients with COVID-19. To develop the model, 4,711 reported cases confirmed as SARS-CoV-2 infections were used for model development. Our computational method was developed using ensemble learning in combination with a genetic algorithm. The best-performing ensemble model achieves an AUCROC (area under the receiver operating characteristic curve) value of 0.7802. The best ensemble model was developed using only 10 features, which means it requires less medical information so that the diagnostic cost may be reduced while the prognostic time may be improved. The results demonstrate the robustness of the used method as well as the efficiency of the combination of machine learning and genetic algorithms in developing the ensemble model.

Fear of Covid 19 during the third wave of infection in Norwegian patients with type 1 diabetes.

To study the fear of Covid 19 infection among Norwegian patients with type 1 diabetes. Fear of Covid 19 scale, a validated scale assessing the fear of Covid 19, was sent electronically to 16255 patients with type 1 diabetes in May 2021. The items are rated on a scale from 1 to 5 (total scores from 7 to 35). The higher the score, the greater the fear. 10145 patients, 52% of the Norwegian adult type 1 diabetes population, completed the questionnaire. The mean total fear score was 13.8 (SD 5.8). Women experienced more fear than men (OR 1.96), and fear increased significantly with increasing age for both genders (p<0.05). Fear increased with increasing BMI, more pronounced for men than women. Fear was positively correlated to HbA1c (Spearman rho 0.067, p<0.05), and significantly increased in patients with micro- and macrovascular complications, compared with patients without complications (p<0.05). Smokers showed increased fear compared with non-smokers, (1.59 (1.39-1.81)), and non-European patients reported more fear than Europeans (OR of 2.02 (95% CI 1.55-2.63). Assessment of fear of Covid 19 in the type 1 diabetes population in Norway revealed an overall low fear during the third wave of infection. Patients considered to be at high risk of serious disease, such as older individuals, smokers and obese individuals expressed more fear than low risk individuals. The degree of fear was also associated with sex, ethnicity, educational/working status, glycemic control and presence of complications.

Standard Definitions of Pneumococcal Immunity May Not Accurately Predict Protection in Adults with Sickle Cell Disease

Patients with sickle cell disease (SCD) are now routinely living into adulthood, but SCD has deleterious effects on multiple organ systems which can lead to increased complications from illness. SCD patients generally auto-splenectomize in childhood secondary to infarctions from their hemoglobinopathy, thus increasing their risk of infection with encapsulated organisms such as S. pneumoniae. Although there are data to demonstrate that vaccination has drastically decreased the incidence of invasive pneumococcal disease (i.e. bacteremia or meningitis) in children, the situation for adults is less clear. There are no data to guide the decision to use conjugated and/or polysaccharide pneumococcus vaccines in adults. In addition, there are few data available on the efficacy of pneumococcal vaccination on non-invasive disease such as pneumonia. Two landmark studies have demonstrated the efficacy of polysaccharide-based pneumococcal vaccines in the general adult population to be approximately 56%. However, there are data to suggest that immune responses in SCD patients may be impaired, and thus responses to vaccines may be suboptimal. Current sickle cell guidelines for pneumococcal vaccination, which are based on expert opinion, recommend one dose of Prevnar 13 (conjugated vaccine) followed by one dose of Pneumovax 23 (polysaccharide vaccine) with a booster of Pneumovax 23 at age 65. However, some clinicians choose to vaccinate every 5 years due to fear of waning immunity. There is a lack of data on which to base guidelines, and there are also no data nor any guidelines to help decide if patients needs additional boosters of vaccine. Besides the potential for suboptimal immune responses in sickle cell patients, the standard definition used to define a responder to pneumococcal vaccine may not translate to protection from disease in the real world. Most studies define a responder as having a protective titer to 50-70% of the serotypes tested. However, this definition has no consideration for the prevalence of serotypes causing disease in the community. Therefore it's possible to have a patient who responds to 50% of the serotypes in the assay and is considered immune, but if those serotypes are all uncommon, then the patient may still be at high risk for serious disease. Determining a better way to identify patients at risk for pneumococcal disease and optimizing vaccination strategies to prevent this disease would help to improve the lives of patients. We performed a retrospective study to investigate immunity to pneumococcus in adult patients with SCD. We used the electronic medical record and collected data on patient demographics, sickle cell genotype, dates of previous pneumococcal vaccination (both conjugated and polysaccharide vaccines), quantitative antibody levels to individual pneumococcus serotypes, as well as information on comorbidities. In our sample of n=28 patients with SCD and available antibody data, 68% met a commonly accepted definition of immunity, which we defined by having an antibody concentration ≥ 1 mcg/mL for at least 50% of any of the serotypes tested. Immunity was inversely correlated with time from last pneumococcal vaccination, and it did not matter whether the most recent vaccine was the conjugated or polysaccharide product (Fig 1a). We then sought to analyze the data with consideration for the prevalence of various serotypes based on epidemiologic data published in The Lancet Infectious Diseases15,301-309 (2015). Interestingly, only 21% of patients who met the traditional definition of being a vaccine responder had protective titers to all 3 of the most prevalent serotypes tested, and 10% of patients who would traditionally be characterized as vaccine responders did not have sufficient antibody production to any of the 3 most prevalent serotypes tested in the assay (Fig. 1b, left). Of the 9 patients who were categorized as vaccine nonresponders based on the traditional definition, one subject was actually immune to all 3 of the most common serotypes in the community (Fig 1b, right), suggesting that he may actually be well-covered for pneumococcus in the real world. This study raises concern about the definition of immunity following vaccination, and highlights the challenge to identify which patients are at risk for disease. Future studies should examine how immunity wanes post vaccination and how the lack of immunity to prevalent serotypes might lead to clinical disease. Disclosures Lanzkron: Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding; NIH: Research Funding; PCORI: Research Funding.

Clinical characteristics and risk of serious disease in patients referred to a diagnostic centre: A cohort study

BackgroundLittle is known about the clinical characteristics of patients referred to a diagnostic centre through the Danish urgent referral pathway for non-specific serious symptoms. We aimed at estimating the distribution of serious disease and the diagnostic value of clinical characteristics for the diagnosis of cancer and serious non-malignant disease in these patients. MethodA cohort study of 938 patients referred by their GP to the diagnostic centre at Silkeborg Regional Hospital. All patients were followed up for three months in national registries. The likelihood ratio (LR) of cancer or serious non-malignant disease were calculated in relation to clinical characteristics. ResultsA total of 327 (34.9%) patients were diagnosed with new serious disease within three months: 118 patients (12.6%) with malignant disease and 209 patients (22.3%) with non-malignant disease. Most patients presented general symptoms. The highest LR of cancer was found for abdominal mass, high lactate dehydrogenase or abnormal findings in the diagnostic imaging. The highest LR of non-malignant disease was found for swollen joints or abnormal auscultation of lung or chest. ConclusionsPatients referred by their GP to the diagnostic centre have high risk of serious disease. A multidisciplinary diagnostic approach is needed to embrace the diagnostic spectrum.

Barriers and Facilitating Factors for Implementation of Genetic Services: A Public Health Perspective.

More than 15 years after the publication of the sequence of the human genome, the resulting changes in health care have been modest. At the same time, some promising examples in genetic services become visible, which contribute to the prevention of chronic disease such as cancer. These are discussed to identify barriers and facilitating factors for the implementation of genetic services. Examples from oncogenetics illustrate a high risk of serious disease where prevention is possible, especially in relatives. Some 5% of breast cancers and colorectal cancers are attributable to an inherited predisposition. These cancers occur at a relatively young age. DNA testing of relatives of affected patients may facilitate primary and secondary prevention. Training of non-genetic health care workers and health technology assessment are needed, as is translational research in terms of bringing genomics to health care practice while monitoring and evaluating. Stratified screening programs could include cascade screening and risk assessment based on family history. New roles and responsibilities will emerge. A clear assessment of the values implied is needed allowing to balance the pros and cons of interventions to further the responsible innovation of genetic services.

Development of new antibacterial agents

Background: Antibiotics, as miraculous drugs, have been used extensively to confront fatal infection, even without prescriptions. However, the inappropriate and disproportionate use of antibiotics have led to the emergence of new drug-resistant bacteria1, which causes a high risk of serious diseases and dramatically aggravates the clinical complications in hospitals.&#x0D; Methods: By using the peptide coupling protocol, a simple straightforward synthesis of functionalized aziridines has been developed. By means of this synthetic strategy from readily available N-phtaloyl acide and 2-methylbenzosulfonate aziridine using DCC as coupling agent, new tosylates aziridines could be obtained. The coupling reactions occurred without a ring opening of the three membered ring.&#x0D; Results: This work describes new results of our ongoing research targeting new derivatives of biological interests. All the compounds were screened for their antibacterial activity; they all showed comparable moderate to good growth inhibitory activity with reference to tetracyclin and gentamicin.&#x0D; Conclusion: In conclusion, we reported the synthesis and a preliminary antibacterial evaluation of novel functionalized tosylaziridines. The synthetic strategy relies on the coupling reactions between tosylaziridines and amino acids. Moreover, and besides showing interesting antibacterial activities, the series of novel compounds can be further improved to serve as potential drug against nosocomial diseases.

HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer.

While combined antiretroviral therapy (cART) can result in undetectable plasma viral loads, it does not eradicate HIV infection. Furthermore, HIV-infected individuals while on cART remain at an increased risk of developing serious comorbidities, such as cancer, neurological disease, and atherosclerosis, suggesting that during cART, tissue-based HIV may contribute to such pathologies. We obtained DNA and RNA env, nef, and pol sequences using single-genome sequencing from postmortem tissues of three HIV(+) cART-treated (cART(+)) individuals with undetectable viral load and metastatic cancer at death and performed time-scaled Bayesian evolutionary analyses. We used a sensitive in situ hybridization technique to visualize HIV gag-pol mRNA transcripts in cerebellum and lymph node tissues from one patient. Tissue-associated virus evolved at similar rates in cART(+) and cART-naive (cART(-)) patients. Phylogenetic trees were characterized by two distinct features: (i) branching patterns consistent with constant viral evolution and dispersal among tissues and (ii) very recently derived clades containing both DNA and RNA sequences from multiple tissues. Rapid expansion of virus near death corresponded to wide-spread metastasis. HIV RNA(+) cells clustered in cerebellum tissue but were dispersed in lymph node tissue, mirroring the evolutionary patterns observed for that patient. Activated, infiltrating macrophages were associated with HIV RNA. Our data provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread. Combined antiretroviral therapy (cART) reduces plasma HIV to undetectable levels; however, removal of cART results in plasma HIV rebound, thus highlighting its inability to entirely rid the body of infection. Additionally, HIV-infected individuals on cART remain at high risk of serious diseases, which suggests a contribution from residual HIV. In this study, we isolated and sequenced HIV from postmortem tissues from three HIV(+) cART(+) individuals who died with metastatic cancer and had no detectable plasma viral load. Using high-resolution evolutionary analyses, we found that tissue-based HIV continues to replicate, evolve, and migrate among tissues during cART. Furthermore, cancer onset and metastasis coincided with increased HIV expansion, suggesting a linked mechanism. HIV-expressing cells were associated with tissue macrophages, a target of HIV infection. Our results suggest the importance of tissues, and macrophages in particular, as a target for novel anti-HIV therapies.

Safety and Effectiveness of Palivizumab in Children at High Risk of Serious Disease Due to Respiratory Syncytial Virus Infection: A Systematic Review.

IntroductionLower respiratory tract infection (LRTI) is the leading cause of infant mortality globally in post-neonatal infants (i.e., 28–364 days of age). Respiratory syncytial virus (RSV) is the most commonly identified pathogen for infant LRTI and is the second most important cause of death in post-neonatal infants. Despite 50 years of RSV vaccine research, there is still no approved vaccine. Therefore, passive immunity with the monoclonal antibody palivizumab is the sole regulatory-approved option for the prevention of serious LRTI caused by RSV in pediatric patients at high risk of RSV disease.MethodsWe conducted a comprehensive systematic literature review of randomized controlled trials (RCTs), open-label non-comparative clinical trials, and prospective observational studies/registries, and summarized the evidence related to the safety, efficacy, and effectiveness of palivizumab.ResultsThe efficacy of palivizumab, as measured by the relative reduction in RSV-related hospitalization rate compared with placebo ranged from 39% to 78% (P < 0.05) in the 2 pivotal RCTs. A meta-analysis of the RSV-related hospitalization rate from 5 randomized placebo-controlled trials yielded an overall odds ratio of 0.41 (95% CI, 0.31–0.55) in favor of palivizumab prophylaxis over placebo (P < 0.00001). Low rates of RSV-related hospitalizations were observed in palivizumab recipients consistently over time in more than 42,000 pediatric subjects across 7 RCTs, 4 open-label non-comparative trials, and 8 observational studies/registries conducted in 34 countries. In addition, among palivizumab-prophylaxed subjects with breakthrough RSV LRTI, rates of intensive care unit admission and mechanical ventilation from RSV hospitalization also were low and consistent across studies. With respect to safety, no differences were observed between palivizumab and placebo in the blinded RCTs.ConclusionRates of RSV hospitalizations and RSV hospitalization-related endpoints in pediatric subjects who received prophylaxis with palivizumab were low and constant over time and across RCTs, open-label non-comparative trials, and observational studies/registries.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0046-6) contains supplementary material, which is available to authorized users.

The Economics of Personalization in Prevention and Public Health.

Personalized prevention uses family history and predictive genetic testing to identify people at high risk of serious diseases. The availability of predictive genetic tests is a newer and still-developing phenomenon. Many observers see tremendous potential for personalized prevention to improve public health. At the same time, the emergence of these new markets raises familiar health policy concerns about costs, cost-effectiveness, and health disparities. This paper first discusses an economic framework for the analysis of personalized prevention. On the demand side, consumers use personalized prevention as a form of information that allows them to make better choices about prevention, including medical care and health behaviors like diet and exercise. On the supply side, an interplay of complex market forces and regulations will determine the prices, advertising, and insurance coverage of predictive genetic tests. Beyond the question of whether health insurance will cover the costs of predictive genetic tests, there is a great deal of concern about whether consumers' use of genetic tests might place them at risk of genetic discrimination or might lead to adverse selection. The paper also reports descriptive analysis of data from the 2000, 2005, and 2010 National Health Interview Surveys on the use of predictive genetic tests. The empirical analysis documents large socioeconomic status-related disparities in consumers having heard of genetic tests: for example, consumers with less schooling, Blacks, and Hispanics were substantially less likely to have heard of genetic tests. Evidence from other empirical studies provides little evidence that genetic testing leads to genetic discrimination in insurance markets. There is more evidence suggesting adverse selection, where genetic testing leads consumers to purchase long-term care insurance. The paper concludes with some preliminary thoughts about important directions for future research. The goal of the paper is to review relevant research to help develop an economic approach and social science research agenda into the determinants and consequences of genetic tests for prevention.

Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity

Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (T(H)2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)-IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.

Cytomegalovirus vaccine strategies

Background: Many patients are at high risk for serious disease caused by human cytomegalovirus (HCMV). These include solid organ and hematopoietic stem cell transplant patients, individuals with HIV infection, and newborn infants, who typically acquire the infection in utero, most commonly via transplacental transmission. Objective: The objective of this review is to provide consideration and overview of the approaches that have been explored to date in design and development of HCMV vaccines. Methods: The literature as well as the United States Patent Office database were reviewed. Conclusion: Considerable effort has been made to develop vaccines at the preclinical level but more effort is required to move these into clinical testing. There is merit in exploring novel technologies and applying these to the design of new vaccine strategies for this significant public health problem.

Interdisciplinary Epidemiologic and Economic Research Needed to Support a Universal Childhood Influenza Vaccination Policy

Recent research indicates that influenza vaccination of children may decrease the influenza disease burden in adults to a greater extent than targeting vaccination to populations at high risk of serious disease. Possible new policies reflecting these results would add groups most likely to transmit disease to existing vaccination recommendations. Interdisciplinary research combining epidemiology with economics is needed to answer critical questions about the desirability and feasibility of potential new policies, such as what additional resources medical providers might need to expand vaccination to larger groups or what opportunity costs parents might incur in vaccinating their children annually. In this paper, the authors provide background for some of the changes in influenza vaccination rates and disease and discuss existing information gaps and research methods capable of closing these gaps. They provide several examples of interdisciplinary studies that have incorporated both economics and epidemiology or health policy issues. These studies are representative of a variety of stakeholder perspectives needed to determine whether community-based, universal childhood vaccination policies would be more efficacious and cost-effective than strategies targeted toward persons at high risk of disease complications.

Influenza Vaccine Programs and Pregnancy: A Need for More Evidence

Influenza viruses are the most common cause of seasonal respiratory morbidity in the world. Annual influenza vaccination is recommended for persons at high risk for serious disease. In the United States, in 2004, the Advisory Committee on Immunization Practices added all pregnant women to its highrisk list. In Canada, the National Advisory Committee on Immunization only includes pregnant women who have other underlying risk factors in the high-priority category for influenza immunization. This commentary provides an overview of maternal morbidity in pandemic and nonpandemic influenza seasons as well as a list of research questions whose answers are needed for evidence-based public health policy in this area.

Treatment and Prevention of RSV Bronchiolitis

Respiratory syncytial virus is a leading cause of bronchiolitis and pneumonia in children worldwide, resulting in significant morbidity and mortality in high-risk individuals. The pediatric populations at high risk for severe RSV infections include patients with cardiac disease, lung disease, immunosuppression, premature birth or healthy infants less than six months of age. Supportive care is the primary treatment of RSV lower respiratory tract infections. Other treatment regimens include the use of bronchodilators and anti-inflammatory agents; however, the use of these agents is controversial due to lack of evidence of efficacy in all studies. Ribavirin, an antiviral agent, has been administered for the treatment of RSV lower respiratory tract infections, but its efficacy has been questioned due to flawed study designs. RSV-IVIG and palivizumab are approved for the prevention of RSV infection in selected children at high risk for serious disease. These agents are equally efficacious and expensive; however, the cost-effectiveness of prophylaxis is unclear. Currently, no vaccines for RSV are available for general use, but research in the area continues. Until a safe, effective and relatively inexpensive method for prophylaxis is available, RSV infections will continue to cause significant morbidity and mortality in children.

ASSESSING DYSPEPSIA IN GENERAL PRACTICE

SUMMARY The value of the symptom pattern in achieving an accurate diagnosis in dyspeptic disease is still controversial. A number of investigators have used it to distinguish those patients who are at a high risk of serious disease (ulcer or cancer) from those who are not. Such findings have important implications for patient management, both in clinical and economic terms.

Neutralizing antibodies to non-polio enteroviruses in human immune serum globulin.

Neutralizing antibodies to selected non-polio enteroviruses were found in three lots of human immune serum globulin (ISG) prepared from the sera of persons from different geographic regions. Reciprocal titers to coxsackieviruses B3 and B4 ranged from 400 to greater than or equal to 2000, whereas titers to coxsackievirus A9 and ECHO viruses 5 and 9 ranged from 100 to 400 in all three lots of ISG. The presence of neutralizing antibodies to commonly occurring (coxsackieviruses B1 to B5 and A9 and ECHO viruses 3, 4 and 9) and infrequently encountered (ECHO viruses 5 and 13) serotypes, coupled with the increasing evidence that antibodies are an important factor in preventing illness, support recommending the administration of ISG to those at high risk for serious disease.