Monoclonal Antibodies with Neutralizing Activity and Fc-Effector Functions against the Machupo Virus Glycoprotein

ABSTRACT Machupo virus (MACV), the causative agent of Bolivian hemorrhagic fever (BHF), is a New World arenavirus that was first isolated in Bolivia from a human spleen in 1963. Due to the lack of a specific vaccine or therapy, this virus is considered a major risk to public health and is classified as a category A priority pathogen by the U.S. National Institutes of Health. In this study, we used DNA vaccination against the MACV glycoprotein precursor complex (GPC) and murine hybridoma technology to generate 25 mouse monoclonal antibodies (MAbs) against the GPC of MACV. Out of 25 MAbs, five were found to have potent neutralization activity in vitro against a recombinant vesicular stomatitis virus expressing MACV GPC (VSV-MACV) as well as against authentic MACV. Furthermore, the five neutralizing MAbs exhibited strong antibody-dependent cellular cytotoxicity (ADCC) activity in a reporter assay. When tested in vivo using VSV-MACV in a Stat2−/− mouse model, three MAbs significantly lowered viral loads in the spleen. Our work provides valuable insights into epitopes targeted by neutralizing antibodies that could be potent targets for vaccines and therapeutics and shed light on the importance of effector functions in immunity against MACV. IMPORTANCE MACV infections are a significant public health concern and lead to high case fatality rates. No specific treatment or vaccine for MACV infections exist. However, cases of Junin virus infection, a related virus, can be treated with convalescent-phase serum. This indicates that a MAb-based therapy for MACV could be effective. Here, we describe several MAbs that neutralize MACV and could be used for this purpose.

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Case fatality as an indicator for the human toxicity of pesticides - a systematic review on the availability and variability of severity indicators of pesticide poisoning

10.1101/126615 ◽

2017 ◽

Author(s):

Susanne Moebus ◽

Wolfgang Boedeker

Keyword(s):

Public Health ◽

Case Fatality ◽

Public Health Problem ◽

Human Case ◽

Health Concern ◽

Pesticide Poisoning ◽

Active Ingredients ◽

Severity Scores ◽

Treatment Facilities ◽

Number Of Publications

AbstractObjectiveTo investigate if case fatality and other indicators of severity of human pesticide poisonings can be used to prioritize pesticides of public health concern. To study the heterogeneity of data across countries, cause of poisonings, and treatment facilities.MethodsWe searched literature databases as well as the internet for studies on case-fatality and severity scores of pesticide poisoning. Studies published between 1990 and 2014 providing information on active ingredients in pesticides or chemical groups of active ingredients were included. The variability of case-fatality-ratios was analyzed by computing the coefficient of variation as the ratio of the standard deviation to the mean.FindingsWe identified 145 studies of which 67 could be included after assessment. Case-fatality-ratio (CFR) on 68 active ingredients and additionally on 13 groups of active ingredients were reported from 20 countries. Mean CFR for group of pesticides is 12 %, for single pesticides 15 %. Of those 12 active ingredients with a CFR above 20 % only two are WHO-classified as “extremely hazardous” or “highly hazardous”, respectively. Two of seven pesticides considered “unlikely to present hazard in normal use” show CFR above 20 %. The variability of reported case fatality was rather low.ConclusionAlthough human pesticide poisoning is a serious public health problem an unexpected small number of publications report on the clinical outcomes. However, CFR of acute human pesticide poisoning are available for several groups of pesticides as well as for active ingredients and show little variability. Therefore the CFR might be utilized to prioritize highly hazardous pesticides especially since there is limited correspondence between the animal-test-based hazard classification and the human CFR of the respective pesticide. Reporting of available poisoning data should be improved, human case-fatality data are a reasonable tool to be included systematically in pesticide registration and regulation.

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YELLOW FEVER PREVENTION STRATEGIES AWARENESS AMONG HIV-INFECTED PATIENTS IN SÃO PAULO, BRAZIL

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652014000500008 ◽

2014 ◽

Vol 56 (5) ◽

pp. 417-420 ◽

Cited By ~ 2

Author(s):

Vivian Iida Avelino-Silva ◽

Hilario Sousa Francelino ◽

Esper Georges Kallás

Keyword(s):

Public Health ◽

Yellow Fever ◽

Specific Treatment ◽

Sao Paulo ◽

Study Data ◽

Health Concern ◽

Preventive Strategy ◽

São Paulo ◽

Public Health Concern ◽

Vaccine Recommendations

Introduction: Vaccination is the main preventive strategy against Yellow Fever (YF), which is a public health concern in Brazil. However, HIV-infected patients might have insufficient knowledge regarding YF, YF prevention, and vaccines in general. Methods: In this questionnaire-based study, data from 158 HIV-infected individuals were addressed in three distinct outpatient clinics in São Paulo. Information was collected on demographic and clinical characteristics, as well as patients' knowledge of vaccines, YF and YF preventive strategies. In addition, individual YF vaccine recommendations and vaccine status were investigated. Results: Although most participants adequately ascertain the vaccine as the main prevention strategy against YF, few participants were aware of the severity and lack of specific treatment for YF. Discrepancy in YF vaccine (patients who should have taken the vaccine, but did not) was observed in 18.8% of participants. Conclusion: YF is an important and preventable public health concern, and these results demonstrate that more information is necessary for the HIV-infected population.

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Charlie ant insect bite-associated preseptal cellulitis

Malaysian Journal of Ophthalmology ◽

10.35119/myjo.v2i2.105 ◽

2020 ◽

Vol 2 (2) ◽

pp. 140-145

Author(s):

Patricia Ann John ◽

Sylves Patrick ◽

Qi Zhe Ngoo ◽

Wan Hazabbah Wan Hitam ◽

Adil Hussein

Keyword(s):

Public Health ◽

Specific Treatment ◽

Health Concern ◽

Public Health Concern ◽

Nasal Bridge ◽

Preseptal Cellulitis ◽

Eyelid Swelling ◽

Spread Of Infection ◽

Contiguous Spread

Preseptal cellulitis is a worrying condition in children. One of the commonest causes is from insect bite. The Charlie ant or Paederus fuscipes has been reported as a dermatitis-causing agent due to its toxin, pederin. The aim is to report a case of preseptal cellulitis secondary to Charlie ant insect bite. A two-year-old girl presented with bilateral eyelid swelling, redness, and pain for two days. The Charlie ant was at the nasal bridge before the presentation. There was presence of generalised bilateral eyelid swelling, redness with multiple pustules, excoriated skin, and eye discharge. She was admitted and started on antibiotics. The pustules ruptured, left the skin exposed, and her condition improved. Preseptal cellulitis is a contiguous spread of infection. An attack by Charlie ant has become a public health concern. There is no specific treatment for this condition. Early detectionmay prevent complications.

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An anti-SARS-CoV-2 non-neutralizing antibody with Fc-effector function defines a new NTD epitope and delays neuroinvasion and death in K18-hACE2 mice

10.1101/2021.09.08.459408 ◽

2021 ◽

Author(s):

Guillaume Beaudoin-Bussières ◽

Yaozong Chen ◽

Irfan Ullah ◽

Jérémie Prévost ◽

William D. Tolbert ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Animal Models ◽

Mouse Model ◽

Transgenic Mouse ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Transgenic Mouse Model ◽

Effector Function ◽

Effector Functions

SummaryEmerging evidence in animal models indicate that both neutralizing activity and Fc- mediated effector functions of neutralizing antibodies contribute to protection against SARS-CoV-2. It is unclear if antibody effector functions alone could protect against SARS-CoV-2. Here we isolated CV3-13, a non-neutralizing antibody from a convalescent individual with potent Fc-mediated effector functions that targeted the N- terminal domain (NTD) of SARS-CoV-2 Spike. The cryo-EM structure of CV3-13 in complex with SAR-CoV-2 spike revealed that the antibody bound from a distinct angle of approach to a novel NTD epitope that partially overlapped with a frequently mutated NTD supersite in SARS-CoV-2 variants. While CV3-13 did not alter the replication dynamics of SARS-CoV-2 in a K18-hACE2 transgenic mouse model, an Fc-enhanced CV3-13 significantly delayed neuroinvasion and death in prophylactic settings. Thus, we demonstrate that efficient Fc-mediated effector functions can contribute to the in vivo efficacy of anti-SARS-CoV-2 monoclonal antibodies in the absence of neutralization.

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Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

Viruses ◽

10.3390/v12030276 ◽

2020 ◽

Vol 12 (3) ◽

pp. 276 ◽

Cited By ~ 4

Author(s):

Rongyuan Gao ◽

Zizhang Sheng ◽

Chithra C. Sreenivasan ◽

Dan Wang ◽

Feng Li

Keyword(s):

Neutralizing Antibodies ◽

Influenza A ◽

Therapeutic Potential ◽

Influenza Infection ◽

Neutralizing Antibody ◽

Health Concern ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Effector Functions ◽

Recent Advances

Influenza causes millions of cases of hospitalizations annually and remains a public health concern on a global scale. Vaccines are developed and have proven to be the most effective countermeasures against influenza infection. Their efficacy has been largely evaluated by hemagglutinin inhibition (HI) titers exhibited by vaccine-induced neutralizing antibodies, which correlate fairly well with vaccine-conferred protection. Contrarily, non-neutralizing antibodies and their therapeutic potential are less well defined, yet, recent advances in anti-influenza antibody research indicate that non-neutralizing Fc-effector activities, especially antibody-dependent cellular cytotoxicity (ADCC), also serve as a critical mechanism in antibody-mediated anti-influenza host response. Monoclonal antibodies (mAbs) with Fc-effector activities have the potential for prophylactic and therapeutic treatment of influenza infection. Inducing mAbs mediated Fc-effector functions could be a complementary or alternative approach to the existing neutralizing antibody-based prevention and therapy. This review mainly discusses recent advances in Fc-effector functions, especially ADCC and their potential role in influenza countermeasures. Considering the complexity of anti-influenza approaches, future vaccines may need a cocktail of immunogens in order to elicit antibodies with broad-spectrum protection via multiple protective mechanisms.

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Differences in Glycoprotein Complex Receptor Binding Site Accessibility Prompt Poor Cross-Reactivity of Neutralizing Antibodies between Closely Related Arenaviruses

Journal of Virology ◽

10.1128/jvi.01454-16 ◽

2017 ◽

Vol 91 (7) ◽

Cited By ~ 9

Author(s):

Rachel B. Brouillette ◽

Elisabeth K. Phillips ◽

Natarajan Ayithan ◽

Wendy Maury

Keyword(s):

Monoclonal Antibodies ◽

Binding Site ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

New World ◽

Cross Reactivity ◽

Receptor Binding Site ◽

Glycoprotein Complex ◽

Machupo Virus ◽

Cross Neutralization

ABSTRACT The glycoprotein complex (GPC) of arenaviruses, composed of stable signal peptide, GP1, and GP2, is the only antigen correlated with antibody-mediated neutralization. However, despite strong cross-reactivity of convalescent antisera between related arenavirus species, weak or no cross-neutralization occurs. Two closely related clade B viruses, Machupo virus (MACV) and Junín virus (JUNV), have nearly identical overall GPC architecture and share a host receptor, transferrin receptor 1 (TfR1). Given structural and functional similarities of the GP1 receptor binding site (RBS) of these viruses and the recent demonstration that the RBS is an important target for neutralizing antibodies, it is not clear how these viruses avoid cross-neutralization. To address this, MACV/JUNV chimeric GPCs were assessed for interaction with a group of α-JUNV GPC monoclonal antibodies (MAbs) and mouse antisera against JUNV or MACV GPC. All six MAbs targeted GP1, with those that neutralized JUNV GPC-pseudovirions competing with each other for RBS binding. However, these MAbs were unable to bind to a chimeric GPC composed of JUNV GP1 containing a small disulfide bonded loop (loop 10) unique to MACV GPC, suggesting that this loop may block MAbs interaction with the GP1 RBS. Consistent with this loop causing interference, mouse anti-JUNV GPC antisera that solely neutralized pseudovirions bearing autologous GP1 provided enhanced neutralization of MACV GPC when this loop was removed. Our studies provide evidence that loop 10, which is unique to MACV GP1, is an important impediment to binding of neutralizing antibodies and contributes to the poor cross-neutralization of α-JUNV antisera against MACV. IMPORTANCE Multiple New World arenaviruses can cause severe disease in humans, and some geographic overlap exists among these viruses. A vaccine that protects against a broad range of New World arenaviruses is desirable for purposes of simplicity, cost, and broad protection against multiple National Institute of Allergy and Infectious Disease-assigned category A priority pathogens. In this study, we sought to better understand how closely related arenaviruses elude cross-species neutralization by investigating the structural bases of antibody binding and avoidance. In our studies, we found that neutralizing antibodies against two New World arenaviruses, Machupo virus (MACV) and Junín virus (JUNV), bound to the envelope glycoprotein 1 (GP1) with JUNV monoclonal antibodies targeting the receptor binding site (RBS). We further show that altered structures surrounding the RBS pocket in MACV GP1 impede access of JUNV-elicited antibodies.

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Epidemia do novo coronavírus (COVID-19): análise dos indicadores nos três primeiros meses, Estado de São Paulo, Brasil

ARCHIVES OF HEALTH INVESTIGATION ◽

10.21270/archi.v9i4.5102 ◽

2020 ◽

Vol 9 (4) ◽

Author(s):

Roudom Ferreira Moura ◽

Ana Paula Miranda Mundim-Pombo ◽

Rosângela Elaine Minéo Biagolini ◽

Janessa de Fátima Morgado de Oliveira

Keyword(s):

Public Health ◽

Case Fatality ◽

Sao Paulo ◽

World Health ◽

Health Concern ◽

Current Status ◽

São Paulo ◽

America Latina ◽

Novel Coronavirus ◽

Health Organization

Introdução: O Estado de São Paulo foi a Unidade da Federação onde ocorreu a notificação do primeiro caso de COVID-19 no Brasil e América Latina,apresentando indicadores de saúde alarmantes e boa parte dos municípios afetados. Objetivo: Analisar os indicadores de saúde do Novo Coronavírus (COVID-19) no Estado de São Paulo (ESP) nos três primeiros meses da epidemia a partir da confirmação do primeiro caso. Material e método: Estudo ecológico, descritivo, considerando os casos confirmados de COVID-19 captados pelo Centro de Vigilância Epidemiológica do ESP para o período de 26 de fevereiro a 26 de maio de 2020. Resultados: Houve crescimento do número de municípios (35, 284 e 510), casos confirmados (1.015, 20.652 e 85.459), óbitos (57, 1.700 e 6.423), coeficientes de incidência (2,21; 44,97 e 186,11 para cada 100.000 habitantes) e mortalidade (0,12; 3,70 e 13,99 para cada 100.000 habitantes) - respectivamente, março, abril e maio. Observou-se declínio do coeficiente de letalidade no terceiro mês comparado ao segundo (respectivamente, 8,23 e 7,52 para cada 100 casos). Conclusão: A magnitude do COVID-19 extrapola os indicadores mundiais em algumas localidades do Estado de São Paulo.Descritores: Infecções por Coronavírus; Pandemias; Epidemiologia Descritiva; Estudos Ecológicos.ReferênciasTan W, Zhao X, Ma X, Wang W, Niu P, Xu W et al. A Novel Coronavirus Genome Identified in a Cluster of Pneumonia Cases — Wuhan, China 2019−2020. China CDC Weekly, 2020;2(4):61-2.Rafael RDMR, Neto M, Carvalho MMB de, David HMSL, Acioli S, Faria MG de A. Epidemiologia, políticas públicas e pandemia de Covid-19: o que esperar no Brasil? Rev enferm UERJ. 2020;28:e49570.Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern [published correction appears in Lancet. 2020. Lancet. 2020;395(10223):470-73.Di Gennaro F, Pizzol D, Marotta C, Antunes M, Racalbuto V, Veronese N et al. Coronavirus Diseases (COVID-19) Current Status and Future Perspectives: A Narrative Review. Int J Environ Res Public Health. 2020;17(8):2690.World Health Organization. Coronavirus disease (COVID-19). Coronavirus disease (COVID-2019) Situation Report - 117. World Heal Organ [Internet]. 2020;8(1):3–8. Available at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200516-covid-19-sitrep-117.pdf?sfvrsn=8f562cc_World Health Organization. Coronavirus disease (COVID-19). Coronavirus disease (COVID-19) Situation Report 138. 2020;(June). Available at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200606-covid-19-sitrep-138.pdf?sfvrsn=c8abfb17_4BRASIL. Ministério da Saúde S de V em S. Boletim Epidemiológico Especial COE COVID-19. Bol Epidemiológico Espec COE-COVID19 [Internet]. 2020; Available at: https://www.saude.gov.br/images/pdf/2020/May/29/2020-05-25---BEE17---Boletim-do-COE.pdf.The Lancet. COVID-19 in Brazil: "So what?". Lancet. 2020;395(10235):1461.Rodriguez-Morales AJ, Gallego V, Escalera-Antezana JP, Mendez CA, Zambrano LI, Franco-Paredes et. al. COVID-19 in Latin America: The implications of the first confirmed case in Brazil. Travel Med Infect Dis. 2020;35:101613.Governo do Estado de São Paulo10 - Secretaria de Estado da Saúde - Coordenadoria de Controle de Doenças - Centro de Vigilância Epidemiológica “Prof. Alexandre Vranjac” – Novo Coronavírus (COVID-19) - Situação Epidemiológica 26 de fevereiro a 26 de maio de 2020, disponíveis em: http://www.saude.sp.gov.br/cve-centro-de-vigilancia-epidemiologica-prof.-alexandre-vranjac/areas-de-vigilancia/doencas-de-transmissao-respiratoria/coronavirus-covid-19/situacao-epidemiologicaIBGE. Instituto Brasileiro de Geografia e Estatística. Brasil. São Paulo. Arandu. Disponível em: https://cidades.ibge.gov.br/brasil/sp/arandu/pesquisa/37/30255Castro Delgado R, Arcos González P. Analyzing the health system's capacity to respond to epidemics: a key element in planning for emergencies. El análisis de la capacidad de respuesta sanitaria como elemento clave en la planificación ante emergencias epidémicas. Emergencias. 2020;32(3):157-59.World-o-Meter. Disponível em: https://www.worldometers.info/coronavirus/. Acesso em: 14 de maio de 2020.Ren H, Zhao L, Zhang A, Song L, Liao Y, Lu W et al. Early forecasting of the potential risk zones of COVID-19 in China's megacities. Sci Total Environ. 2020;729:138995.Morgenstern H. Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Public Health. 1995;16:61-81. Organização Pan-americana de Saúde. REDE Interagencial de Informação para a Saúde – RIPSA. Indicadores Básicos para a Saúde no Brasil: conceitos e aplicações. 2. ed. – Brasília: Organização Pan-Americana da Saúde, 2008. p. 144. Disponível em: http://tabnet.datasus.gov.br/tabdata/livroidb/2ed/CapituloC.pdfMedeiros de Figueiredo A, Daponte A, Moreira Marculino de Figueiredo DC, Gil-García E, Kalache A. Letalidad del COVID-19: ausencia de patrón epidemiológico [Case fatality rate of COVID-19: absence of epidemiological pattern] Gac Sanit. 2020;S0213-9111(20)30084-4.SEADE – Fundação Sistema Estadual de Análise de Dados. Perfil dos Municípios Paulistas. Disponível em: https://perfil.seade.gov.br/. Acessado em: 10/06/2020.Governo de São Paulo. SP Contra o Novo Coronavírus. Adesão ao Isolamento Social em São Paulo. Disponível em: https://www.saopaulo.sp.gov.br/coronavirus/isolamento/. Acessado em 10/06/2020.

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Antibodies to SARS-CoV-2 and Their Potential for Therapeutic Passive Immunization

10.20944/preprints202004.0326.v1 ◽

2020 ◽

Author(s):

P.J. Klasse ◽

John P. Moore

Keyword(s):

Public Health ◽

Monoclonal Antibodies ◽

Antibody Response ◽

Causative Agent ◽

Neutralizing Antibodies ◽

Passive Immunization ◽

S Protein

We review aspects of the antibody response to SARS-CoV-2, the causative agent of the COVID- 19 pandemic. The topics we cover are relevant to immunotherapy with plasma from recovered patients and with monoclonal antibodies against the viral S-protein. The development of vaccines against SARS-CoV-2, an essential public health tool, will also be informed by an understanding of the antibody response in infected patients. Although virus-neutralizing antibodies are likely to protect, antibodies could potentially trigger immunopathogenic events in SARS-CoV-2-infected patients or enhance infection. An awareness of these possibilities may benefit clinicians and the developers of antibody-based therapies and vaccines.

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Antibodies to SARS-CoV-2 and their potential for therapeutic passive immunization

eLife ◽

10.7554/elife.57877 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 10

Author(s):

PJ Klasse ◽

John P Moore

Keyword(s):

Public Health ◽

Monoclonal Antibodies ◽

Antibody Response ◽

Angiotensin Converting Enzyme ◽

Causative Agent ◽

Neutralizing Antibodies ◽

Passive Immunization ◽

Converting Enzyme ◽

S Protein ◽

Angiotensin Converting Enzyme 2

We review aspects of the antibody response to SARS-CoV-2, the causative agent of the COVID-19 pandemic. The topics we cover are relevant to immunotherapy with plasma from recovered patients, monoclonal antibodies against the viral S-protein, and soluble forms of the receptor for the virus, angiotensin converting enzyme 2. The development of vaccines against SARS-CoV-2, an essential public health tool, will also be informed by an understanding of the antibody response in infected patients. Although virus-neutralizing antibodies are likely to protect, antibodies could potentially trigger immunopathogenic events in SARS-CoV-2-infected patients or enhance infection. An awareness of these possibilities may benefit clinicians and the developers of antibody-based therapies and vaccines.

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A Serious Public Health Concern for India due to Newly Discovered Virus (COVID-19): Early Detection of all Possible Cases is the Only Way to Combat

Journal of Clinical and Medical Research ◽

10.37191/mapsci-2582-4333-2(4)-040 ◽

2020 ◽

Author(s):

Vijay Kumar Mishra

Keyword(s):

Public Health ◽

Surveillance System ◽

Case Fatality Rate ◽

Case Fatality ◽

Public Health Problem ◽

World Health ◽

Health Concern ◽

Family Welfare ◽

Fatality Rate ◽

Monitoring And Surveillance

Background: It is well known that India is having a massive population (around 130 crores) after China. So, it's more likely to be similar or more positive cases of corona among Indians. However, we are following the ways of social distancing and all possible ways to weaken the corona outbreak. But, India needs a good monitoring and surveillance system to tackle this problem otherwise it may become a serious public health problem. Objectives: This study has done to understand the severity of corona in India and its states and to device a tool based on symptoms suggested by the World Health Organization on the corona. Methods: We have utilized data extracted through the Ministry of Health & Family Welfare, GoI from 30th Jan to 26th March 2020. We have estimated the case fatality rate and cured rate to understand the severity of the newly discovered virus (COVID-19). Results: Out of 694 confirmed corona cases, 47 were foreigners and 647 Indians. Our study found that the case fatality rate due to COVID-19 was 23.1 per 1000 persons in India while the people who were still hospitalized under isolation wards were about 91 percent. The cure rate was estimated at around 64.8 per 1000 persons. Conclusions: Looking at the recovery rate, we may think about the severity of corona among Indians. We can reduce the chances of rapidly increasing corona cases through good monitoring and surveillance system. It is recommended that Government should not only focus on testing the passengers arriving at the airport but also test as much as possible cases based on the symptoms of corona in all the districts so that an actual number of cases can be estimated.

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