scholarly journals Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

2020 ◽  
Author(s):  
Adam McNee ◽  
Trevor Smith ◽  
Barbara Holzer ◽  
Becky Clark ◽  
Emily Bessell ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Viral Load ◽  
Influenza Virus Infection ◽  
Small Animal ◽  
H1n1 Influenza ◽  
Lung Pathology ◽  
Host Animal ◽  
Viral Shedding ◽  
Robust Model

AbstractMonoclonal antibodies are a possible adjunct to vaccination and drugs in treatment of influenza virus infection. However questions remain whether small animal models accurately predict efficacy in humans. We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing monoclonal antibodies. We show that a strongly neutralizing monoclonal antibody (2-12C) against the hemagglutinin head administered prophylactically at 15 mg/kg reduced viral load and lung pathology after pandemic H1N1 influenza challenge. A lower dose of 1 mg/kg of 2-12C or a DNA plasmid encoded version of 2-12C, reduced pathology and viral load in the lungs, but not viral shedding in nasal swabs. We propose that the pig influenza model will be useful for testing candidate monoclonal antibodies and emerging delivery platforms prior to human trials.

scholarly journals Low dose pig anti-influenza virus monoclonal antibodies reduce lung pathology but do not prevent virus shedding

2021 ◽  
Author(s):  
Basudev Paudyal ◽  
Adam McNee ◽  
Pramila Rijal ◽  
B Veronica Carr ◽  
Alejandro Nunez ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Intravenous Administration ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Lung Pathology ◽  
Host Animal ◽  
Virus Shedding ◽  
Virus Load ◽  
Robust Model ◽  
High Doses

We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing the therapeutic potential of monoclonal antibodies (mAbs). In this study we demonstrated that prophylactic intravenous administration of 15mg/kg of porcine mAb pb18, against the K160-163 site of the haemagglutinin, significantly reduced lung pathology and nasal virus shedding and eliminated virus from the lung of pigs following H1N1pdm09 challenge. When given at 1mg/kg, pb18 significantly reduced lung pathology and lung and BAL virus loads, but not nasal shedding. Similarly, when pb18 was given in combination with pb27, which recognised the K130 site, at 1mg/kg each, lung virus load and pathology were reduced, although without an apparent additive or synergistic effect. No evidence for mAb driven virus evolution was detected. These data indicate that intravenous administration of high doses was required to reduce nasal virus shedding, although this was inconsistent and seldom complete. In contrast the effect on lung pathology and lung virus load is consistent and is also seen at one log lower doses, strongly indicating that a lower dose might be sufficient to reduce severity of disease, but for prevention of transmission other measures would be needed.

scholarly journals Low Dose Pig Anti-Influenza Virus Monoclonal Antibodies Reduce Lung Pathology but Do Not Prevent Virus Shedding

2021 ◽  
Vol 12 ◽  
Author(s):  
Basudev Paudyal ◽  
Adam McNee ◽  
Pramila Rijal ◽  
B. Veronica Carr ◽  
Alejandro Nunez ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Intravenous Administration ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Lung Pathology ◽  
Host Animal ◽  
Virus Shedding ◽  
Virus Load ◽  
Robust Model ◽  
High Doses

We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing the therapeutic potential of monoclonal antibodies (mAbs). In this study we demonstrated that prophylactic intravenous administration of 15 mg/kg of porcine mAb pb18, against the K160–163 site of the hemagglutinin, significantly reduced lung pathology and nasal virus shedding and eliminated virus from the lung of pigs following H1N1pdm09 challenge. When given at 1 mg/kg, pb18 significantly reduced lung pathology and lung and BAL virus loads, but not nasal shedding. Similarly, when pb18 was given in combination with pb27, which recognized the K130 site, at 1 mg/kg each, lung virus load and pathology were reduced, although without an apparent additive or synergistic effect. No evidence for mAb driven virus evolution was detected. These data indicate that intravenous administration of high doses was required to reduce nasal virus shedding, although this was inconsistent and seldom complete. In contrast, the effect on lung pathology and lung virus load is consistent and is also seen at a one log lower dose, strongly indicating that a lower dose might be sufficient to reduce severity of disease, but for prevention of transmission other measures would be needed.

scholarly journals Higher Viral Load and Prolonged Viral Shedding Period is Associated with Impaired Th17 Cell Response in Patients with H1N1 Influenza A

2012 ◽  
Vol 1 (3) ◽  
pp. 137-145
Author(s):  
Gui-lin Yang ◽  
Ying-xia Liu ◽  
Mu-tong Fang ◽  
Wei-long Liu ◽  
Xin-chun Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
Cell Response ◽  
Th17 Cell ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Cell Frequency ◽  
Viral Loads ◽  
Viral Shedding ◽  
Ifn Γ

Abstract Objective To explore whether age, disease severity, cytokines and lymphocytes in H1N1 influenza A patients correlate with viral load and clearance. Methods Total of 70 mild and 16 severe patients infected with H1N1 influenza A virus were enrolled in this study. Results It was found that the patients under 14 years old and severe patients displayed significantly higher viral loads and prolonged viral shedding periods compared with the patients over 14 years old and mild patients, respectively (P < 0.05). Moreover, the patients under 14 years old and severe patients displayed significantly lower Th17 cell frequency than the patients over 14 years old and mild patients (P < 0.01). The viral shedding period inversely correlated with the frequency of IL-17+IFN-γ-CD4+ T cells. Additionally, the decreased concentration of serum TGF-β correlated with the decreased frequency of IL-17+IFN-γ-CD4+ T cells. Conclusions Both younger and severe patients are associated with higher viral loads and longer viral shedding periods, which may partially be attributed to the impaired Th17 cell response.

scholarly journals Immune Responses to Pandemic H1N1 Influenza Virus Infection in Pigs Vaccinated with a Conserved Hemagglutinin HA1 Peptide Adjuvanted with CAF®01 or CDA/αGalCerMPEG

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 751
Author(s):  
Sergi López-Serrano ◽  
Lorena Cordoba ◽  
Mónica Pérez-Maillo ◽  
Patricia Pleguezuelos ◽  
Edmond J. Remarque ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Post Infection ◽  
Influenza Virus Infection ◽  
H1n1 Influenza ◽  
The Novel ◽  
H1n1 Influenza Virus ◽  
Viral Loads ◽  
Viral Shedding ◽  
Trivalent Influenza Vaccine

This study aimed to evaluate the immune response and protection correlates against influenza virus (IV) infection in pigs vaccinated with the novel NG34 HA1 vaccine candidate adjuvanted with either CAF®01 or CDA/αGalCerMPEG (αGCM). Two groups of six pigs each were vaccinated intramuscularly twice with either NG34 + CAF®01 or NG34 + CDA/αGCM. As controls, groups of animals (n = 6 or 4) either non-vaccinated or vaccinated with human seasonal trivalent influenza vaccine or NG34 + Freund’s adjuvant were included in the study. All animal groups were challenged with the 2009 pandemic (pdm09) strain of H1N1 (total amount of 7 × 106 TCID50/mL) via intranasal and endotracheal routes 21 days after second vaccination. Reduced consolidated lung lesions were observed both on days three and seven post-challenge in the animals vaccinated with NG34 + CAF®01, whereas higher variability with relatively more severe lesions in pigs of the NG34 + CDA/αGCM group on day three post-infection. Among groups, animals vaccinated with NG34 + CDA/αGCM showed higher viral loads in the lung at seven days post infection whereas animals from NG34 + CAF®01 completely abolished virus from the lower respiratory tract. Similarly, higher IFNγ secretion and stronger IgG responses against the NG34 peptide in sera was observed in animals from the NG34 + CAF®01 group as compared to the NG34 + CDA/αGCM. NG34-vaccinated pigs with adjuvanted CAF®01 or CDA/αGCM combinations resulted in different immune responses as well as outcomes in pathology and viral shedding.

scholarly journals The efficacy and safety of monoclonal antibody treatments against COVID-19: A systematic review and meta-analysis of randomized clinical trials

2021 ◽  
Author(s):  
Ifan Ali Wafa ◽  
Nando Reza Pratama ◽  
David Setyo Budi ◽  
Henry Sutanto ◽  
Alfian Nur Rosyid ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Mechanical Ventilation ◽  
Monoclonal Antibodies ◽  
Viral Load ◽  
Hospital Discharge ◽  
Random Effects ◽  
Mortality Risk ◽  
Safety Profile ◽  
Fixed Effect ◽  
Efficacy And Safety

Objectives: The use of monoclonal antibody for COVID-19 showed conflicting results in prior studies and its efficacy remains unclear. We aimed to comprehensively determine the efficacy and safety profile of monoclonal antibodies in COVID-19 patients. Methods: Sixteen RCTs were analyzed using RevMan 5.4 to measure the pooled estimates of risk ratios (RRs) and standardized mean differences (SMDs) with 95% CIs. Results: The pooled effect of monoclonal antibodies demonstrated mortality risk reduction (RR=0.89 (95%CI 0.82-0.96), I2=13%, fixed-effect). Individually, tocilizumab reduced mortality risk in severe to critical disease (RR=0.90 (95%CI 0.83-0.97), I2=12%, fixed-effect)) and lowered mechanical ventilation requirements (RR=0.76 (95%CI 0.62-0.94), I2=42%, random-effects). Moreover, it facilitated hospital discharge (RR=1.07 (95%CI 1.00-1.14), I2=60%, random-effects). Meanwhile, bamlanivimab-etesevimab and REGN-COV2 decrease viral load ((SMD=-0.33 (95%CI -0.59 to -0.08); (SMD=-3.39 (95%CI -3.82 to -2.97)). Interestingly, monoclonal antibodies did not improve hospital discharge at day 28-30 (RR=1.05 (95%CI 0.99-1.12), I2=71%, random-effects) and they displayed similar safety profile with placebo/standard therapy (RR=1.04 (95%CI 0.76-1.43), I2=54%, random-effects). Conclusion: Tocilizumab improved hospital discharge and reduced mortality as well as the need for mechanical ventilation, while bamlanivimab-etesevimab and REGN-COV2 reduced viral load in mild to moderate outpatients. In general, monoclonal antibodies are safe and should be considered in severe to critical COVID-19 patients.

scholarly journals Recombinant Soluble, Multimeric HA and NA Exhibit Distinctive Types of Protection against Pandemic Swine-Origin 2009 A(H1N1) Influenza Virus Infection in Ferrets

2010 ◽  
Vol 84 (19) ◽  
pp. 10366-10374 ◽  
Author(s):  
Berend Jan Bosch ◽  
Rogier Bodewes ◽  
Robert P. de Vries ◽  
Joost H. C. M. Kreijtz ◽  
Willem Bartelink ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Expression System ◽  
Influenza Virus Infection ◽  
Body Weight Loss ◽  
H1n1 Influenza ◽  
Clinical Effects ◽  
Lung Pathology ◽  
Challenge Inoculation ◽  
Mammalian Expression ◽  
Vaccine Potential

ABSTRACT The emergence and subsequent swift and global spread of the swine-origin influenza virus A(H1N1) in 2009 once again emphasizes the strong need for effective vaccines that can be developed rapidly and applied safely. With this aim, we produced soluble, multimeric forms of the 2009 A(H1N1) HA (sHA3) and NA (sNA4) surface glycoproteins using a virus-free mammalian expression system and evaluated their efficacy as vaccines in ferrets. Immunization twice with 3.75-μg doses of these antigens elicited strong antibody responses, which were adjuvant dependent. Interestingly, coadministration of both antigens strongly enhanced the HA-specific but not the NA-specific responses. Distinct patterns of protection were observed upon challenge inoculation with the homologous H1N1 virus. Whereas vaccination with sHA3 dramatically reduced virus replication (e.g., by lowering pulmonary titers by about 5 log10 units), immunization with sNA4 markedly decreased the clinical effects of infection, such as body weight loss and lung pathology. Clearly, optimal protection was achieved by the combination of the two antigens. Our observations demonstrate the great vaccine potential of multimeric HA and NA ectodomains, as these can be easily, rapidly, flexibly, and safely produced in high quantities. In particular, our study underscores the underrated importance of NA in influenza vaccination, which we found to profoundly and specifically contribute to protection by HA. Its inclusion in a vaccine is likely to reduce the HA dose required and to broaden the protective immunity.

scholarly journals A Phase 2 randomized, double-blind, placebo-controlled trial of the monoclonal antibody MHAA4549A in patients with acute uncomplicated influenza A infection

2021 ◽  
Author(s):  
Jeremy J Lim ◽  
Sadia Dar ◽  
Dirk Venter ◽  
Juan P Horcajada ◽  
Priya Kulkarni ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Viral Load ◽  
Median Time ◽  
Influenza A ◽  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Phase 2 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Viral Shedding

Abstract Background MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, neutralizes influenza A virus in animal and human volunteer challenge studies. We investigated MHAA4549A safety and tolerability, efficacy, and pharmacokinetics in outpatients with acute, uncomplicated influenza A infection. Methods This was a Phase 2, randomized, double-blind, placebo-controlled trial of single intravenous (IV) doses of 3600 mg or 8400 mg MHAA4549A, or IV placebo in adult outpatients testing positive for influenza A. Patients were enrolled across 35 sites in 6 countries. Randomization and dosing occurred ≤ 72 hours of symptom onset; study duration was 14 weeks. The primary endpoint was the nature and frequency of adverse events (AEs). Secondary endpoints included median time to alleviation of all influenza symptoms, effects on nasopharyngeal viral load and duration of viral shedding, and MHAA4549A serum pharmacokinetics. Results Of 125 randomized patients, 124 received study treatment, with 99 confirmed positive for influenza A by central testing. Frequency of AEs between MHAA4549A and placebo groups was similar; nausea was most common (8 patients; 6.5%). MHAA4549A serum exposure was confirmed in all MHAA4549A-treated patients and was dose proportional. No hospitalizations or deaths occurred. Between MHAA4549A and placebo groups, no statistically significant differences occurred in median time to alleviation of all symptoms, nasopharyngeal viral load, or duration of viral shedding. Conclusions While MHAA4549A was safe and well-tolerated with confirmed exposure, the antibody did not improve clinical outcomes in patients with acute uncomplicated influenza A infection.

scholarly journals Monoclonal Antibody Cocktail therapy for COVID-19: A Pharmacological innovation

2021 ◽  
Vol 10 (2) ◽  
pp. 103-105
Author(s):  
Jared Robinson ◽  
Indrajit Banerjee
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
International Health ◽  
The Novel ◽  
Multifaceted Approach ◽  
Mortality And Morbidity ◽  
Viral Shedding ◽  
Human Igg1 ◽  
Ongoing Phase ◽  
Antibody Cocktail

The novel SARS-CoV-2 infection has ripped through international health systems and protocols causing unprecedented mortality, morbidity and global trade deficits amounting to billions. Various monoclonal antibodies have been proposed for use in the treatment of COVID-19 infections. One such drug is LY-CoV555 which in an ongoing phase two trial study conducted by Chen P et al, showed to have an elimination of 99.97% of the viral RNA. The monoclonal antibody 47D11 discovered by Wang et al, binds to SARS-CoV-2. The 47D11 has been reconfigured into a human IgG1 isotope. It has shown that the 47D11 mAb effectively neutralizes the SARS-COV-2 virus. The stance and development however for the treatment of COVID-19 with monoclonal antibodies has shifted from a monotherapy to a so-called monoclonal antibody “cocktail” therapy. REGN-COV2 is such a cocktail developed with the use of two monoclonal antibodies REGN10987 and REGN10933 which have subsequently been named Imdevimab and Casirivimab. REGN-COV2 is currently under study in four phase 2 and 3 trial studies. These studies are multicentric in nature and are being conducted to evaluate the drug’s efficacy, dosing and clinical use as compared to the placebo. The mechanism of action of such monoclonal antibodies is related chiefly to the inhibition of the virus’s ability to perform its invasion and multiplication within the human body. The severity coupled with the sheer novelty of the SARSCoV-2 virus demands the use of newer therapies to both decrease the mortality and morbidity in patients suffering from the infection. The use of a combination of monoclonal antibodies is thereby well established and evident to both decrease the viral infection load, but is also useful in disrupting the virus’s life cycle and thus decreases the replication and viral shedding. It is therefore poignant that a combination of monoclonal antibodies, a “cocktail” therapy is employed so as to attack the virus at its various stages and thus this multifaceted approach may enhance the patient’s prognosis.

scholarly journals Protective immunity of the primary SARS-CoV-2 infection reduces disease severity post re-infection with Delta variants in Syrian hamsters

2021 ◽  
Author(s):  
Sreelekshmy Mohandas ◽  
Pragya Yadav ◽  
Anita Shete ◽  
Dimpal Nyayanit ◽  
Rajlaxmi Jain ◽  
...  
Keyword(s):  
Viral Load ◽  
Protective Immunity ◽  
Herd Immunity ◽  
Neutralizing Antibody ◽  
Lung Pathology ◽  
Upper Respiratory Tract ◽  
Weight Changes ◽  
Syrian Hamsters ◽  
Viral Shedding ◽  
Prolonged Duration

Delta variant has evolved to become dominant SARS-CoV-2 lineage worldwide and there are reports of secondary infections with varying severity in vaccinated and unvaccinated naturally recovered COVID-19 patients. As the protective immunity following the infection wanes within few months, studies of re-infection after prolonged duration is needed. Hence we assessed the potential of re-infection by Delta, Delta AY.1 and B.1 in COVID-19 recovered hamsters after 3 months of infection. Re-infection with Delta and B.1 variants in hamsters showed reduced viral shedding, lung pathology and lung viral load, whereas the upper respiratory tract viral load remained similar to that of first infection. The reduction in viral load and lung pathology after re-infection with Delta AY.1 variant was not marked. Further we assessed the disease characteristics of Delta AY.1 to understand whether it has any replication advantage over Delta variant and B.1 variant, an early isolate in Syrian hamsters. Body weight changes, viral load in respiratory organs, lung pathology, cytokine response and neutralizing antibody response were assessed. Delta AY.1 variant produced milder disease in comparison to Delta variant and the neutralizing response was similar against Delta, B.1 and B.1.351 variant in contrast to Delta or B.1 infected hamsters which showed a significant reduction in neutralization titres against B.1.351. Elevation of IL-6 levels was observed post infection in hamsters after primary infection. The prior infection could not produce sterilizing immunity but the protective effect was evident following re-infection. This indicates the importance of the transmission prevention efforts even after achieving herd immunity.

Rapid quantification and in situ detection of nitrifying bacteria in biofilms by monoclonal antibody method

2000 ◽  
Vol 41 (4-5) ◽  
pp. 301-308 ◽  
Author(s):  
N. Noda ◽  
H. Ikuta ◽  
Y. Ebie ◽  
A. Hirata ◽  
S. Tsuneda ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Fluorescent Antibody ◽  
Nitrifying Bacteria ◽  
Fluorescent Antibody Technique ◽  
Antibody Technique ◽  
Antibody Method ◽  
In Situ Detection ◽  
Rapid Quantification

Fluorescent antibody technique by the monoclonal antibody method is very useful and helpful for the rapid quantification and in situ detection of the specific bacteria like nitrifiers in a mixed baxterial habitat such as a biofilm. In this study, twelve monoclonal antibodies against Nitrosomonas europaea (IFO14298) and sixteen against Nitrobacter winogradskyi (IFO14297) were raised from splenocytes of mice (BALB/c). It was found that these antibodies exhibited little cross reactivity against various kinds of heterotrophic bacteria. The direct cell count method using monoclonal antibodies could exactly detect and rapidly quantify N. europaea and N. winogradskyi. Moreover, the distribution of N. europaea and N. winogradskyi in a biofilm could be examined by in situ fluorescent antibody technique. It was shown that most of N. winogradskyi existed near the surface part and most of N. europaea existed at the inner part of the polyethylene glycol (PEG) gel pellet, which had entrapped activated sludge and used in a landfill leachate treatment reactor. It was suggested that this monoclonal antibody method was utilized for estimating and controlling the population of nitrifying bacteria as a quick and favorable tool.

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