SARS-CoV-2 Neutralizing Human Antibodies Protect Against Lower Respiratory Tract Disease in a Hamster Model

Haagmans, Bart L.; Noack, Danny; Okba, Nisreen M.A.; Li, Wentao; Wang, Chunyan; Bestebroer, Theo M.; Vries, Rory D. de; Herfst, Sander; Meulder, Dennis de; Verveer, Elwin P; Run, Peter van; Lamers, Mart M.; Rijnders, Bart; Rokx, Casper; Kuppeveld, Frank J. M. van; Grosveld, Frank; Drabek, Dubravka; Kessel, Corine Geurts van; Koopmans, Marion; Bosch, Berend Jan; Kuiken, Thijs; Rockx, Barry

doi:10.1093/infdis/jiab289

Cited by 31 publications

(24 citation statements)

References 33 publications

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“…Considering that the same amounts of purified IgG effectively blocked the replication of the virus in the lung ( Fig. 5b ), the present data are in line with the findings by Zhou et al ( 41 ) and Haagmans et al ( 42 ) that SARS-CoV-2 replication is more susceptible to the SARS-CoV-2-blocking effect of monoclonal antibodies or convalescent plasma samples in lungs than in nasal turbinate.…”

Section: Resultssupporting

confidence: 93%

“…Chan et al also demonstrated that convalescent-phase sera from SARS-CoV-2-infected hamsters effectively reduced the replication of the virus in SARS-CoV-2-inoculated animals as assessed by qRNA-PCR and immunohistochemistry ( 43 ). Further, Haagmans et al reported that the administration of neutralizing activity-confirmed human convalescent plasma ( hn -plasma) or SARS-CoV-2-neutralizing human monoclonal antibody effectively protected Syrian hamsters from the occurrence of SARS-CoV-2-induced lung lesions when the animals were prophylactically (24 h prior to the viral inoculation) treated, while the diluted hn -plasma failed to show such protective effects ( 42 ). In the present study, we extended the observations by groups, including Chan et al and Haagmans et al, and demonstrated that hn -plasmas reduced the severity of lung lesions in SARS-CoV-2-exposed Syrian hamsters even when such plasmas were given to the animals 24 h after the inoculation compared to those receiving a nonneutralizing (control) plasma or moderately neutralizing plasmas ( mn -plasmas) as assessed with micro-CT-captured images (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Highly Neutralizing COVID-19 Convalescent Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters

Takamatsu

Imai

Maeda

et al. 2022

J Virol

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Despite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly-neutralizing COVID-19-convalescent plasma ( hn -plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn -plasmas, which were in the best 1% of 340 neutralizing-activity-determined convalescent plasma samples, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in significant reduction of viral titers in lungs by up to 32-fold as compared to the viral titers in hamsters receiving control non-neutralizing plasma, while with two moderately neutralizing plasmas ( mn -plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn -plasmas also reduced viral titers in lungs than those from the two mn -plasmas. The severity of lung lesions seen in hamsters receiving hn -plasmas was minimal to moderate as assessed using micro-computerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19-convalescent-plasmas variably contained antibodies against SARS-CoV-2 components including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent-neutralizing-activity-confirmed COVID-19-convalescent plasmas would be efficacious in treating patients with COVID-19. Importance Convalescent plasmas obtained from patients, who recovered from a specific infection, have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized-controlled-clinical-trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94-95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly-neutralizing-effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally-induced lung lesions. The present data provide a proof-of-concept that the presence of highly-neutralizing antibody in COVID-19-convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly-neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Highly Neutralizing COVID-19 Convalescent Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters

Takamatsu

Imai

Maeda

et al. 2022

J Virol

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“…Preceding the viral challenge, the animals received 0.5 ml of human ConvP, which is 10% of the plasma volume of hamsters and therefore comparable to a 300ml ConvP transfusion in humans. While ConvP with a NAb titer of 1/320 did not prevent disease, ConvP with a NAb titer of 1/2560 fully prevented weight loss and limited viral pneumonitis ( 4 ). This study, therefore, confirmed that ConvP with extremely high NAb titers of 1/2560 would be required if only 300ml of ConvP is used.…”

Section: Pharmacokinetics and Dynamics In Animal Studiesmentioning

confidence: 99%

Evidence-based dosing of convalescent plasma for COVID-19 in future trials

Rijnders

Huygens

Mitjà

2022

Clinical Microbiology and Infection

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Background Two years into the pandemic, convincing evidence in favor of convalescent plasma(ConvP) as a treatment for COVID-19 is still lacking. This contrasts sharply with the efficacy of potent virus-neutralizing monoclonal antibodies. However, resistance of the Omicron variant against almost all licensed monoclonals turns back the clock and we can expect that ConvP will regain interest. Indeed, the effectivity of virus-neutralizing monoclonal antibodies supports the premise that ConvP will work when used at the right time, at the right dose, containing antibodies with the right affinity. Objectives Review available evidence on dosing of ConvP for COVID-19 and provide guidance for future trials or patient care. Sources As no dose finding human trials were ever performed, we reviewed COVID-19 animal model studies and human trials that provide (in)direct data on the pharmacokinetics and pharmacodynamics of ConvP. We also discuss the identification of appropriate ConvP donors in the context of emerging SARS-COV2 variants. Content Compared with dosing in animal studies, almost all human trials used substantially lower doses. Identifying donors with sufficiently high virus neutralizing antibody titers is challenging, in particular when new variants escape immunity induced by ancestral variants. Ways to avoid underdosing are 1. The use of ConvP from two different donors 2. Only use ConvP known to neutralize the variant the patient is infected with. 3. Use 2 convalescent plasma units with a NAb titer ≥1/1250. When only one plasma unit is available, a NAb titer of ≥1/2500 is recommended. 4. Use an antibody test that correlates well with virus neutralization. The use of international units for virus neutralization is strongly encouraged. 5. The use of donors shortly after a third mRNA vaccination may simplify the donor selection process. Implications In future trials on ConvP for COVID-19, more stringent donor selection criteria and/or higher volume transfusions should be used.

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“…Here it becomes clear that even with this hamster model, animals start to recover on their own already 5–8 days after virus inoculation. Therefore, the drugs to be tested are given pre‐inoculation (prophylactically) of SARS‐CoV‐2 virus infections (Haagmans et al, 2021 ; Kreye et al, 2020 ; Yuan et al, 2020 ), or almost parallel to the inoculation (Kreye et al, 2020 ). Very few studies have tested the application at 1, or a maximum 3, days post inoculation in order to still meet the small time window of being able to show an effect compared to controls (Chan et al, 2021 ; Yuan et al, 2020 ) (see also Table 1 , column “animal experiments”).…”

Section: What Does An In ‐ Vivo Sars‐cov‐2 Animal Experiments Tell Us When Comparing the Anmentioning

confidence: 99%

“…Then, (iv) direct attack on the virus by application of convalescent serum, especially in severe cases, seemed to be a lifeline (Rajendran et al, 2020 ). Derived from the principle of convalescent serum containing anti‐SARS‐CoV‐2 antibodies, the development of therapeutic monoclonal anti‐SARS‐CoV‐2 antibodies was a next logical step (Chan et al, 2021 ; Haagmans et al, 2021 ; Kreer et al, 2020 ; Yang et al, 2020 ), with several players in at the start (DeFrancesco, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Lack of efficacy of mono‐mode of action therapeutics in COVID‐19 therapy ‐ How the lack of predictive power of preclinical cell and animal studies leads developments astray

Haberland

Müller

2021

Chem Biol Drug Des

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The diverse experiences regarding the failure of tested drugs in the fight against COVID‐19 made it clear that one should at least question the requirement to apply classical preclinical development strategies that demand cell and animal efficacy models to be tested before going into clinical trials. Most animals are not susceptible to infection with SARS‐CoV‐2, and so this led to one‐sided virus replication experiments in cells and the use of animal models that have little in common with the complex pathogenesis of COVID‐19 in humans. Therefore, non‐clinical development strategies were designed to meet regulatory requirements, but they did not truly reflect the situation in the clinic. This has led the search for effective agents astray in many cases. As proof of this statement, we now bring together the results of such required preclinical experiments and compare with the results in clinical trials. Two clear conclusions that can be drawn from the experience to date: The required preclinical models are unsuitable for the development of innovative treatments medical devices in the case of COVID‐19 and mono‐action strategies (e.g. direct antivirals) are of very little or no benefit to patients under randomized,blinded conditions. Our hypothesis is that the complex situation of COVID‐19 may benefit from multi‐mode drugs. Here, the molecular class of aptamers could be a solution.

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SARS-CoV-2 Neutralizing Human Antibodies Protect Against Lower Respiratory Tract Disease in a Hamster Model

Cited by 31 publications

References 33 publications

Highly Neutralizing COVID-19 Convalescent Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters

Highly Neutralizing COVID-19 Convalescent Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters

Evidence-based dosing of convalescent plasma for COVID-19 in future trials

Lack of efficacy of mono‐mode of action therapeutics in COVID‐19 therapy ‐ How the lack of predictive power of preclinical cell and animal studies leads developments astray

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