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      Convalescent plasma to treat critically ill patients with COVID-19: framing the need for randomised clinical trials

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      1 , 2 , , 3 , 4 , 5 , 6 , 3 , 4 , 7 , On behalf of the United Kingdom SARS-CoV-2 Convalescent Plasma Evaluation (SCoPE) Consortium
      Critical Care
      BioMed Central

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          Abstract

          We are in a severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) pandemic, causing coronavirus disease (COVID-19). SARS-CoV-2 is an enveloped RNA virus with cell entry facilitated by spike (S) protein that has a cleavage site at the S1–S2 boundary and other structural proteins such as membrane (M), envelope (E), and nucleocapsid (N) proteins [1]. Currently, there are two lineages of SARS-CoV-2 virus infecting humans, with similar virulence and clinical outcomes, derived from a common ancestor that originated in December 2019 in Wuhan [1, 2]. Most patients who recover from SARS-CoV-2 illness will develop antibodies and memory lymphocytes against these proteins, which gives them immunity [3]. In this editorial, we discuss the biological, operational, and methodological questions that arise when designing a randomised controlled trial (RCT) of convalescent plasma in COVID-19. What is convalescent plasma therapy? Convalescent plasma refers to acellular plasma fraction of blood, containing antibodies against SARS-CoV-2 antigens, with virus neutralisation properties, collected from patients who have recovered from SARS-CoV-2 infections. Passive immunisation with ABO blood group-compatible convalescent plasma will reduce viral burden as neutralising antibodies will binding to the viral spike protein to either prevent interaction with angiotensin-converting enzyme-2 receptor or block the conformational changes in spike protein preventing fusion to host cell membrane and provide immunomodulation. What do we know thus far about convalescent plasma therapy in COVID-19 illness? Since the recent Cochrane review that highlighted very low-certainty evidence on the effectiveness and safety of convalescent plasma in COVID-19 patients [4], Joyner and colleagues have reported safety results from a compassionate use convalescent plasma therapy programme in 5000 adults with COVID-19. They highlight that convalescent plasma is a safe treatment with an overall serious adverse event rate of < 1% (n = 36 events), with TACO occuring in 7 patients, TRALI in 11 patients, and allergic transfusion reaction in 3 patients [5]. To date, one RCT has been published. This open-label trial stopped early after recruiting 103 of a planned 200 patients sample size were enrolled. The stoppage was due to low patient recruitment, as the pandemic abated in China, and importantly not for safety reasons [6]. The participants had either severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation) COVID-19 illness. The intervention, ABO-compatible convalescent plasma at a dose of 4 to 13 ml/kg of recipient body weight, and with an S-RBD-specific IgG titre of at least 1:640. The primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale. The overall trial result was no statistically significant improvement in time to clinical improvement within 28 days between convalescent plasma with standard of care versus standard of care alone. However, any inference from this trial is limited by it's early termination. Why do we need more RCTs of convalescent plasma? The risks of administering plasma screened for common blood-borne pathogens are small, but include allergy/anaphylaxis, transfusion-related acute lung injury (TRALI), and transfusion-associated circulatory overload (TACO) [7]. TRALI and TACO are relevant as many COVID-19 patients have incipient respiratory failure that may worsen with convalescent plasma transfusion-related volume loading. Another specific concern with this intervention is antibody-dependent enhancement (ADE). In SARS-1 coronaviruses, ADE occurs by S protein neutralising antibodies enhancing viral entry into cells though fragment-crystallisable (Fc) receptor expressing cells such as monocytes [8]. This has been shown to worsen lung injury in SARS-1 patients [9]. Non-randomised clinical use (compassionate) will not provide evidence of efficacy, which is an important consideration, as passive immunotherapy was ineffective in severe influenza A [10], and Ebola [11]. The impact of these harms would be difficult to identify outside a well-conducted RCT that collects adverse event data in a standardised way, whilst answering the efficacy question. Can we rapidly provide convalescent plasma with neutralising antibodies during a pandemic? Convalescent plasma can be collected safely from individuals who have recovered from laboratory-confirmed SARS-CoV-2 infection, as neutralising antibody responses begin by 14 days and continue to increase over the next few weeks. Currently, it is uncertain how long these antibodies persist, but in other coronavirus infections, neutralising antibodies may persist at high titres for at least 3 months before declining [12]. Therefore, collection of plasma around 28 days after recovery will provide an effective product with high titres of neutralising antibodies. However, neither the method to assess viral neutralisation ability of convalescent plasma prior to administration nor the minimum titre of neutralising antibody that is required for treating critically ill patients with COVID-19 is known. There are two methods to assess viral neutralisation ability—pseudotype and live-virus assays. Pseudotype assays using harmless viruses that express the coronavirus spike protein, the target of neutralising antibodies, are a safer, easier, and more sensitive method for detecting neutralising antibody than live-virus assays that assess neutralisation of invasion of tissue culture cells by live virus [13]. The titres of antibody dose vary between studies, from 400 ml of ABO-compatible convalescent plasma with neutralising antibody titre > 1:40 [14] to single 200 ml dose of inactivated convalescent plasma with neutralising antibody titre > 1:640 [15]. What are the key design issues to consider in RCTs of convalescent plasma? Current trials include participants with a range of COVID-19 illness spectrum, the intervention (convalescent plasma different timing, different doses, and need for molecular evidence of viral infection) and comparators are different, ranging from standard of care to use of regular plasma for blinding that adds transfusion-related risks in comparator population, and outcomes differ between trials. It is conceivable that the treatment effect of convalescent plasma may differ by illness severity, by dose in terms of volume, concentration of neutralisation antibody, and the risk of ADE along with other adverse events during COVID-19 illness (Table 1) [4]. Table 1 Ongoing randomised controlled trials of convalescent plasma in COVID-19 illness assessed using the PICO framework. These RCTs were identified in a recent Cochrane review by Valk et al. [4]. Participants: We report the setting (severely ill/critically ill versus general wards). In high-risk non-ventilated patients (high inspired oxygen, and/or non-invasive ventilation), this could reduce the need for mechanical ventilation. In ventilated patients, this may translate into improved mortality and reduced length of critical care stay. Intervention: For intervention, we report the description of convalescent plasma volume and titres if highlighted. In SARS-1 patients, convalescent plasma improved outcomes when administered within 14 days of illness onset and in those without detectable antibodies against coronavirus at the time of infusion. Only four studies use a predetermined neutralising titre cutoff with convalescent plasma. Comparator: We highlight whether the ordinary plasma or standard of care was chosen. In five RCTs, the comparator is ordinary plasma transfusion, which may enhance blinding but comes with risks of blood product. When summarising the ongoing current trials, it is unlikely that an efficacy signal would be generated from many of these trials due their methodological limitations (such as small sample size) and biological limitations (such as lack of pre-defined cutoff for neutralising antibody titres). For outcome, we list only the primary outcome for the trial. We also highlight the proposed sample size in the trial. Trial ID [country] Participants Intervention Comparator Outcome N ChiCTR2000029757 [China] Severely ill/critically ill Volume = NR Standard of care 2-point improvement in clinical symptoms in a 6-point scale 200 Titres = NR ChiCTR2000030010 [China] Severely ill adults less than 70 years Volume = NR Ordinary plasma 2-point improvement in clinical symptoms in a 6-point scale 100 Titres = NR ChiCTR2000030179 [China] Severely ill adults less than 66 years Volume = NR Standard of care Cure rate 100 Titres = NR Mortality ChiCTR2000030627 [China] Severely ill/critically ill Volume = NR Standard of care Temperature control 30 Titres = NR ChiCTR2000030702 [China] Hospitalised patients Volume = NR Standard of care Time to clinical recovery after randomisation 50 Titres = NR ChiCTR2000030929 [China] Severely ill adults less than 70 years Volume = NR Ordinary plasma 2-point improvement in clinical symptoms in a 6-point scale 60 Titres = NR EUCTR2020-001310-38 [Germany] Severely ill/critically ill adults less than 75 years Volume = up to 960 ml Standard of care Composite endpoint: - Survival and no longer fulfilling criteria of severe COVID-19 within 21 days after randomisation 120 Titres = NR IRCT20200310046736N1 [Iran] Adult (20 to 45 years) Volume = 800 ml Standard of care N/A 45 Titres = NR IRCT20200404046948N1 [Iran] Severely ill/critically ill adults less than 70 years Volume = up to 500 ml Standard of care 2-point improvement in clinical symptoms at 14 days 60 Titres = NR IRCT20200409047007N1 [Iran] Critically ill adults 50–75 years with Pao2/FIO2 ratio < 300; normal IgA level and within 7 days of admission Volume = up to 500 ml Standard of care 1-month mortality 35 Titres = NR IRCT20200413047056N1 [Iran] Severely ill/critically ill adults less than 50 years Volume = up to 400 ml Standard of care or intravenous immunoglobulin NR 15(1:1:1) 3-arm study Titres = NR NCT04332835 [Columbia] Hospitalised adults less than 60 years Volume = up to 500 ml Hydroxychloroquine Change in viral load 60 Titres = NR Change in antibody titres Coadministration of hydroxychloroquine NCT04333251 [USA] Hospitalised adults Volume = 2 doses Standard of care Reduction in oxygen and ventilation support 115 Titres = > 1:64 NCT04342182 [Netherlands] Hospitalised adults Volume = up to 300 ml Standard of care Mortality 426 Titres = NR NCT04344535 [USA] Hospitalised adults Volume = up to 550 ml Standard plasma Ventilator-free days up to day 28 500 Titres = > 1:320 NCT04345289 [Denmark] Hospitalised adults with pneumonia Volume = 600 ml Multiple interventions; adaptive platform trial Composite endpoint of all-cause mortality or need of invasive mechanical ventilation up to 28 days 1500 Titres = NR 1:1:1:1:1:1 NCT04345523 [Spain] Hospitalised adults with pneumonia Volume = 800 ml Standard of care WHO ordinal scale 278 Titres = NR NCT04345991 [France] Mild severity as described in the WHO scale, within 8 days Volume = 800 ml Standard of care Survival without needs of ventilator utilisation or use of immunomodulatory drugs at 14 days 120 Titres = NR NCT04346446 [India] Severely ill/critically ill adults less than 65 years Volume = up to 600 ml Standard of care Proportion of patients remaining free of mechanical ventilation at 7 days 40 Titres = NR NCT04348656 [Canada] Hospitalised adults receiving supplemental oxygen Volume = up to 500 ml Standard of care Intubation or hospital mortality within 30 days 1200 Titres = NR NCT04355767 [USA] Adults requiring emergency department evaluation Volume = up to 600 ml Standard plasma Time to disease progression at 15 days 206 Titres = > 1:80 NCT04356534 [Bahrain] Adults > 21 years with severely ill with radiological evidence of pneumonia Volume = up to 600 ml Standard of care Requirement for invasive ventilation 40 Titres = > 1:80 NCT02735707 [Multinational] Severely ill/critically ill adults Volume = up to 600 ml Multiple interventions; adaptive platform trial Days alive and outside of ICU at 21 days 7100 platform Titres = > 1:64 In summary, there is a clear biological framework for considering convalescent plasma as a potential intervention in COVID-19 illness. However, we need high-quality randomised controlled trials prior to using convalescent plasma as standard care in SARS-CoV-2 infections.

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          The proximal origin of SARS-CoV-2

          To the Editor — Since the first reports of novel pneumonia (COVID-19) in Wuhan, Hubei province, China 1,2 , there has been considerable discussion on the origin of the causative virus, SARS-CoV-2 3 (also referred to as HCoV-19) 4 . Infections with SARS-CoV-2 are now widespread, and as of 11 March 2020, 121,564 cases have been confirmed in more than 110 countries, with 4,373 deaths 5 . SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms 6 . Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-CoV-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus. Notable features of the SARS-CoV-2 genome Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (i) on the basis of structural studies 7–9 and biochemical experiments 1,9,10 , SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2; and (ii) the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary through the insertion of 12 nucleotides 8 , which additionally led to the predicted acquisition of three O-linked glycans around the site. 1. Mutations in the receptor-binding domain of SARS-CoV-2 The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome 1,2 . Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses 7 . With coordinates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which correspond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-2 7 . Five of these six residues differ between SARS-CoV-2 and SARS-CoV (Fig. 1a). On the basis of structural studies 7–9 and biochemical experiments 1,9,10 , SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology 7 . Fig. 1 Features of the spike protein in human SARS-CoV-2 and related coronaviruses. a, Mutations in contact residues of the SARS-CoV-2 spike protein. The spike protein of SARS-CoV-2 (red bar at top) was aligned against the most closely related SARS-CoV-like coronaviruses and SARS-CoV itself. Key residues in the spike protein that make contact to the ACE2 receptor are marked with blue boxes in both SARS-CoV-2 and related viruses, including SARS-CoV (Urbani strain). b, Acquisition of polybasic cleavage site and O-linked glycans. Both the polybasic cleavage site and the three adjacent predicted O-linked glycans are unique to SARS-CoV-2 and were not previously seen in lineage B betacoronaviruses. Sequences shown are from NCBI GenBank, accession codes MN908947, MN996532, AY278741, KY417146 and MK211376. The pangolin coronavirus sequences are a consensus generated from SRR10168377 and SRR10168378 (NCBI BioProject PRJNA573298) 29,30 . While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal 7 and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding 7,11 . Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation. 2. Polybasic furin cleavage site and O-linked glycans The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at the junction of S1 and S2, the two subunits of the spike 8 (Fig. 1b). This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity and host range 12 . In addition, a leading proline is also inserted at this site in SARS-CoV-2; thus, the inserted sequence is PRRA (Fig. 1b). The turn created by the proline is predicted to result in the addition of O-linked glycans to S673, T678 and S686, which flank the cleavage site and are unique to SARS-CoV-2 (Fig. 1b). Polybasic cleavage sites have not been observed in related ‘lineage B’ betacoronaviruses, although other human betacoronaviruses, including HKU1 (lineage A), have those sites and predicted O-linked glycans 13 . Given the level of genetic variation in the spike, it is likely that SARS-CoV-2-like viruses with partial or full polybasic cleavage sites will be discovered in other species. The functional consequence of the polybasic cleavage site in SARS-CoV-2 is unknown, and it will be important to determine its impact on transmissibility and pathogenesis in animal models. Experiments with SARS-CoV have shown that insertion of a furin cleavage site at the S1–S2 junction enhances cell–cell fusion without affecting viral entry 14 . In addition, efficient cleavage of the MERS-CoV spike enables MERS-like coronaviruses from bats to infect human cells 15 . In avian influenza viruses, rapid replication and transmission in highly dense chicken populations selects for the acquisition of polybasic cleavage sites in the hemagglutinin (HA) protein 16 , which serves a function similar to that of the coronavirus spike protein. Acquisition of polybasic cleavage sites in HA, by insertion or recombination, converts low-pathogenicity avian influenza viruses into highly pathogenic forms 16 . The acquisition of polybasic cleavage sites by HA has also been observed after repeated passage in cell culture or through animals 17 . The function of the predicted O-linked glycans is unclear, but they could create a ‘mucin-like domain’ that shields epitopes or key residues on the SARS-CoV-2 spike protein 18 . Several viruses utilize mucin-like domains as glycan shields involved immunoevasion 18 . Although prediction of O-linked glycosylation is robust, experimental studies are needed to determine if these sites are used in SARS-CoV-2. Theories of SARS-CoV-2 origins It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. As noted above, the RBD of SARS-CoV-2 is optimized for binding to human ACE2 with an efficient solution different from those previously predicted 7,11 . Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used 19 . However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone 20 . Instead, we propose two scenarios that can plausibly explain the origin of SARS-CoV-2: (i) natural selection in an animal host before zoonotic transfer; and (ii) natural selection in humans following zoonotic transfer. We also discuss whether selection during passage could have given rise to SARS-CoV-2. 1. Natural selection in an animal host before zoonotic transfer As many early cases of COVID-19 were linked to the Huanan market in Wuhan 1,2 , it is possible that an animal source was present at this location. Given the similarity of SARS-CoV-2 to bat SARS-CoV-like coronaviruses 2 , it is likely that bats serve as reservoir hosts for its progenitor. Although RaTG13, sampled from a Rhinolophus affinis bat 1 , is ~96% identical overall to SARS-CoV-2, its spike diverges in the RBD, which suggests that it may not bind efficiently to human ACE2 7 (Fig. 1a). Malayan pangolins (Manis javanica) illegally imported into Guangdong province contain coronaviruses similar to SARS-CoV-2 21 . Although the RaTG13 bat virus remains the closest to SARS-CoV-2 across the genome 1 , some pangolin coronaviruses exhibit strong similarity to SARS-CoV-2 in the RBD, including all six key RBD residues 21 (Fig. 1). This clearly shows that the SARS-CoV-2 spike protein optimized for binding to human-like ACE2 is the result of natural selection. Neither the bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. Although no animal coronavirus has been identified that is sufficiently similar to have served as the direct progenitor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled. Mutations, insertions and deletions can occur near the S1–S2 junction of coronaviruses 22 , which shows that the polybasic cleavage site can arise by a natural evolutionary process. For a precursor virus to acquire both the polybasic cleavage site and mutations in the spike protein suitable for binding to human ACE2, an animal host would probably have to have a high population density (to allow natural selection to proceed efficiently) and an ACE2-encoding gene that is similar to the human ortholog. 2. Natural selection in humans following zoonotic transfer It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it 1,2 . All SARS-CoV-2 genomes sequenced so far have the genomic features described above and are thus derived from a common ancestor that had them too. The presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we can infer this was also probably in the virus that jumped to humans. This leaves the insertion of polybasic cleavage site to occur during human-to-human transmission. Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence data point to emergence of the virus in late November 2019 to early December 2019 23 , compatible with the earliest retrospectively confirmed cases 24 . Hence, this scenario presumes a period of unrecognized transmission in humans between the initial zoonotic event and the acquisition of the polybasic cleavage site. Sufficient opportunity could have arisen if there had been many prior zoonotic events that produced short chains of human-to-human transmission over an extended period. This is essentially the situation for MERS-CoV, for which all human cases are the result of repeated jumps of the virus from dromedary camels, producing single infections or short transmission chains that eventually resolve, with no adaptation to sustained transmission 25 . Studies of banked human samples could provide information on whether such cryptic spread has occurred. Retrospective serological studies could also be informative, and a few such studies have been conducted showing low-level exposures to SARS-CoV-like coronaviruses in certain areas of China 26 . Critically, however, these studies could not have distinguished whether exposures were due to prior infections with SARS-CoV, SARS-CoV-2 or other SARS-CoV-like coronaviruses. Further serological studies should be conducted to determine the extent of prior human exposure to SARS-CoV-2. 3. Selection during passage Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and/or animal models has been ongoing for many years in biosafety level 2 laboratories across the world 27 , and there are documented instances of laboratory escapes of SARS-CoV 28 . We must therefore examine the possibility of an inadvertent laboratory release of SARS-CoV-2. In theory, it is possible that SARS-CoV-2 acquired RBD mutations (Fig. 1a) during adaptation to passage in cell culture, as has been observed in studies of SARS-CoV 11 . The finding of SARS-CoV-like coronaviruses from pangolins with nearly identical RBDs, however, provides a much stronger and more parsimonious explanation of how SARS-CoV-2 acquired these via recombination or mutation 19 . The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios. New polybasic cleavage sites have been observed only after prolonged passage of low-pathogenicity avian influenza virus in vitro or in vivo 17 . Furthermore, a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described. Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described. Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system 18 . Conclusions In the midst of the global COVID-19 public-health emergency, it is reasonable to wonder why the origins of the pandemic matter. Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events. For example, if SARS-CoV-2 pre-adapted in another animal species, then there is the risk of future re-emergence events. In contrast, if the adaptive process occurred in humans, then even if repeated zoonotic transfers occur, they are unlikely to take off without the same series of mutations. In addition, identifying the closest viral relatives of SARS-CoV-2 circulating in animals will greatly assist studies of viral function. Indeed, the availability of the RaTG13 bat sequence helped reveal key RBD mutations and the polybasic cleavage site. The genomic features described here may explain in part the infectiousness and transmissibility of SARS-CoV-2 in humans. Although the evidence shows that SARS-CoV-2 is not a purposefully manipulated virus, it is currently impossible to prove or disprove the other theories of its origin described here. However, since we observed all notable SARS-CoV-2 features, including the optimized RBD and polybasic cleavage site, in related coronaviruses in nature, we do not believe that any type of laboratory-based scenario is plausible. More scientific data could swing the balance of evidence to favor one hypothesis over another. Obtaining related viral sequences from animal sources would be the most definitive way of revealing viral origins. For example, a future observation of an intermediate or fully formed polybasic cleavage site in a SARS-CoV-2-like virus from animals would lend even further support to the natural-selection hypotheses. It would also be helpful to obtain more genetic and functional data about SARS-CoV-2, including animal studies. The identification of a potential intermediate host of SARS-CoV-2, as well as sequencing of the virus from very early cases, would similarly be highly informative. Irrespective of the exact mechanisms by which SARS-CoV-2 originated via natural selection, the ongoing surveillance of pneumonia in humans and other animals is clearly of utmost importance.
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            Effectiveness of convalescent plasma therapy in severe COVID-19 patients

            Significance COVID-19 is currently a big threat to global health. However, no specific antiviral agents are available for its treatment. In this work, we explore the feasibility of convalescent plasma (CP) transfusion to rescue severe patients. The results from 10 severe adult cases showed that one dose (200 mL) of CP was well tolerated and could significantly increase or maintain the neutralizing antibodies at a high level, leading to disappearance of viremia in 7 d. Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within 3 d. Radiological examination showed varying degrees of absorption of lung lesions within 7 d. These results indicate that CP can serve as a promising rescue option for severe COVID-19, while the randomized trial is warranted.
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              Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals

              Summary The World Health Organization has declared SARS-CoV-2 virus outbreak a world-wide pandemic. However, there is very limited understanding on the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in 8 newly discharged patients. Follow-up analysis on another cohort of 6 patients 2 weeks post discharge also revealed high titers of IgG antibodies. In all 14 patients tested, 13 displayed serum neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells. Our work provides a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It has also implications in developing an effective vaccine to SARS-CoV-2 infection.
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                Author and article information

                Contributors
                manu.shankar-hari@kcl.ac.uk
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                20 July 2020
                20 July 2020
                2020
                : 24
                : 449
                Affiliations
                [1 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, School of Immunology & Microbial Sciences, , Kings College London, ; 5th Floor, Southwark Wing, London, SE1 9RT UK
                [2 ]GRID grid.420545.2, Guy’s and St Thomas’ NHS Foundation Trust, ; ICU Support Offices, 1st Floor, East Wing, St Thomas’ Hospital, London, SE1 7EH UK
                [3 ]GRID grid.8348.7, ISNI 0000 0001 2306 7492, NHS Blood and Transplant, Level 2, , John Radcliffe Hospital, ; Oxford, OX3 9BQ UK
                [4 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Radcliffe Department of Medicine, , University of Oxford, ; Oxford, UK
                [5 ]GRID grid.436365.1, ISNI 0000 0000 8685 6563, National Microbiology Services, NHS Blood and Transplant, ; Charcot Road, Colindale, NW9 5BG UK
                [6 ]GRID grid.83440.3b, ISNI 0000000121901201, Division of Infection and Immunity, , University College of London, ; London, WC1E 6JF UK
                [7 ]GRID grid.5335.0, ISNI 0000000121885934, Division of Anaesthesia, Department of Medicine, , University of Cambridge, ; Box 93, Addenbrooke’s Hospital, Cambridge, CB2 0NUI UK
                Author information
                http://orcid.org/0000-0002-5338-2538
                Article
                3163
                10.1186/s13054-020-03163-3
                7370253
                32690059
                06417505-f1b0-47ee-a022-f00e47a33da5
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 2 July 2020
                : 9 July 2020
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                © The Author(s) 2020

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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