Emergency Use of Convalescent Plasma: Perception of the Regulatory Framework from a Clinical Perspective.

The pandemic spread of an infectious disease poses a plethora of challenges to society, clinicians, health care providers and regulating authorities. In order to mount a rapid response and to provide hope in a potentially catastrophic situation as the current COVID-19 pandemic, emergency plans, regulations and funding strategies have to be developed on regional, national and international levels. The speed needed to establish rapid response programs is challenged by the dynamics of the spread of the disease, the concurrent and competing development of different and potentially more effective treatment options, and not the least by regulatory uncertainty. Convalescent plasma, that is plasma collected from patients who have recovered from COVID-19 infections, has emerged as one of the first potential treatment options in the absence of drugs or vaccines with proven efficacy against SARS-CoV-2. The societal aspects of convalescent plasma and the public awareness gave an additional boost to the rapid employment of convalescent plasma donation platforms immediately after the SARS-CoV-2 outbreak. At the same time, uncertainty remains as to the efficacy of convalescent plasma. With evidence mostly limited to empirical reports, convalescent plasma has been used for decades for the prophylaxis and treatment of various infectious diseases. Clinical trials have addressed different infectious agents, stages of disease, target groups of patients and yielded sometimes inconclusive results. The aim of this short review is to delineate the regulatory background for the emergency use of convalescent plasma in the USA, in the European Union and in Germany, and the transition to the setting of clinical trials. In addition, we describe observations made in the process of collecting COVID-19 convalescent plasma (herein referred to as CCP), and formulate proposals to further improve the framework for rapid responses in future emergency situations.

Sensitivity of two SARS-CoV-2 variants with spike protein mutations to neutralising antibodies.

SARS-CoV-2 infections elicit a humoral immune response capable of neutralising the virus. However, multiple variants have emerged with mutations in the spike protein amongst others, the key target of neutralising antibodies. We evaluated the neutralising efficacy of 89 serum samples from patients, infected with SARS-CoV-2 in the beginning of 2020, against two virus variants isolated from acutely infected patients and harbouring spike protein mutations. One isolate was assigned to lineage B.1.351 (MUC-IMB-B.1.351) whilst the other (MUC-484) was isolated from an immunocompromised patient, sharing some but not all mutations with B.1.351 and representing a transitional variant. Both variants showed a significant reduction in neutralisation sensitivity compared to wild-type SARS-CoV-2 with MUC-IMB-B.1.351 being almost completely resistant to neutralisation. The observed reduction in neutralising activity of wild-type-specific antibodies against both variants suggests that individual mutations in the spike protein are sufficient to confer a potent escape from the humoral immune response. In addition, the effect of escape mutations seems to accumulate, so that more heavily mutated variants show a greater loss of sensitivity to neutralisation up to complete insensitivity as observed for MUC-IMB-B.1.351. From a clinical point of view, this might affect the efficacy of (monoclonal) antibody treatment of patients with prolonged infections as well as patients infected with variants other than the donor. At the same, this could also negatively influence the efficacy of current vaccines (as they are based on wild-type spike protein) emphasising the need to thoroughly surveil the emergence and distribution of variants and adapt vaccines and therapeutics accordingly.

Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection.

Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.

Emerging SARS-CoV-2 variant B.1.1.7 reduces neutralisation activity of antibodies against wild-type SARS-CoV-2.

Spike-specific antibodies contribute significantly to the neutralising activity against SARS-CoV-2 and are important for the therapeutic effect of convalescent plasma. B.1.1.7 is a recently emerged variant of SARS-CoV-2 that has several mutations in the gene encoding for the spike-protein. To assess the potential effect these mutations could have on the neutralising efficacy of antibodies, we evaluated 96 serum samples from convalescent plasma donors collected before the first occurrence of B.1.1.7 and tested their neutralising effect on wild-type SARS-CoV-2 and B.1.1.7. We found that B.1.1.7 is more resistant to neutralisation by convalescent plasma from patients infected with wild-type SARS-CoV-2 with an overall decrease in neutralising activity of 47.7%. Thus, the neutralising effect of convalescent plasma should be determined against the major circulating virus clades whenever possible to ensure the best possible therapeutic effect.

D-Dimer Predicts Disease Severity but Not Long-Term Prognosis in Acute Pulmonary Embolism.

D-dimer might be correlated with prognosis in pulmonary embolism (PE). The predictive value of plasma D-dimer for disease severity and survival was investigated in the lowest and highest D-dimer quartile among 200 patients with PE. Patients with high D-dimers were significantly more often hypotensive (P = .001), tachycardic (P = .016), or hypoxemic (P = .001). Pulmonary arterial obstruction index (PAOI) values were significantly higher in the high D-dimer quartile (P < .001). Elevated troponin I (TNI) levels (P < .001), simplified PE severity indices ≥1 (P < .001), right-to-left ventricular (RV/LV) diameter ratios ≥1 (P < .001), and thrombolysis (P = .001) were more frequent in the high D-dimer quartile. D-dimer was associated with RV/LV ratios ≥1 (P = .021), elevated PAOI (P < .001) or TNI levels (P < .001), hypotension (P < .001), tachycardia (P = .003), and hypoxemia (P < .001), but not with long-term all-cause mortality. D-dimer predicts disease severity but not long-term prognosis in acute PE, possibly due to a more aggressive treatment strategy in severely affected patients.