代わりにエイズウイルスでやや古いのですが、IgA抗体によるADEに関して、IgGよりもその関与は薄いのではないかとしながらも、普遍的なメカニズムとしてクラススウィッチング（Immunoglobulin class switching）が働き、わずかに惹起されるIgGによってADEが引き起こされ（ワクチン開発に影響した）たとあります↓。
その辺りが今後の課題。
J Immunol 1995 Jun 1;154(11):6163-73.
High prevalence of serum IgA HIV-1 infection-enhancing antibodies in HIV-infected persons. Masking by IgG
Is global BCG vaccination‐induced trained immunity relevant to the progression of SARS‐CoV‐2 pandemic?
ではSARS‐CoV‐2の重症化率に統計学的有意差を導き出している↓。
Our results demonstrated a statistically significant difference in deaths/million on day 7 since the daily confirmed deaths reached 0.1/million (Mann‐Whitney U test; P = .0109) between countries that had ceased vaccination in the last 2 vs the last 3‐4 decades (Figure 1D). This result suggests that BCG vaccination‐induced heterologous non‐specific protective effect could be of long‐lasting duration (~20 years) and therefore could potentially impact the dynamics of SARS‐CoV‐2‐associated community spread and/or disease severity.
We thus propose that induction of trained immunity by BCG could provide protection against COVID-19, but this hypothesis needs to be tested in rigorous randomized clinical trials.
そして、一気にCOVID19と関連づけてコメントしているものもあります↓。
Is global BCG vaccination‐induced trained immunity relevant to the progression of SARS‐CoV‐2 pandemic?
COVID-19 has inflicted high morbidity and mortality to only that segment of the world population, [11] which has low Th1 immunity due to poor or no exposure to strong Th1 antigens like Mycobacteria, Salmonella, even Bee stings, etc.
Mycobacteria is one of the strongest antigens to induce Th1 immunity [36]; while, Salmonella has also been considered a model pathogen for inducing strong Th1 response [37]. Vaccination of both of these pathogens shall restore the forgotten and decreased Th1 immunity among the immunologically useful antigen starved population of the developed nations, shall downregulate the Th2 bias environment of cytokine storm with IL6 and, thus, help reducing local tissue destruction in COVID-19 patients [38].
The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6,7,8,9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.
Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia
を読んでみるとアビガン との比較についてしっかり述べてあります。
Discussion
（略）Our next-generation sequencing analysis of EIDD-2801-experienced virus populations indicated a high genetic barrier to influenza virus resistance to inhibition in cell culture. This observation was reminiscent of slowly emerging influenza virus escape from T-705 (favipiravir) (29), a nucleoside analog currently approved in Japan for use against pandemic influenza viruses that do not respond to conventional therapies. However, a potential for teratogenicity (30) compromises the clinical use of favipiravir especially against seasonal influenza, and we noted that anabolism of favipiravir to the bioactive tri-phosphate is inefficient in some primary human cells of disease-relevant respiratory origin (10). Although it was originally thought that escape of influenza virus from favipiravir was unlikely (31, 32), a recent study combining continued virus passaging in the presence of sub-sterilizing compound concentrations with deep sequencing revealed a 2-step escape pathway (33). Over the course of ten passages, a virus population emerged in which a mutation in the polymerase basic 1 (PB1) subunit mediated resistance to favipiravir, albeit at a fitness cost, which was compensated for by a second mutation in the PA subunit. The equivalent adaptation approach applied in our study to EIDD-2801 did not yield any polymerase allele variations that became fixed in the virus population, providing promise that EIDD-2801 addresses a major limitation of current influenza virus therapeutics, although only prolonged viral exposure to the compound in vivo will ultimately reveal whether some degree of resistance can be achieved.
Deep-sequencing of an EIDD-2801-experienced virus population furthermore revealed that the compound caused specifically C-to-U and G-to-A transition mutations in influenza virus genomes, demonstrating that tautomeric interconversions of NHC (34) base pair as cytosine or uracil at replication or transcription once NHC has been integrated into the viral RNA.
Notably, A-to-G transition mutations were absent in genomes of NHC-experienced influenza viruses, although we had previously observed that transcripts of respiratory syncytial virus, a member of the distantly related pneumovirus family of non-segmented RNA viruses (35), harbored C-to-U, G-to-A, and A-to-G transitions after exposure to NHC (10).
We consider it most likely that initial recognition of NHC-TP by orthomyxovirus and pneumovirus polymerases for incorporation into nascent RNAs is distinct.
Based on transition mutation characteristics, influenza virus polymerase appears to accept NHC at the stage of incorporation only in place of cytosine and not uracil, and tautomeric interconversion must therefore occur subsequently at the replication stage. In contrast, respiratory syncytial virus polymerase appears capable of incorporating NHC in either tautomeric form, resulting in transitions originating from primary incorporation of NHC-TP in place of uracil and subsequent base pairing as cytosine (A-to-G), post-incorporation tautomeric interconversion and base pairing as uracil (G-to-A), and tautomeric interconversion of NHC incorporated in progeny viral genomes prior to reverse transcription and sequence analysis (C-to-U).
These results are consistent with the induction of viral error catastrophe (36) as the predominant mechanistic principle of NHC activity influenza viruses and other RNA viruses such as respiratory syncytial virus.
We demonstrated that substitution of cytidine triphosphate for NHC-TP partially restores respiratory syncytial virus polymerase activity in a comparable in vitro assay (10), but it remains to be addressed whether NHC increases the frequency of delayed chain termination or interrupts RNA extension after tandem incorporation by influenza virus polymerase.
Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets
に戻り、
フェレットにおける「副作用に関する記載部分」を読んでみる↓
The animals in the high-inoculum group experienced a transient drop in body weight that reached a low plateau on days 5–6 after infection but recovered fully by the end of the study (Fig. 1f and Supplementary Table 5). One animal in the low-inoculum group showed a gradual slight reduction in body weight until the end of the study (day 10). No other clinical signs, such as fever or respiratory discharge, were noted. The complete blood counts (CBCs) taken every second day revealed no significant deterioration from the normal range in the overall white-blood-cell counts as well as lymphocyte, neutrophil and platelet populations of either inoculum group (Fig. 1g and Supplementary Table 6). The relative expression levels of type I and II interferon in the ferret peripheral blood mononuclear cells (PBMCs) sampled at 48-h intervals reached a plateau approximately 3 d after infection and stayed moderately elevated until the end of the study (Fig. 1h,i and Supplementary Table 7). IL-6 levels were moderately elevated in some animals but these changes did not reach statistical significance (Fig. 1j). However, we noted a prominent expression peak of select interferon-stimulated genes (ISGs) with antiviral effector function (MX1 and ISG15) 4 d after infection, followed by a return to baseline expression by the end of the study (Fig. 1k,l).
This view is consistent with the frequent observation (such as in ref. 28) that many mutant viruses can be propagated in cell culture but are attenuated in vivo and incapable of productive host invasion.
Ivermectin tablets are approved for use in people for the treatment of some parasitic worms (intestinal strongyloidiasis and onchocerciasis) and ivermectin topical formulations are approved for human use by prescription-only for the treatment of external parasites such as headlice and skin conditions such as rosacea.
Ivermectin is FDA-approved for use in animals for prevention of
heartworm disease in some small animal species, and for treatment of
certain internal and external parasites in various animal species.
Ivermectin prophylaxis was taken by 77 controls and 38 cases. Two-dose ivermectin prophylaxis (0.27, 95% CI, 0.15-0.51) was associated with 73% reduction of COVID-19 infection among healthcare workers for the following one month, those who were involved in physical activity (3.06 95% CI, 1.18-7.93) for more than an hour/day were more likely to contract COVID-19 infection. Type of household, COVID duty, single-dose ivermectin prophylaxis, vitamin-C prophylaxis and hydroxychloroquine prophylaxis were not associated with COVID-19 infection.
Discussion
Our study findings throw light in the same direction that ivermectin may play a vital role in the prevention strategy of COVID-19 infection.
Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.
結論
レムデシビルはCovid-19で入院中の患者の回復期間を短くし、呼吸障害を抑制する根拠が示された。
この中の結論の部分
Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).
WHO has issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients.
