Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

The SARS-CoV-2 Omicron variant of concern evades antibody mediated immunity with an unprecedented magnitude due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and X-ray crystal structures of the spike and RBD bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a structural framework for understanding the marked reduction of binding of all other therapeutic mAbs leading to dampened neutralizing activity. We reveal electrostatic remodeling of the interactions within the spike and those formed between the Omicron RBD and human ACE2, likely explaining enhanced affinity for the host receptor relative to the prototypic virus.

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab, S2X259 and S2H97, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Amantadine Variants Activity Against Multiple Influenza A Viruses

Future pandemic influenza necessitates the development of new drugs against the current circulating, amantadine and rimantadine drugs resistant, influenza A M2 S31N viruses. The possibility of an antigenic shift to M2 S31 necessitates ranking the biological activities of amantadine variants. Several amantadine variants have been tested by different laboratories, but various M2 wild type influenza A strains have been used with different sensitivity against amantadine and the unambiguous comparison between potencies is not straightforward. Here, we compared the anti-influenza activities of 57 synthetic amantadine variants against influenza A WSN/33 viruses with amantadine-sensitive M2 WT, with a range of over three digits providing a reference set of potencies for structure-activity relationships, and amantadine-resistant M2 S31N proteins (and observed no potent compounds). 17 compounds were selected and tested against M2 L26F, V27A, A30T, G34E viruses. We tested few reference compounds using electrophysiology and explored point mutations which both showed that M2 is the target of potent antiviral potency against the M2 WT, L26F, V27A viruses. Major findings are: (a) Several amantadine variants from Kolocouris group block only M2 WT and M2 L26F-mediated proton current and the corresponding viruses replication. (b) A compound from Vazquez’s group is a triple blocker of M2 WT, L26F, V27A channels and viruses replication. (c) A compound from Vazquez’s group blocks only M2 L26 channel and virus replication. (d) Several compounds from Kolocouris group have potent activity against several influenza A M2 WT and three M2 S31N viruses, eg. the pandemic A/H1N1/California/07/2009 (H1N1pdm09) or A/H1N1/PuertoRico/08/1934 without blocking M2 S31N. The compounds and their cocktails while not to be more toxic than amantadine might be useful for re-purposing of amantadine class of drugs in the case (i) of the prevalence of M2 L26F and or M2 V27A strains (ii) of an antigenic shift of the virus to M2 WT and (iii) because they inhibited a broad panel of M2 WT and M2 S31N viruses including the H1N1pdm09). (d) We showed that the mechanism of antiviral activity against A/California/07/2009 or A/PR/08/1934 and possibly also M2 WT viruses compared to WSN/33 viruses is not due to inhibition of an early stage of virus infection or a late stage of M2 channel function during endocytosis or inhibition of HA binding to host cells or a different pH for HA fusion or a lysosomotropic effect.

Broadly Reactive IgG Responses to Heterologous H5 Prime-Boost Influenza Vaccination Are Shaped by Antigenic Relatedness to Priming Strains

The antigenic shift and draft of hemagglutinin (HA) in influenza viruses is accepted as one of the major reasons for immune evasion. The analysis of B cell immune responses to influenza infection and vaccination is complicated by the impact of exposure history and antibody cross-reactions between antigenically similar influenza strains.

SARS-CoV-2 on the move: Reviewing Innate vs Acquired for Covid-19

In this article we have put down certain facts reported so far and raised some pertinent questions to understand the progress of Covid-19 disease. We have discussed the important role of innate immunity to tame Covid-19. Basics of innate and adaptive immunity has been discussed for general audience. Subsequently, we have discussed why immunity fails leading to ‘immunity escape’. We have asked and tried to address few concerns such as: Can vaccines drive the pathogen to mutate to a higher virulent strain?; Evolution of more virulent pathogens; Evidence of new variants; Evidence of variants evading immunity; Antibody cocktail demand for new design of vaccine; Evidence of SARS-CoV-2 evades T cell responses; Imperfect leaky vaccine; Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain; Where is the originally identified SARS-CoV-2 (labeled as D614) found first in Wuhan, China; Deletion of spike glycoprotein itself: How to fix missing?; What is the present status?; To be or not to be vaccinated?; The challenge of antigenic drift and antigenic shift; What causes variant and can it be controlled?; A new dawn in the fight against the disease, to be or not to be worried?; Judging the risk “risk management”; Prophylactic measures for covid 19: Changing Diet and life style; Maneuvering the pandemic and finally the “Take away message”.

COVID-19: No Guaranteed Protection from Future Infection after the Initial Diagnosis

The world of microbiology is vast in nature, and viruses continue to be a subset containing a lot of unknowns. Initial infection with certain viruses, such as varicella zoster virus and measles, allows for development of lifelong immunity; on the other hand, the influenza virus requires yearly vaccination, which may not provide adequate immunity. This can be attributed to antigenic shift and drift, rendering previously made antibodies ineffective against new strains of influenza. This article describes six cases of patients who presented with mild acute respiratory symptoms and tested positive for COVID-19 virus. After recovering from initial illness and being asymptomatic for several months, they developed recurrence of acute respiratory symptoms and, again, tested positive for COVID-19 virus, in more severe form than initial presentation. In the current state of the world, COVID-19 has created a lot of unknowns in the medical community, including patient presentation and treatment. COVID-19 research is evolving daily, but many questions remained unanswered. “Will a sufficient antibody response be created by the human body in those infected with COVID-19 and how long will that immunity last?” “Will antigenic drift occur quickly allowing the virus to evade previously made antibodies?” During initial surveillance of the COVID-19 virus, we were expecting development of an immune response comparable to SARS-CoV-1 and MERS-CoV, given the viral similarities. Unfortunately, based on our observations, this may not necessarily be true and will be further discussed in the presented article.