A combination of vaccination and naturally acquired infection appears to boost the production of maximally potent antibodies against the COVID virus, new UCLA research finds. The study was conducted prior to the emergence of delta and omicron, but Dr. Yang said it is not yet known whether the same benefits would be realized for people who have repeated vaccinations but who have not contracted COVID The article must also clearly indicate why any statistics presented are relevant.
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All news articles must include appropriate background information and context for the specific condition or topic. Experts say Omicron symptoms seem to be similar so far to other coronavirus variants. Cases also appear to be mild, but that may help the virus spread. President Joe Biden announced new measures today in an effort to fight the Omicron variant of the coronavirus.
As Omicron surges, when is the right time to seek medical care at the emergency room? Biden doubles the order of Pfizer's antiviral medication. Florida officials are encouraging COVID testing only for certain groups of people who are at higher risk of serious illness. Experts say it's due to the skyrocketing number of new cases linked to Omicron.
New research says past exposure to the common cold could offer significant protection against developing COVID from exposure. Health Conditions Discover Plan Connect. Vaccines Basics Testing Symptoms. Large drop in omicron neutralization by antibodies from vaccines The new study tested the ability of antibodies generated by vaccination to neutralize the omicron variant in laboratory assays that pitted antibodies against live viruses and against pseudoviruses constructed in the lab to mimic omicron.
Blackburn, Bernadett I. Gosnell, Salim S. Lessells, Mahomed-Yunus S. Moosa, Miles P. Davenport, Tulio de Oliveira, Penny L. Moore, Alex Sigal. Omicron extensively but incompletely escapes Pfizer BNTb2 neutralization. Nature , ; DOI: ScienceDaily, 23 December However, several studies that appeared during the last major outbreak showed that humanized mouse-derived mAbs, when used in combination, could provide protection.
Two of these therapies, ZMab and MB , were recombined into the tri-mAb cocktail ZMapp TM, , which demonstrated complete protection in non-human primates at late stages of infection One vaccine trial, however, did show great promise and there is evidence for long-term sustained protection in survivors of natural infection These studies demonstrate the polyclonal diversity of anti-filovirus antibodies.
Additionally, several human-derived antibodies have been isolated that show broad cross-reactivity across ebolaviruses or marburgviruses and are actively being evaluated for use as immunotherapies. As for HIV and influenza, these bnAbs will likely be more restricted to particular germlines or sets of germlines. Humanized mice offer an alternative platform to study for antibody reponses than human survivors of pandemic and epidemic viral infection, A recent study in which VelocImmune mice were vaccinated with either DNA-encoded or soluble EBOV GP Makona variant demonstrated that fully human IgGs could be produced in mice that bind to common sites of vulnerability on filoviruses that are targeted by the human immune system.
This study shows that, in principal, these mice can be vaccinated against any pathogen to produce antibodies that may offer protection in humans, but on a much faster timeline, making them an attractive option to learn how to combat other emerging infectious diseases.
The plethora of structural information that has been generated in the past decade has opened many doors for understanding how the adaptive immune system recognizes and neutralizes enveloped and other viruses, resulting in exciting new vaccine and antibody therapeutic development opportunities. Upward angles are unfavorable for soluble IgGs as the membrane provides a steric constraint for approaching glycoproteins for binding , although strain-specific neutralizing antibodies that approach GP at such an angle are not unheard of for filoviruses 61 , , Additionally, the density of viral spikes on the surface of a virus can facilitate bivalent binding, which is possible for GP and HA 38 , 51 , 52 , , but perhaps less so for HIV, where the spike density can be quite low 75 , — In this case, engineering bivalent binding within a single antigen may be an effective approach to overcoming lower monovalent binding affinity to broadly reactive epitopes , The examples above demonstrate the near infinite capacity of the adaptive immune system to evolve in response to diverse antigenic insults that humans and animals encounter.
The diverse epitopes targeted by acute ebolavirus infection demonstrate how a polyclonal antibody response with low SHM can be very effective, while the incredible breadth and potency of monoclonal bnAbs isolated from chronically infected HIV patients reveal the extremes of SHM that antibodies can accommodate to overcome huge antigenic diversity — Despite this adaptive potential, the immune system still has a difficult time to keep pace with antigenically variable viruses like influenza and HIV that have high mutations rates Superficially, one would expect influenza to be an easier target for antibodies, particularly with yearly boosts via seasonal infection or vaccination.
Yet, bnAbs are rare and typically do not persist and means that the world-wide human population is under constant threat of a new influenza pandemic. On the other hand, ebolaviruses may well be a relatively easy target for the adaptive immune system, but its spectacularly rapid pathogenesis normally results in mortality before effective antibodies can made. We sometimes take for granted the wonderful arsenal of vaccines that have already been developed, largely by empirical methods, and which result in lasting immunity with impressive potency.
Of course, most of the viruses for which these vaccines are aimed at have little variability. Ironically, we have a relatively limited understanding of the sequence and molecular of antibody responses to historical vaccines and a much greater understanding of the antibody responses to pathogens that continue to outpace current vaccines.
Even then, the monoclonal antibodies that have been successfully isolated and structurally characterized are almost certainly underrepresent the true diversity of immune responses.
Thus, the pursuit of new antibodies, and therefore new pathways to bnAbs, remains highly valuable. As noted above, structure-based design for HIV has already generated some encouraging results in animal models that demonstrate it is possible to drive the path of antibody evolution towards a neutralizing but not a broadly neutralizing response at present by vaccination with candidate immunogens , , , , , Here, vaccine design increasingly benefits from a deeper understanding of the basic biological processes that happen in B-cell germinal centers , , , as well as antigen display and uptake.
There is also renewed interest in the role of the innate immune pathways in antibody-based protection, as well as the role of non-neutralizing antibodies , — Fc-mediated protection has been shown to play at least some part in providing protection from all viruses discussed here.
Even neutralizing antibodies have often been found to rely on some level of Fc-mediated function to realize their full potency , While there is a basic understanding of the antibody-based innate immune response — , there is still much to be learned about the subtleties of the molecular nature of effector cell activation. Future studies to address the role of Fc-mediated protection in individuals that effectively control HIV replication, as well as in those that survive filovirus infection, will enhance vaccine and therapeutic research.
A more detailed molecular understanding of the immune activation complex, and what type of antibody-antigen interaction results in a potent innate immune response, could help to improve antibody therapeutic selection and engineering. Further, these types of studies may provide information that will guide antibody designs that can specifically recruit effector cell subsets and immune responses, such as NK cells and ADCC, which have shown great promise in augmenting antibody neutralization Based on the incredible advances described above, it is conceivable that, in the not so distant future, we will be able to rationally design vaccines that elicit antibodies with epitope specificity and broad antigen reactivity.
An exciting new challenge will be the design of vaccines that also elicit antibodies that can also potently and specifically recruit desired effector functions. Integrating lessons from different viruses, including those described here and others, will continue to provide insights to arm researchers in their quest to vanquish the most formidable of pathogens.
The authors declare no competing interests. National Center for Biotechnology Information , U. Nat Microbiol. Author manuscript; available in PMC Oct Charles D Murin , 1 Ian A.
Wilson , 1, 2, 3 and Andrew B. Ward 1, 2, 4. Ian A. Andrew B. Author information Copyright and License information Disclaimer. Ward, Ph. Copyright notice. The publisher's final edited version of this article is available at Nat Microbiol.
See other articles in PMC that cite the published article. Abstract Antibodies serve as critical barriers to viral infection. Introduction Enveloped viruses are found across diverse viral families and cause some of the deadliest diseases known to man. Open in a separate window. Figure 1. Points of antibody blockade to enveloped virus entry and egress. Table 1. Comparison of HIV, influenza and filoviral biology, taxonomy and pathogenesis. This table is not meant to convey all aspects of the viruses but rather to provide broad generalizations that allow some level of comparison.
Neutralizing antibody and glycoprotein structures Immunoglobulins Ig are produced in a wide variety in humans, each with different roles in the immune response. Figure 2. Antibody structure and domain topology. Figure 3. Shared structural features of type I glycoproteins. Common and divergent themes of antibody binding to enveloped glycoproteins Antibodies can provide sterilizing protection against viral pathogens and finding antibodies that are potent against diverse strains of related viruses is highly desirable.
Receptor binding site and structural mimicry All viruses utilize a host receptor in some capacity to gain entry into cells. Figure 4. Examples of enveloped virus common and divergent sites of vulnerability targeted by neutralizing antibodies. Fusion peptide Recent work has revealed the fusion peptide at the N-terminus of the membrane-proximal envelope glycoprotein as a common site of vulnerability 64 — The glycoprotein stalk and membrane-proximal external region MPER The viral stalk or stem emerges from the transmembrane anchor of glycoproteins, and contains the membrane fusion machinery.
Virus-specific sites of vulnerability In addition to the inherently common structural features that underlie all type-I viral glycoproteins, there are many unique features that can also serve as hotspots for eliciting potent antibodies. Antibody allostery Antibodies have also been shown to provide allosteric influence on glycoproteins, where binding in one location essentially alters a distal site. Structures illuminate sites-of-vulnerability The structures described here indicate that there are essentially no surfaces on viral glycoproteins that cannot be targeted by the adaptive immune response Figure 5 , Table S1.
Figure 5. The immunogenic landscape of enveloped viruses illuminated by structural biology. Implications for vaccine, therapeutic and diagnostic development Structural data that have been amassed for enveloped viral glycoproteins in the past few decades have informed a more fundamental understanding of the complex viral lifecycle, but have also been used to directly and significantly advance efforts to generate and improve vaccines, therapeutics and diagnostics for these viruses.
Future perspectives The plethora of structural information that has been generated in the past decade has opened many doors for understanding how the adaptive immune system recognizes and neutralizes enveloped and other viruses, resulting in exciting new vaccine and antibody therapeutic development opportunities. References 1. Traffic 17 , —, doi Harrison SC Viral membrane fusion.
Virology —, —, doi Refined structure of an intact IgG2a monoclonal antibody. Biochemistry 36 , —, doi Harris LJ, Skaletsky E. Crystallographic structure of an intact IgG1 monoclonal antibody. J Mol Biol , —, doi Saphire EO et al. Science , —, doi Scapin G. Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. Nat Struct Mol Biol 22 , —, doi Microbiol Spectr 2 , doi AID Curr Opin Struct Biol 4 , — Nature , 37—43, doi Nature , — Julien JP et al.
Crystal structure of a soluble cleaved HIV-1 envelope trimer. Lyumkis D. Cell 89 , — Nature , —, doi Lee JE et al. Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor.
Mol Cell 2 , — PLoS Pathog 9 , e, doi Tate MD et al. Playing hide and seek: how glycosylation of the influenza virus hemagglutinin can modulate the immune response to infection. Viruses 6 , —, doi Annu Rev Biophys , doi Cao L. Global site-specific N-glycosylation analysis of HIV envelope glycoprotein. Nat Commun 8 , , doi Structure 23 , —, doi Ekiert DC et al. Antibody recognition of a highly conserved influenza virus epitope.
Flyak AI et al. Mechanism of human antibody-mediated neutralization of Marburg virus. Cell , —, doi Kong L. Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp Nat Struct Mol Biol 20 , —, doi Murin CD et al.
Structure of 2G12 Fab2 in complex with soluble and fully glycosylated HIV-1 Env by negative-stain single-particle electron microscopy. J Virol 88 , —, doi Williams KL et al. Cell Rep 23 , —, doi Bianchi M. Immunity 49 , — e, doi Ozorowski G. Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike. Zhou T. A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin.
Garcia-Sastre A. Influenza virus receptor specificity: disease and transmission. Am J Pathol , —, doi Stevens J. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Wu NC et al. A complex epistatic network limits the mutational reversibility in the influenza hemagglutinin receptor-binding site. Nat Commun 9 , , doi Cell Host Microbe 22 , —, doi Lee PS et al. Receptor mimicry by antibody F— facilitates universal binding to the H3 subtype of influenza virus.
Nat Commun 5 , , doi In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity. Immunol Rev , —, doi Antiviral Res 98 , —, doi Curr Top Microbiol Immunol , —, doi Bornholdt ZA et al. MBio 7 , e—, doi Miller EH et al. Ebola virus entry requires the host-programmed recognition of an intracellular receptor. EMBO J 31 , —, doi Gnirss K.
Virology , 3—10, doi King LB et al. Cell Host Microbe 23 , — e, doi Hashiguchi T. Structural basis for Marburg virus neutralization by a cross-reactive human antibody. Wang H.
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