1b) (as in mRNA and adenovirus vector vaccines as well as for production of recombinant subunit vaccines), the pathway of biosynthesis is very similar.
Hershey's faces backlash over putting trans woman on candy bar wrapper The potency of these antibodies depends on high-affinity interactions with specific parts of the complex three-dimensional structure of the spike in a native conformation10,11. he voted for an austerity budget that reduced health services in the middle of the COVID-19 pandemic. Commun. 5a) (https://patents.google.com/patent/CN111218459B/en). Sci. Res. Zost, S. J. et al. Extensive modifications by N- and O-glycosylation occur in the compartments encountered by S during its intracellular transport18.
Feature Article: Wondering about Coronavirus? | Children's Hospital of In conclusion, since the emergence of COVID-19 pneumonia and due to its similar radiological patterns, we believe that a SARS-CoV-2 RT-PCR should be systematically realized in case of respiratory . Irrespective of these categories, all vaccines have to cope with the intrinsic problem of conformational instability of the spike protein, whether it is synthesized in the vaccinee after genetic vaccination or in cell culture systems for production of conventional vaccines. The RBD oscillates between an up and down position, and interaction with the cellular receptor (ACE2) is only possible with the transiently exposed RBD in the up position20,21. Adenovirus 5 is used in the CanSino vaccine and the second dose of Gamaleya vaccines (section Adenovirus-vector vaccines and Table1). 100, 309354 (2018). Slider with three articles shown per slide. Article Independent of such antigenic effects, the fundamentally different mechanisms of action and ways of production are likely to introduce additional variation to the characteristics of immune responses and possible adverse reactions.
Have you got a cold or Covid? Here's how to tell the difference J. Med.383, 26032615 (2020). Efforts are also underway to replace existing vaccine strains and corresponding sequences for those of the most relevant circulating strains114. Given the same antigenic difference of all vaccines relative to VOCs, the most important parameter determining cross-protection may be the quantity of neutralizing antibodies and relevant cellular immune reactivity at the time of infection. The two protease cleavage sites are indicated by arrows. Here, we briefly discuss existing data and describe distinguishing features that can contribute to differences among vaccine responses independent of the structure and presentation of the S immunogen. Suryadevara, N. et al. Hunter, P. R. Thrombosis after covid-19 vaccination. Constituents in the Oxford-AstraZeneca vaccine were recently analyzed in the context of a search for potential causes of venous sinus thrombosis as a rare post-vaccinal complication121. In vitro transcription is followed by several steps of mRNA purification, including the removal of dsRNA, which could lead to an excessive innate immune response and concomitant reactogenicity48,50. Nature 595, 344345 (2021).
Prof. Robert Howarth's Climate Research, Outreach Makes Waves Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses. 11, 576622 (2020). Liang, Z. et al. containing the mutation D614G in S) may be more stable95,96 and therefore could serve as an improved substrate for the production of inactivated vaccines. In the CanSino vaccine, the signal peptide of S is replaced by that of human tPA (https://patents.google.com/patent/CN111218459B/en).
PDF Retrospective case control study to evaluate hypocalcaemia as a Distinguishing feature definition: If you can distinguish one thing from another or distinguish between two things, you can. 1; Black students are more likely than White students to receive harsher consequences .
The Concept of the Crown and Its Potential Role in the Downfall of 12, 372 (2021). The total amount of protein per dose was found to be 35 to 40g, most of which can be assumed to be cellular protein, because the protein of 51010 adenovirus particles per dose would account for only about 8g (for calculation see122). Google Scholar. J. Med. Both modifications are intended to avoid conversion of S into the post-fusion structure (Fig. Get full coverage of the Coronavirus pandemic including the latest news, analysis, advice and explainers from across the UK and around the world. Google Scholar.
Coronavirus symptoms tend to begin in certain order: Fever first, then Share information from trusted sources. 383, 23202332 (2020). Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Immunol. J. Med. This halo of spikes is what led scientists to name these "coronaviruses.". It consists of the trimeric full-length spike that is produced as a recombinant protein in insect Sf9 (Spodoptera frugiperda) cells using a baculovirus expression system and contains mutations to stabilize S2 (K986P and V987P) as well as to delete the furin cleavage site (682-RRAS-685 changed to QQAQ)99 (Table1 and Fig. Information on cellular impurities are so far restricted to ChAdOx1 and comparative analyses of all adenovector vaccines are not yet available. Coronavirus disease (COVID-19) / Feature stories; COVID feature stories. Preprint at https://www.biorxiv.org/content/10.1101/2021.04.20.440647v2 (2021). First identified in the Guangdong province in southern China, according to the. In Plotkins Vaccines 7th edn (eds Orenstein, W. A., Offit, P. A. proteins that help give the virus its structure and enable it to replicate. They all rely on the native viral spike protein (S) of SARS-CoV-2 for inducing potently neutralizing antibodies, but the presentation of this key antigen to the immune system differs substantially between the different categories of vaccines. 80).
Cold Vs COVID - How Do I Tell The Difference In Symptoms? - Women's Health Correspondence to Some of these mutants are considered Variants of Concern (VOCs) because of their highly efficient transmission, the concomitant replacement of previously circulating strains, and the presence of mutations in the spike protein that can lead to immune escape (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). Correct processing of the signal peptide by signal peptidase to generate the final N-terminus of S (Fig. International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection.
5G mmWave: Facts and fictions you should definitely - Android Authority iPad vs. iPad Air: which is right for you? - Hartford Courant https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018215766. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Our case report highlights the difficulty of distinguishing SARS-CoV-2 infection in the context of PAP, as the chest CT features are similar. 11, 3618 (2020). 1, 2) in tissues after intramuscular application. Plante, J. Impact of mRNA chemistry and manufacturing process on innate immune activation. Cell 184, 39363948.e3910 (2021). Tatsis, N. et al. Article Watanabe, Y. et al. 133).
Uruguay quietly beats coronavirus, distinguishing itself from its South Efficient formation of such antibodies by B cells requires helper functions of CD4 T cells that are specifically stimulated by peptides derived from the same antigen in complex with MHCII molecules. Manipulations of the authentic viral signal sequence may cause inhomogeneities of the N-terminus and impair native folding of S19 (see also section Adenovirus-vector vaccines and Fig. Coronavirus is mostly spread through the air, when people are in close contact with each other. https://doi.org/10.1056/NEJMoa2107659 (2021). Therefore, for production of the engineered particles as a vaccine, immortalized helper cell lines are used that contain the E1 gene in their chromosomal DNA and provide the missing function, allowing the biosynthesis of structural proteins, replication of modified genomic DNA, and finally assembly of replication-incompetent virus particles in the cells (Fig. Duan, L. et al. The results from a hydrogeological study at LithiumBank Resources Corp (TSX-V:LBNK)'s 100%-owned Park Place lithium brine project, located in Alberta are "surprisingly favorable," according to analysts at Noble Capital.. In most people, common cold symptoms usually peak within the first two to three days of infection, while the effects of Covid appear two to 14 days after exposure. The World Health Organization (WHO) has increased the assessment of the risk of spread and the risk of impact of COVID-19 to very high at a global level . One of Johnson's distinguishing features is his long-standing relationship with the Chicago Teachers Union. Earle, K. A. et al. Z., Jacobsen, S. & Ndeupen, S. Future considerations for the mRNA-lipid nanoparticle vaccine platform. Lancet 397, 13511362 (2021). 81, 65946604 (2007). Immunol. AZD1222-induced neutralising antibody activity against SARS-CoV-2 Delta VOC. The effect of residual Triton X-100 on structural stability and infection activity of adenovirus particles. ; Approval of final manuscript: F.X.H. Cell 184, 42204236.e13 (2021). Another inactivated whole-virus vaccine using similar technology is produced by the Indian company Bharat and has received emergency use authorization in India even before completion of phase III clinical trials91 (Table1).
COVID-19: Clinical features - UpToDate 118, e2104241118 (2021). The variant gambit: COVID-19s next move. b Trimeric pre-fusion spike with one RBD in up position. Head-to-head comparisons of mRNA vaccines will be informative to identify and evaluate differences of innate and adaptive responses as well as reactogenicity between representatives of this class of COVID-19 vaccines. Importantly, the human neutralizing antibody response in SARS-CoV-2 infection appears to be dominated by RBD-specific antibodies, whichon averagewere shown to contribute 90% of the total neutralizing activity of human post-infection sera39.
SARS-CoV-2 - Wikipedia Chi, X. et al. There are open questions concerning the structure of S in the inactivated vaccines.
Features, Evaluation, and Treatment of Coronavirus (COVID-19) The effect of dissociation of soluble S1 from the trimer complex on the quality of immune responses is incompletely understood, but some data suggest it may contribute to a higher proportion of non-neutralizing relative to neutralizing antibodies19,81. Vaccines (Basel) 9, 326 (2021). -Coronaviruses use lysosomes for egress instead of the biosynthetic secretory pathway. These considerations of vector immunity also prompted the development of non-human adenovirus vectors such as ChAdOx1 derived from chimpanzee adenovirus Y2564, now used in the Oxford-AstraZeneca vaccine77. Winkler, E. S. et al. Heath, P. T. et al. Immunol. 3,4 Although the . Electron microscopical pictures of the viral spikes in the Sinovac vaccine have been interpreted differently, either as displaying the pre-fusion structure86 or the post-fusion structure25,92. Jagannathan, P. & Wang, T. T. Immunity after SARS-CoV-2 infections. Details of manufacturing processes may differ between the companies, and subtle product-specific variations of RNA sequences were recently confirmed by comparative analyses of RNA extracted from original vials of the two vaccines (https://github.com/NAalytics/Assemblies-of-putative-SARS-CoV2-spike-encoding-mRNA-sequences-for-vaccines-BNT-162b2-and-mRNA-1273/blob/main/Assemblies%20of%20putative%20SARS-CoV2-spike-encoding%20mRNA%20sequences%20for%20vaccines%20BNT-162b2%20and%20mRNA-1273.docx.pdf). Science. Several of the 291 candidates listed in the COVID-19 vaccine pipeline by WHO (184 pre-clinical and 107 in clinical development) (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines, accessed on July 9, 2021), have already reached the market and are used for mass immunization. Distinguishing characteristics and unknown features are highlighted in the context of protective antibody responses and reactogenicity of vaccines. Both vaccines use aluminum hydroxide as an adjuvant. Immunol. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Ma, J. et al. https://doi.org/10.1038/s41591-021-01413-7 (2021).
Comparison of Clinical Features of COVID-19 vs Seasonal - JAMA Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. E1 and E3: Early adenovirus genes 1 and 3, respectively. Article 5b). Nat. Release 333, 511520 (2021). Graham, C. et al. It is believed (but not systematically studied and formally shown) that muscle cells, fibroblasts, endothelial cells, and/or immune cells such as dendritic cells contribute to the expression of S after intramuscular vaccination40,41,42. In addition, the viral DNA itself can be sensed after endosomal rupture by cytosolic DNA sensors such as cGAS and the inflammasome, resulting in downstream signaling cascades for producing antiviral factors such as type I interferons41. CAS Severe acute respiratory syndrome, also known as SARS, is the other coronavirus that can cause more severe symptoms. According to published literature, manufacturing of the Sinovac and Novavax vaccines involves extensive purification procedures86,101, suggesting that the antigenic contents of these products consists primarily of the proteins of the virus particle or the isolated spike trimer, respectively. The current global pandemic, caused by the coronavirus SARS-CoV-2, emerged in December 2019. J. Med. According to research published in Rhinology, COVID-19 can cause a loss of taste and smell even without congestion. Mol. Cell 183, 10241042.e1021 (2020). Corbett, K.S. Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine. Kowarz, E. et al. Vaccine 39, 865867 (2021). & Stiasny, K. Profiles of current COVID-19 vaccines. Trends. Zost, S. J. et al. Madhi, S. A. et al. Xia, S. et al. Investig. Google Scholar.
COVID-19, cold, allergies and the flu: What are the - Mayo Clinic Vaccine 34, 38823893 (2016). 4a) and the additional deletion of E319,61,62,64,65,69. Collectively, there are subtle differences between the two vaccines, both with respect to the RNA and the LNP carriers, and a higher amount of RNA per dose is used in the Moderna vaccine (100g) than in the BioNTech-Pfizer vaccine (30g)46,47. The two mRNA vaccines in current widespread application (BioNTech-Pfizer and Moderna) (Table1) are technologically very similar. Article You may also have heard about "low band" frequencies and "sub-6GHz," both of which are also part of the standard . Amanat, F. et al. Cell Host Microbe 29, 508515 (2021). Development of chimpanzee adenoviruses as vaccine vectors: challenges and successes emerging from clinical trials. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Mercado, N. B. et al. Pollard, A. J. Sadoff, J. et al. Chen, N. et al. Due to their capacity to stimulate innate responses, the genetic vaccines are referred to as being self-adjuvanted55,136.
COVID-19 vaccine: What's RNA research got to do with it? volume6, Articlenumber:104 (2021) Except for mRNA vaccines, different eukaryotic cell cultures are used in the production of current COVID-19 vaccines (see sections Biosynthesis and key properties of the spike protein and Vaccine-specific differences of S-antigen structure and presentation and Table1). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.
No, It's Not Surprising That A Nurse Got COVID-19 After His First Phase 1 assessment of the safety and immunogenicity of an mRNA- Lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. 384, 18851898 (2021). CAS 13, eabi9915.
Experts know the new coronavirus is not a bioweapon. They disagree on et al. Curr. Excessive innate responses can not only result in strong reactogenicity of vaccination but also restrict antigen translation from the vaccine RNA, thus impairing adaptive immune responses. This adjuvant results in polarization towards a Th2 response, which has been regarded as unfavorable in the case of coronavirus and other viral infections and vaccinations118,139,140. Rogers, T. F. et al. . Nat. Preprint at https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China .
LithiumBank Resources distinguishing itself with industry-leading After amplification in bacterial cells, the plasmid DNA is linearized and impurities are removed before in vitro transcription into RNA. Vaccination of millions or even billions of people within a short time window allows identification of rare adverse reactions that would otherwise be difficult to be linked causally to vaccination. https://doi.org/10.1056/NEJMoa2108891 (2021). Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. Tumban, E. Lead SARS-CoV-2 candidate vaccines: expectations from phase III Trials and recommendations post-vaccine approval. This enormous progress was achieved with fundamentally different vaccine technologies used in parallel. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans, Adenoviral vector vaccine platforms in the SARS-CoV-2 pandemic, SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates, COVID-19 vaccines: where we stand and challenges ahead, Comparative analysis of COVID-19 vaccine responses and third booster dose-induced neutralizing antibodies against Delta and Omicron variants, Versatility of live-attenuated measles viruses as platform technology for recombinant vaccines, ChAdOx1 nCoV-19 (AZD1222) or nCoV-19-Beta (AZD2816) protect Syrian hamsters against Beta Delta and Omicron variants, A randomized controlled trial of heterologous ChAdOx1 nCoV-19 and recombinant subunit vaccine MVC-COV1901 against COVID-19, Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19, https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines, https://github.com/NAalytics/Assemblies-of-putative-SARS-CoV2-spike-encoding-mRNA-sequences-for-vaccines-BNT-162b2-and-mRNA-1273/blob/main/Assemblies%20of%20putative%20SARS-CoV2-spike-encoding%20mRNA%20sequences%20for%20vaccines%20BNT-162b2%20and%20mRNA-1273.docx.pdf, https://www.curevac.com/en/2021/06/16/curevac-provides-update-on-phase-2b-3-trial-of-first-generation-covid-19-vaccine-candidate-cvncov/, https://www.who.int/publications/m/item/considerations-for-the-assessment-of-covid-19-vaccines-for-listing-by-who, https://patents.google.com/patent/CN111218459B/en, https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/, https://www.biorxiv.org/content/10.1101/2021.04.20.440647v2, https://doi.org/10.1038/s41591-021-01413-7, https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1, https://www.researchsquare.com/article/rs-558954/v1, https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018215766, https://doi.org/10.1016/s0140-6736(21)01462-8, https://doi.org/10.1038/s41586-021-03777-9, https://www.medrxiv.org/content/10.1101/2021.05.07.21256809v1, https://www.researchsquare.com/article/rs-440461/v1, https://doi.org/10.1080/08820139.2021.1904977, https://www.biorxiv.org/content/10.1101/2021.04.14.439844v1, http://creativecommons.org/licenses/by/4.0/, Baculovirus displaying SARS-CoV-2 spike RBD promotes neutralizing antibody production in a mouse model, Comparative effectiveness of BNT162b2 and ChAdOx1 nCoV-19 vaccines against COVID-19, COVID-19 vaccines adverse events: potential molecular mechanisms, Neutralizing antibody and T cell responses against SARS-CoV-2 variants of concern following ChAdOx-1 or BNT162b2 boosting in the elderly previously immunized with CoronaVac vaccine, SARS-Cov-2 incubation period according to vaccination status during the fifth COVID-19 wave in a tertiary-care center in Spain: a cohort study, COVID-19 two years on: development and implementation of vaccines against SARS-CoV-2. With this kind of vaccines, the specific design of genetic sequences for the correct formation and presentation of properly folded spike proteins to B cells are in the foreground of interest. The authors speculate that such secreted forms may bind to ACE2-expressing endothelial cells and could contribute to thrombotic events via antibody-mediated mechanism as observed after vaccination with adenovirus vector COVID-19 vaccines74,75 (see also section Reactions due to vaccine constituents other than the immunogen). Convergent antibody responses to SARS-CoV-2 in convalescent individuals. 6, eaaz6893 (2020). Vaccines 9, 453 (2021). Science 372, 525 (2021). Immunol. Biosci. Rey, F. Structure-function relations of the SARS-CoV-2 spike protein and impact of mutations in the variants of concern. Delrue, I., Verzele, D., Madder, A. A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. 17, 13331339 (2009). It is unclear, at present, which influences anti-vector responses will have on necessary COVID-19 booster vaccinations in the future. In the course of cellular SARS-CoV-2 infection (Fig. BMJ 373, n958 (2021). Vaccine 29, 52035209 (2011). Nature 584, 437442 (2020).
Feature stories - World Health Organization The impact of COVID-19 on healthcare-associated infections. Internet Explorer). Therefore, isolation of the final product includes detergent solubilization of the cells and several steps of purification101. Corresponding studies are in progress (Com-Cov study: Oxdorf-AstraZeneca and BionTech-Pfizer, launched in February132).
Coronavirus Rumor Control | FEMA.gov SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD and S2. Adv. Janssen-Johnson&Johnson and Gamaleya-Institute use the authentic SARS-CoV-2 S protein signal sequence19,67, whereas CanSino replaced it with that of human tissue plasminogen activator (tPA) (Fig. Google Scholar. Zhao, P. et al. Rev. UTRuntranslated region.
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Coronavirus - BBC News Currently, a slightly but significantly increased risk of thrombotic events (including cerebral venous sinus thrombosis) was reported after vaccination with Oxford-AstraZeneca and Janssen adenovirus vector vaccines and has raised considerable concern74,75. There is an urgent need to clarify the pathogenic mechanism underlying the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Lancet 397, 16461657 (2021). BMJ 372, n196 (2021). Nat. npj Vaccines 2, 29 (2017). Dicks, M. D. J. et al.
What is coronavirus? | Facts for kids - National Geographic Kids Opin. Article
Coronavirus Disease (COVID-19): Symptoms, Causes & Prevention The uniting feature of current genetic COVID-19 vaccines is the provision of mRNAs for the whole, membrane-anchored spike protein (Figs. Wrapp, D. et al. Understanding of COVID-19 is evolving. 8, 654866 (2021). Another BPL-inactivated whole-virus vaccine in development (by the European company Valneva) makes use of Alum in combination with CpG to induce preferentially a desired Th1 response138, and a similar effect has been attributed to the Matrix-MTM adjuvant used in the Novavax subunit vaccine99,101,102.
Frontiers | Features of Cytokine Storm Identified by Distinguishing Med. Control. Literature data indicate that production of the Sinovac vaccine includes several steps of virus purification, leading to a product that contains primarily the viral proteins and consists of essentially pure viral particles86,87. J. A number of monoclonal antibodies were isolated from COVID-19 patients and used for antigenic characterization of the S trimer, including 3D structure determinations of complexes between S (or parts thereof) and antibody Fab fragments. Huang, Q. The impact of coronavirus disease 2019 (COVID-19) on healthcare-associated infections in 2020: a summary of data reported to the National Healthcare Safety Network. Science Translational Medicine. Emary, K. R. W. et al. The signal sequence is cleaved off by signal peptidase attached to the inner ER membrane, generating the final N-terminus of the viral spike protein (14-QCVNL).
The Differences Between COVID-19 and the Common Cold - Verywell Family Amanat, F. et al. Teijaro, J. R. & Farber, D. L. COVID-19 vaccines: modes of immune activation and future challenges. 2d)19. The first category consists of mRNA and adenoviral vector vaccines (herein referred to as genetic vaccines, sections: Genetic vaccinesgeneral, mRNA vaccines, Adenovirus-vector vaccines), both of which do not contain the spike protein but provide genetic information for its biosynthesis in body cells of the vaccinee. & Nauwynck, H. J. Inactivated virus vaccines from chemistry to prophylaxis: merits, risks and challenges. Genome Med.
NYU scientists: Largest US study of COVID-19 finds obesity the single 384, 20922101 (2021). Capone, S. et al. Nelson, J. et al. In addition to direct triggers of innate immunity by RNA, other constituents of LNPs can contribute to vaccine-induced inflammatory reactions and provide adjuvant activity for adaptive immune responses. Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. d Trimeric post-fusion structure of S2, with the three dissociated S1 subunits, shaded in light colors. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. Front. PubMed Central ERendoplasmic reticulum; ERGICendoplasmic reticulum Golgi intermediate compartment; TGNTrans Golgi Network; RNPRibonucleoprotein; Viral proteins: Sspike, Mmembrane; Eenvelope; Nnucleoprotein. Collectively, these data showed that the most potently neutralizing antibodies were specific for the RBD27,28,29,30,31,32,33,34, but several strongly neutralizing antibodies also recognized the NTD27,34,35,36,37, and some were dependent on the quaternary assembly of the trimer27,38.