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Circulation cytometry was performed with an IQue (Intellicyt) and analysis was performed on IntelliCyt ForeCyt (v8.1). == Antibody-dependent NK cell degranulation == Antibody-dependent NK cell degranulation was conducted as previously described59. to the presence of combined, but distinct, compartment-specific neutralization and Fc-mechanisms as key determinants of protective immunity against contamination. Moreover, NVX-CoV2373 elicited antibodies functionally A-769662 target emerging SARS-CoV-2 variants, collectively pointing to the crucial collaborative role for Fab and Fc in driving maximal protection against SARS-CoV-2. Collectively, the data offered here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants. Keywords:NVX-CoV2373 vaccine, Matrix-M adjuvant, SARS-CoV-2 spike glycoprotein, non-human primate, COVID-19 == Introduction == SARS-CoV-2 causes a spectrum of respiratory disease from asymptomatic to moderate and severe coronavirus disease (COVID-19). Since it crossed into humans, the computer virus has spread globally with over 90 million confirmed cases and over 2 million deaths1. COVID-19 manifests with a range of clinical symptoms from asymptomatic to severe disease, with 5075% of infected individuals exhibiting asymptomatic contamination and only a small proportion (25%) developing severe disease, requiring mechanical ventilation24. The vaccines authorized for emergency use, mRNA-1273 and BNT162b2, have been successful in preventing severe infections and inducing anti-SARS-CoV-2 CD4 + T cell, CD8 + T cell, and potent neutralizing antibody responses57However, whether these vaccines confer protection against transmission as well as disease remains unclear. Emerging Phase 3 data suggest that vaccine-mediated protection emerges as early as 10 days following main vaccination8,9, at a time when neutralizing antibodies are low or undetectable57. Similarly, emerging correlates of immunity following administration of DNA- and adenoviral-vector SARS-CoV-2 vaccination point to a potential additional role for added antibody effector functions, in collaboration with neutralization, as important correlates of immunity against SARS-CoV-210,11. However, whether these responses evolve following the primary or the boost, provide differential protection across the upper and lower respiratory tract, and provide protection against variants remains unclear. In this study, we deeply interrogated humoral correlates of protection in a cohort of rhesus macaques immunized with one A-769662 or two doses 5 or 25 g of a stabilized recombinant full-length SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) with 50 g Matrix-M adjuvant. Animals immunized with the two-dose regimen, regardless if given the high (25g) or low (5g) antigen dose, were protected against upper and lower respiratory contamination (URTI and LRTI) and shedding of replicating computer virus, while a single vaccine injection (regardless of antigen dose) was only partially protective against infection. Unique combinations of Fc-features and neutralizing antibody responses were associated with protection in the upper and lower respiratory tract, pointing to potential mechanistic differences required to control the computer virus at these unique immunological locations. Critically, the NVX-CoV2373 generated binding A-769662 and functional humoral immune responses to several emerging SARS-CoV-2 variants. These data point to boosting-driven functional maturation of the humoral immune response as a key immune event required to accomplish full protection against contamination and transmission of SARS-CoV-2 and emerging mutants. == Results == == Subgenomic computer virus mRNA in respiratory samples == Emerging Phase 3 data from mRNA vaccine platforms suggest that vaccine-induced protection against disease is usually observable as early as 10 days following vaccine hJAL priming, prior to the presence of strong neutralizing antibody levels8,9. However, whether these responses are associated with total sterilizing immunity remains unclear. To define the specific humoral profiles that track with protective immunity against disease and contamination, we profiled the humoral immune response induced by a stabilized, full-length SARS-CoV-2 Spike (S) vaccine (NVX-CoV2373) following a prime-only or primary/boost vaccine regimen administered at 2 different antigen doses (5 and 25g) with Matrix-M adjuvant (50g). Groups of rhesus macaques (n = 5) were immunized with one vaccine dose (study day 0) or two vaccine doses, spaced 3 weeks apart (study day 0 and 21). Control animals (n = 4) received one or two injections of A-769662 formulation buffer (placebo). Serum was collected prior to immunization (day 0) and 21 and 31/32 days after the first dose (Fig. 1A) Protection was assessed by analyzing viral loads across the upper (nasal washes and nasal pharyngeal swabs) and lower (bronchoalveolar lavage; BAL) respiratory tract on days 28 post-infection (dpi). The highest levels of viral subgenomic RNA (sgRNA) were observed in placebo animals across the upper and lower-respiratory tract samples, with peak viral loads observed 2dpi and prolonged sgRNA until day 7/8 (Fig. 1B, C, D). Animals immunized with a single dose of 5g or 25g NVX-CoV2373 experienced lower levels of replicating computer virus at day 2 in all tissues compared to placebo, however the 25g dose was able to obvious sgRNA in BAL and nasal pharyngeal swabs at day 7/8, while the 5g only cleared BAL. The animals that received 5g or 25g antigen in a primary/boost regimen experienced no detectable viral A-769662 loads in BAL or nasal pharyngeal swabs at any day and.