ABSTRACT
The current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum neutralizing activity against diverse coronaviruses. Through single B cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, one potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1 and SARS-CoV viral challenge in golden Syrian hamsters, respectively. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.
Subject(s)
Lung Diseases , Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
The mutation pattern of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is constantly changing with the places of transmission, but the reason remains to be revealed. Here, we presented the study that comprehensively analyzed the potential selective pressure of immune system restriction, which can drive mutations in circulating SARS-CoV-2 isolates. The results showed that the most common mutation sites of SARS-CoV-2 proteins were located on the non-structural protein ORF1ab and the structural protein Spike. Further analysis revealed mutations in cross-reactive epitopes between SARS-CoV-2 and seasonal coronavirus may help SARS-CoV-2 to escape cellular immunity under the long-term and large-scale community transmission. Meanwhile, the mutations on Spike protein may enhance the ability of SARS-CoV-2 to enter the host cells and escape the recognition of B-cell immunity. This study will increase the understanding of the evolutionary direction and warn about the potential immune escape ability of SARS-CoV-2, which may provide important guidance for the potential vaccine design.
Subject(s)
Coronavirus InfectionsABSTRACT
Background The epidemic caused by SARS-CoV-2 was first reported in Wuhan, China, and now is spreading worldwide. The Chinese government responded to this epidemic with multiple public health policies including locking down the city of Wuhan, establishing multiple temporary hospitals, and prohibiting public gathering events. Here, we constructed a new real-time status dynamic model of SEIO (MH) to reveal the influence of national public health policies and to model the epidemic in Wuhan. Methods A real-time status dynamic model was proposed to model the population of Wuhan in status Susceptible (S), Exposed (E), Infected with symptoms (I), with Medical care (M), and Out of the system (O) daily. Model parameters were fitted according to the daily report of new infections from Jan. 27th, 2020 to Feb. 2nd, 2020. Using the fitted parameters, the epidemic under different conditions was simulated and compared with the current situation. Finding According to our study, the first patient is most likely appeared on Nov. 29th, 2019. There had already been 4,153 infected people and 6,536 exposed ones with the basic reproduction number R_0 of 2.65 before lockdown, whereas R_0 dropped to 1.98 for the first 30 days after the lockdown. The peak point is Feb. 17th, 2020 with 24,115 infected people and the end point is Jun. 17th, 2020. In total, 77,453 people will be infected. If lockdown imposed 7 days earlier, the total number of infected people would be 21,508, while delaying the lockdown by 1-6 days would expand the infection scale 1.23 to 4.94 times. A delay for 7 days would make the epidemic finally out of control. Doubling the number of beds in hospitals would decrease the total infections by 28%, and further investment in bed numbers would yield a diminishing return. Last, public gathering events that increased the transmission parameter by 5% in one single day would increase 4,243 infected people eventually. Interpretation Our model forecasted that the peak time in Wuhan was Feb. 17th, 2020 and the epidemic in Wuhan is now under control. The outbreak of SARS-CoV-2 is currently a global public health threat for all nations. Multiple countries including South Korea, Japan, Iran, Italy, and the United States are suffering from SARS-CoV-2. Our study, which simulated the epidemic in Wuhan, the first city in the world fighting against SARS-CoV-2, may provide useful guidance for other countries in dealing with similar situations.