4/6/2023 0 Comments Nyu macvectorMu and C.1.2 were somewhat more resistant with a 6.8- and 7.3-fold decrease in titer, respectively. The neutralizing titers against Beta, Delta, and Delta+N501S were decreased 4.8-, 3.4-, and 3.4-fold, respectively. BNT162b2 sera neutralized virus with the D614G spike with a mean titer of 862, a 2.6-fold increase compared with convalescent sera. Neutralization of Beta, Delta, Delta+, and Mu variants showed a modest 3.7- to 4.7-fold decrease in neutralizing titer, while C.1.2 was more resistant to neutralization with a 7.8-fold decrease ( Figure 2A). Convalescent sera neutralized D614G spike with a mean titer of 334. The vaccine sera analyzed were collected from individuals at similar time points after final injection (a mean of 90 days for BNT162b2, 80 for mRNA-1273, and 82 for Table S1), and all participants tested negative for antibodies against the SARS-CoV-2 N protein, suggesting no history of SARS-CoV-2 infection ( Table S1). To determine the susceptibility of the viruses with the variant spike proteins to antibody neutralization, we analyzed the neutralizing titers of serum antibodies elicited by the BNT162b2 and mRNA-1273 mRNA vaccines and the adenoviral vector-based vaccine on the variants. Neutralization of variants by convalescent and vaccine-elicited antibodies Similar infectivity ratios were obtained on ACE2.A549 cells. A spike containing the CTD mutations (H655Y, N679K, T716I, T859) of C.1.2 was decreased 15-fold. A spike protein with the NTD C.1.2 mutations (P9L-C136F-Δ144-190S-D215G-Δ242-243) also had wild-type infectivity, while a spike with the C.1.2 RBD mutations had a significant increase in infectivity (1.9-fold). Analysis of the individual point mutations ( Figure S1C) showed the individual Beta and Delta RBD mutations (R346K, Y449H, E484K, N501Y, N501S) did not significantly increase infectivity. The pattern of infectivity was similar on ACE2.A549 cells, except that the infectivity differences were greater, most likely because of the low level of ACE2 on these cells. Results Prevalence and infectivity of Mu, C.1.2, and Delta+N501S variantsĪnalysis of the infectivity of viruses with the variant spike proteins on ACE2.293T and ACE2.A549 cells showed a slight decrease for the Beta spike compared with D614G (1.8-fold) on ACE2.293T cells, while Delta, Delta+N501S, and Mu were slightly increased ( Figure 1C). This encouraging finding suggests that although the viral spike protein has managed to mutate to escape neutralizing antibodies, this resulted in a fitness cost that will limit its spread through the human population. However, the mutation resulted in a significant decrease in avidity of the spike protein for angiotensin-converting enzyme 2 (ACE2). The resistance of the C.1.2 spike protein to neutralization was largely mediated by the Y449H mutation in the RBD. Sera from previously infected patients vaccinated with BNT162b2 had high neutralizing titer against all of the variants, providing a strong rationale for the vaccination of previously infected individuals. The C.1.2 variant, which is highly mutated, was the most resistant. Viruses with the variant spikes were partially resistant to neutralization. In this study, we measured the infectivity of viruses with the Mu, C.1.2, and Delta+N501S spike proteins and determined their susceptibility to neutralization by convalescent and vaccine-elicited antibodies, both in previously infected and uninfected individuals. It may be difficult for the spike protein to evolve to escape neutralizing antibodies while maintaining high affinity for ACE2. This finding suggests that the virus evolved to escape the humoral response but has a decrease in fitness, suggesting that it may cause milder disease or be less transmissible. The heavily mutated C.1.2 spike is the most antibody neutralization-resistant spike to date however, the avidity of C.1.2 spike protein for angiotensin-converting enzyme 2 (ACE2) is low. In contrast, sera from individuals with a previous history of SARS-CoV-2 infection who were subsequently vaccinated neutralize variants with titers 4- to 11-fold higher, providing a rationale for vaccination of individuals with previous infection. Analysis of neutralizing antibody titers in the sera of vaccinated individuals without previous history of infection and from convalescent individuals show partial resistance of the viruses. Recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants Mu and C.1.2 have spike proteins with mutations that may confer resistance to natural and vaccine-elicited antibodies.
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