This present study found that neutralizing antibodies were challenging to generated for mutations in S MHC-like regions 127-194 and 144-162. It occurred with delta variant infections. The delta variant was the SARS-COV-2 virus with a robust transmission. The S 62-80 mutations of SARS-COV-2 alpha, beta, lambda variants had a similar situation.McCallum, M. et al. found : R246A substitution reduces the binding of S2L28, S2M28, and S2X333. This substitution significantly affected the binding of S2X28 and mAb 4A8. The L18F, D80A, D253G/Y, or S255F variants only abolish the combination of S2L28 and NTD. The L18F substitution exists in B.1.351 and P. 1 pedigree. The Y144 deletion abolished the binding to S2M28, S2X28, S2X333, and 4A8 instead of S2L28. It explains that these mAbs have lost the ability to neutralize the B.1.1.7 S pseudovirus, which contains this deletion. The H146Y mutant reduces S2M28 , S2X28, especially the combination of 4A8. The binding of all site i-specific NTD mAbs to B.1.351 NTD is abolished, and 4A8 does not recognize this NTD variant. The evidence indicates that the NTD variants located in MHC-like regions 127-194 and 144-162 enhance the immune escape of the virus and increase the efficiency of virus transmission.