Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization

Ho, David D.; Wang, Pengfei; Liu, Lihong; Iketani, Sho; Luo, Yang; Guo, Yicheng; Wang, Maple; Yu, Jian; Zhang, Baoshan; Kwong, Peter D.; Graham, Barney S.; Mascola, John R.; Chang, Joseph; Yin, Michael T.; Sobieszczyk, Magdalena E.; Kyratsous, Christos A.; Shapiro, Lawrence; Sheng, Zizhang; Nair, Manoj S.; Huang, Yaoxing

doi:10.21203/rs.3.rs-155394/v1

Cited by 79 publications

(79 citation statements)

References 22 publications

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“…Sera from mRNA-1273 vaccinated NHP or human sera was shown to have 6-8 fold reduced neutralizing activity against the B.1.351 variant SARS-CoV-2 in several assessments, although the level of neutralization remained at levels that are predicted to be protective. 26,39 Results in this study, however, showed that after the primary series of mRNA-1273, only a 2-fold reduced neutralization against the B.1.351 virus was evident 2 weeks after the second dose. A 6.6-fold reduction was seen at day 212, more relevant to what has been measured from human sera.…”

Section: Discussionsupporting

(Expert classified)

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Choi

Koch

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic that has led to more than 2.8 million deaths worldwide. Safe and effective vaccines are now available, including Moderna's COVID-19 vaccine (mRNA-1273) that showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. mRNA-1273 encodes for a prefusion stabilized full length spike (S) protein of the Wuhan-Hu-1 isolate. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several emerging variants have shown decreased susceptibility to neutralization by vaccine induced immunity, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of two updated COVID-19 mRNA vaccines designed to target emerging SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the S protein found in the B.1.351 lineage and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with 2-doses of mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against the B.1.351 lineage, while mRNA-1273.211 was most effective at providing broad cross-variant neutralization in mice. In addition, these results demonstrated a third dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are currently being evaluated in additional pre-clinical challenge models and in phase 1/2 clinical studies.

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Section: Discussionsupporting

(Expert classified)

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Choi

Koch

et al. 2021

Preprint

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“…Shortly after the first Wuhan Hu-1 (WA-1) genome sequence was published ( 2 ), spike proteins were generated for use in spike-specific antibody discovery ( 3 – 5 ). Recently, virus variants first detected in the UK (e.g., B.1.1.7)( 6 ), South Africa (e.g., B.1.351) ( 7 ) and Brazil (P.1) ( 8,9 ) have been shown to contain mutations that mediate resistance to therapeutic monoclonal antibodies, have increased transmissibility and to potentially increase pathogenicity ( 10 – 14 ). Additionally, vaccines designed based on the original WA-1 outbreak strain sequence elicit antibody responses that show decreased in vitro neutralizing activity against variants ( 14 – 16 ).…”

Section: Main Textmentioning

confidence: 99%

“…Recently, virus variants first detected in the UK (e.g., B.1.1.7)( 6 ), South Africa (e.g., B.1.351) ( 7 ) and Brazil (P.1) ( 8,9 ) have been shown to contain mutations that mediate resistance to therapeutic monoclonal antibodies, have increased transmissibility and to potentially increase pathogenicity ( 10 – 14 ). Additionally, vaccines designed based on the original WA-1 outbreak strain sequence elicit antibody responses that show decreased in vitro neutralizing activity against variants ( 14 – 16 ). In this study, we investigated antibodies isolated from convalescent subjects who were infected by the WA-1 strain during the first few months of the outbreak, determined their reactivity against variants of concern (VOCs) and defined the structural features of their binding to spike.…”

Section: Main Textmentioning

confidence: 99%

Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants

Wang

Zhou

Zhang

et al. 2021

Preprint

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The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 μ g/mL; IC80 < 0.0006 to 0.0251 μ g/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies, and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs.

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“…The isolation of RBD-specific cross-reactive mAbs neutralizing SARS-CoV-2 and SARS-CoV suggests that RBD-based vaccines could in principle elicit Abs that neutralize distantly related sarbecoviruses 18,19,53 . RBD-based vaccines are also unaffected by S mutations outside of the RBD, especially in the highly variable N-terminal domain (NTD) 37,54–59 . Here, we explored dose-sparing strategies for the RBD-NP vaccine and evaluated the impact of genetic diversity among SARS-CoV-2 clinical isolates and sarbecoviruses on vaccine-elicited Ab responses.…”

Section: Introductionmentioning

confidence: 99%

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines

Walls

Miranda

Pham

et al. 2021

Preprint

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Understanding the ability of SARS-CoV-2 vaccine-elicited antibodies to neutralize and protect against emerging variants of concern and other sarbecoviruses is key for guiding vaccine development decisions and public health policies. We show that a clinical stage multivalent SARS-CoV-2 receptor-binding domain nanoparticle vaccine (SARS-CoV-2 RBD-NP) protects mice from SARS-CoV-2-induced disease after a single shot, indicating that the vaccine could allow dose-sparing. SARS-CoV-2 RBD-NP elicits high antibody titers in two non-human primate (NHP) models against multiple distinct RBD antigenic sites known to be recognized by neutralizing antibodies. We benchmarked NHP serum neutralizing activity elicited by RBD-NP against a lead prefusion-stabilized SARS-CoV-2 spike immunogen using a panel of single-residue spike mutants detected in clinical isolates as well as the B.1.1.7 and B.1.351 variants of concern. Polyclonal antibodies elicited by both vaccines are resilient to most RBD mutations tested, but the E484K substitution has similar negative consequences for neutralization, and exhibit modest but comparable neutralization breadth against distantly related sarbecoviruses. We demonstrate that mosaic and cocktail sarbecovirus RBD-NPs elicit broad sarbecovirus neutralizing activity, including against the SARS-CoV-2 B.1.351 variant, and protect mice against severe SARS-CoV challenge even in the absence of the SARS-CoV RBD in the vaccine. This study provides proof of principle that sarbecovirus RBD-NPs induce heterotypic protection and enables advancement of broadly protective sarbecovirus vaccines to the clinic.

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Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization

Cited by 79 publications

References 22 publications

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines

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