key: cord-1044811-qiz3t8gt
authors: Bartsch, Yannic C.; Atyeo, Caroline; Kang, Jaewon; Cai, Yongfei; Chen, Bing; Gray, Kathryn J.; Edlow, Andrea G.; Alter, Galit
title: Preserved recognition of Omicron Spike following COVID-19 mRNA vaccination in pregnancy
date: 2022-04-14
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2022.04.009
sha: 6bbf6831ba19076a4bb18d3ca50f6a58694cc6ae
doc_id: 1044811
cord_uid: qiz3t8gt

Background SARS-CoV-2 infection is associated with enhanced disease severity in pregnant women. Despite the potential of COVID-19 vaccines to reduce severe disease, vaccine uptake remained relatively low among pregnant women. Just as coordinated messaging from the CDC and leading obstetrics organizations began to increase vaccine confidence in this vulnerable group, the evolution of SARS-CoV-2 variants of concerns (VOC) including the Omicron VOC raised new concerns about vaccine efficacy, given their ability to escape vaccine-induced neutralizing antibodies. Early data point to a milder disease course following omicron VOC infection in vaccinated individuals. Thus, these data suggest that alternate vaccine induced immunity, beyond neutralization, may continue to attenuate omicron disease, such as antibody-Fc-mediated activity. Objectives To test whether vaccine induced antibodies raised in pregnancy continue to bind and leverage Fc-receptors against VOCs including the Omicron variant. Study Design VOC including Omicron receptor binding domain (RBD) or full Spike specific antibody isotype binding titers and FcγR binding were analyzed in pregnant women after the full dose regimen of either Pfizer/BioNTech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay. Results Reduced, isotype recognition was observed to the Omicron receptor binding domain (RBD) following both vaccines, with relatively preserved, albeit reduced, recognition of Omicron full Spike by IgM and IgG antibodies. Despite the near complete loss of Fc-receptor binding to the Omicron RBD, Fc-receptor binding was more variable but largely preserved to the Omicron Spike. Conclusion Reduced binding titers to the Omicron RBD aligns with observed loss of neutralizing activity. Despite the loss of neutralization, preserved, albeit reduced, Omicron Spike recognition and Fc-receptor binding potentially continues to attenuate disease severity in pregnant women.

pregnancy was an exclusion criteria from initial vaccine trials, resulting in delayed vaccine roll outs for this 89 medically complex population 1,2 . However, following EUA approval of COVID-19 vaccines, eligible 90 pregnant individuals volunteered for vaccine trials and observational studies, providing highly needed 91 data related to safety and immunogenicity to inform vaccine policy. mRNA vaccines proved to be both 92 safe and highly immunogenic when administered throughout pregnancy, giving rise to robust antibody 93 titers that provided critical immunity not only to the mother, but to the infant via transfer of maternal 94 antibodies across the placenta and into breastmilk. 95

Despite the exciting progress in mRNA vaccine development in pregnancy, the emergence of 96 SARS-CoV-2 variants of concern that can evade neutralizing antibody responses 3,4 , including the novel 97

Omicron variant, has led to a global surge in infections 5 . However, severe disease and death rates have 98 not increased in parallel, pointing to the persistence of alternate vaccine-induced immune responses that 99 may continue to attenuate disease. Among the proposed mechanisms by which vaccine-induced 100 antibodies may still prevent severe disease include, antibody Fc-effector functions, including Fc-mediated 101 opsonophagocytosis and cytotoxicity, which have been linked to survival in severe COVID-19 6 as well as 102 vaccine mediated protection in animal models 7,8 . 103

While pregnant individuals exhibit delayed Fc-effector function maturation after the first dose 104 mRNA vaccine, they elicit a fully functional vaccine-induced Fc-response after the second dose 9,10 . 105

However, whether the COVID-19 mRNA vaccines elicit antibody-mediated protection against emerging 106 VOCs, including Omicron, is not well understood. Thus, here we profiled the cross VOC binding titers and Inc. Stabilized (hexa-pro) Spike of D614G ("wildtype" variant) or VOCs was produced in HEK293 cells as 129 described before 11 . 130

Antigen-specific antibody subclass and isotypes, and FcγR binding was analyzed by Luminex multiplexing. 133

The antigens were coupled to magnetic Luminex beads (Luminex Corp, TX, USA) by carbodiimide-NHS 134 ester-coupling with an individual region per antigen. Coupled beads were incubated with different plasma 135 dilutions (1:100 for IgG2, IgG3, IgG4, IgM and IgA1, 1:500 for IgG1 and 1:1,000 for FcγR probing) for 2 136 hours at room temperature in 384 well plates (Greiner Bio-One, Germany). Unbound antibodies were 137 washed away and subclasses, isotypes were detected with a respective PE-conjugated antibody (anti- concern receptor binding domain (A) or full Spike (B) specific antibodies were determined by Luminex. 346

Background corrected data is shown and negative values were set to 100 for graphing purposes. A Kruskal-347

Wallis test with a Benjamini-Hochberg post-test correcting for multiple comparisons was used to test for 348 statistical differences between wildtype variant and Omicron titer. P-values for significant different 349 features are shown above and fold-change reduction of Omicron titer compared to wildtype below each 350 dataset. 

Distinct conformational states of SARS-CoV-2 spike protein

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BNT162b2 mRNA Vaccine or SARS-CoV-2 Infection. Vaccines (Basel)

Mouse and human FcR effector functions

IgG subclasses and allotypes: from structure to effector 318 functions

Structural diversity of the SARS-CoV-2 Omicron 320 spike

Preserved Omicron Spike specific antibody binding and Fc-322 recognition across COVID-19 vaccine platforms. medRxiv