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 Centers for Disease Control and Prevention and leading obstetrics organizations began to increase vaccine confidence in this vulnerable group, the evolution of SARS-CoV-2 variants of concerns, including the Omicron variant, raised new concerns about vaccine efficacy because of their ability to escape vaccine-induced neutralizing antibodies. Early data point to a milder disease course following infection with the Omicron variant in vaccinated individuals. Thus, these data suggest that alternate vaccine-induced immunity beyond neutralization may continue to attenuate Omicron variant–induced disease, such as Fc-mediated antibody activity.
Objective
This study aimed to test whether vaccine-induced antibodies raised during pregnancy continue to bind to and leverage Fc receptors to protect against variants of concern including the Omicron variant.
Study Design
The receptor binding domain or whole spike-specific antibody isotype binding titers and Fc gamma receptor binding directed toward variants of concern, including the Omicron variant, were analyzed in pregnant women after receiving the full dose regimen of either the Pfizer/BioNTech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay.
Results
Reduced isotype recognition of the Omicron receptor binding domain was observed following administration of either vaccine with relatively preserved, albeit reduced, recognition of the whole Omicron spike by immunoglobulin M and G antibodies. Despite the near complete loss of Fc receptor binding to the Omicron receptor binding domain, Fc receptor binding to the Omicron spike was more variable but largely preserved.
Conclusion
Reduced binding titers to the Omicron receptor binding domain aligns with the observed loss of neutralizing activity. Despite the loss of neutralization, preserved, albeit reduced, Omicron spike recognition and Fc receptor binding potentially continue to attenuate disease severity in pregnant women.
Introduction
Although SARS-CoV-2 infection is more likely to cause severe COVID-19 in pregnant individuals, pregnancy was an exclusion criterion in initial vaccine trials, leading to delayed vaccine roll-outs for this medically complex population. , However, following Emergency Use Authorization approval of COVID-19 vaccines, eligible pregnant individuals volunteered for vaccine trials and observational studies, providing highly needed data on the safety and immunogenicity to inform vaccine policy. Messenger RNA (mRNA) vaccines proved to be both safe and highly immunogenic when administered throughout pregnancy, giving rise to robust antibody titers that provided critical immunity not only to the mother, but also to the infant via transfer of maternal antibodies across the placenta and into breastmilk.
Why was this study conducted?
This study aimed to investigate the COVID-19 messenger RNA vaccine-mediated antibody response to variants of concern in pregnant individuals.
Key findings
Antibody binding titers and Fc gamma receptor (FcγR) binding to the whole Omicron spike were preserved despite marked reductions in the titer and FcγR binding to the Omicron receptor binding domain.
What does this add to what is known?
These data are consistent with the apparent loss of Omicron variant neutralizing titers but demonstrate that preserved Omicron spike-specific antibody binding and Fc receptor ligation may provide a second line of defense against Omicron variant infections.
Despite the exciting progress in mRNA vaccine development with the inclusion of pregnant individuals, the emergence of SARS-CoV-2 variants of concern (VOC), including the novel Omicron variant, that can evade neutralizing antibody responses , has led to a global surge in infections. However, the incidence of severe disease and death rates have not increased in parallel, pointing to the persistence of alternate vaccine-induced immune responses that may continue to attenuate disease. Among the proposed mechanisms by which vaccine-induced antibodies may still prevent severe disease include Fc-mediated antibody effector functions, such as Fc-mediated opsonophagocytosis and cytotoxicity, which have been linked to survival in severe COVID-19 and vaccine-mediated protection in animal models. ,
Although pregnant individuals exhibit delayed Fc-mediated effector function maturation after the first mRNA vaccine dose, they elicit a fully functional vaccine-induced Fc-mediated response after the second dose. , However, whether the COVID-19 mRNA vaccines elicit antibody-mediated protection against emerging VOCs, including Omicron, is not yet known. Thus, in this study, we profiled the binding titers across VOCs and the Fc receptor binding profiles after 2 doses of either the Pfizer/BioNtech BNT162b2 or Moderna mRNA-1273 vaccine at peak immunogenicity in a group of fully vaccinated pregnant individuals.
Despite the decline in immunoglobulin (Ig)M, IgA, and IgG binding to the receptor binding domain (RBD) or whole spike of the Omicron variant when compared with other VOCs, spike-specific Fc gamma receptor 2a (FcγR2a) and FcγR3a binding was more variable but relatively preserved across both mRNA vaccine platforms for all VOCs, including Omicron. Thus, despite the significant loss of neutralizing antibody responses to Omicron, the preservation of spike-specific Fc receptor binding immunity may permit ongoing capture and clearance of the virus, providing persistent Fc-mediated protection against severe disease and death.
Materials and Methods
Study population
To compare vaccine-induced antibody responses against SARS-CoV-2 VOCs in pregnant individuals, samples were obtained from 10 pregnant patients who received the full 2-dose BNT162b2 (Pfizer) vaccine regimen and from 10 pregnant patients who received the full 2-dose mRNA-1273 (Moderna) vaccine regimen at 2 to 4 weeks after the second dose ( Table ). All participants were ≥18 years old and had an uncomplicated singleton pregnancy. All participants gave informed consent before enrollment and this study was approved by the Mass General Brigham Institutional Review Board (protocol #2020P003538).
| Sample ID | Vaccine | Gestational age at vaccine dose 1 | Gestational age at vaccine dose 2 | Maternal age | Prepregnancy BMI |
|---|---|---|---|---|---|
| 1 | Moderna mRNA-1273 | 10.4 | 14.4 | 38 | 30.9 |
| 2 | Moderna mRNA-1273 | 6.1 | 10.1 | 35 | 21.5 |
| 3 | Moderna mRNA-1273 | 12.3 | 16.3 | 42 | 21.8 |
| 4 | Moderna mRNA-1273 | 21.6 | 26 | 32 | 21.3 |
| 5 | Moderna mRNA-1273 | 12.4 | 16.6 | 33 | 21.8 |
| 6 | Moderna mRNA-1273 | 13.5 | 17.5 | 33 | 25.2 |
| 7 | Moderna mRNA-1273 | 15.1 | 19.1 | 37 | 31 |
| 8 | Moderna mRNA-1273 | 22.0 | 26 | 33 | 22.9 |
| 9 | Moderna mRNA-1273 | 19.4 | 24 | 30 | 23.2 |
| 10 | Moderna mRNA-1273 | 32.4 | 36.4 | 33 | 19.5 |
| 11 | Pfizer BNT162b2 | 6 | 9 | 29 | 22.5 |
| 12 | Pfizer BNT162b2 | 4 | 8 | 41 | 20.9 |
| 13 | Pfizer BNT162b2 | 3 | 6 | 35 | 23.6 |
| 14 | Pfizer BNT162b2 | 3 | 6.6 | 35 | 27.9 |
| 15 | Pfizer BNT162b2 | 22 | 25 | 32 | 20.8 |
| 16 | Pfizer BNT162b2 | 19.2 | 23.1 | 31 | 20.8 |
| 17 | Pfizer BNT162b2 | 15.6 | 19 | 34 | 20.5 |
| 18 | Pfizer BNT162b2 | 16.2 | 19.3 | 34 | 20.8 |
| 19 | Pfizer BNT162b2 | 16.1 | 19.1 | 30 | 20.9 |
| 20 | Pfizer BNT162b2 | 19 | 22 | 33 | 26 |
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