Waning Immunity and IgG4 Responses Following Bivalent MRNA Boosting

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Feb 23

PMID 38394195

Authors

Ninaad Lasrado

Ai-Ris Y Collier

Jessica Miller

Nicole P Hachmann

Jinyan Liu

Trisha Anand

Esther A Bondzie

Jana L Fisher

Camille R Mazurek

Robert C Patio

Stefanie L Rodrigues

Marjorie Rowe

Nehalee Surve

Darren M Ty

Cindy Wu

Taras M Chicz

Xin Tong

Bette Korber

Ryan P McNamara

Dan H Barouch

Affiliations

Soon will be listed here.

Abstract

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

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References

Goel R, Painter M, Apostolidis S, Mathew D, Meng W, Rosenfeld A . mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science. 2021; 374(6572):abm0829. PMC: 9284784. DOI: 10.1126/science.abm0829. View

Wang Q, Guo Y, Tam A, Valdez R, Gordon A, Liu L . Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine. Cell Rep Med. 2023; 4(11):101258. PMC: 10694617. DOI: 10.1016/j.xcrm.2023.101258. View

Sadoff J, Gray G, Vandebosch A, Cardenas V, Shukarev G, Grinsztejn B . Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med. 2021; 384(23):2187-2201. PMC: 8220996. DOI: 10.1056/NEJMoa2101544. View

Liu J, Yu J, McMahan K, Jacob-Dolan C, He X, Giffin V . CD8 T cells contribute to vaccine protection against SARS-CoV-2 in macaques. Sci Immunol. 2022; 7(77):eabq7647. PMC: 9407944. DOI: 10.1126/sciimmunol.abq7647. View

Grifoni A, Weiskopf D, Ramirez S, Mateus J, Dan J, Rydyznski Moderbacher C . Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell. 2020; 181(7):1489-1501.e15. PMC: 7237901. DOI: 10.1016/j.cell.2020.05.015. View

Wang Q, Bowen A, Valdez R, Gherasim C, Gordon A, Liu L . Antibody Response to Omicron BA.4-BA.5 Bivalent Booster. N Engl J Med. 2023; 388(6):567-569. PMC: 9847504. DOI: 10.1056/NEJMc2213907. View

Narowski T, Raphel K, Adams L, Huang J, Vielot N, Jadi R . SARS-CoV-2 mRNA vaccine induces robust specific and cross-reactive IgG and unequal neutralizing antibodies in naive and previously infected people. Cell Rep. 2022; 38(5):110336. PMC: 8769879. DOI: 10.1016/j.celrep.2022.110336. View

Aalberse R, Stapel S, Schuurman J, Rispens T . Immunoglobulin G4: an odd antibody. Clin Exp Allergy. 2009; 39(4):469-77. DOI: 10.1111/j.1365-2222.2009.03207.x. View

Lilienthal G, Rahmoller J, Petry J, Bartsch Y, Leliavski A, Ehlers M . Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways. Front Immunol. 2018; 9:958. PMC: 5954034. DOI: 10.3389/fimmu.2018.00958. View

10.

Brown E, Licht A, Dugast A, Choi I, Bailey-Kellogg C, Alter G . High-throughput, multiplexed IgG subclassing of antigen-specific antibodies from clinical samples. J Immunol Methods. 2012; 386(1-2):117-23. PMC: 3475184. DOI: 10.1016/j.jim.2012.09.007. View

11.

Bruhns P, Iannascoli B, England P, Mancardi D, Fernandez N, Jorieux S . Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. 2008; 113(16):3716-25. DOI: 10.1182/blood-2008-09-179754. View

12.

Reinscheid M, Luxenburger H, Karl V, Graeser A, Giese S, Ciminski K . COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation. Nat Commun. 2022; 13(1):4631. PMC: 9358914. DOI: 10.1038/s41467-022-32324-x. View

13.

Davis-Gardner M, Lai L, Wali B, Samaha H, Solis D, Lee M . Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster. N Engl J Med. 2022; 388(2):183-185. PMC: 9812288. DOI: 10.1056/NEJMc2214293. View

14.

Yue C, Song W, Wang L, Jian F, Chen X, Gao F . ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5. Lancet Infect Dis. 2023; 23(3):278-280. PMC: 9897732. DOI: 10.1016/S1473-3099(23)00010-5. View

15.

Zhu D, Gorman M, Yuan D, Yu J, Mercado N, McMahan K . Defining the determinants of protection against SARS-CoV-2 infection and viral control in a dose-down Ad26.CoV2.S vaccine study in nonhuman primates. PLoS Biol. 2022; 20(5):e3001609. PMC: 9071142. DOI: 10.1371/journal.pbio.3001609. View

16.

Collier A, Miller J, Hachmann N, McMahan K, Liu J, A Bondzie E . Immunogenicity of BA.5 Bivalent mRNA Vaccine Boosters. N Engl J Med. 2023; 388(6):565-567. PMC: 9847505. DOI: 10.1056/NEJMc2213948. View

17.

Uriu K, Ito J, Zahradnik J, Fujita S, Kosugi Y, Schreiber G . Enhanced transmissibility, infectivity, and immune resistance of the SARS-CoV-2 omicron XBB.1.5 variant. Lancet Infect Dis. 2023; 23(3):280-281. PMC: 9889095. DOI: 10.1016/S1473-3099(23)00051-8. View

18.

Nimmerjahn F, Ravetch J . Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2007; 8(1):34-47. DOI: 10.1038/nri2206. View

19.

Wang Q, Iketani S, Li Z, Liu L, Guo Y, Huang Y . Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2022; 186(2):279-286.e8. PMC: 9747694. DOI: 10.1016/j.cell.2022.12.018. View

20.

Buhre J, Pongracz T, Kunsting I, Lixenfeld A, Wang W, Nouta J . mRNA vaccines against SARS-CoV-2 induce comparably low long-term IgG Fc galactosylation and sialylation levels but increasing long-term IgG4 responses compared to an adenovirus-based vaccine. Front Immunol. 2023; 13:1020844. PMC: 9877300. DOI: 10.3389/fimmu.2022.1020844. View