Booster doses of COVID-19 vaccine enhance neutralization efficiency against XBB.1.5
Authors: Elsa Sakr, Nisha D. Almeida, Marc-Andre Langlois, Kaberi Dasgupta, Bruce D. Mazer
Journal: Journal of Allergy and Clinical Immunology (2023)

The swift emergence of XBB.1.5 highlights the rapid mutation dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Renewed urgency led to development of bivalent vaccines to counter the potential threat of XBB.1.5. Considering that most individuals received earlier versions of coronavirus disease 2019 (COVID-19) vaccine, the effectiveness of those versions in protecting against XBB.1.5 remains uncertain. We assessed whether available booster vaccines induce neutralizing antibodies against XBB.1.5 and the Wuhan wild-type strain and whether bivalent vaccines (BVs) against BA.4/5 are superior to monovalent vaccines (MVs) in inducing XBB.1.5-neutralizing antibodies. Our prospective cohort study included 44 participants from the Living Lab Seroprevalence Study (Almeida et al, 2023, unpublished data). Matched serum samples were obtained 28 days after the third dose and 28 days after the fourth dose. We used surrogate neutralization ELISAs1Abe K.T. Li Z. Samson R. Samavarchi-Tehrani P. Valcourt E.J. Wood H. et al.A simple protein-based surrogate neutralization assay for SARS-CoV-2.JCI Insight. 2020; 5e142362Crossref Scopus (139) Google Scholar that had been optimized for compatibility with a Hamilton Robotic liquid handler. Plates were coated with XBB.1.5 or Wuhan spike proteins. We calculated the median infective dose [ID50] through a 5-point sample titration and utilized a 3-parameter log-logarithmic regression to determine the ID50, the reciprocal dilution factor needed for inhibiting 50% of angiotensin-converting enzyme 2 (ACE2) antigen binding. A multivariable mixed-effects model interrogating age, sex, vaccine type (MV vs BV), blood sample procurement after the third and fourth doses ("visits"), and recent infection (defined as positive if the anti–N-IgG signal-to-cutoff ratio was greater than 1.0) was used to examine associations between different predictor variables and the log-transformed outcome variable ID50 for XBB.1.5 and Wuhan. Sensitivity analyses were conducted using linear regression for model validation. The statistical modeling packages lme4 and lm within R, version 4.2.3, were used for model fitting. Almost all of the subjects produced neutralizing antibodies against XBB.1.5 (Fig 1). Multivariable mixed-effects modeling indicated that the ID50 levels against XBB.1.5 were 70% higher after the fourth dose than after the third dose (95% CI = 32%-120% [P < .001]). Participants who received a fourth dose of MV had ID50 levels against XBB.1.5 that were 30% lower than those who received a fourth dose of BV, which was not a statistically significant difference (95% CI = –53% to 5% [P < .081]). The ID50 for sera just before the fourth dose were significantly below the levels achieved 28 days after dose 3 (P < .003). Moreover, participants with recent infection (ie, detectable anti–N-IgG) had ID50 levels 60% higher (95% CI = 11%-132% [P = .014]) than those of participants without detectable anti–N-IgG. Our results confirm that COVID-19 boosters, even those not targeting XBB.1.5, induce neutralizing antibodies against this variant. This may be a positive consequence of epitope spreading, namely, the development of an immune response to epitopes distinct from and non–cross-reactive with previously encountered pathogens,2Vanderlugt C.L. Miller S.D. Epitope spreading in immune-mediated diseases: implications for immunotherapy.Nat Rev Immunol. 2002; 2: 85-95Crossref PubMed Scopus (736) Google Scholar whereby the immune system recognizes similar epitopes on different viral variants. Immune responses generated against ancestral viral strains may cross-react with new variants, conferring partial protection. Additionally, we observed no statistical advantage of the BV over the MV. This may be due to immune imprinting, when memory B-cell responses expand following exposure to related viral variants.3Zhou Z. Barrett J. He X. Immune imprinting and implications for COVID-19.Vaccines. 2023; 1: 875Crossref Scopus (9) Google Scholar Hojjat Jodaylami et al showed that vaccination and confirmed infection enhance antibody levels and improve cross-reactive inhibition of variants.4Hojjat Jodaylami M. Djaïleb A. Ricard P. Lavallée É. Cellier-Goetghebeur S. Parker M.-F. et al.Cross-reactivity of antibodies from non-hospitalized COVID-19 positive individuals against the native, B.1.351, B.1.617.2, and P.1 SARS-CoV-2 spike proteins.Sci Rep. 2021; 1121601Google Scholar Despite more than 30% of subjects having a history of COVID-19 at blood procurement after the fourth dose, only those with detectable anti–N-IgG had augmented responses to XBB1.5, suggesting that more recent infection may contribute to production of neutralizing antibodies. Considering that 20% to 54% of Americans have received 3 doses of COVID-19 vaccines, our findings show that 4 doses elicit greater immune responses. Upcoming boosters target XBB1.5, and as BA2.63 is emerging, our data suggest that receiving a booster, regardless of type, can provide protection against severe COVID-19 outcomes. Supported by the McGill University Health Centre Foundation. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. We thank the Living Laboratory Serology Study research team (Ian Schiller, Dr Danbing Ke, Dr Maria Plesa, Maria Bazan, Dr Corey Arnold, and Yannick Galipeau) for their invaluable contribution.