Rapid decline in vaccine-boosted neutralizing antibodies against SARS-CoV-2 Omicron variant

Abstract

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. We assess the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. All prime-boost combinations substantially increase the neutralization titers to Omicron, although the boosted titers decline rapidly within 2 months from the peak response compared with boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers are substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared with homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generates nearly equivalent neutralizing activity against Omicron sublineages BA.1, BA.2, and BA.3 but modestly reduced neutralizing activity against BA.2.12.1 and BA.4/BA.5 compared with BA.1. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2. This trial was conducted under ClincalTrials.gov: NCT04889209.

Keywords: BA.2.12.1; BA.4/BA.5; COVID-19; Omicron variant; SARS-CoV-2; booster; mRNA vaccine; neutralizing antibody; recombinant adenovirus vaccine; sublineage.

Conflict of interest statement

Declaration of interests R.L.A., C.D.I., C.M.P., D.S., R.P.C., M.E.D., A.E., H.M.E.S., R.E.R., M.B., A.C.K., T.M.B., D.D., R.N.C., J.I.A., S.C., J.A.Z., S.U.N., E.R.B., and D.J.P. report no competing interests. K.E.L. receives grant awards from Pfizer, Inc., COVID-19 vaccine research. L.A.J.’s institution receives grant funding from NIH and CDC for vaccine-related assessments, including those of COVID-19 vaccines. A.R.B. has grant funding from Pfizer, Janssen, Merck, and Cyanvac for non-COVID-19-related work and serves as a consultant for GSK and Janssen. C.A.R.'s institution has received funds to conduct clinical research from the National Institutes of Health, CDC, BioFire, Inc., Genentech, GSK, Janssen, MedImmune, Merck, Micron, Moderna, Novavax, PaxVax, Pfizer, Regeneron, and Sanofi-Pasteur. She is co-inventor of patented RSV vaccine technology, which has been licensed to Meissa Vaccines, Inc. J.M.M. has served as a consultant for Merck, Sharp, and Dohme for non-Covid-related work. C.J. receives funding from the Bill and Melinda Gates Foundation, NIH, and CDC, consults for Gilead and Abbvie, serves on a DSMB for MedPace, and receives royalties from UpToDate. M.J.M. has laboratory research and clinical trials contracts for vaccines or MAB versus SARS-CoV-2 with Lilly, Pfizer (exclusive of the current work), and Sanofi and personal fees for Scientific Advisory Board service from Merck, Meissa Vaccines, Inc., and Pfizer. R.C.B. receives funding for vaccine trials from Path Nipah and Pfizer. R.W.F. receives funding to perform clinical trials from Pfizer, Moderna, Astra Zeneca, and Emergent Health, and he serves on advisory boards for Johnson & Johnson, Merck, Sanofi Pasteur, and Seqirus. S.E. receives funding to her institution from Sanofi Pasteur for a non-COVID-19 vaccine study. K.M.N. holds a grant from Pfizer, without salary support, for a COVID-19 vaccine study and salary support from the National Institutes of Health (NIH) for work on multiple COVID-19 vaccine trials. D.S.S. is supported by grant awards from NIH/NIAID. P.C.R. and J.H.B. report a pending US patent application no. 63/025918 entitled “Coronavirus RNA vaccines and methods of use.” D.C.M. receives funding from NIH and Moderna for laboratory studies of COVID-19 vaccine antibody responses. M.S.S. receives funding from Moderna, Inc., and Ocugen. D.C.M. receives funding from Moderna, Inc.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract

Figure 1

Pseudovirus neutralization expressed as 50% inhibitory dilution (ID50) to the D614G variant and Omicron at day 1 (pre-booster) and days 29 and 91 post-booster (A) mRNA-1273 vaccine boosted with mRNA-1273 100 μg. (B) Ad26.COV2.S vaccine boosted with Ad26.COV2.S. (C) BNT162b2 vaccine boosted with BNT162b2. (D) mRNA-1273 vaccine boosted with mRNA-1273 50 μg. (E) Ad26.COV2.S vaccine boosted with BNT162b2. (F) BNT162b2 vaccine boosted with Ad26.COV2.S. Each group consisted of ∼50 participants (n = ∼25 age 18–55 years old; n = ∼25 age ≥ 56 years old); the actual number of samples assayed for each study are shown at the top of each panel as gray text. The PsVNA (neutralizing antibody [nAb]) results for the D614G variant were previously reported for all groups except the homologous 50 μg mRNA-1273-boosted group. Values and colored text represent the geometric means; error bars represent 95% confidence intervals of ID50 titers. The geometric mean fold reduction in ID50 for Omicron relative to the D614G variant is depicted in black text for days 29 and 91 post-booster. Technical duplicates were performed.

Figure 2

Neutralization of Omicron sublineages BA.1, BA.2, BA.2.12.1, BA.3, and BA.4/BA.5 Omicron sublineage neutralization titers (ID50) in serum samples obtained before (day 1) and 29 days after homologous mRNA-1273 boosting (50 μg) in 16 study participants who received two inoculations of mRNA-1273 (100 μg) under emergency-use authorization. Box plots represent median (horizontal line within the box) and 25th and 75th percentiles (lower and upper borders of the box), with the whiskers drawn to the value nearest to, but within, 1.5× interquartile range above and below the borders of the box and individual results depicted in open circles. GMTs are shown above each box plot. The fold change neutralization titers relative to D614G are depicted in black text at the bottom of the panels. Technical duplicates were performed.

Figure 3

Six month durability of SARS-CoV-2 pseudovirion neutralizing antibody titers after three inoculations of mRNA-1273 (100 μg dose) Results for participants with available PsVNA data up to day 181 visit (n = 49), from participants who received the two standard inoculations of mRNA-1273 100 μg and were boosted with mRNA-1273 (100 μg). Left: Values and colored text represent the geometric means; error bars represent 95% confidence intervals of ID50 titers. The geometric mean fold reduction in ID50 for Omicron relative to D614G is depicted in black text for days 29,91, and 181 post-booster. Right: Spaghetti plot by study day showing differences in PsVNA levels for D614G and Omicron. Box plots represent median (horizontal line within the box) and 25th and 75th percentiles (lower and upper borders of the box), with the whiskers drawn to the value nearest to, but within, 1.5× interquartile range above and below the borders of the box. The geometric mean fold reduction in ID50 for Omicron relative to D614G is depicted in black text.

Figure 4

Live virus focus-reduction neutralization expressed ID50 in Vero-TMPRSS2 cells to D614G, Beta, Delta, and Omicron variants at days 1 (pre-booster) and 29 post-booster (A) mRNA-1273 vaccine boosted with mRNA-1273 100 μg. (B) Ad26.COV2.S vaccine boosted with Ad26.COV2.S. (C) BNT162b2 vaccine boosted with BNT162b2. (D) mRNA-1273 vaccine boosted with mRNA-1273 50 μg. (E) Ad26.COV2.S vaccine boosted with BNT162b2. (F) BNT162b2 vaccine boosted with Ad26.COV2.S. Each point represents the GMT from two duplicates per specimen (within the same assay run). A value equivalent to half the lower limit of detection (LLOD = 20) was assigned to observations with no detectable response. A specimen was considered as having a positive response if at least one of the duplicates was above the LLOD. Box plots represent median (horizontal line within the box) and 25th and 75th percentiles (lower and upper borders of the box), with the whiskers drawn to the value nearest to, but within, 1.5× interquartile range above and below the borders of the box.