Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial

doi:10.1038/s41591-023-02503-4

Clinical Trial

. 2023 Sep;29(9):2334-2346.

doi: 10.1038/s41591-023-02503-4. Epub 2023 Aug 28.

Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial

Angela R Branche^#¹, Nadine G Rouphael^#², David J Diemert³, Ann R Falsey⁴, Cecilia Losada², Lindsey R Baden⁵, Sharon E Frey⁶, Jennifer A Whitaker⁷, Susan J Little⁸, Evan J Anderson⁹, Emmanuel B Walter¹⁰, Richard M Novak¹¹, Richard Rupp¹², Lisa A Jackson¹³, Tara M Babu¹⁴, Angelica C Kottkamp¹⁵, Anne F Luetkemeyer¹⁶, Lilly C Immergluck¹⁷, Rachel M Presti¹⁸, Martín Bäcker¹⁹, Patricia L Winokur²⁰, Siham M Mahgoub²¹, Paul A Goepfert²², Dahlene N Fusco²³, Elissa Malkin³, Jeffrey M Bethony³, Edward E Walsh⁴, Daniel S Graciaa², Hady Samaha², Amy C Sherman⁵, Stephen R Walsh⁵, Getahun Abate⁶, Zacharoula Oikonomopoulou⁶, Hana M El Sahly⁷, Thomas C S Martin⁸, Satoshi Kamidani⁹, Michael J Smith¹⁰, Benjamin G Ladner¹¹, Laura Porterfield¹², Maya Dunstan¹³, Anna Wald¹⁴, Tamia Davis¹⁵, Robert L Atmar⁷, Mark J Mulligan¹⁵, Kirsten E Lyke²⁴, Christine M Posavad²⁵, Megan A Meagher²⁵, David S Stephens²⁶, Kathleen M Neuzil²⁴, Kuleni Abebe²⁷, Heather Hill²⁸, Jim Albert²⁹, Kalyani Telu²⁹, Jinjian Mu²⁹, Teri C Lewis³⁰, Lisa A Giebeig³⁰, Amanda Eaton^{10

28}, Antonia Netzl³¹, Samuel H Wilks³¹, Sina Türeli³¹, Mamodikoe Makhene³², Sonja Crandon³², David C Montefiori^{10

28}, Mat Makowski²⁹, Derek J Smith³¹, Seema U Nayak³², Paul C Roberts^#³², John H Beigel^#³²; COVAIL Study Group

Collaborators, Affiliations

Collaborators

COVAIL Study Group:
Edward Walsh, Patrick Kingsley, Kari Steinmetz, Michael Peasley, Cassie Grimsley Ackerley, Kristen E Unterberger, Aimee Desrosiers, Marc Siegel, Alexandra Tong, Rebecca Rooks, Daniel F Hoft, Irene Graham, Wendy A Keitel, C Mary Healy, Nicole Carter, Steven Hendrickx, Christina A Rostad, Etza Peters, Lauren Nolan, M Anthony Moody, Kenneth E Schmader, Andrea Wendrow, Jessica Herrick, Rebecca Lau, Barbara Carste, Taylor Krause, Kirsten Hauge, Celia Engelson, Vijaya Soma, Chloe Harris, Azquena Munoz Lopez, Erica Johnson, Austin Chan, Fatima Ali, Trisha Parker, Jane A O'Halloran, Ryley M Thompson, Kimberly Byrnes, Asif Noor, Jeffery Meier, Jack Stapleton, Celia Maxwell, Sarah Shami, Arnaud C Drouin, Florice K Numbi, Julie McElrath, Mike Gale, Holly Baughman, Lisa McQuarrie, Theresa M Engel, Caleb J Griffith, Wendi L McDonald, Alissa E Burkey, Lisa B Hoopengardner, Jessica E Linton, Nikki L Gettinger, Marina Lee, Mohamed Elsafy, Rhonda Pikaart-Tautges, Janice Arega, Binh Hoang, Dan Curtin, Hyung Koo, Elisa Sindall, Marciela M DeGrace, Diane J Post, David S Stephens, Kathleen M Neuzil, Monica M Farley, Jeanne Marrazzo, Sidnee Paschal Young, Jeffery Lennox, Robert L Atmar, Linda McNeil, Elizabeth Brown

Affiliations

¹ Department of Medicine, Division of Infectious Diseases, University of Rochester, Rochester, NY, USA. angela_branche@urmc.rochester.edu.
² Hope Clinic, Emory University, Decatur, GA, USA.
³ George Washington Vaccine Research Unit, George Washington University, Washington D.C., WA, USA.
⁴ Department of Medicine, Division of Infectious Diseases, University of Rochester, Rochester, NY, USA.
⁵ Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Center for Vaccine Development, Saint Louis University, St. Louis, MO, USA.
⁷ Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, TX, USA.
⁸ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁹ Center for Childhood Infections and Vaccines (CCIV) of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, GA, USA.
¹⁰ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
¹¹ Project WISH, University of Illinois at Chicago, Chicago, IL, USA.
¹² University of Texas Medical Branch, Galveston, TX, USA.
¹³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
¹⁴ Departments of Medicine, Epidemiology and Laboratory Medicine and Pathology, University of Washington, Vaccines and Infectious Diseases Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁵ NYU VTEU Manhattan Research Clinic, NYU Grossman School of Medicine, New York, NY, USA.
¹⁶ Zuckerberg San Francisco General, University of California San Francisco, San Francisco, CA, USA.
¹⁷ Department of Microbiology, Biochemistry and Immunology, and Clinical Research Center, Morehouse School of Medicine, Atlanta, GA, USA.
¹⁸ Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ NYU VTEU Long Island Research Clinic, NYU Long Island School of Medicine, Mineola, NY, USA.
²⁰ College of Medicine, University of Iowa, Iowa City, IA, USA.
²¹ Howard University College of Medicine, Howard University Hospital, Washington D.C., WA, USA.
²² Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²³ Tulane University School of Medicine, New Orleans, LA, USA.
²⁴ Center for Vaccine Development and Global Health, University of Maryland School of Medicine Baltimore, Baltimore, MD, USA.
²⁵ IDCRC Laboratory Operations Unit, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁶ Department of Medicine and Woodruff Health Sciences Center, Emory University, Atlanta, GA, USA.
²⁷ FHI 360, Durham, NC, USA.
²⁸ Department of Surgery, Duke University Medical Center, Durham, NC, USA.
²⁹ The Emmes Company, LLC, Rockville, MD, USA.
³⁰ Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
³¹ Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK.
³² Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

^# Contributed equally.

PMID: 37640860
PMCID: PMC10504073
DOI: 10.1038/s41591-023-02503-4

Clinical Trial

Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial

Angela R Branche et al. Nat Med. 2023 Sep.

. 2023 Sep;29(9):2334-2346.

doi: 10.1038/s41591-023-02503-4. Epub 2023 Aug 28.

Authors

Collaborators

COVAIL Study Group:
Edward Walsh, Patrick Kingsley, Kari Steinmetz, Michael Peasley, Cassie Grimsley Ackerley, Kristen E Unterberger, Aimee Desrosiers, Marc Siegel, Alexandra Tong, Rebecca Rooks, Daniel F Hoft, Irene Graham, Wendy A Keitel, C Mary Healy, Nicole Carter, Steven Hendrickx, Christina A Rostad, Etza Peters, Lauren Nolan, M Anthony Moody, Kenneth E Schmader, Andrea Wendrow, Jessica Herrick, Rebecca Lau, Barbara Carste, Taylor Krause, Kirsten Hauge, Celia Engelson, Vijaya Soma, Chloe Harris, Azquena Munoz Lopez, Erica Johnson, Austin Chan, Fatima Ali, Trisha Parker, Jane A O'Halloran, Ryley M Thompson, Kimberly Byrnes, Asif Noor, Jeffery Meier, Jack Stapleton, Celia Maxwell, Sarah Shami, Arnaud C Drouin, Florice K Numbi, Julie McElrath, Mike Gale, Holly Baughman, Lisa McQuarrie, Theresa M Engel, Caleb J Griffith, Wendi L McDonald, Alissa E Burkey, Lisa B Hoopengardner, Jessica E Linton, Nikki L Gettinger, Marina Lee, Mohamed Elsafy, Rhonda Pikaart-Tautges, Janice Arega, Binh Hoang, Dan Curtin, Hyung Koo, Elisa Sindall, Marciela M DeGrace, Diane J Post, David S Stephens, Kathleen M Neuzil, Monica M Farley, Jeanne Marrazzo, Sidnee Paschal Young, Jeffery Lennox, Robert L Atmar, Linda McNeil, Elizabeth Brown

Affiliations

¹ Department of Medicine, Division of Infectious Diseases, University of Rochester, Rochester, NY, USA. angela_branche@urmc.rochester.edu.
² Hope Clinic, Emory University, Decatur, GA, USA.
³ George Washington Vaccine Research Unit, George Washington University, Washington D.C., WA, USA.
⁴ Department of Medicine, Division of Infectious Diseases, University of Rochester, Rochester, NY, USA.
⁵ Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Center for Vaccine Development, Saint Louis University, St. Louis, MO, USA.
⁷ Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, TX, USA.
⁸ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁹ Center for Childhood Infections and Vaccines (CCIV) of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, GA, USA.
¹⁰ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
¹¹ Project WISH, University of Illinois at Chicago, Chicago, IL, USA.
¹² University of Texas Medical Branch, Galveston, TX, USA.
¹³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
¹⁴ Departments of Medicine, Epidemiology and Laboratory Medicine and Pathology, University of Washington, Vaccines and Infectious Diseases Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁵ NYU VTEU Manhattan Research Clinic, NYU Grossman School of Medicine, New York, NY, USA.
¹⁶ Zuckerberg San Francisco General, University of California San Francisco, San Francisco, CA, USA.
¹⁷ Department of Microbiology, Biochemistry and Immunology, and Clinical Research Center, Morehouse School of Medicine, Atlanta, GA, USA.
¹⁸ Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ NYU VTEU Long Island Research Clinic, NYU Long Island School of Medicine, Mineola, NY, USA.
²⁰ College of Medicine, University of Iowa, Iowa City, IA, USA.
²¹ Howard University College of Medicine, Howard University Hospital, Washington D.C., WA, USA.
²² Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²³ Tulane University School of Medicine, New Orleans, LA, USA.
²⁴ Center for Vaccine Development and Global Health, University of Maryland School of Medicine Baltimore, Baltimore, MD, USA.
²⁵ IDCRC Laboratory Operations Unit, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁶ Department of Medicine and Woodruff Health Sciences Center, Emory University, Atlanta, GA, USA.
²⁷ FHI 360, Durham, NC, USA.
²⁸ Department of Surgery, Duke University Medical Center, Durham, NC, USA.
²⁹ The Emmes Company, LLC, Rockville, MD, USA.
³⁰ Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
³¹ Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK.
³² Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

^# Contributed equally.

PMID: 37640860
PMCID: PMC10504073
DOI: 10.1038/s41591-023-02503-4

Abstract

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID₅₀ titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID₅₀ titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 .

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Conflict of interest statement

L.G. has received funding from Leidos Biomedical Research. E.J.A. has received funding from Pfizer, Moderna, Janssen, GSK, Sanofi Pasteur, Micron and Regeneron (payment made to institution); and serves a safety monitoring role for Sanofi Pasteur, ACI Clinical/WCG and Kentucky Bioscience (payment made to E.J.A.). J.A. has received funding from the Division of Microbiology and Infectious Diseases, contract no. 75N93021C00012. A.R.B. has received grant funding from NIH, NIAID, Pfizer, Cyanvac and Merck (payment to institution); and has received consulting fees from Janssen and GSK (payment made to A.R.B.). L.R.B. has received grant funding from NIH, NIH/Harvard Medical School, Wellcome Trust and the Gates Foundation; and serves in a data safety monitoring role for NIH, US Food and Drug Administration (payment made to institution). She is involved in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Crucell/Janssen, Moderna, Military HIV Research Program, the Gates Foundation and Harvard Medical School. D.J.D. has received funding from Leidos Biomedical (research contract to his institution) to conduct a clinical trial. A.E. has received DMID funding via NIH subcontract to Duke University for the CIVICS Option 21 and Moderna. H.M.E.S. has received funding support from the NIH (grant no. 22CTA-DM0002). A.R.F. has received grant funding from Janssen, Pfizer, Merck, BioFire Diagnostics and CyanVac (payment made to institution); and has received consultant fees from Arrowhead, Icosavax, Moderna and GlaxoSmithKline (payable to A.R.F.). A.R.F. also reports travel meeting support from GlaxoSmithKline, and serving in a data safety monitoring role for Novavax. S.E.F. has received funding from Leidos to Saint Louis University to conduct the protocol, DMID22-0004. D.N.F. has received a contract from the CDC and is the site PI for clinical trials from Gilead, Regeneron and MetroBiothech. She is the PI on one investigator-initiated award from Gilead and served on an advisory board for Gilead in 2021. P.A.G. has received COVAIL clinical trial funding and consulting fees from Janssen Vaccines (payment made to P.A.G.). D.S.G. has received funding from NIAID/IDCRC, Henry M. Jackson Foundation Contract, and consulting fees from Critica (payment to a nonprofit organization). H.H. has received funding support from the Division of Microbiology and Infectious Diseases, contract no. 75N93021C00012. L.C.I. has received funding from NIH/NIAID/DMID, Moderna and Pfizer (payment made to Sanofi); grant support from GSK, Merck, Sharpe & Dohme and CDC (payment made to institution); consulting fees from Moderna Scientific Advisory Board, CDC, Pediatric Emergency Medicine Associates, American Academy of Pediatrics, Rockefeller University and American Academy of Pediatrics–Georgia Chapter; and travel support from American Academy of Pediatrics and Moderna. L.C.I. serves as in a data safety monitoring role for NIH-Phase 2 Vaccine Trial for Monkeypox, Moderna Scientific Advisory Board North America, COVID-19 Task Force, Georgia, Pediatric Infectious Disease Society, Emory University–Pediatric and Reproductive Environmental Health Scholars–Southeastern (board member), Center for Spatial Analytics, Georgia Institute of Technology (board member) and American Academy of Pediatrics (executive board for section on infectious diseases). L.A.J. has received funding from Pfizer to support a clinical trial, contract funding for research support from the CDC (to institution). Financial support for study was provided to L.A.J.’s institution by the NIH. L.A.J. also reports unpaid participation for service on data safety monitoring boards for NIH-funded clinical trials. S.K. has received funding from the NIH to conduct the COVAIL clinical trial of COVID-19 vaccines, Moderna and Janssen for COVID-19 vaccines, Pfizer to conduct clinical trials of Pfizer–BioNTech COVID-19 vaccines, and CDC to conduct surveillance for COVID-19 VE. Payments were made to Emory University. B.G.L. has received gifts from Gilead Dinner at CROI 2023. S.J.L. has received funding from NIH grants, payment made to institution. A.F.L. has received funding from Merck, Gilead and Viiv (payment to UCSF); consulting fees from Vir Biotechnology; travel support from Merck to attend a required investigator meeting; and testing kits and supplies to support research study from Hologic. K.E.L. has received funding from Pfizer–BioNTech for trial operations. M. Matkowski has received funding from the Division of Microbiology and Infectious Diseases, contract no. 75N93021C00012. T.C.S.M. has received funding from Gilead Sciences as coinvestigator and travel support for conference attendance from Gilead. M.A.M. has received funding from NIAID UM1AI148684. D.C.M. has received funding from NIH 75N93019C00050-21A: CIVICS A- Option 21A-DMID Trials of COVID-19 Vaccines. J.M. has received funding from the Division of Microbiology and Infectious Diseases contract no. 75N93021C00012. A.N. has received funding or grant support from NIH–NIAID and CEIRR, Gates Cambridge Trust and NIH–NIAID R01. K.M.N. has received grants support from the NIH to participate in the overall organization of COVID-19 trials and for participation in vaccines trials, Center for Vaccine Development and Global Health and Pfizer to conduct clinical trials of COVID-19 vaccines without salary support. R.M.N. has received funding from Moderna and Janssen, and travel support from Moderna. Z.O. has received funding from Leidos subcontract agreement no. 22CTA-DM0006 (for role as subinvestigator; clinical trial conduct, manuscript review). Payments were made to Saint Louis University. C.M.P. has received funding from NIAID UM1AI148684. R.M.P. has received funding from NIH, DMID, COVAIL, Janssen and Moderna. N.G.R. has received research grants from Pfizer, Merck, Sanofi, Quidel and Lilly. Her institution has also received funding from NIH to conduct clinical trials. N.G.R. serves on safety committees for ICON and EMMES and is on the advisory boards of Moderna and Sanofi. D.J.S. has received funding from NIH–NIAID CEIRR (NIH–NIAID R01). N.G.R. reports travel-related meetings from NIH–NIAID CEIRR. D.S.S. has received a funding grant from the NIH IDCRC. M.J.S. has received grant support from Pfizer (through institution) as a research contract for COVID-19 vaccine and therapy clinical trials, expert consulting fees from Garau Germano Medicolegal (paid to M.J.S.). M.J.S. reports serving as chair of the Section on Epidemiology, Public Health and Evidence (volunteer position) for American Academy of Pediatrics. K.T. has received funding from the Division of Microbiology and Infectious Diseases, contract no. 75N93021C00012. S.T. has received NIH–NIAID R01, CEIRR. A.W. has received funding from NIH, Sanofi and GSK (payments made to institution), and consulting fees from Aicuris, Crozet Auritec and DxNow. A.W. reports serving in a data safety monitoring role for Merck X-Vax, Vir and Curevo, and receiving other financial interest from Merck for a vaccine clinical trial. E.E.W. has received grant funding from NIH–DMID, Pfizer and Merck (with payment made to the institution), and consulting fees from Merck (payment made to E.E.W.). E.B.W. has received funding from Leidos Biomedical Research (agreement no. 22CTA-DM0009), Pfizer, Moderna, Sequiris, Clinetic and Najit Technologies (PI for vaccine study), with payments made to institution; and honoraria as a speaker from College of Diplomates of the American Board of Pediatric Dentistry (payment made to E.B.W.). He received travel support from the American Academy of Pediatrics and consulting fees from Iliad Biotechnologies. He reports serving as an advisory board member for Vaxcyte Scientific (payment made to E.B.W.). S.R.W. has received funding from NIH, Pfizer, Sanofi Pasteur, Janssen Vaccines/Johnson & Johnson, Moderna Tx, Vir Biotechnology and Worcester HIV Vaccine; and travel support from Sanofi Pasteur, with payments made to institution. S.R.W. serves in a data safety monitoring role and on an advisory board for Janssen Vaccines/Johnson & Johnson. S.R.W.’s spouse is an employee of Regeneron Pharmaceuticals and holds stock/stock options. P.L.W. has received subcontract funding from NIH, grant funding from NIH, contract funding from Pfizer to University of Iowa. P.L.W. serves in a data safety monitoring role and is an advisory board member for Emmes Corporation. The other authors declare no competing interests.

Figures

**Fig. 1. Consort diagram for the study.**
a–c, Shown are the consort diagrams for stage 1 (a), stage 2 (b) and stage 3 (c) of the study. A description of the number of participants screened for eligibility, enrolled, allocated to a vaccine arm and the number vaccinated is included for each stage. Additional details are provided on the follow-up of participants at the time of data cut-off and the analysis populations. Immuno, immunogenicity.

**Fig. 2. Pseudovirus neutralization ID₅₀ titers by time point and variant in uninfected participants by vaccine arm and platform.**
Time points were Day 1 (D1), day 29 (D29) and day 91 (D91). Variants were D614G, Delta, Beta, Omicron BA.1 (B.1.1.529) and Omicron BA.4/BA.5. Circles denote GMT, with 95% CI. GMTs at prevaccination baseline, obtained on day 1, are shown in blue and postvaccination day 29 GMTs and day 91 GMTs are shown in red and yellow, respectively.

**Fig. 3. Pseudovirus neutralization ID₅₀ titers by time point and variant in a subset (n = 22–23) of participants who were uninfected.**
Time points were days 1, 15 and 91. Variants were D614G and Omicron BA.1, BA.2.12.1, BA.4/BA.5, BA.2.75, BA.4.6, BF.7, BA.2.75.2, BQ.1.1 and XBB.1. a, Stage 1 mRNA-1273 prototype monovalent vaccine. b, Stage 1 mRNA-1273 Omicron BA.1 + prototype bivalent vaccine. In a and b, boxes and horizontal bars denote interquartile range and median ID₅₀, respectively; whiskers denote 95% CI; and n represents the number of samples tested. c,d, Radar plots of the pseudovirus neutralization GMTs at day 15 (c) and day 91 (d) for the two vaccine arms in stage 1 mRNA-1273 prototype monovalent vaccine (red) and mRNA-1273 Omicron BA.1 + prototype bivalent vaccine (blue). Circles are GMT estimates for each variant. In the radar plots, each variant is represented by its own vertical line or spoke, and the spokes are evenly distributed around the circle. Each horizontal line along a vertical spoke represents the GMT at a ten-fold dilution, with the value closest to the center being 1 and farthest from the center being 10,000 or 10⁴. A line is drawn connecting the GMT data values for vaccine arm at the individual variants represented by its vertical spoke.

**Fig. 4. Antigenic cartography.**
a, An antigenic map by ref. served as the base map for all antibody landscapes. Virus variants are shown as color-filled circles. Variants with additional substitutions from their root variant are shown as smaller circles. Variants associated with significant outbreaks or pandemic waves are secondarily encircled in red. Individual sera from individuals who were infected are displayed as open squares in the color of their root variant or gray for mRNA-1273 vaccinated sera; small dark squares represent clinical trial participants. One grid unit in the map corresponds to a twofold dilution in the neutralization assay. Within the x and y axes, the map orientation is free as antigenic distances are relative. Small triangles point to sera outside the shown map area. b, Day 1 and day 91 GMT antibody landscapes for individuals who were uninfected and infected in different arms for the three stages. Impulse lines extending from the base map to the landscapes show the GMT against the specific variant. Lower landscapes correspond to day 1 and upper landscapes to day 91 immunity. To interpret landscapes, a day 91 response where the upper landscape is flat indicates the responses to all the variants were equivalent, whereas skewing up or down indicates an uneven response across variants. The landscapes are ordered by height of their GMT against BA.4/5. The surface colors represent study arms: pink, prototype; red, prototype + Omicron BA.1; black, Omicron BA.1; light green, Delta + Omicron BA.1; blue, Beta + Omicron BA.1; purple, Beta + prototype; yellow, Beta.

**Extended Data Fig. 1. Frequency and severity of local solicited adverse events by stage and vaccine arm.**
Maximum severity of local solicited events for stage 1 (A), stage 2 (B) and stage 3 (C).

**Extended Data Fig. 2. Frequency and severity of systemic solicited adverse events by stage and vaccine arm.**
Maximum severity of systemic solicited events for stage 1 (A), stage 2 (B) and stage 3 (C).

**Extended Data Fig. 3. Frequency and severity of all adverse events by stage and vaccine arm.**
Number of severity of all adverse events by MedDRA® System Organ Class and vaccination group for stage 1 (A), stage 2 (B) and stage 3 (C).

**Extended Data Fig. 4**
Pseudovirus neutralization ID₅₀ titers by timepoint (D1, D29 and Day 91) and variant (D614G, Delta, Beta, Omicron BA.1 and Omicron BA.4/5) in infected participants by vaccine arm and platform.

**Extended Data Fig. 5**
Comparison of pseudovirus neutralization ID₅₀ titers at D1 and D29 (A) and D1 and D90 (B) as well as by variant (D614G, Delta, Beta, Omicron BA.1 and Omicron BA.4/5) in uninfected participants by vaccine arm and platform.

**Extended Data Fig. 6**
Comparison of pseudovirus neutralization ID₅₀ titers at D1e and D29 (A) and D1 and D91 (B) as well as by variant (D614G, Delta, Beta, Omicron BA.1 and Omicron BA.4/5) in previously infected participants by vaccine arm and platform.

See this image and copyright information in PMC

Update of

Bivalent and Monovalent SARS-CoV-2 Variant Vaccine Boosters Improve coverage of the known Antigenic Landscape: Results of the COVID-19 Variant Immunologic Landscape (COVAIL) Trial.
Branche A, Rouphael N, Diemert D, Falsey A, Losada C, Baden LR, Frey S, Whitaker J, Little S, Anderson E, Walter E, Novak R, Rupp R, Jackson L, Babu T, Kottkamp A, Luetkemeyer A, Immergluck L, Presti R, Backer M, Winokur P, Mahgoub S, Goepfert P, Fusco D, Malkin E, Bethony J, Walsh E, Graciaa D, Samaha H, Sherman A, Walsh S, Abate G, Oikonomopoulou Z, El Sahly H, Martin T, Kamidani S, Smith M, Ladner B, Porterfield L, Dunstan M, Wald A, Davis T, Atmar R, Mulligan M, Lyke K, Posavad C, Meagher M, Stephens D, Neuzil K, Abebe K, Hill H, Albert J, Telu K, Mu J, Lewis T, Giebeig L, Eaton A, Netzl A, Wilks S, Tureli S, Makhene M, Crandon S, Montefiori D, Makowski M, Smith D, Nayak S, Roberts P, Beigel J. Branche A, et al. Res Sq [Preprint]. 2023 May 5:rs.3.rs-2653179. doi: 10.21203/rs.3.rs-2653179/v1. Res Sq. 2023. Update in: Nat Med. 2023 Sep;29(9):2334-2346. doi: 10.1038/s41591-023-02503-4. PMID: 37205592 Free PMC article. Updated. Preprint.

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References

1. Weekly operational update on COVID-19. World Health Organizationhttps://www.who.int/emergencies/diseases/novel-coronavirus-2019/situatio... (2020).
1. COVID-19 dashboard by the Center for Systems Science and Engineering (CCSE) at Johns Hopkins University (JHU). Johns Hopkins Universityhttps://coronavirus.jhu.edu/map.html (2022).
1. Baden LR, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021;384:403–416. doi: 10.1056/NEJMoa2035389. - DOI - PMC - PubMed
1. Bos R, et al. Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 spike immunogen induces potent humoral and cellular immune responses. npj Vaccines. 2020;5:91. doi: 10.1038/s41541-020-00243-x. - DOI - PMC - PubMed
1. Polack FP, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577. - DOI - PMC - PubMed

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[1] Weekly operational update on COVID-19. World Health Organizationhttps://www.who.int/emergencies/diseases/novel-coronavirus-2019/situatio... (2020).

[2] Weekly operational update on COVID-19. World Health Organizationhttps://www.who.int/emergencies/diseases/novel-coronavirus-2019/situatio... (2020).

[3] COVID-19 dashboard by the Center for Systems Science and Engineering (CCSE) at Johns Hopkins University (JHU). Johns Hopkins Universityhttps://coronavirus.jhu.edu/map.html (2022).

[4] COVID-19 dashboard by the Center for Systems Science and Engineering (CCSE) at Johns Hopkins University (JHU). Johns Hopkins Universityhttps://coronavirus.jhu.edu/map.html (2022).

[5] Baden LR, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021;384:403–416. doi: 10.1056/NEJMoa2035389. - DOI - PMC - PubMed

[6] Baden LR, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021;384:403–416. doi: 10.1056/NEJMoa2035389. - DOI - PMC - PubMed

[7] Bos R, et al. Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 spike immunogen induces potent humoral and cellular immune responses. npj Vaccines. 2020;5:91. doi: 10.1038/s41541-020-00243-x. - DOI - PMC - PubMed

[8] Bos R, et al. Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 spike immunogen induces potent humoral and cellular immune responses. npj Vaccines. 2020;5:91. doi: 10.1038/s41541-020-00243-x. - DOI - PMC - PubMed

[9] Polack FP, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577. - DOI - PMC - PubMed

[10] Polack FP, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577. - DOI - PMC - PubMed

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Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial

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Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial

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