Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial
Angela R Branche, Nadine Rouphael, David Diemert, Ann R. Falsey, Cecilia Losada, Lindsey R. Baden, Sharon E. Frey, Jennifer A. Whitaker, Susan J. Little, Evan J. Anderson, Emmanuel B. Walter, Richard M. Novak, Richard Rupp, Lisa A. Jackson, Tara M Babu, Angelica C Kottkamp, Anne F. Luetkemeyer, Lilly Cheng Immergluck, Rachel M. Presti, Martín Bäcker, Patricia Winokur, Siham Mahgoub, Paul Goepfert, Dahlene N. Fusco, Elissa Malkin, Jeffrey Bethony, Edward E. Walsh, Daniel S. Graciaa, Hady Samaha, Amy C Sherman, Stephen R. Walsh, Getahun Abate, Zacharoula Oikonomopoulou, Hana M. El Sahly, Thomas Martin, Satoshi Kamidani, Michael J. Smith, Benjamin G Ladner, Laura Porterfield, Maya Dunstan, Anna Wald, Tamia Davis, Robert L. Atmar, Mark J. Mulligan, Kirsten E. Lyke, Christine M. Posavad, Megan A Meagher, David S. Stephens, Kathleen M. Neuzil, Kuleni Abebe, Heather Hill, Jim Albert, Kalyani Telu, Jinjian Mu, Teri C Lewis, Lisa Giebeig, Amanda Eaton, Antonia Netzl, Samuel Wilks, Sina Türeli, Mamodikoe Makhene, Sonja Crandon, David C. Montefiori, Mat Makowski, Derek J. Smith, Seema Nayak, Paul C. Roberts, John H. Beigel, the COVAIL Study Group, Edward E. Walsh, Patrick Kingsley, Kari Steinmetz, Michael Peasley, Cassie Grimsley Ackerley, Kristen Unterberger, Aimee Desrosiers, Marc Siegel, Alexandra Tong, Rebecca Rooks, Daniel F. Hoft, Irene Graham, Wendy A. Keitel, Catherine Healy, Nicole Carter, Steven Hendrickx, Christina A. Rostad, Etza Peters, L. Nolan, M. Anthony Moody, Kenneth E. Schmader, Andrea Wendrow, Jessica Herrick, Rebecca Lau, Barbara Carste, Taylor Krause, Kirsten Hauge, Celia Engelson, Vijaya L Soma, Chloe Harris, Azquena Munoz Lopez
Abstract
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 (ID 50 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 ID 50 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 .