Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial
Authors: Branche Angela R. , Rouphael Nadine G. , Diemert David J. , Falsey Ann R. , Losada Cecilia , Baden Lindsey R. , Frey Sharon E. , Whitaker Jennifer A. , Little Susan J. , Anderson Evan J. , Walter Emmanuel B. , Novak Richard M. , Rupp Richard , Jackson Lisa A. , Babu Tara M. , Kottkamp Angelica C. , Luetkemeyer Anne F. , Immergluck Lilly C. , Presti Rachel M. , Bäcker Martín , Winokur Patricia L. , Mahgoub Siham M. , Goepfert Paul A. , Fusco Dahlene N. , Malkin Elissa , Bethony Jeffrey M. , Walsh Edward E. , Graciaa Daniel S. , Samaha Hady , Sherman Amy C. , Walsh Stephen R. , Abate Getahun , Oikonomopoulou Zacharoula , El Sahly Hana M. , Martin Thomas C. S. , Kamidani Satoshi , Smith Michael J. , Ladner Benjamin G. , Porterfield Laura , Dunstan Maya , Wald Anna , Davis Tamia , Atmar Robert L. , Mulligan Mark J. , Lyke Kirsten E. , Posavad Christine M. , Meagher Megan A. , Stephens David S. , Neuzil Kathleen M. , Abebe Kuleni , Hill Heather , Albert Jim , Telu Kalyani , Mu Jinjian , Lewis Teri C. , Giebeig Lisa A. , Eaton Amanda , Netzl Antonia , Wilks Samuel H. , Türeli Sina , Makhene Mamodikoe , Crandon Sonja , Montefiori David C. , Makowski Mat , Smith Derek J. , Nayak Seema U. , Roberts Paul C. , Beigel John H. ,   the COVAIL Study Group, Walsh Edward , Kingsley Patrick , Steinmetz Kari , Peasley Michael , Ackerley Cassie Grimsley , Unterberger Kristen E. , Desrosiers Aimee , Siegel Marc , Tong Alexandra , Rooks Rebecca , Hoft Daniel F. , Graham Irene , Keitel Wendy A. , Healy C. Mary , Carter Nicole , Hendrickx Steven , Rostad Christina A. , Peters Etza , Nolan Lauren , Moody M. Anthony , Schmader Kenneth E. , Wendrow Andrea , Herrick Jessica , Lau Rebecca , Carste Barbara , Krause Taylor , Hauge Kirsten , Engelson Celia , Soma Vijaya , Harris Chloe , Lopez Azquena Munoz , Johnson Erica , Chan Austin , Ali Fatima , Parker Trisha , O’Halloran Jane A. , Thompson Ryley M. , Byrnes Kimberly , Noor Asif , Meier Jeffery , Stapleton Jack , Maxwell Celia , Shami Sarah , Drouin Arnaud C. , Numbi Florice K. , McElrath Julie , Gale Mike , Baughman Holly , McQuarrie Lisa , Engel Theresa M. , Griffith Caleb J. , McDonald Wendi L. , Burkey Alissa E. , Hoopengardner Lisa B. , Linton Jessica E. , Gettinger Nikki L. , Lee Marina , Elsafy Mohamed , Pikaart-Tautges Rhonda , Arega Janice , Hoang Binh , Dan Curtin  , Koo Hyung , Sindall Elisa , DeGrace Marciela M. , Post Diane J. , Stephens David S. , Neuzil Kathleen M. , Farley Monica M. , Marrazzo Jeanne , Young Sidnee Paschal , Lennox Jeffery , Atmar Robert L. , McNeil Linda , Brown Elizabeth 
Published: August 2023

AbstractVaccine 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.