. 2023 Apr 10;77(4):560–564. doi: 10.1093/cid/ciad209

Immunogenicity of the BA.1 and BA.4/BA.5 Severe Acute Respiratory Syndrome Coronavirus 2 Bivalent Boosts: Preliminary Results From the COVAIL Randomized Clinical Trial

Angela R Branche ^1,¹, Nadine G Rouphael ^2,^1,^✉, Cecilia Losada ³, Lindsey R Baden ⁴, Evan J Anderson ⁵, Anne F Luetkemeyer ⁶, David J Diemert ⁷, Patricia L Winokur ⁸, Rachel M Presti ⁹, Angelica C Kottkamp ¹⁰, Ann R Falsey ¹¹, Sharon E Frey ¹², Richard Rupp ¹³, Martín Bäcker ¹⁴, Richard M Novak ¹⁵, Emmanuel B Walter ¹⁶, Lisa A Jackson ¹⁷, Susan J Little ¹⁸, Lilly C Immergluck ¹⁹, Siham M Mahgoub ²⁰, Jennifer A Whitaker ²¹, Tara M Babu ²², Paul A Goepfert ²³, Dahlene N Fusco ²⁴, Robert L Atmar ²⁵, Christine M Posavad ²⁶, Antonia Netzl ²⁷, Derek J Smith ²⁸, Kalyani Telu ²⁹, Jinjian Mu ³⁰, Mat Makowski ³¹, Mamodikoe K Makhene ³², Sonja Crandon ³³, David C Montefiori ³⁴, Paul C Roberts ³⁵, John H Beigel ^36,³

¹ Department of Medicine, University of Rochester VTEU, Rochester, New York, USA

² Department of Medicine, Emory University Hope Clinic, Decatur, Georgia, USA

³ Department of Medicine, Emory University Hope Clinic, Decatur, Georgia, USA

⁴ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

⁵ Center for Childhood Infections and Vaccines (CCIV) of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA

⁶ Zuckerberg San Francisco General, University of California San Francisco, San Francisco, California, USA

⁷ George Washington Vaccine Research Unit, George Washington University, Washington DC, USA

⁸ Department of Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA

⁹ Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

¹⁰ Department of Medicine, New York University (NYU) Vaccine and Treatment Evaluation Unit (VTEU) Manhattan Research Clinic at NYU Grossman School of Medicine, New York, New York, USA

¹¹ Department of Medicine, University of Rochester VTEU, Rochester, New York, USA

¹² Saint Louis University, Center for Vaccine Development, St. Louis, Missouri, USA

¹³ Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA

¹⁴ Department of Medicine, NYU VTEU Long Island Research Clinic at NYU Long Island School of Medicine, Mineola, New York, USA

¹⁵ Department of Medicine, University of Illinois at Chicago-Project WISH, Chicago, Illinois, USA

¹⁶ Department of Pediatrics, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA

¹⁷ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA

¹⁸ Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, California, USA

¹⁹ Department of Microbiology/Biochemistry/Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA

²⁰ Department of Medicine, Howard University College of Medicine, Howard University Hospital, Washington DC, USA

²¹ Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas, USA

²² Departments of Medicine, Epidemiology, and Laboratory Medicine & Pathology, University of Washington, Vaccines and Infectious Diseases Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA

²³ Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

²⁴ Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA

²⁵ Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas, USA

²⁶ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center and Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA

²⁷ Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom

²⁸ Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom

²⁹ The Emmes Company, LLC, Rockville, Maryland, USA

³⁰ The Emmes Company, LLC, Rockville, Maryland, USA

³¹ The Emmes Company, LLC, Rockville, Maryland, USA

³² Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

³³ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

³⁴ Department of Surgery, Duke University, Durham, North Carolina, USA

³⁵ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

³⁶ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

Angela R. Branche and Nadine G. Rouphael joint co-authors.

^✉

Correspondence: Nadine G. Rouphael, Department of Medicine, Emory University, Hope Clinic, Emory Vaccine Center, 500 Irvin Ct, Ste 200, Decatur, GA, 30030, USA. (nroupha@emory.edu).

Potential conflicts of interest. E. J. A. has received grants from Pfizer, Moderna, Janssen, GSK, Sanofi, Micron, and Regeneron through institution as well as consulting fees from Pfizer, Janssen, Moderna, and Sanofi. E. J. A. serves on safety/advisory boards for Sanofi, ACI Clinical/WCG and Kentucky Bioscience, Inc. A. R. B. has received research support from NIH-NIAID, grants from Pfizer, Cyanvac, and Merck as well as consulting fees from Janssen and GSK. L. R. B. has received grants from Wellcome Trust, Gates Foundation, NIH/Harvard Medical School through institution. Serves as member of DSMB for NIH and AMDAC for Food and Drug Administration (FDA). L. R. B. is involved in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), COVID Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School. D. J. D. has received a contract from Leidos Biomedical research to conduct the clinical trial through institution. A. R. F. has received grants from Janssen, Pfizer, Merck, BioFire Diagnostics, and CyanVac through institution, consultant fees from Arrowhead and Icosavax, and honoraria as a speaker from Moderna and GlaxoSmithKline. A. R. F. also serves on safety/advisory boards for Novavax and received travel/meeting support from GlaxoSmithKline. S. E. F. has received funding from Leidos to Saint Louis University to conduct Protocol DMID22-0004. D. N. F. has as a contract from Centers for Disease Control and Prevention (CDC) and is the site principal investigator (PI) for clinical trials from Gilead, Regeneron, and MetroBiotech, LLC. She is the PI on 1 investigator-initiated award from Gilead and the co-PI on another investigator-initiated award from Gilead. D. N. F. served on an HBV Advisory board for Gilead in 2021 and received payment for expert testimony not related to COVID in 2022. P. A. G. has received funding for COVAIL clinical trial. P. A. G. has also received consulting fees from Janssen Vaccines. L. C. I. has received support for the present manuscript from NIH-NIAID/DMID, Moderna, Pfizer, and Sanofi. L. C. I. has also received grants from GSK, Merck, Sharpe & Dohme Corp, CDC, Novavax, AHRQ, and NIH/NLM/NIMHD as well as consulting fees from Moderna, CDC, and Pediatric Emergency Medicine Associates, LLC. L. C. I. has received honoraria as a speaker from American Academy of Pediatrics, Rockefeller University, and American Academy of Pediatrics- Georgia Chapter. L. C. I. serves on Data Safety Monitoring for NIH-Phase 2 Vaccine Trial for Monkeypox, Moderna Scientific Advisory Board- North America, and COVID-19 Task Force, Georgia. L. C. I. has a leadership role in the Pediatric Infectious Disease Society, serves as board member on the Emory University- Pediatric and Reproductive Environmental Health Scholars-Southeastern, the Center for Spatial Analytics of the Georgia Institute of Technology, and the American Academy of Pediatrics (Executive Board for Section on Infectious Diseases). L. C. I. has received travel/meeting support from the American Academy of Pediatrics and Moderna. L. A. J. has received funding from NIH for support for this study, funding from Pfizer to support a clinical trial and contract funding for research support from the CDC and the NIH, all through institution. L. A. J. also reports unpaid participation on Data Safety Monitoring Boards for NIH funded clinical trials. S. J. L. has received NIH grants through institution. A. F. L. has received grants from Merck, Gilead, and ViiV through institution as well as consulting fees from Vir Biotechnology. A. F. L. has also received travel support from Merck to attend a required investigator meeting, testing kits and supplies to support research study from Hologic, and medication donated by Mayne Pharma to support research study. M. M. has received funding from Division of Microbiology and Infectious Diseases for contract number 75N93021C00012. 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 Division of Microbiology and Infectious Diseases, contract number 75N93021C00012. A. N. has received support from NIH-NIAID, CEIRR (Centers of Excellence for Influenza Research and Response) and Gates Cambridge Trust as well as grants from NIH-NIAID R01. R. M. N. has received grants from Moderna and Janssen and travel/meeting support from Moderna. C. M. P. has received funding from NIAID UM1AI148684. R. M. P. has received funding from NIH DMID COVAIL as well as grants from Janssen, Moderna, and NIH through institution. N. G. R. has received research grants from Pfizer, Merck, Sanofi, Quidel, and Lilly through institution, consulting fees from Krog, honoraria as speaker for Virology education, and travel support from Sanofi. N. G. R. serves on safety committees for ICON and EMMES and is a member of the Moderna Advisory board. D. J. S. has received support from NIH-NIAID CEIRR, grants from NIH-NIAID R01, and travel support from NIH-NIAID CEIRR for NIH-related meetings. K. T. has received funding from Division of Microbiology and Infectious Diseases contract number 75N93021C00012. E. B. W. has received funding from Leidos Biomedical Research agreement number. 22CTA-DM0009 as well as grants from Pfizer, Moderna, Sequiris, Clinetic, and Najit Technologies, with payments made to institution. E. B. W. has also received honoraria as a speaker from College of Diplomates of the American Board of Pediatric Dentistry, consulting fees from Iliad Biotechnologies, and travel/meeting support from the American Academy of Pediatrics. E. B. W. serves as member of Vaxcyte Scientific Advisory board. P. L. W. has received subcontract funding from NIH for this study as well as NIH grant funding and contract funding from Pfizer through University of Iowa. P. L. W. has also received consulting fees from Pfizer and serves on safety/advisory board for Emmes Corporation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

PMCID: PMC10443997 PMID: 37036397

Abstract

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Keywords: SARS-CoV-2, variant, vaccine

The emergence of Omicron subvariants and waning immunity led to the authorization in various countries of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) bivalent vaccines that combine wildtype (ancestral) spike and either Omicron BA.1 or BA.4/BA.5 spike [1, 2]. Currently, the predominant circulating Omicron subvariants contain key mutations in the spike protein receptor binding domain (eg, R346T) that enhance viral escape from neutralizing antibodies. The Coronavirus Variant Immunologic Landscape Trial (COVAIL) is an adaptive phase 2, open-label, randomized clinical trial assessing the immunogenicity of variant-containing SARS-CoV-2 vaccines, from different platforms, in previously vaccinated adults. Here we describe results from stage 4, where participants were randomized to a second boost with either the bivalent Pfizer/BioNTech BNT162b2 Wildtype/Omicron BA.1 vaccine or Wildtype/Omicron BA.4/BA.5 vaccine to determine their ability to produce antibodies that neutralize past and contemporaneous variants.

METHODS

Study Design and Eligibility Criteria

The study was performed at US sites (Supplementary Table 1), enrolling participants in October 2022. Eligible persons were healthy adults between the ages of 18 and 49 years of age (with or without prior SARS-CoV-2 infection) who had received a primary series and a single boost with an approved or emergency use authorized wild-type coronavirus disease 2019 (COVID-19) vaccine (Supplementary Table 2) confirmed by a review of their vaccination card. The most recent vaccination and prior infection, if applicable, must have occurred at least 16 weeks prior to randomization. Full eligibility criteria are described at clinicaltrials.gov (NCT 05289037).

After providing written informed consent, participants underwent screening, including medical history, a targeted physical examination, and a urine pregnancy test (if indicated). Eligible participants were randomly assigned to 1 of 2 vaccines in a 1:1 ratio, and immunogenicity samples were collected pre-vaccination (day 1) and after vaccination on days 15 and 29, and 3, 6, 9, and 12 months. Intercurrent SARS-CoV-2 infections were collected by passive surveillance. The trial was reviewed and approved by a central institutional review board and overseen by an independent Data and Safety Monitoring Board. The trial was sponsored and funded by the National Institutes of Health.

Trial Vaccine

The bivalent Pfizer/BioNTech BNT162b2 Wildtype/Omicron BA.1 and Wildtype/Omicron BA.4/BA.5 vaccines were provided by Pfizer BioNTech (total amount of 30 mcg messenger RNA [mRNA] per vaccine; 15 mcg for each strain). The vaccine candidates are manufactured similarly to their corresponding authorized/approved vaccines.

Study Outcomes

The primary objective was to evaluate humoral immune responses of candidate SARS-CoV-2 variant vaccines. The secondary objective was to evaluate the safety of these vaccines assessed by solicited injection site and systemic adverse events (AEs), which were collected for 7 days after vaccination; unsolicited AEs through day 29; and serious adverse events (SAEs), new-onset chronic medical conditions (NOCMCs), adverse events of special interest (AESIs), AEs leading to withdrawal, and medically attended adverse events (MAAEs) through the duration of the trial. Safety and immnologic data are currently available through days 29 and 91.

Immunogenicity Assays

SARS-CoV-2 neutralization titers, expressed as the serum inhibitory dilution required for 50% neutralization (ID₅₀), were assessed at baseline and at days 15, 29 and 91, as described previously, using pseudotyped lentiviruses [3, 4] presenting SARS-CoV-2 spike mutations for different strains. All samples (101 per vaccine arm) were tested in a commercial lab (Monogram Biosciences, California, USA) for the following variants: the D614G (Wuhan-1 containing a single D614G spike mutation), B.1.617.2, B.1.351, B.1.1.529 (Omicron BA.1) and Omicron BA.4/BA.5. Omicron BQ.1.1 and Omicron XBB.1 neutralization titers were assessed on a random subset of 25 samples per vaccine arm, distributed roughly equally between previously infected and uninfected participants in the Montefiori Lab at Duke University. Electrochemiluminescence immunoassays (ELECSYS) were used for the detection of anti-nucleocapsid (N) (N-ELECSYS; Elecsys Anti-SARS-CoV-2 N, Roche, Indianapolis, Indiana, USA) at baseline [5].

Statistical Analysis of Immunogenicity Endpoints

The primary objective of this study is to evaluate the magnitude, breadth, and durability of SARS-CoV-2 specific immune responses measured by geometric mean antibody titers (GMT) with associated 95% confidence intervals (CI). No formal hypothesis tests were planned. The geometric mean fold rise (GMFR) is calculated as the geometric mean of titers at a timepoint divided by titers at day 1. The geometric mean ratio to D614G (GMR_D614G) is the ratio of the GMTs for a variant of concern to titers against D614G. The GMFD was calculated by dividing the result at Day 29 by the result of D91 and then calculating the geometric mean. Seropositivity rate is calculated as the proportion of participants with titers above the lower limit of detection (LLOD). The 95% CI for GMT, GMFR, and GMR_D614G are calculated using the Student t-distribution, and the 95% CI is calculated using the Clopper-Pearson binomial method. For analysis, participants were defined as previously infected by self-report of a confirmed positive antigen or polymerase chain reaction (PCR) test or by a positive anti-nucleocapsid (N) antibody test at enrollment. Participants with COVID-19 occurring between vaccination and a pre-specified immunogenicity timepoint were excluded from the immunogenicity analyses at all timepoints post infection.

RESULTS

Study Population

Previously vaccinated and boosted participants were enrolled between 4 and 28 October 2022 and received either the bivalent Pfizer/BioNTech BNT162b2 Wildtype/Omicron BA.1 (n = 101) or Wildtype/Omicron BA.4/BA.5 vaccines (n = 101). Baseline characteristics were similar between the 2 study arms (Supplementary Table 3). Median age was 31 years (range: 18–49). The majority of participants (93% per arm) had received an mRNA-based primary series and boost vaccine. At enrollment, 77% were defined as previously infected by anti-N antibody seropositivity at baseline and/or by self-reported positive SARS-CoV-2 testing (Supplementary Table 3). Median duration (range) between study vaccination and the last previous vaccination or infection was 293 (112–585) days.

Safety

Solicited local and systemic AEs after vaccination were similar to other booster trials [6] and did not differ between arms (94% for the Wildtype/Omicron BA.1 arm and 92% for the Wildtype/Omicron BA.4/BA.5 arm). The most frequently reported solicited local AE was injection-site pain (80%). The most common solicited systemic AEs were fatigue (68%) and myalgia (53%). Most solicited AEs were mild to moderate; only 1% of local AEs (induration/swelling), and 3% of systemic AEs (predominantly headache and fatigue in addition to fever, arthralgia, myalgia) in 7 participants were graded as severe. There were no AESI, SAEs, or AEs leading to withdrawal from the study at the time of interim analysis (Supplementary Figures 1 and 2 and Supplementary Tables 10–12).

Neutralizing Antibody Responses

All participants were seropositive against all variants after the boost, with titers peaking at Day 15 for all variants except D614G, which peaked at Day 29 (Figure 1). At day 15, ID₅₀ GMTs in the Wildtype/Omicron BA.1 arm were numerically similar (with overlapping confidence intervals) to corresponding titers in the Wildtype/Omicron BA.4/BA.5 arm for D614G (ID₅₀ 27 000 vs 34 109), BA.1 (ID₅₀ 6506 vs 6603), B.1.351 (ID₅₀ 15 183 vs 19 265) and B.1.617.2 (ID₅₀ 14 362 vs 18 332). However, day 15 titers against Omicron BA.4/BA.5 were >1.5 higher with the Wildtype/Omicron BA.4/BA.5 (GMT_BA.4/BA.5 = 5939) compared to titers after vaccination with the Wildtype/Omicron BA.1 vaccine (GMT_BA.4/BA.5 = 3546) (Figure 1, Supplementary Tables 4–7). Similar findings were observed at Day 29. The geometric mean fold drop in titers at Day 91 was similar for both the Wildtype/Omicron BA.1 and Wildtype/Omicron BA.4/BA.5 vaccines, and lowest against Omicron BA.1 (1.3,1.4) and BA.4/BA.5 (1.5,1.4) when compared to D614G, B.1.351 and B.1.617.2 (Supplementary Tables 4 and 5), though numerically higher against BA.4/BA.5 for the Wildtype/Omicron BA.4/BA.5 vaccine (GMT 2067 vs 3842) (Supplementary Tables 4 and 5). Titers from participants without a history of prior infection were lower at all timepoints (Supplementary Tables 6 and 7) than those with hybrid immunity (Supplementary Tables 4 and 5).

Titers against all Omicron subvariants were lower than against D614G; the lowest titers were observed against XBB.1 (Figure 1). Notably, titers against BQ.1.1 and XBB.1 were similar between the two arms (with overlapping confidence intervals). Titers against BQ.1.1 and XBB.1 were 8–22 times and 13–35 times lower than against BA.1 and D614G, respectively, with the Wildtype/Omicron BA.1 vaccine. Titers against BQ.1.1 and XBB.1 were 4–12 times and 8–22 times lower than against BA.4/BA.5 and D614G, respectively, with the Wildtype/Omicron BA.4/BA.5 vaccine (Figure 1, Supplementary Tables 8 and 9).

DISCUSSION

Our study is the only randomized trial to date to report results from a head-to-head comparison of the 2 mRNA Wildtype/Omicron (BA.1 or BA.4/BA.5) bivalent vaccines currently authorized worldwide as a boost in individuals previously immunized with a first generation COVID-19 vaccine series. Our early immunogenicity results demonstrate better neutralization against BA.4/BA.5 with the Wildtype/Omicron BA.4/BA.5 vaccine. However, there was increasing neutralization escape with the late 2022 Omicron subvariants (BQ.1.1 and XBB.1). This escape is similar between the two bivalent vaccines as demonstrated by numerically similar GMTs with overlapping confidence intervals, even though BA.1 and BA.4/BA.5 spike sequences are known to have different mutations in the receptor binding domain [7].

Although modest serologic advantages to Omicron BA.1 and BA.4/BA.5 have been previously reported with bivalent compared to wildtype vaccines [8], we do not currently have precise immune correlates of protection for emerging variants. Moreover, we did not evaluate the immunogenicity of the wildtype vaccine because this vaccine is no longer recommended as a boost in the United States. We conducted passive surveillance for SARS-CoV-2 intercurrent infections, and some cases could have been missed that could confound our immunogenicity results. These early preliminary results also do not address durability beyond 3 months and the conclusions about protection are limited by the small sample size. Finally, serologic data from timepoints up to 1 year after vaccination, and cellular responses, which are known to influence disease severity, are also pending.

However, our findings highlight ongoing concern that the breadth of antibody response from current updated vaccines is not optimal for the pace of virus evolution. Consequently, although early vaccine effectiveness (VE) data with bivalent vaccines have emerged [9, 10], continuous surveillance is crucial to assess for potential VE waning.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Supplementary Material

ciad209_Supplementary_Data

Click here for additional data file.^{(767.8KB, docx)}

Contributor Information

Angela R Branche, Department of Medicine, University of Rochester VTEU, Rochester, New York, USA.

Nadine G Rouphael, Department of Medicine, Emory University Hope Clinic, Decatur, Georgia, USA.

Cecilia Losada, Department of Medicine, Emory University Hope Clinic, Decatur, Georgia, USA.

Lindsey R Baden, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Evan J Anderson, Center for Childhood Infections and Vaccines (CCIV) of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.

Anne F Luetkemeyer, Zuckerberg San Francisco General, University of California San Francisco, San Francisco, California, USA.

David J Diemert, George Washington Vaccine Research Unit, George Washington University, Washington DC, USA.

Patricia L Winokur, Department of Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA.

Rachel M Presti, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Angelica C Kottkamp, Department of Medicine, New York University (NYU) Vaccine and Treatment Evaluation Unit (VTEU) Manhattan Research Clinic at NYU Grossman School of Medicine, New York, New York, USA.

Ann R Falsey, Department of Medicine, University of Rochester VTEU, Rochester, New York, USA.

Sharon E Frey, Saint Louis University, Center for Vaccine Development, St. Louis, Missouri, USA.

Richard Rupp, Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.

Martín Bäcker, Department of Medicine, NYU VTEU Long Island Research Clinic at NYU Long Island School of Medicine, Mineola, New York, USA.

Richard M Novak, Department of Medicine, University of Illinois at Chicago-Project WISH, Chicago, Illinois, USA.

Emmanuel B Walter, Department of Pediatrics, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.

Lisa A Jackson, Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.

Susan J Little, Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, California, USA.

Lilly C Immergluck, Department of Microbiology/Biochemistry/Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA.

Siham M Mahgoub, Department of Medicine, Howard University College of Medicine, Howard University Hospital, Washington DC, USA.

Jennifer A Whitaker, Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas, USA.

Tara M Babu, Departments of Medicine, Epidemiology, and Laboratory Medicine & Pathology, University of Washington, Vaccines and Infectious Diseases Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.

Paul A Goepfert, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Dahlene N Fusco, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

Robert L Atmar, Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas, USA.

Christine M Posavad, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center and Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

Antonia Netzl, Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.

Derek J Smith, Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom.

Kalyani Telu, The Emmes Company, LLC, Rockville, Maryland, USA.

Jinjian Mu, The Emmes Company, LLC, Rockville, Maryland, USA.

Mat Makowski, The Emmes Company, LLC, Rockville, Maryland, USA.

Mamodikoe K Makhene, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Sonja Crandon, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

David C Montefiori, Department of Surgery, Duke University, Durham, North Carolina, USA.

Paul C Roberts, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

John H Beigel, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Notes

Acknowledgments. The authors would like to thank all participants who contributed to the study and the NIAID SARS-CoV-2 Assessment of Viral Evolution (SAVE) program team for their consultation regarding the study arm design and variant vaccine selection.

Financial support. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024 Task Order No. 75N91022F00007 and for EMMES LLC under Division of Microbiology and Infectious Diseases contract # 75N93021C00012. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

References

1.European Medicines Agency. EMA/117973/2021 - Reflection paper on the regulatory requirements for vaccines intended to provide protection against variant strain(s) of SARS-CoV-2. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-regulatory-requirements-vaccines-intended-provide-protection-against-variant_en.pdf. Accessed February 2023.
2.U.S. Food and Drug Administration, COVID-19 Vaccines webpage. Available at: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines. Accessed February 2023.
3. Shen X, Chalkias S, Feng J, et al. . Neutralization of SARS-CoV-2 Omicron BA.2.75 after mRNA-1273 vaccination. N Engl J Med 2022; 387:1234–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Huang Y, Borisov O, Kee JJ, et al. . Calibration of two validated SARS-CoV-2 pseudovirus neutralization assays for COVID-19 vaccine evaluation. Sci Rep 2021; 11:23921. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Sridhar S, Joaquin A, Bonaparte MI, et al. . Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study. Lancet Infect Dis 2022; 22:636–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Atmar RL, Lyke KE, Deming ME, et al. . Homologous and heterologous Covid-19 booster vaccinations. N Engl J Med 2022; 386:1046–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Shrestha LB, Foster C, Rawlinson W, Tedla N, Bull RA. Evolution of the SARS-CoV-2 omicron variants BA.1 to BA.5: implications for immune escape and transmission. Rev Med Virol 2022; 32:e2381. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Winokur P, Gayed J, Fitz-Patrick D, et al. . Bivalent omicron BA.1-adapted BNT162b2 booster in adults older than 55 years. N Engl J Med 2023; 388:214–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Andersson NW, Thiesson EM, Baum U, et al. . Comparative effectiveness of the bivalent BA.4-5 and BA.1 mRNA-booster vaccines in the Nordic countries. medRxiv. 2023:2023.2001.2019.23284764. [Google Scholar]
10. Link-Gelles R, Ciesla AA, Fleming-Dutra KE, et al. . Effectiveness of bivalent mRNA vaccines in preventing symptomatic SARS-CoV-2 infection—increasing community access to testing program, United States, September-November 2022. MMWR Morb Mortal Wkly Rep 2022; 71:1526–30. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ciad209_Supplementary_Data

Click here for additional data file.^{(767.8KB, docx)}

PERMALINK

Immunogenicity of the BA.1 and BA.4/BA.5 Severe Acute Respiratory Syndrome Coronavirus 2 Bivalent Boosts: Preliminary Results From the COVAIL Randomized Clinical Trial

Angela R Branche

Nadine G Rouphael

Cecilia Losada

Lindsey R Baden

Evan J Anderson

Anne F Luetkemeyer

David J Diemert

Patricia L Winokur

Rachel M Presti

Angelica C Kottkamp

Ann R Falsey

Sharon E Frey

Richard Rupp

Martín Bäcker

Richard M Novak

Emmanuel B Walter

Lisa A Jackson

Susan J Little

Lilly C Immergluck

Siham M Mahgoub

Jennifer A Whitaker

Tara M Babu

Paul A Goepfert

Dahlene N Fusco

Robert L Atmar

Christine M Posavad

Antonia Netzl

Derek J Smith

Kalyani Telu

Jinjian Mu

Mat Makowski

Mamodikoe K Makhene

Sonja Crandon

David C Montefiori

Paul C Roberts

John H Beigel