[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
Adjuvanted H5N1 influenza vaccine enhances both cross-reactive memory B cell and strain-specific naive B cell responses in humans
Ali H. Ellebedy, Raffael Nachbagauer, Katherine J. L. Jackson, Ya-Nan Dai, Julianna Han, Wafaa B. Alsoussi, Carl W. Davis, Daniel Stadlbauer, Nadine Rouphael, Veronika Chromikova, Megan McCausland, Cathy Y. Chang, Mario Cortese, Mary Bower, Chakravarthy Chennareddy, Aaron J. Schmitz, Veronika I. Zarnitsyna, Lilin Lai, Arvind Rajabhathor, Cheyann Kazemian, Rustom Antia, Mark J. Mulligan, Andrew B. Ward, Daved H. Fremont, Scott D. Boyd, Bali Pulendran, Florian Krammer, and Rafi Ahmed
PNAS first published July 13, 2020 https://doi.org/10.1073/pnas.1906613117
Contributed by Rafi Ahmed, November 8, 2019 (sent for review April 19, 2019; reviewed by Robert L. Coffman and Marc K. Jenkins)
The development of a universal influenza vaccine is a major public health need globally, and identifying the optimal formulation will be an important first step for developing such a vaccine. Here we show that a two-dose immunization of humans with an inactivated, AS03-adjuvanted H5N1 avian influenza virus vaccine engaged both the preexisting memory and naive B cell compartments. Importantly, we show that the recruited memory B cells after first immunization were directed against conserved epitopes within the H5 HA stem region while the responses after the second immunization were mostly directed against strain-specific epitopes within the HA globular head. Taken together these findings have broad implications toward optimizing vaccination strategies for developing more effective vaccines against pandemic viruses.
There is a need for improved influenza vaccines. In this study we compared the antibody responses in humans after vaccination with an AS03-adjuvanted versus nonadjuvanted H5N1 avian influenza virus inactivated vaccine. Healthy young adults received two doses of either formulation 3 wk apart. We found that AS03 significantly enhanced H5 hemagglutinin (HA)-specific plasmablast and antibody responses compared to the nonadjuvanted vaccine. Plasmablast response after the first immunization was exclusively directed to the conserved HA stem region and came from memory B cells. Monoclonal antibodies (mAbs) derived from these plasmablasts had high levels of somatic hypermutation (SHM) and recognized the HA stem region of multiple influenza virus subtypes. Second immunization induced a plasmablast response to the highly variable HA head region. mAbs derived from these plasmablasts exhibited minimal SHM (naive B cell origin) and largely recognized the HA head region of the immunizing H5N1 strain. Interestingly, the antibody response to H5 HA stem region was much lower after the second immunization, and this suppression was most likely due to blocking of these epitopes by stem-specific antibodies induced by the first immunization. Taken together, these findings show that an adjuvanted influenza vaccine can substantially increase antibody responses in humans by effectively recruiting preexisting memory B cells as well as naive B cells into the response. In addition, we show that high levels of preexisting antibody can have a negative effect on boosting. These findings have implications toward the development of a universal influenza vaccine.
1 Present address: Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
2 Present address: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
3 Present address: Departments of Pathology, and Microbiology & Immunology, Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305.
4 Present address: Division of Infectious Diseases and Immunology, Department of Medicine, New York University, New York, NY 10016.
5 To whom correspondence may be addressed. Email: email@example.com.
Author contributions: A.H.E. and R. Ahmed designed research; A.H.E., R.N., Y.-N.D., J.H., W.B.A., D.S., N.R., V.C., M.M., C.Y.C., and C.K. performed research; K.J.L.J., M.C., M.B., C.C., A.J.S., L.L., A.R., M.J.M., A.B.W., D.H.F., S.D.B., B.P., and F.K. contributed new reagents/analytic tools; A.H.E., K.J.L.J., C.W.D., V.I.Z., R. Antia, D.H.F., and S.D.B. analyzed data; and A.H.E. and R. Ahmed wrote the paper.
Reviewers: R.L.C., University of California; and M.K.J., University of Minnesota.
The authors declare no competing interest.
Data deposition: Structures have been deposited in the Electron Microscopy Data Bank (accession codes: 1F03: EMD-20570 1H09: EMD-20571 1C01: EMD-20569) and BioProject Sequence Read Archive (accession no. PRJNA533650).
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1906613117/-/DCSupplemental. Published under the PNAS license.
Keywords: Avian Influenza; H5N1; Vaccines.