Abstract
This study demonstrates the impact of adjuvant on the development of T follicular helper (Tfh) and B cells, and their influence on antibody responses in mice vaccinated with SARS-CoV-2-spike-ferritin-nanoparticle (SpFN) adjuvanted with either Army Liposome Formulation containing QS-21 (SpFN + ALFQ) or Alhydrogel® (SpFN + AH). SpFN + ALFQ increased the size and frequency of germinal center (GC) B cells in the vaccine-draining lymph nodes and increased the frequency of antigen-specific naive B cells. A single vaccination with SpFN + ALFQ resulted in a higher frequency of IL-21-producing-spike-specific Tfh and GC B cells in the draining lymph nodes and spleen, S-2P protein-specific IgM and IgG antibodies, and elicitation of robust cross-neutralizing antibodies against SARS-CoV-2 variants as early as day 7, which was enhanced by a second vaccination. This was associated with the generation of high titer, high avidity binding antibodies. The third vaccination with SpFN + ALFQ elicited high levels of neutralizing antibodies against the Omicron variant. No cross-neutralizing antibodies against Omicron were induced with SpFN + AH. These findings highlight the importance of ALFQ in orchestrating early induction of antigen-specific Tfh and GC B cell responses and long-lived plasma cells in the bone marrow. The early engagement of S-2P specific naive B cells and high titer IgM antibodies shape the development of long-term neutralization breadth.
| Original language | English |
|---|---|
| Article number | 43 |
| Journal | npj Vaccines |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
| Externally published | Yes |
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SARS-CoV-2 spike-ferritin-nanoparticle adjuvanted with ALFQ induces long-lived plasma cells and cross-neutralizing antibodies. / Shrivastava, Shikha; Carmen, Joshua M.; Lu, Zhongyan et al.
In: npj Vaccines, Vol. 8, No. 1, 43, 12.2023.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - SARS-CoV-2 spike-ferritin-nanoparticle adjuvanted with ALFQ induces long-lived plasma cells and cross-neutralizing antibodies
AU - Shrivastava, Shikha
AU - Carmen, Joshua M.
AU - Lu, Zhongyan
AU - Basu, Shraddha
AU - Sankhala, Rajeshwer S.
AU - Chen, Wei Hung
AU - Nguyen, Phuong
AU - Chang, William C.
AU - King, Jocelyn
AU - Corbitt, Courtney
AU - Mayer, Sandra
AU - Bolton, Jessica S.
AU - Anderson, Alexander
AU - Swafford, Isabella
AU - Terriquez, Guillermo D.
AU - Trinh, Hung V.
AU - Kim, Jiae
AU - Jobe, Ousman
AU - Paquin-Proulx, Dominic
AU - Matyas, Gary R.
AU - Gromowski, Gregory D.
AU - Currier, Jeffrey R.
AU - Bergmann-Leitner, Elke
AU - Modjarrad, Kayvon
AU - Michael, Nelson L.
AU - Joyce, M. Gordon
AU - Malloy, Allison M.W.
AU - Rao, Mangala
N1 - Funding Information: We thank Mr. Manuel Lopez for assisting with the mice vaccinations, bleeds and organ collections. We thank Histowiz for the immunohistochemistry staining of the mice lymph node section. Mouse anti-RBD monoclonal antibody was produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Spike Glycoprotein Receptor Binding Domain (RBD) from SARS-Related Coronavirus 2, Wuhan-Hu-1 with C-Terminal Histidine Tag, Recombinant from HEK293F Cells, NR-52366. This work was supported by Restoral FY20 funds from the US Department of Defense, Defense Health Agency. USUHS Department of Pediatrics RAMP grants PED-86-10342 and NIH R01 AI154619. This work was also partially executed through a cooperative agreement between the US Department of Defense and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (W81XWH-18-2-0040). The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of USUHS, the US Air Force, the US Army, the US Navy, the US military at large, or the US Department of Defense. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a “United States Government work” as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties Funding Information: We thank Mr. Manuel Lopez for assisting with the mice vaccinations, bleeds and organ collections. We thank Histowiz for the immunohistochemistry staining of the mice lymph node section. Mouse anti-RBD monoclonal antibody was produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Spike Glycoprotein Receptor Binding Domain (RBD) from SARS-Related Coronavirus 2, Wuhan-Hu-1 with C-Terminal Histidine Tag, Recombinant from HEK293F Cells, NR-52366. This work was supported by Restoral FY20 funds from the US Department of Defense, Defense Health Agency. USUHS Department of Pediatrics RAMP grants PED-86-10342 and NIH R01 AI154619. This work was also partially executed through a cooperative agreement between the US Department of Defense and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (W81XWH-18-2-0040). The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of USUHS, the US Air Force, the US Army, the US Navy, the US military at large, or the US Department of Defense. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a “United States Government work” as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties Funding Information: The construction of the various plasmids and the neutralization assay have been described in detail. The S expression plasmid sequences for SARS-CoV-2 [Wuhan1, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529/BA.1 (Omicron)] were codon optimized and modified to remove an 18 amino acid endoplasmic reticulum retention signal in the cytoplasmic tail, which allowed increased S incorporation into pseudovirions (PSV) and thereby improved infectivity. Virions pseudotyped with the vesicular stomatitis virus (VSV) G protein were used as a nonspecific control. SARS-CoV-2 pseudovirions (PSV) were produced by co-transfection of HEK293T/17 cells with a SARS-CoV-2 S plasmid (pcDNA3.4) and HIV-1 NL4-3 luciferase reporter plasmid (The reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: Human Immunodeficiency Virus 1 (HIV-1) NL4-3 DEnv Vpr Luciferase Reporter Vector (pNL4- 3.Luc.R-E-), ARP-3418, contributed by Dr. Nathaniel Landau and Aaron Diamond). The SARS-CoV-2 S expression plasmid sequence was derived from the Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1, complete genome (GenBank: MN908947). Infectivity and neutralization titers were determined using ACE2-expressing HEK293 target cells (Integral Molecular) in a semiautomated assay format using robotic liquid handling (Biomek NXp Beckman Coulter). Test sera were diluted 1:40 in growth medium and 3-fold serially diluted; then 25 mL/well was added to a white 96-well plate followed by the addition of an equal volume of diluted SARS-CoV-2 PSV to each well. The plates were incubated for 1 h at 37 °C. Target cells were added to each well (40,000 cells/well) and plates were incubated for an additional 48 h in a CO incubator at 37 °C. RLUs were measured with the EnVision Multimode Plate Reader (Perkin Elmer, Waltham, MA) using the Bright-Glo Luciferase Assay System (Promega Corporation, Madison, WI). Neutralization dose–response curves were fitted by nonlinear regression with a five-parameter curve fit using the LabKey Server and the final titers are reported as the reciprocal of the dilution of serum necessary to achieve 50% neutralization (ID50, 50% inhibitory dilution) and 80% neutralization (ID80, 80% inhibitory dilution). The horizontal black dotted lines in the Figures represent the lower limit of detection for the assay. Assay equivalency for SARS-CoV-2 was established by participation in the SARS-CoV-2 Neutralizing Assay Concordance Survey (SNACS) run by the Virology Quality Assurance Program and External Quality Assurance Program Oversite Laboratory (EQAPOL) at the Duke Human Vaccine Institute, sponsored through programs supported by the National Institute of Allergy and Infectious Diseases, Division of AIDS. 2 Publisher Copyright: © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/12
Y1 - 2023/12
N2 - This study demonstrates the impact of adjuvant on the development of T follicular helper (Tfh) and B cells, and their influence on antibody responses in mice vaccinated with SARS-CoV-2-spike-ferritin-nanoparticle (SpFN) adjuvanted with either Army Liposome Formulation containing QS-21 (SpFN + ALFQ) or Alhydrogel® (SpFN + AH). SpFN + ALFQ increased the size and frequency of germinal center (GC) B cells in the vaccine-draining lymph nodes and increased the frequency of antigen-specific naive B cells. A single vaccination with SpFN + ALFQ resulted in a higher frequency of IL-21-producing-spike-specific Tfh and GC B cells in the draining lymph nodes and spleen, S-2P protein-specific IgM and IgG antibodies, and elicitation of robust cross-neutralizing antibodies against SARS-CoV-2 variants as early as day 7, which was enhanced by a second vaccination. This was associated with the generation of high titer, high avidity binding antibodies. The third vaccination with SpFN + ALFQ elicited high levels of neutralizing antibodies against the Omicron variant. No cross-neutralizing antibodies against Omicron were induced with SpFN + AH. These findings highlight the importance of ALFQ in orchestrating early induction of antigen-specific Tfh and GC B cell responses and long-lived plasma cells in the bone marrow. The early engagement of S-2P specific naive B cells and high titer IgM antibodies shape the development of long-term neutralization breadth.
AB - This study demonstrates the impact of adjuvant on the development of T follicular helper (Tfh) and B cells, and their influence on antibody responses in mice vaccinated with SARS-CoV-2-spike-ferritin-nanoparticle (SpFN) adjuvanted with either Army Liposome Formulation containing QS-21 (SpFN + ALFQ) or Alhydrogel® (SpFN + AH). SpFN + ALFQ increased the size and frequency of germinal center (GC) B cells in the vaccine-draining lymph nodes and increased the frequency of antigen-specific naive B cells. A single vaccination with SpFN + ALFQ resulted in a higher frequency of IL-21-producing-spike-specific Tfh and GC B cells in the draining lymph nodes and spleen, S-2P protein-specific IgM and IgG antibodies, and elicitation of robust cross-neutralizing antibodies against SARS-CoV-2 variants as early as day 7, which was enhanced by a second vaccination. This was associated with the generation of high titer, high avidity binding antibodies. The third vaccination with SpFN + ALFQ elicited high levels of neutralizing antibodies against the Omicron variant. No cross-neutralizing antibodies against Omicron were induced with SpFN + AH. These findings highlight the importance of ALFQ in orchestrating early induction of antigen-specific Tfh and GC B cell responses and long-lived plasma cells in the bone marrow. The early engagement of S-2P specific naive B cells and high titer IgM antibodies shape the development of long-term neutralization breadth.
UR - http://www.scopus.com/inward/record.url?scp=85150880920&partnerID=8YFLogxK
U2 - 10.1038/s41541-023-00638-6
DO - 10.1038/s41541-023-00638-6
M3 - Article
AN - SCOPUS:85150880920
SN - 2059-0105
VL - 8
JO - npj Vaccines
JF - npj Vaccines
IS - 1
M1 - 43
ER -