Vaccination with a replication-defective cytomegalovirus vaccine elicits a glycoprotein B-specific monoclonal antibody repertoire distinct from natural infection - PubMed (original) (raw)

doi: 10.1038/s41541-023-00749-0.

Eric Rochat 1, Melissa J Harnois 1, Maria Dennis 2, Helen S Webster 1, Bhavna Hora 1, Amit Kumar 1, Hsuan-Yuan Sherry Wang 1 2, Leike Li 3, Daniel Freed 4, Ningyan Zhang 3, Zhiqiang An 3, Dai Wang 4, Sallie R Permar 5

Affiliations

Vaccination with a replication-defective cytomegalovirus vaccine elicits a glycoprotein B-specific monoclonal antibody repertoire distinct from natural infection

Sarah M Valencia et al. NPJ Vaccines. 2023.

Abstract

Human Cytomegalovirus (HCMV) is the leading infectious congenital infection globally and the most common viral infection in transplant recipients, therefore identifying a vaccine for HCMV is a top priority. Humoral immunity is a correlate of protection for HCMV infection. The most effective vaccine tested to date, which achieved 50% reduction in acquisition of HCMV, was comprised of the glycoprotein B protein given with an oil-in-water emulsion adjuvant MF59. We characterize gB-specific monoclonal antibodies isolated from individuals vaccinated with a disabled infectious single cycle (DISC) CMV vaccine, V160, and compare these to the gB-specific monoclonal antibody repertoire isolated from naturally-infected individuals. We find that vaccination with V160 resulted in gB-specific antibodies that bound homogenously to gB expressed on the surface of a cell in contrast to antibodies isolated from natural infection which variably bound to cell-associated gB. Vaccination resulted in a similar breadth of gB-specific antibodies, with binding profile to gB genotypes 1-5 comparable to that of natural infection. Few gB-specific neutralizing antibodies were isolated from V160 vaccinees and fewer antibodies had identifiable gB antigenic domain specificity compared to that of naturally-infected individuals. We also show that glycosylation of gB residue N73 may shield binding of gB-specific antibodies.

© 2023. Springer Nature Limited.

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Conflict of interest statement

S.R.P consults for Merck, Pfizer, GSK, Moderna, Hoopika, and Dynavax CMV vaccine programs and led sponsored programs from Merck, Moderna, and Dynavax around CMV vaccine immunity. D.W and D.F are Merck employees. Other authors (S.M.V, L.L, N.Z, Z.A, E.R, M.J.H., M.D., H.S.W, A.K., B.H. and H-Y.W). declare that there are no competing interests.

Figures

Fig. 1

Fig. 1. Epitope domain mapping of gB-specific monoclonal antibodies isolated from V160 vaccinated individuals.

a Heat map of gB-specific monoclonal antibodies binding represented as EC50 ng/mL to FL gB Δ transmembrane domain (TM) or gB ectodomain. b Heat map of binding kinetics of gB-specific monoclonal antibodies measured by SPR (Kd (M)) to FL gB ΔTM. c Pi chart representing number of gB-specific monoclonal antibodies binding to specific gB domains measured by binding antibody multiplex assay. Out of either 24 total monoclonal antibodies from naturally infected (binding data from ref. ) or 29 monoclonal antibodies from V-160-vaccinated individuals (binding data in Supplementary Fig. 1). AD-3/MPER indicates binding to full length gB but not gB ectodomain. Conformational binding indicates binding to full length gB and gB ectodomain, but no other domain. d Diagram of gB antigenic domains.

Fig. 2

Fig. 2. HCMV gB-specific monoclonal antibodies isolated from V160-vaccinated individuals and naturally-infected individuals have similar gB genotype binding breadth.

ELISA measuring binding of gB-specific monoclonal antibodies from naturally infected individuals (a) or V160 vaccinated individuals (b) to gB ectodomain genotypes 1–5 with an EC50 < 1 ug/ml.

Fig. 3

Fig. 3. V160-vaccinated individuals produced gB-specific monoclonal antibodies with homogenous high binding to cell-associated gB.

a Cell associated binding of gB-specific mAbs from V160-vaccinated individuals. b Violin plot representing gB cell associate binding from gB mAbs isolated from naturally infected or V-160 vaccinated individuals. Data from naturally infected mAbs is from ref. . Dashed line represents median binding and dotted line represents quartile binding within each cohort. c mAb 13–929 uniquely binds to cell-associated gB, but poorly to FL gBΔTM and gB ectodomain genotype 1–5.

Fig. 4

Fig. 4. Glycosylation of N73 in the AD-2 site 1 region shields gB antibody binding.

a Table of gB-specific monoclonal antibody binding to FL gB ΔTM, gB ectodomain or gB ectodomain treated with PNGase F to remove N linked glycosylation and neutralizing titer NT50 (Neutralization titer is described in ref. ). b Figure representing N terminal gB indicating where the asparagines were mutated to glutamine by site directed mutagenisis. c ELISA showing binding of AD-2 site 1 potently neutralizing specific mAbs (TRL-345 and 3–25), 1–223, and 12–874 to gB ectodomain or gB ectodomain with asparagine mutated to glutamine at the indicated amino acid.

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