HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions

Abstract

Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ∼50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.

Genetic signatures of human cytomegalovirus variants acquired by seronegative glycoprotein B vaccinees

“…Furthermore, in 73 allograft recipients, the same gB vaccine reduced duration of HCMV viremia and antiviral therapy 74 (7). The mechanism of this partial vaccine protection remains unknown, though we and others 75 have observed this vaccine platform was particularly poor at eliciting heterologous neutralizing 76 antibodies in these populations and that non-neutralizing antibody responses may have played a 77 role (8,9). Previously, we reported population-level virus sequencing of HCMV hypervariable 78 genes in this cohort, revealing no differences in virus phylogeny between vaccinees and placebo 79 recipients (10).…”

“…Lastly, we observed an interesting trend that gB/MF59 vaccine recipients had reduced considering the genotypes identified by full gB ORF NGS, though not significant when considering viruses with genetic/antigenic similarity to the vaccine strain. Complementarily, we have observed 337 in the same gB/MF59 vaccinee cohort that gB-elicited neutralization activity was increased 338 against the autologous Towne strain virus, but not heterologous viruses AD169 and TB40/E (8).…”

Vaccine innovations for emerging infectious diseases—a symposium report

“…In a Phase 2 clinical trial, the CMV vaccine candidate gB/MF59 showed approximately 50% efficacy in preventing primary infection among postpartum women . Permar compared the vaccine‐elicited immune response to naturally CMV seropositive women and showed that gB/MF59 elicited negligible heterologous virus neutralization but robust nonneutralizing activity . Permar is looking at these immune correlates in other clinical trials with different populations to understand how patient factors affect vaccine response, and to define vaccine‐elicited immune correlates of protection.…”

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

“…Analysis of samples obtained from both postpartum and transplant-recipient gB vaccinees revealed two key observations regarding the target and function of gB-elicited antibody responses that inform our understanding of the partial vaccine efficacy. First, we identified that vaccination elicited an extraordinarily robust response against antigenic domain 3 (AD-3), a cytosolic non-neutralizing epitope in the C-terminal region of the protein [15]. Second, we noted that gB-specific antibodies elicited in postpartum women and transplant-recipients were predominantly non-neutralizing, suggesting that the mechanism of partial protection against viral acquisition was not the induction of neutralizing antibodies [15, 16].…”

“…First, we identified that vaccination elicited an extraordinarily robust response against antigenic domain 3 (AD-3), a cytosolic non-neutralizing epitope in the C-terminal region of the protein [15]. Second, we noted that gB-specific antibodies elicited in postpartum women and transplant-recipients were predominantly non-neutralizing, suggesting that the mechanism of partial protection against viral acquisition was not the induction of neutralizing antibodies [15, 16]. However, the protective non-neutralizing function remains unclear: we identified that gB/MF59 vaccinees had high-magnitude viral phagocytosis activity, though magnitude was not associated with infection status [15].…”