Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies

Abstract

Human cytomegalovirus (HCMV) is an important pathogen in transplant patients and in congenital infection. Previously, we demonstrated that vaccination with a recombinant viral glycoprotein B (gB)/MF59 adjuvant formulation before solid organ transplant reduced viral load parameters post transplant. Reduced posttransplant viremia was directly correlated with antibody titers against gB consistent with a humoral response against gB being important. Here we show that sera from the vaccinated seronegative patients displayed little evidence of a neutralizing antibody response against cell-free HCMV in vitro. Additionally, sera from seronegative vaccine recipients had minimal effect on the replication of a strain of HCMV engineered to be cell-associated in a viral spread assay. Furthermore, although natural infection can induce antibody-dependent cellular cytotoxicity (ADCC) responses, serological analysis of seronegative vaccinees again presented no evidence of a substantial ADCC-promoting antibody response being generated de novo. Finally, analyses for responses against major antigenic domains of gB following vaccination were variable, and their pattern was distinct compared with natural infection. Taken together, these data argue that the protective effect elicited by the gB vaccine is via a mechanism of action in seronegative vaccinees that cannot be explained by neutralization or the induction of ADCC. More generally, these data, which are derived from a human challenge model that demonstrated that the gB vaccine is protective, highlight the need for more sophisticated analyses of new HCMV vaccines over and above the quantification of an ability to induce potent neutralizing antibody responses in vitro.

Specificity and effector functions of non-neutralizing gB-specific monoclonal antibodies isolated from healthy individuals with human cytomegalovirus infection

“…Counterintuitively, the gB/MF59 vaccination elicited limited neutralizing responses when compared with HCMV seropositive individuals [13, 14]; yet, gB/MF59 vaccination elicited effector-cell mediated antibody responses, including antibody dependent cellular phagocytosis (ADCP). This observation prompted a hypothesis that non-neutralizing antibodies against gB may contribute to protection against HCMV acquisition [13, 14]. Moreover, effector antibody functions mediated by NK cells may be crucial for targeting HCMV-infected cells, further underlying the significance of non-neutralizing antibodies in anti-HCMV immunity [15, 16].…”

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).…”

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

“…Furthermore, the gB/MF59 vaccine reduced viremia and demonstrated a protective benefit in transplant recipients [14]. Importantly, these partial successes were achieved without the elicitation of robust neutralizing antibody responses [16, 25]. In this investigation we sought to improve upon the gB immunogen antigenicity and vaccine/delivery platform, comparing novel vaccine immunogenicity head-to-head against the gB/MF59 vaccine in a preclinical model.…”

“…Specifically, antibodies targeting gB AD-2 are correlated with reduced incidence of viremia and congenital disease [19, 20], though AD-2-specific antibodies were not elicited to any appreciable extent by the vaccines tested in this investigation ( Figure 4H ). Furthermore, non-neutralizing antibodies targeting gB and other surface glycoproteins are well described to have a protective role in preventing HCMV acquisition [16, 25], reducing viremia [16, 30], and blocking tissue-invasive replication [30, 31], though the precise mechanism remains unknown. Lastly, HCMV-specific CD4 + and CD8 + T cells have been widely implicated in reducing HCMV acquisition [32, 33], viral replication [26, 34-42], and the incidence of congenital/transplant-associated disease [43, 44].…”

“…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].…”