• Abstract and Figures
• Public Full-text

COMMENTARY COMMENTARY Recombinant cytomegalovirus glycoprotein B vaccine: Rethinking the immunological basis of protection Mark R. Schleissa,1 Development and licensure of a vaccine against hu- is a subunit vaccine based on the viral envelope glyco- man CMV infection is a major public health priority. protein B (gB; gpUL55). Two important papers published Although the major driving force for a CMV vaccine is in PNAS (3, 4) provide surprising and novel insights into prevention of congenital infection—since CMV is the the protecting mechanisms conferred by this gB vaccine. most common viral cause of permanent neurodevelop- How did the CMV gB emerge as a leading vaccine mental disability in infants globally (1)—other patient candidate? CMV gB is a type 1 envelope glycoprotein populations, in particular recipients of hematopoietic and class III viral fusogen (5). It is synthesized as a 906- or stem cells and solid organ transplant (SOT) patients, could 907-aa polypeptide (depending upon the strain of CMV) benefit from a vaccine. A number of CMV vaccines have that undergoes extensive posttranslational modification, been evaluated in clinical trials in recent years (2). These including glycosylation at N-andO-linked sites, followed have included live, attenuated vaccines; vectored vac- by cleavage by the ubiquitous cellular endoprotease, cines expressing CMV-encoded immunogens; and puri- furin, into amino (gp90)- and carboxy (gp58)-terminal fied recombinant protein vaccines coadministered with moieties (refs. 6 and 7 and Fig. 1). The gp90 and adjuvant. The most extensively studied vaccine to date gp58 subunits are covalently connected by disulfide bonds and the mature, glycosylated gB assumes a tri- meric configuration; the trimer subsequently dimerizes AD-4 AD-4 as the protein assumes its final envelope conformation (8). CMV gB interacts with the virally encoded glycopro- II I tein H/L (gH/gL) complex as an essential component of 1 906 SS TMR Cyto the core fusion machinery required for infection and cell- to-cell spread of virus (9). Up to 70% of the virus- AD-2 AD-5 AD-1 Furin AD-3 neutralizing capacity of CMV immune sera recognizes Cleavage Site gB (10). Although recent studies of anti-CMV immune Fig. 1. Schematic representation of the linear full-length CMV gB polypeptide. globulin suggest that virus-neutralizing responses target- Disulfide bond sites are represented with black brackets. AD 1–5 are indicated. The ing the CMV pentameric complex (gH/gL/UL128/ gB vaccine examined in refs. 3 and 4 is derived from the Towne strain sequence; it UL130/UL131A) are essential for optimized protective has a targeted deletion of the furin site and hence is uncleaved when expressed in immunity (11), gB remains a cornerstone component of CHO cells. In addition, the transmembrane region (TMR, between amino acids 677–752) was deleted, to facilitate secretion, but the polypeptide retains the all CMV vaccines currently in development. A subunit gB cytoplasmic tail (2). The recombinant protein is secreted as an 807-aa protein with 19 vaccine was developed in the late 1980s, composed of a N-linked glycosylation sites. The AD of the gB protein are illustrated. AD-1 region CHO cell-derived protein admixed with an oil-in-water consists of ∼80 aa between positions 560 and 640 of gp58 (based on AD169 emulsion, MF59 (12). In the design of this vaccine, gB sequence). AD-2 contains two discontinuous binding sites: Site I, located between was truncated at the transmembrane domain, and amino acids 68 and 77, is highly conserved among strains and is a target of neutralizing responses, while site II, located between amino acids 50 and 54, is the furin protease site was deleted, to facilitate puri- unconserved. A linear epitope, AD-3, maps to the intraluminal part of the gB fication from CHO cell supernatants. The vaccine molecule (between amino acids 798–805); thus, this region is not expected to be was found to be safe and immunogenic in phase I exposed to neutralizing antibodies (see text for discussion). The AD-5 domain is a studies (13) and elicited potent anti-gB responses structural epitope, located between amino acids 133 and 343, and AD-4 is a discontinuous domain mapping to amino acids 121–132 and amino acids 344–438 in vaccinees (14). (18). Cyto, cytoplasmic domain; SS, signal sequence. Adapted with permission from Driven by these positive findings of safety and ref. 11 and ref. 29, which is licensed under CC BY 4.0. immunogenicity in phase I trials, the recombinant aDepartment of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 Author contributions: M.R.S. wrote the paper. The author declares no conflict of interest. Published under the PNAS license. See companion articles on pages 6267 and 6273. 1Email: [email protected]. Published online June 6, 2018. 6110–6112 | PNAS | June 12, 2018 | vol. 115 | no. 24 www.pnas.org/cgi/doi/10.1073/pnas.1806420115 Downloaded by guest on September 27, 2021 gB/MF59 vaccine subsequently underwent a series of phase II (4), no responses to AD-2 were detectable in CMV-seronegative studies. Three clinical trials have been reported to date. The first SOT vaccinees. Thus, for seronegative SOT subjects no direct was in CMV-seronegative women, immunized in the immediate correlate of protection relative to AD-2 could be established for postpartum period (15). Since study subjects in this trial were recipients of gB/MF59 vaccine. known to be at high risk for acquisition of a primary CMV infection, Similar analyses of gB epitope responses reported in ref. 3 also this study offered an opportunity to evaluate gB/MF59 efficacy demonstrated that, although vaccination elicited high levels of against acquisition of CMV in a key group of individuals targeted gB-binding antibody, there was limited targeting of key neutral- for vaccine development, namely, young women of child-bearing izing epitopes. There was one novel and striking exception: in- age. The gB/MF59 vaccine was demonstrated to have an efficacy duction of antibody responses to the gB AD-3 domain. In gB/ of 50% for prevention of primary CMV infection. A second study in MF59 vaccinees, an average of 76% of the total anti-gB response seronegative adolescent girls, using the same three-dose regimen was directed against this region, whereas in CMV-seropositive (16), demonstrated similar efficacy (43%). A third study conducted controls only 32% of the response targeted this domain. As the in SOT patients employed endpoints different from those exam- ined in postpartum women and adolescent girls, namely, reduction In summary, the reports by Nelson et al. and of CMV disease and decreased utilization of anti-CMV antivirals in the posttransplant period (17). In seronegative SOT recipients with Baraniak et al. indicate that we must rethink our seropositive organ donors, duration of CMV viremia and total days understanding of the protective mechanisms of of antiviral treatment were both significantly reduced in vaccinees, gB/MF59 vaccine response and reconsider our compared with placebo recipients (P < 0.05). The benefit of gB/MF59 vaccine was generally presumed, at presumptions about vaccine-induced correlates least in the initial interpretation of study results, to derive primarily of protection against acquisition of CMV infection. from induction of virus-neutralizing antibody responses. This pre- sumption was apparently incorrect, as is now reported in two authors point out, it is difficult to envision a proposed mechanism innovative and provocative papers in PNAS (3, 4). Intriguingly, using of protection, given the nature of the AD-3 epitope. The AD- stored serum samples from vaccinees in both the SOT study (4) and 3 region is intracellular —and presumably not recognized by the the study in postpartum women (3), these new data reveal that immune system when gB is expressed on a cell membrane—and, although vaccination elicited IgG responses with gB-binding mag- hence, anti–AD-3 antibodies would not be predicted to bind to or nitude comparable to natural infection, minimal induction of virus- neutralize infectious virus during the initial phase of infection (Fig. neutralizing responses was observed—despite the fact that protec- 1). An as-yet-unexplained contribution to vaccine-mediated pro- tion against CMV infection/disease was conferred. These results tection, possibly mediated by ADCP, could be at play. Nelson suggest that the antiviral IgG response to gB/MF59 vaccine confers – protection through nonneutralizing mechanisms that may be quite et al. (3) also provocatively suggest that anti AD-3 responses may distinct from those occurring in the context of natural infection. If the paradoxically compromise the efficacy of gB/MF59 by diverting correlate of antiviral immunity is not virus-neutralizing antibody, then responses away from neutralization epitopes, and they propose what is it? Both studies examined whether antibody-dependent that an improved gB vaccine could be contemplated in which the cellular cytotoxicity (ADCC), a nonneutralizing function of notable AD-3 coding region was removed from the polypeptide se- importance noted in the RV144 HIV vaccine trial (18), was responsi- quence. A similar suggestion has been made with respect to the ble. However, ADCC was not induced by gB/MF59 vaccine in either AD-1 domain, since it has been proposed that induction of non- study, although it was demonstrable in CMV-seropositive controls. neutralizing responses to AD-1 may promote antibody binding to An alternative nonneutralizing IgG-mediated function, antibody- gB that, in turn, may block access to the more potent virus- dependent cellular phagocytosis (ADCP), was identified by Nelson neutralizing AD-2 epitope (21, 22). et al. in the postpartum women vaccinees (3), and ADCP may A key question in the study by Nelson et al. (3) is whether a emerge as a novel CMV immune correlate warranting additional serological correlate of protection could be identified, in light of attentioninfuturestudies.

Load more

  3

Copy Link