The Status of Vaccine Development Against the Human Cytomegalovirus

Abstract

Numerous candidate vaccines against cytomegalovirus (CMV) infection and disease are in development. Whereas the previous article [1] provides background and opinions about the issues relating to vaccination, this article provides specifics about the vaccines in active development, as reported at a National Institutes of Health-sponsored meeting in Bethesda on September 4-6, 2018. Here, vaccine developers provide synopses of their candidate vaccines to immunize women to protect against congenital CMV disease and to prevent the consequences of CMV disease in recipients of transplanted organs or hematopoietic stem calls. The projects are presented here roughly in the descending order of their stage of development in the opinion of the first author.

Keywords: cytomegalovirus; fetal infection; organ transplant; stem cell transplant.

Figure 1.

Responses to Sanofi-Pasteur glycoprotein B (gB). CMV, cytomegalovirus; GMT, geometric mean titers.

Figure 2.

Neutralizing antibody responses to glycoprotein B with various adjuvants. GMT, geometric mean titers.

Figure 3.

Hookipa HP-101 elicited significant human cytomegalovirus (HCMV)-neutralizing antibody titers compared with placebo: Cohort (Coh) 1, 2.6 × 10⁶ focus-forming units (FFU); Coh 2, 2.6 × 10⁷ FFU; Coh 3, 2.6 × 10⁸ FFU. CI, confidence interval; GMT, geometric mean titers.

Figure 4.

Hookipa HB-101 elicited a significant, durable pp65-specific cellular immune response: Cohort (Coh) 1, 2.6 × 10⁶ focus-forming units (FFU); Coh 2, 2.6 × 10⁷ FFU; Coh 3, 2.6 × 10⁸ FFU. ELISPOT, enzyme-linked immunospot; PBMC, peripheral blood mononuclear cells; SEM, standard error of the mean; SFC, spot-forming cells.

Figure 5.

Kinetics of cytomegalovirus (CMV)-specific humoral and B-cell responses to GSK glycoprotein B (gB) combined with AS01E adjuvant. At the indicated time points (A), anti-gB immunoglobulin (Ig)G antibodies were measured by enzyme-linked immunosorbent assay; (B) anti-CMV neutralizing antibodies (Nabs) were measured by microneutralization test using MRC5 fibroblast cells and the AD169 CMV strain; (C) anti-gB IgG avidity indexes were measured by avidity enzyme-linked immunosorbent assay using a chaotropic agent (8 M urea); and (D) gB-specific antibody-secreting B-cells were determined by enzyme-linked immunospot assay. (A) and (B) show geometric mean titer (GMT)/geometric mean concentrations (GMC) and 95% confidence interval (CI). (C) and (D) show boxplots: the box represents the upper and lower quartiles; the horizontal line within the box represents the median value; the whiskers represent the minimum and maximum values. Arrows represent time of vaccine dose administration. Natural infection levels of anti-gB IgG (and avidity index) and anti-CMV neutralizing antibodies were determined at the month 0 timepoint from 39 CMV-seropositive healthy male subjects (dotted line).

Figure 6.

Persistence of vaccine-induced neutralizing antibody (Nab) and CD4⁺ T-cell response after GSK glycoprotein B (gB) vaccine. A subset of 27 vaccinated subjects were re-evaluated for (A) anti-cytomegalovirus (CMV) neutralizing antibodies in sera at month 48 (42 months after the third vaccination) determined by microneutralization test as described in Figure 1 (natural infection levels are indicated with a star). In (B), CMV gB-specific T cells were quantified by flow cytometry, using intracellular cytokine staining of peripheral blood mononuclear cells (PBMCs), cultured in the presence of gB-derived peptides. The PBMCs were stained for CD40L, interferon-γ, interleukin-2, and tumor necrosis factor-α. The number of CD4⁺ T cells per 1 × 10⁶ cells expressing at least 2 markers is shown at the indicated time points.

Figure 7.

Moderna PC+gB messenger ribonucleic acid (mRNA)/lipid nanoparticle (LNP) vaccine elicits high neutralizing titers against human cytomegalovirus (hCMV) infection of epithelial and fibroblast cells. Neutralizing antibodies in mouse immune sera. (A) Schematic of dosing regimen. Indicated are days of dosing and blood draws. (B and C) Neutralizing titers in sera from mice immunized with PC+gB vaccine at the indicated doses or empty LNP (LNP only) against (B) VR1814 infection in ARPE-19 epithelial cells and against (C) AD169 infection in HEL299 fibroblast cells. Shown also is the neutralizing activity in Cytogam. Titers in Cytogam are shown for an approximate maximum concentration (2 mg/mL) in human sera after dosing, which was calculated based on an average body weight of 70 kg (assuming 5L of blood). CI, confidence interval; gB, glycoprotein B; LOD, limit of detection; PC, pentameric complex.