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. 2023 Oct 24;11(11):1629.
doi: 10.3390/vaccines11111629.

Re-Evaluating Human Cytomegalovirus Vaccine Design: Prediction of T Cell Epitopes

Peter A Barry  1   2 , Smita S Iyer  3 , Laura Gibson  4
Affiliations

Re-Evaluating Human Cytomegalovirus Vaccine Design: Prediction of T Cell Epitopes

Peter A Barry et al. Vaccines (Basel). .

Abstract

HCMV vaccine development has traditionally focused on viral antigens identified as key targets of neutralizing antibody (NAb) and/or T cell responses in healthy adults with chronic HCMV infection, such as glycoprotein B (gB), the glycoprotein H-anchored pentamer complex (PC), and the unique long 83 (UL83)-encoded phosphoprotein 65 (pp65). However, the protracted absence of a licensed HCMV vaccine that reduces the risk of infection in pregnancy regardless of serostatus warrants a systematic reassessment of assumptions informing vaccine design. To illustrate this imperative, we considered the hypothesis that HCMV proteins infrequently detected as targets of T cell responses may contain important vaccine antigens. Using an extant dataset from a T cell profiling study, we tested whether HCMV proteins recognized by only a small minority of participants encompass any T cell epitopes. Our analyses demonstrate a prominent skewing of T cell responses away from most viral proteins-although they contain robust predicted CD8 T cell epitopes-in favor of a more restricted set of proteins. Our findings raise the possibility that HCMV may benefit from evading the T cell recognition of certain key proteins and that, contrary to current vaccine design approaches, including them as vaccine antigens could effectively take advantage of this vulnerability.

Keywords: bioinformatics; cytomegalovirus; unconventional T cell antigen candidates; vaccine.

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Conflict of interest statement

P.A.B. and S.S.I. declare no conflicts of interest. LG received grant funding from Moderna Therapeutics, Inc. (Cambridge, MA, USA).

Figures

Figure 1
Figure 1
Data analysis algorithm. Tools and thresholds were applied sequentially to yield a Final Set of HCMV proteins predicted to have robust CD8 T cell epitopes. See Methods for description of algorithm and protein sets and Table S1 for details of proteins included and excluded at each step.
Figure 2
Figure 2
HCMV-specific T cell responses sorted by number of T cell responders. (A) Number of participants (y-axis) in the original study cohort (n = 33; (55)) with detectable CD4 (left panel) or CD8 (right panel) T cell responses against the Revised Set of 148 HCMV proteins (x-axis). The far-right end of each x-axis notes only the number rather than names of low-frequency proteins. Horizontal lines separate no/few (0–4), some (5–16), and many (≥17) T cell responders. Shaded boxes indicate proteins with no/few responders to which the next step in the algorithm was applied. (B) Number of proteins (y-axis) recognized by CD4 (white) or CD8 (black) T cells of responders (x-axis). Some proteins were recognized by both T cell types. #, number.
Figure 3
Figure 3
HCMV-specific T cell responses sorted by participants and proteins. (A) CD4 (white) or CD8 (black) T cell responses detected in each participant P1–P33 against the Revised Set of 148 HCMV proteins. Shaded boxes highlight examples of participants with predominantly CD8 (P1) or CD4 (P15) or with a wide range (P32 and P33) of responses. (B) Number of proteins targeted by CD4 only, CD8 only, or both CD4 and CD8 T cells. Bottom row (“Dominant”) indicates number (%) of participants with more CD4 or more CD8 T cell responses (summary of (A)). NA, not applicable.
Figure 4
Figure 4
Patterns of T cell responders. (A) HCMV proteins in the Revised Set (x-axis) recognized by CD4 or CD8 T cells (patterns on y-axis) for no (0; white bars), few (1–4; gray bars), or many (>4; black bars) participants. #, number. (B) Numbers (percentages) of proteins in each T cell category depicted in (A). For example, 38 of 148 (25.7%) HCMV proteins were recognized by few (1–4) CD8 T cell responders and by few (1–4) CD4 T cell responders (boxes in both panels), (summary of (A)).
Figure 5
Figure 5
Immunogenicity prediction scores for proteins in the Affinity-HLA Set (n = 35) compared to those of UL83 (far left x-axis). Shaded areas indicate proteins with median score significantly lower than that of UL83 (Mann-Whitney). Median scores for each protein (solid lines) are noted.
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Grants and funding

This research received no external funding.