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. 2024 Jan 12;12(1):77.
doi: 10.3390/vaccines12010077.

A Mixture of T-Cell Epitope Peptides Derived from Human Respiratory Syncytial Virus F Protein Conferred Protection in DR1-TCR Tg Mice

Hong Guo  1 , Yang Song  1 , Hai Li  1 , Hongqiao Hu  1 , Yuqing Shi  1 , Jie Jiang  1 , Jinyuan Guo  1 , Lei Cao  1 , Naiying Mao  1 , Yan Zhang  1   2
Affiliations

A Mixture of T-Cell Epitope Peptides Derived from Human Respiratory Syncytial Virus F Protein Conferred Protection in DR1-TCR Tg Mice

Hong Guo et al. Vaccines (Basel). .

Abstract

Human respiratory syncytial virus (HRSV) poses a significant disease burden on global health. To date, two vaccines that primarily induce humoral immunity to prevent HRSV infection have been approved, whereas vaccines that primarily induce T-cell immunity have not yet been well-represented. To address this gap, 25 predicted T-cell epitope peptides derived from the HRSV fusion protein with high human leukocyte antigen (HLA) binding potential were synthesized, and their ability to be recognized by PBMC from previously infected HRSV cases was assessed using an ELISpot assay. Finally, nine T-cell epitope peptides were selected, each of which was recognized by at least 20% of different donors' PBMC as potential vaccine candidates to prevent HRSV infection. The protective efficacy of F-9PV, a combination of nine peptides along with CpG-ODN and aluminum phosphate (Al) adjuvants, was validated in both HLA-humanized mice (DR1-TCR transgenic mice, Tg mice) and wild-type (WT) mice. The results show that F-9PV significantly enhanced protection against viral challenge as evidenced by reductions in viral load and pathological lesions in mice lungs. In addition, F-9PV elicits robust Th1-biased response, thereby mitigating the potential safety risk of Th2-induced respiratory disease during HRSV infection. Compared to WT mice, the F-9PV mice exhibited superior protection and immunogenicity in Tg mice, underscoring the specificity for human HLA. Overall, our results demonstrate that T-cell epitope peptides provide protection against HRSV infection in animal models even in the absence of neutralizing antibodies, indicating the feasibility of developing an HRSV T-cell epitope peptide-based vaccine.

Keywords: T-cell epitope; human respiratory syncytial virus; peptide vaccine.

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Conflict of interest statement

We do not have conflicts of interest associated with this publication, and there has been no financial support for this work that could have influenced its outcome. This manuscript is original, has not been previously published, and is not currently under consideration by another journal.

Figures

Figure 1
Figure 1
Schematic representation of groups, immunization procedure, and challenge schedule. (A) Linear diagram of the HRSV fusion (F) protein ectodomain based on the protein sequence of HRSV-A Long. Site of the nine peptides with more than 20% positivity on the F protein. The nine-peptide mixture from the F protein was named ‘F-9P’ (B) DR1-TCR Tg mice and C57BL/6J were subcutaneously injected with either F-9PV (n = 4) or adjuvant buffer (n = 4) on days 0 and 21. On day 35, they were challenged with 1 × 106 PFU of HRSV-A Long. Mice were monitored daily for symptoms and body weight changes. On day 4 post-infection, blood, lung, and spleen tissues were harvested for neutralizing antibody, histological assessments, viral load analyses, and immune response assays.
Figure 2
Figure 2
Mice exhibited Th1-biased T-cell responses. Mice splenocytes harvested 4 days after HRSV challenge were stimulated with F-9 PV for (A) IFN-γ spot-forming unit (SFU), (B) TNF-α SFU, (C) IL-2 SFU, (D) IL-10 SFU, (E) IL-4 SFU, and (F) Ratio of IL-4-secreting splenocytes and IFN-γ-secreting splenocytes, respectively. Points represent individual mice. Statistically significant differences were measured by one-way or two-way ANOVA with Fisher’s LSD test. **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05, “ns” indicates no significance.
Figure 3
Figure 3
F-9PV provided protective efficacy against HRSV infection. Mice were monitored daily for symptoms and body weight changes. On day 4 dpi, the subjects were euthanized, and their lung tissues were collected to evaluate immunological responses. Points represent individual mice. (A) The same group of immune mice were challenged with HRSV and then weighed each day. (B) The copies of HRSV RNA in the lung. (C) Scoring of total pathology after HRSV challenge of immunized mice. (D) Left lungs histopathological analysis from adjuvant control and peptide mixture-treated DR1-TCR Tg mice and C57BL/6J at 4 dpc. Red arrows indicate inflammatory cell infiltrate dominated by lymphocytes. Green arrows indicate fibrinoid exudation. Black arrows indicate some bronchiolar epithelial cells shed into the lumen. H&E staining. Bars: 2×, 800 μm to 1000 mm; 10×, 200 μm; 40×, 60 μm. Results are expressed as the mean ± SEM from 4 mice for each group. *** p < 0.001, ** p < 0.01.
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