Immunization of macaques with formalin-inactivated respiratory syncytial virus (RSV) induces interleukin-13-associated hypersensitivity to subsequent RSV infection - PubMed (original) (raw)
Immunization of macaques with formalin-inactivated respiratory syncytial virus (RSV) induces interleukin-13-associated hypersensitivity to subsequent RSV infection
Rik L De Swart et al. J Virol. 2002 Nov.
Abstract
Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. RSV vaccine development has been hampered by results of clinical trials in the 1960s, when formalin-inactivated whole-RSV preparations adjuvated with alum (FI-RSV) were found to predispose infants for enhanced disease following subsequent natural RSV infection. We have reproduced this apparently immunopathological phenomenon in infant cynomolgus macaques and identified immunological and pathological correlates. Vaccination with FI-RSV induced specific virus-neutralizing antibody responses accompanied by strong lymphoproliferative responses. The vaccine-induced RSV-specific T cells predominantly produced the Th2 cytokines interleukin-13 (IL-13) and IL-5. Intratracheal challenge with a macaque-adapted wild-type RSV 3 months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia. The challenge resulted in a rapid boosting of IL-13-producing T cells in the FI-RSV-vaccinated animals but not in the FI-measles virus-vaccinated control animals. Two out of seven FI-RSV-vaccinated animals died 12 days after RSV challenge with pulmonary hyperinflation. Surprisingly, the lungs of these two animals did not show overt inflammatory lesions. However, upon vaccination the animals had shown the strongest lymphoproliferative responses associated with the most pronounced Th2 phenotype within their group. We hypothesize that an IL-13-associated asthma-like mechanism resulted in airway hyperreactivity in these animals. This nonhuman primate model will be an important tool to assess the safety of nonreplicating candidate RSV vaccines.
Figures
FIG. 1.
RSV-specific (A and C) and MV-specific (B and D) VN antibody responses measured in plasma samples of macaques vaccinated with FI-RSV (A and B) or FI-MV (C and D). Arrows, times of vaccination; asterisks, times of RSV challenge. Symbols represent the titers in the individual animals, while lines connect the geometric means of the groups over time. Animals RS1 to RS6 and MV1 to MV6 are represented shaded and open circles, squares, triangles, diamonds, and hexagons, respectively. Animal RS7 is represented by a shaded circle with a plus.
FIG. 2.
Proliferative PBMC responses of macaques vaccinated with FI-RSV (A to C) or FI-MV (D to F) after in vitro stimulation with BPL-RSV (A and D), BPL-MV (B and E), or BPL-Vero antigen (C and F). Arrows, times of vaccination; asterisks, times of RSV challenge. Symbols represent the means of the individual animals (the correlation between symbols and animals is the same as that for Fig. 1), while lines connect the geometric means of the groups over time.
FIG. 3.
Cytokine levels in supernatants of PBMC collected from macaques 3 weeks after the third vaccination with FI-RSV (A and B) or FI-MV (C and D) and stimulated in vitro with BPL-RSV (A and C) or BPL-MV (B and D). The cytokines measured are indicated on the x axis, and levels are presented above the detection limits. Symbols represent the measurements of the individual animals (the correlation between symbols and animals is the same as that for Fig. 1), while horizontal lines represent the geometric mean values for the groups.
FIG. 4.
Semiquantitative RSV-specific RT-PCR signals (A and B) and percentages of eosinophils (C and D) in BAL samples collected at different time points after RSV challenge. Symbols represent the measurements of the individual animals (the correlation between symbols and animals is the same as that for Fig. 1), while lines connect the geometric means of the groups over time. Both parameters were significantly different between the two groups (mixed analysis of variance; P < 0.01).
FIG. 5.
IL-13 (A and B), IL-5 (C and D), and IFN-γ (E and F) levels in culture supernatants of PBMC collected from macaques vaccinated with FI-RSV (A, C, and E) or FI-MV (B, D, and F) at days 0 and 6 after RSV challenge (indicated on the x axes). PBMC were stimulated in vitro with BPL-RSV, BPL-MV, or BPL-Vero antigen as indicated. Symbols represent the measurements of the individual animals (the correlation between symbols and animals is the same as that for Fig. 1), while horizontal lines represent the geometric mean values of the groups.
FIG. 6.
(A) Diffuse infiltration of eosinophils (arrows) in the bronchial wall, as seen in the FI-RSV-primed monkeys euthanized at 7 or 13 days after challenge; (B to D) multifocal infiltration of inflammatory cells in the pulmonary parenchyma (B) with multinucleated syncytial cells (arrow; C) and eosinophilic intracytoplasmic inclusion bodies (arrows; D) characteristic of RSV infection, as seen in all four animals euthanized at 7 or 13 days after challenge irrespective of their vaccination history; (E to G) quantification of eosinophil numbers in bronchial (E) and bronchiolar (F) walls and in alveolar lumina (G) of FI-MV-primed (blue bars) and FI-RSV-primed (red bars) animals euthanized at 7 (solid bars) or 13 (hatched bars) days after challenge; (H and I) chest X rays of one of the FI-RSV-primed animals that died at day 12 after challenge, showing the normal image at day 9 (H) and pulmonary hyperinflation at day 12 (I). Bright vertical marks, identification chip; hpf, high-power field; SD, standard deviation.
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