Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis
<p>rLCMV elicits high frequencies of polyfunctional CD8 and CD4 T cells. (<b>A</b>,<b>B</b>): Schematic representation of the wildtype LCMV (<b>A</b>) and rLCMV vector (<b>B</b>) genomes. (<b>C</b>–<b>F</b>): We immunized C57BL/6 mice with 10<sup>6</sup> PFU of rLCMV either s.c., i.m., or i.v. Controls were left unimmunized (no vaccine, panels (<b>C</b>,<b>E</b>) only). After 28 days, we measured T cell responses to Ag85B-TB10.4 in the spleen. (<b>C</b>): TB10.4-dextramer-binding CD8 T cells. (<b>D</b>): TB10.4-specific cytokine-producing CD8 T cells. (<b>E</b>): Ag85B-tetramer-binding cells amongst activated (CD44<sup>+</sup>CD62L<sup>low</sup>) CD4 T cells. (<b>F</b>): Ag85B-TB10.4-specific cytokine-producing CD4 T cells. Bars represent the mean +/− SD of five mice per group. Black circles show individual mice. Values in (<b>D</b>,<b>F</b>) are background-subtracted (cytokine secretion upon peptide/antigen stimulation minus cytokine secretion in medium-only control wells). One representative experiment of two similar ones is shown. Responses of mice immunized by the i.v., i.m., and s.c. routes were compared by one-way ANOVA with Bonferroni’s post-test. Only statistically significant differences (<span class="html-italic">p</span> > 0.05) are indicated. ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 2
<p>rLCMV-induced CD8 T cell responses are augmented by homologous boosting. We immunized C57BL/6 mice with 10<sup>6</sup> PFU of rLCMV i.m. on day 0 and day 28 (prime-boost) or on day 28 only (prime). Controls were left unimmunized (no vaccine, panels (<b>A</b>,<b>C</b>) only). On day 56, we measured T cell responses to Ag85B-TB10.4 in the spleen. (<b>A</b>): TB10.4-dextramer-binding CD8 T cells. (<b>B</b>): TB10.4-specific cytokine-producing CD8 T cells. (<b>C</b>): Ag85B-tetramer-binding cells amongst activated (CD44<sup>+</sup>CD62L<sup>low</sup>) CD4 T cells. (<b>D</b>): Ag85B-TB10.4-specific cytokine-producing CD4 T cells. Bars represent the mean +/− SD of five mice per group. Black circles show individual mice. Values in (<b>B</b>,<b>D</b>) are background-subtracted (cytokine secretion upon peptide/antigen stimulation minus cytokine secretion in medium-only control wells). One representative experiment of two similar ones is shown. Responses of mice immunized with either one or two doses of rLCMV were compared by unpaired two-tailed Student’s <span class="html-italic">t</span>-test. ** <span class="html-italic">p</span> < 0.01; n.s.: not statistically significant, <span class="html-italic">p</span> ≥ 0.05.</p> "> Figure 3
<p>Neonatal mice mount robust CD8 and CD4 T cell responses to rLCMV vaccination. We immunized 1-week-old C57BL/6 mice s.c. with 10<sup>5</sup> PFU of rLCMV and analyzed T cell responses in spleen 10 days later. Adult C57BL/6 mice immunized s.c. served as positive controls, and unvaccinated adult animals served as negative control (no vaccine). (<b>A</b>): TB10.4-dextramer-binding CD8 T cells. (<b>B</b>): TB10.4-specific IFN-γ+ TNF- α+ double-producing CD8 T cells. (<b>C</b>): Ag85B<sub>301-320</sub>-specific IFN-γ+ TNF-α+ double-producing CD4 T cells. Black circles show individual mice, of which bars represent the mean +/− SD. Values for cytokine-producing T cells are background-subtracted (cytokine secretion upon peptide/antigen stimulation minus cytokine secretion in medium-only control wells). One representative experiment of two is shown.</p> "> Figure 4
<p>rLCMV can be co-administered with human infant vaccines. A,B: We immunized 1-week-old C57BL/6 mice with 10<sup>5</sup> PFU rLCMV s.c. (“rLCMV”), with DTPa-6 i.p. and i.m. (“DTPa-6”), or simultaneously with rLCMV plus DTPa-6 by the same respective routes (“rLCMV + DTPa-6”). (<b>A</b>): At the age of 20 days, we determined CD8 and CD4 T cell responses in spleen. Left: TB10.4-dextramer-binding CD8 T cells. Center: TB10.4-specific IFN-γ+ TNF-α+ double-producing CD8 T cells. Right. Ag85B-TB10.4-specific IFN-γ+ TNF-α+ double-producing CD4 T cells. (<b>B</b>). DTPa-6-induced antibody responses against tetanus toxoid (TT), pertussis toxoid (PT), (<b>B</b>): pertussis pertactin (PRN) and pertussis filamentous hemagglutinin (FHA) at the age of 20 days. (<b>C</b>,<b>D</b>): We immunized 1-week-old C57BL/6 mice with DTPa-6 i.p. and i.m. or left them unvaccinated. At 8 weeks of age, the animals were immunized with rLCMV s.c., with DTPa-6 i.p. + i.m. or were given both vaccines as outlined in the chart. At the age of 9.5 weeks we determined CD8 and CD4 T cell responses in spleen. Left: TB10.4-dextramer-binding CD8 T cells. Center: TB10.4-specific IFN-γ+ TNF-α+ double-producing CD8 T cells. Right. Ag85B-TB10.4-specific IFN-γ+ TNF-α+ double-producing CD4 T cells. (<b>D</b>): DTPa-6-induced antibody responses in the groups having received neonatal DTPa-6. Black circles show individual mice, of which bars represent the mean +/− SD. Values for cytokine-producing T cells are background-subtracted (cytokine secretion upon peptide/antigen stimulation minus cytokine secretion in medium-only control wells). One representative experiment of two similar ones is shown. The indicated pairwise comparisons of T cell responses were conducted by unpaired two-tailed Student’s <span class="html-italic">t</span>-tests. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; n.s.: not statistically significant, <span class="html-italic">p</span> ≥ 0.05.</p> "> Figure 5
<p>T cell responses upon rLCMV- and/or BCG immunization and subsequent <span class="html-italic">Mtb</span> aerosol challenge. (<b>A</b>): We immunized adult C57BL/6 mice with BCG s.c. and with rLCMV i.m. at the time points in the combinations indicated in the chart. rLCMV-induced TB10.4-specific CD8 T cells as well as Ag85B-specific CD4 T cells were determined in blood, spleen, and lung at the indicated time points prior to and after <span class="html-italic">Mtb</span> aerosol challenge. (<b>B</b>). We determined the frequencies of TB10.4 dextramer-binding CD8 T cells 2 weeks prior to and 2–3 weeks after <span class="html-italic">Mtb</span> challenge in blood and 4 weeks after <span class="html-italic">Mtb</span> challenge in spleen and lung. (<b>C</b>): We determined the frequencies of Ag85B tetramer-binding CD4 T cells 2 weeks prior to and 2–3 weeks after <span class="html-italic">Mtb</span> challenge in blood, and 4 weeks after <span class="html-italic">Mtb</span> challenge in spleen and lung. Symbols in (<b>B</b>,<b>C</b>) show individual animals from two groups of five mice each that were immunized and challenged independently. Bars show the mean+/- SEM. Data were analyzed by one-way ANOVA followed by Bonferroni’s post-test. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01; only statistically significant differences (<span class="html-italic">p</span> > 0.05) are indicated.</p> "> Figure 6
<p>rLCMV immunization reduces <span class="html-italic">Mtb</span> loads in lung, improves lung pathology, and augments CD8 T cell recruitment to the lung. Mice were immunized with BCG s.c. and/or with rLCMV i.m. and challenged with <span class="html-italic">Mtb</span> as outlined in <a href="#ijms-23-02700-f005" class="html-fig">Figure 5</a>A, and lungs were analyzed at week 4 after challenge. (<b>A</b>): Bacterial loads in lung. (<b>B</b>): Exemplary microscopy image of a whole-lung cross section stained by hematoxylin/eosin (left). Ventilated and non-ventilated regions were determined by computer-assisted image analysis and are color-coded for illustration purposes in red and yellow, respectively (right). (<b>C</b>): The percentage of ventilated surface on whole-lung cross sections, computer-assessed as in (<b>B</b>), was calculated as “(ventilated surface):(ventilated + non-ventilated surface)”. (<b>D</b>–<b>F</b>): Lung sections were processed for immunohistochemical detection of infiltrating CD8 and CD4 T cells. <b>D</b>: Representative images from ventilated (top) and non-ventilated (bottom) lung areas of rLCMV-only vaccinated animals and PBS controls. Arrows point out infiltrating CD8 T cells in the alveolar walls of ventilated lung. Magnification bars: 50 µm. (<b>E</b>,<b>F</b>): Infiltration densities of CD8 (<b>E</b>) and CD4 T cells (<b>F</b>) in ventilated (top) and non-ventilated (bottom) areas of the lung were determined by computer-assisted image analysis. Symbols in (<b>A</b>,<b>C</b>) show individual animals from two independently conducted experiments, which each consisted of two groups of five mice that were immunized and challenged independently. Symbols in (<b>E</b>,<b>F</b>) show results from one of these experiments with two groups of five mice immunized and challenged independently. Bars show the mean+/− SEM. Data were analyzed by one-way ANOVA followed by Bonferroni’s post-test. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, n.s.: not statistically significant, <span class="html-italic">p</span> ≥ 0.05. In (<b>E</b>,<b>F</b>) only statistically significant differences (<span class="html-italic">p</span> > 0.05) are indicated.</p> ">
Abstract
:1. Introduction
2. Results
2.1. rLCMV Vector Delivering Ag85B-TB10.4 Elicits High Frequencies of Polyfunctional CD8 and CD4 T Cells
2.2. rLCMV-Induced CD8 T Cell Responses Are Augmented by Homologous Boosting
2.3. Neonatal Mice Mount Robust CD8 and CD4 T Cell Responses to rLCMV Vaccination
2.4. rLCMV Can Be Co-Administered with Human Infant Vaccines
2.5. T Cell Responses upon rLCMV- and/or BCG Immunization and Subsequent Mtb Aerosol Challenge
2.6. rLCMV Immunization Reduces Mtb Loads in Lung, Improves Lung Pathology, and Augments CD8 T Cell Recruitment to the Lung
3. Discussion
4. Materials and Methods
4.1. Mice
4.2. BCG and Mtb Production, Mtb Challenge, and Bacterial Titer Determination
4.3. Viral Vectors and Vaccines
4.4. Determination of Antigen-Specific T Cell Responses
4.5. Histology, Immunohistochemistry, and Quantitative Assessment of T Cell Infiltration and Lung Ventilation
4.6. Determination of DTPa-6-Induced Antibody Responses
4.7. Statistical Analysis
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Ethics Statement
References
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Belnoue, E.; Vogelzang, A.; Nieuwenhuizen, N.E.; Krzyzaniak, M.A.; Darbre, S.; Kreutzfeldt, M.; Wagner, I.; Merkler, D.; Lambert, P.-H.; Kaufmann, S.H.E.; et al. Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis. Int. J. Mol. Sci. 2022, 23, 2700. https://doi.org/10.3390/ijms23052700
Belnoue E, Vogelzang A, Nieuwenhuizen NE, Krzyzaniak MA, Darbre S, Kreutzfeldt M, Wagner I, Merkler D, Lambert P-H, Kaufmann SHE, et al. Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis. International Journal of Molecular Sciences. 2022; 23(5):2700. https://doi.org/10.3390/ijms23052700
Chicago/Turabian StyleBelnoue, Elodie, Alexis Vogelzang, Natalie E. Nieuwenhuizen, Magdalena A. Krzyzaniak, Stephanie Darbre, Mario Kreutzfeldt, Ingrid Wagner, Doron Merkler, Paul-Henri Lambert, Stefan H. E. Kaufmann, and et al. 2022. "Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis" International Journal of Molecular Sciences 23, no. 5: 2700. https://doi.org/10.3390/ijms23052700