2347. Blood Transcriptional Correlates of Vaccine-Induced Protection Against TB in Macaques (2022)

Abstract Background Identifying correlates of vaccine-induced protection against tuberculosis (TB) is essential for improved vaccine development and evaluation. Prior efforts have focused on antigen-specific CD4 T cell responses measured weeks following vacination, which have repeatedly failed to correlate with protection. Methods Here, we analyzed the blood transcriptional response to vaccination in rhesus macaques vaccinated intravenously (IV) with high- (N=16) or low-dose (N=18) BCG that exhibited varying protection against Mtb challenge six months later. We identified correlates of protection in high-dose recipients and validated in low-dose recipients and in an independent cohort of BCG-vaccinated macaques. We also compared the blood transcriptional response to adaptive responses in the bronchoalveolar lavage (BAL). Results We identified and independently validated seven modules of 2,499 genes induced two days, two weeks, four weeks, and/or twelve weeks post-vaccination. Adaptive modules were associated with protection against challenge in low-dose recipients but not high-dose recipients. In contrast, an innate module (Module 1) on day 2 post-vaccination was associated with protection outcomes eight months later in both high- and low-dose recipients, as well as in an independent cohort of macaques. Module 1 scores at day 2 post-vaccination were also highly correlated with BAL adaptive responses, including Mtb-specific IgA and IgG titers at week 4, log T cell (CD4+, CD8+, MAIT, Vg9) counts at week 4, and antigen-specific CD4+ T cell responses (IFNg, IL2, IL21, TNF) at week 8 (r &amp;gt;0.7, p&amp;lt; 0.0001). None of these lung adaptive markers could reliably predict protection in both high- and low-dose recipients. However, module 1 scores at day 2 post-vaccination accurately predicted protection following Mtb challenge six months later (high-dose recipients, AUC=0.8; low-dose recipients, AUC=0.99). The early innate response in peripheral blood correlates with outcomes post-challenge 8 months later. Correlation between module 1 (innate) scores on day 2 post-vaccination and total thoracic colony forming units (CFU) and number of granulomas following challenge eight months later in high- and low-dose recipients (A-B) and in an independent cohort of macaques vaccinated with BCG through different routes (C-D). AE, aerosol; HD-ID, high dose intradermal; ID, intradermal; ID/AE, intradermal and aerosol; IV, intravenous. The early innate response in peripheral blood is highly correlated with lung CD4 T cell responses 8 weeks post-vaccination. Correlation between module 1 (innate) scores at day 2 post-vaccination and cytokine expression by CD4 T cells in bronchoalveolar lavage (BAL) upon whole cell lysate restimulation. Anyg2T17, any of IFNg, IL2, TNF, or IL17. Conclusion These results suggest that adaptive responses are necessary but not sufficient for BCG-induced protection. Instead, the early innate response in peripheral blood may be a more reliable and generalizable correlate of BCG-induced protection. Disclosures Purvesh Khatri, PhD, Cepheid, Inc.: Advisor/Consultant|Inflammatix, Inc.: Advisor/Consultant|Inflammatix, Inc.: Inflammatix is in negotiations to license the 9-gene signature discussed here.|Inflammatix, Inc.: Stocks/Bonds.