T cell and memory B cell responses in tetravalent DNA, tetravalent inactivated and tetravalent live-attenuated prime-boost dengue vaccines in rhesus macaques

Abstract

We previously reported the efficacy of prime-boost vaccination using three tetravalent (T) dengue vaccines, DNA (TDNA), purified inactivated vaccine (TPIV), and live attenuated vaccine (TLAV). We demonstrated that the TPIV/TLAV prime-boost vaccination yielded the highest and most durable neutralizing antibodies and 100% protection to all 4 serotypes of dengue virus in rhesus macaques. This study compares gene transcription, T and B cell responses elicited by these prime-boost combinations in rhesus macaques. This study shows that the TLAV vaccine increased the expression of the innate immune genes, DDX58 and TLR7, IL1A, IL1B, TNF, CXCL8, CXCL10, IRF1, IRF7, and IFNB, more robustly as compared to TDNA and TPIV vaccines. Overall, two doses of TDNA and one dose of TLAV efficiently elicited a T cell IFNγ response to PrM/E with a comparable magnitude. Compared to TDNA vaccine, the TLAV vaccine elicited additional IFNγ response to C, NS1, NS3, and NS5. The TPIV vaccine alone produced poor IFNγ response; however, the TLAV significantly boosted its IFNγ response. The T cell response repertoire associated with TPIV/TLAV prime-boost was to both the structural C/PrM/E and NS proteins, and the T cells were multifunctional as the CD4⁺ T cells produced IFNγ, TNF α, and IL2 and the CD8⁺ cells produced TNF α and IFNγ. Opposite to the pattern of CMI, the TPIV vaccine alone elicited the highest B_Mem compared to the other two vaccines, which continuously remained as the highest after boosting. In summary, the TDNA and TLAV vaccines elicited a strong T cell response whereas the TPIV vaccine elicited a superior B_Mem. The T cell response of the TPIV vaccine was significantly boosted by the TLAV vaccine. The elevated T cell response may have provided T cell help for a sustained antibody response for TPIV/TLAV vaccines, which is required for a protective immunity against a live virus challenge.

Keywords: Non-human primates; Prime-boost; Tetravalent dengue DNA vaccine; Tetravalent dengue inactivated vaccine; Tetravalent dengue live-attenuated vaccine.