Multivalent dengue vaccine composition comprising a mixture of attenuated dengue viruses from different serotypes
A highly safe dengue vaccine was invented that induced a neutralizing antibody response against all of the four serotypes of dengue virus without developing more than a fixed level of viremia with single administration. A tetravalent dengue virus formulation is provided that is excellent in both efficacy (neutralizing antibody response) and safety (viremia).
1. An attenuated dengue virus (DENV) vaccine composition comprising one or more non-naturally-occurring attenuated DENVs selected from the group consisting of a mixture of attenuated serotype 1 dengue viruses (DENV1), a mixture of attenuated serotype 2 dengue viruses (DENV2), a mixture of attenuated serotype 3 dengue viruses (DENV3), and a mixture of attenuated serotype 4 dengue viruses (DENV4), wherein said vaccine has the following features:
(a) said attenuated DENV1 mixture comprises DENV1 viruses with the following mutations: K482E/K, E483K, K484R/K, K568R, N1663K, I/T2353T, and A2364T/A;
wherein said numbering is based upon the DENV1 parent strain 03135 comprising SEQ ID NO:1;
(b) said attenuated DENV2 mixture comprises DENV2 viruses with the following mutations: D143N, T400K, D1102N, L1308F, E1654K, P2347P/L and T2828T/M;
wherein said numbering is based upon the DENV2 parent strain 99345 comprising SEQ ID NO:2;
(c) said attenuated DENV3 mixture comprises DENV3 viruses with the following mutations: I209L, S582G, K/R671K, A687V, T764I/T, F1211L, A1237T, and Q1563K;
wherein said numbering is based upon the DENV3 parent strain 16562 comprising SEQ ID NO:3; and,
(d) said attenuated DENV4 mixture comprises DENV4 viruses with the following mutations: L2187F and F/L2354S,
wherein said numbering is based upon the DENV4 parent strain 1036 comprising SEQ ID NO:4.
2. The attenuated tetravalent dengue virus vaccine of claim 1 , wherein a mixing ratio of the attenuated serotype 1, 2, 3 and 4 dengue viruses is 1:1:1:1, 5:3:5:3, or 5:3:3:3.
3. The attenuated tetravalent dengue virus vaccine of claim 1 , wherein a respective antigenic amount of the attenuated serotype 1, 2, 3 and 4 dengue viruses is 1 to 7 log 10 FFU/dose.