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Alphavirus replicon-based adjuvants enhance the immunogenicity and effectiveness of Fluzone® in rhesus macaques

Carroll, Timothy D., Matzinger, Shannon R., Barro, Mario, Fritts, Linda, McChesney, Michael B., Miller, Christopher J., Johnston, Robert E.
Vaccine 2011 v.29 no.5 pp. 931-940
CD4-positive T-lymphocytes, Macaca mulatta, Orthomyxoviridae, RNA, Venezuelan equine encephalitis virus, adjuvants, humans, immune response, immunization, immunoglobulin A, immunoglobulin G, influenza, interferon-gamma, interleukin-2, mice, monkeys, replicon, transgenes, vaccines, virus replication, viruses
Venezuelan equine encephalitis virus replicon particles (VRP) without a transgene (null VRP) have been used to adjuvant effective humoral [1], cellular [2], and mucosal [3] immune responses in mice. To assess the adjuvant activity of null VRP in the context of a licensed inactivated influenza virus vaccine, rhesus monkeys were immunized with Fluzone® alone or Fluzone® mixed with null VRP and then challenged with a human seasonal influenza isolate, A/Memphis/7/2001 (H1N1). Compared to Fluzone® alone, Fluzone®+null VRP immunized animals had stronger influenza-specific CD4⁺ T cell responses (4.4 fold) with significantly higher levels of virus-specific IFN-γ (7.6 fold) and IL-2 (5.3 fold) producing CD4+ T cells. Fluzone®+null VRP immunized animals also had significantly higher plasma anti-influenza IgG (p<0.0001, 1.3 log) and IgA (p<0.05, 1.2 log) levels. In fact, the mean plasma anti-influenza IgG titers after one Fluzone®+null VRP immunization was 1.2 log greater (p<0.04) than after two immunizations with Fluzone® alone. After virus challenge, only Fluzone®+null VRP immunized monkeys had a significantly lower level of viral replication (p<0.001) relative to the unimmunized control animals. Although little anti-influenza antibody was detected in the respiratory secretions after immunization, strong anamnestic anti-influenza IgG and IgA responses were present in secretions of the Fluzone®+null VRP immunized monkeys immediately after challenge. There were significant inverse correlations between influenza RNA levels in tracheal lavages and plasma anti-influenza HI and IgG anti-influenza antibody titers prior to challenge. These results demonstrate that null VRP dramatically improve both the immunogenicity and protection elicited by a licensed inactivated influenza vaccine.