Alphavirus replicon-based adjuvants enhance the immunogenicity and effectiveness of Fluzone ® in rhesus macaques.
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.
Center for Comparative Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA. tdcarroll@ucdavis.edu
Timothy D
TD
Carroll
Shannon R
SR
Matzinger
Mario
M
Barro
Linda
L
Fritts
Michael B
MB
McChesney
Christopher J
CJ
Miller
Robert E
RE
Johnston
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004337:Drug Carriers; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D005260:Female; D005822:Genetic Vectors; D006385:Hemagglutination Inhibition Tests; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000097:blood; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D018419:Primate Diseases / Q000517:prevention & control; D014132:Trachea / Q000821:virology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D004337:Drug Carriers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D007376:Interleukin-2; D015164:Vaccines, Inactivated; D007371:Interferon-gamma