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Seasonal influenza remains a serious public health concern as the viral infection spreads easily from person to person and due to antigenic drift of neutralizing epitopes. Vaccination is the best method for disease prevention, however current seasonal influenza vaccines stimulate antibodies which are often effective against only antigenically similar strains. To boost the immune responses and increase vaccine effectiveness, adjuvants have been used for the past 20 years. The current study explores the use of oil-in-water adjuvant, AF03 to improve an immunogenicity of 2 licensed vaccines. A standard-dose inactivated quadrivalent influenza vaccine (IIV4-SD), containing both hemagglutinin (HA) and neuraminidase (NA) antigens, and recombinant quadrivalent influenza vaccine (RIV4), containing only HA-antigen were adjuvanted with AF03 in naïve BALB/c mouse model. Functional HA-specific antibody titers against all four homologous vaccine strains were enhanced by AF03, indicating potential increase in protective immunity. An increase in HA-specific total immunoglobulin G (IgG) binding titers were detected against homologous HAs, heterologous panel of 30 H3 HAs and seven Influenza B HAs. The neuraminidase inhibition (NAI) activity was significantly higher in IIV4-SD-AF03 group. Use of AF03 adjuvant improved the immune response to two influenza vaccines in a mouse model via an increase in functional and total antibodies against NA and a broad panel of HA-antigens., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [I.V.U., S.P., T.F., T.S., V.G., K.B.Z, S.C., and A.P.G are employees of Sanofi and as such, may be eligible for Sanofi stock and stock options. M.B. was employed with Sanofi at the time of study conduct and currently affiliated with RA Ventures, Boston, MA, USA.]., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

During the 2009 H1N1 influenza pandemic, vaccines for the virus became available in large quantities only after human infections peaked. To accelerate vaccine availability for future pandemics, we developed a synthetic approach that very rapidly generated vaccine viruses from sequence data. Beginning with hemagglutinin (HA) and neuraminidase (NA) gene sequences, we combined an enzymatic, cell-free gene assembly technique with enzymatic error correction to allow rapid, accurate gene synthesis. We then used these synthetic HA and NA genes to transfect Madin-Darby canine kidney (MDCK) cells that were qualified for vaccine manufacture with viral RNA expression constructs encoding HA and NA and plasmid DNAs encoding viral backbone genes. Viruses for use in vaccines were rescued from these MDCK cells. We performed this rescue with improved vaccine virus backbones, increasing the yield of the essential vaccine antigen, HA. Generation of synthetic vaccine seeds, together with more efficient vaccine release assays, would accelerate responses to influenza pandemics through a system of instantaneous electronic data exchange followed by real-time, geographically dispersed vaccine production.

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., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Production lots of a live influenza vaccine made of strains A/47/T (N1H1), A/47/6/2 (H3N2), and B/60/32 were used for vaccination of 3663 children aged from 5 to 14 years inoculated twice with monovaccines, a trivaccine made of the above strains, or placebo. Both mono- and polyvaccine were practically areactogenic. An average per cent of subjects with a significant rise in antibody titres to the respective three antigens was 60%. The efficacy of the vaccination was 31.0-42.8% for monopreparations and 36.3% for the trivaccine. The studies showed the possibility and expedience of using for children the live influenza vaccine in the form of a polyvalent preparation including current influenza type A and B viruses.

The reactogenicity and immunizing activity of vaccine influenza virus A (H1N1) and B strains used as mono- and bi-preparations in children of 3 to 14 years was studied. No increased reactogenicity after the use of bivaccine was observed in the children. Febrile reactions as well as 9 other clinical symptoms which could indicate the reactogenicity of the vaccines were identical for mono- and bivaccine and corresponded to the requirements of the technical documents for the vaccine. The optimal conditions for the evaluation of the immunogenicity of the B component by HI test were developed, and the necessity of using additionally the enzyme immunoassay for this purpose is substantiated. The above method demonstrated that the immunogenicity of the live influenza type A and B vaccine was high in children. No significant inhibition of immunological parameters was observed when the two viruses were combined in the bivaccine.