Adjuvanted influenza vaccine

The current status of adjuvanted influenza vaccines has been reviewed (26). The authors concluded that the vaccine produces a higher titer of antibodies than non-adjuvanted or virosomal vaccines. Local reactions occur more often, but are mild and transient. The results of a trial with two doses of an intranasally administered inactivated virosome-formulated influenza vaccine containing Escherichia coli heat-labile toxin as a mucosal adjuvant in 106 volunteers aged 33-63 years have been reported (27). About 50% of vaccinees had local adverse reactions (44% after the first dose and 54% after the second dose) or systemic adverse reactions (48 and 46%) after administration of the vaccine. Rhinorrhea, sneezing, and headache were the most common reactions they were mild and transient and resolved within 24-48 hours. No febrile reactions were associated with immunization. Between 77 and 92% of vaccinees developed protective hemagglutination inhibition antibody titers against the two influenzae A strains of the vaccine, whereas protective antibody titers against the B strain of the vaccine were achieved in only 49-58%. 

De Donato S, Granoff D, Minutello M, Lecchi G, Faccini M, Agnello M, Senatore F, Verweij P, Fritzell B, Podda A. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine 1999 17(23-24) 3094-101. 

Pellegrini M, Nicolay U, Lindert K, Groth N, Della Cioppa G. MF59-adjuvanted versus non-adjuvanted influenza vaccines integrated analysis from a large safety database. Vaccine 2009 27(49) 6959-65. 

Lethality studies of three Quillaja HPLC-fractions, QH-A, QH-B, QH-C in ICR mice showed higher toxicity associated with QH-B (7/10 deaths at 400 pg) than with QH-A or QH-C (0/10 deaths at 400 pg for both) or when QH-C was incorporated into ISCOM matrix (0/10 deaths at 800 pg) [38]. These results explained that these fractions were added in a ratio of 7 0 3 in the new ISCOM-adjuvanted influenza vaccine. 

The discussions aroxmd the AS03-adjuvanted influenza vaccine and an association with narcolepsy continue. A rebospective analysis of background rates of narcolepsy was essential to investigate a causal relationship. A study that addressed this used a dynamic rebospective cohort approach in order to assess rates of narcolepsy between... 

Podda A. 2001. The adjuvanted influenza vaccines with novel adjuvants Experience with the MF59-adjuvanted vaccine. Vaccine 19(17-19) 2673-2680. 

Thymosin is an immunomodulatory peptide produced by the thymus gland and other cells. Thymosin alfa 1, a 28-amino acid peptide, is one member of the family of thymosins that collectively appear to influence a variety of regulatory and counter-regulatory functions in terms of T-cell maturation and antigen recognition, stimulation of native interferons and cytokines such as interleukin-2, and activity of natural killer cell-mediated cytotoxicity. In some countries it is approved as an adjuvant for influenza vaccine or as a treatment for chronic hepatitis B and, in combination with interferon for hepatitis C. Thymosin alfa 1 has been used with some success to treat children with the severe form of Di-George Syndrome. 

The most potent mucosal adjuvants have been shown to be the toxins derived from Vibrio cholerae or Escherichia coli, which should not be surprising since these organisms invade the body through the GI tract. Obviously too toxic for human use because they are the source of cholera or diarrhoea, heat labile enterotoxins have been tested in mice and shown to be potent adjuvants for orally or nasally administered influenza vaccine. The potency of heat-labile enterotoxin mutants may also be enhanced by formulation into bioadhesive particulate delivery systems, and this is an area under current exploration. 

The immunostimulating activity of chitosan has also been reported. A 70% DD chitosan showed immunostimulating effects by activating macrophages and natural killer cells in rats when infected with . coli and Sendai virus (Nishimura et al., 1984). Chang et al. (2004) also reported the immune-enhancing effects of chitosan as a novel adjuvant to an inactivated influenza vaccine, and the antibody content in serum remarkably increased the antiviral defenses of mice. 

Chang, H. Y., Chen, J. J., Fang, F., and Chen, Z. (2004). Enhancement of antibody response by chitosan, a novel adjuvant of inactivated influenza vaccine. Chin. J. Biol. 17, 21-24. 

Cataldo DM, Van Nest G. The adjuvant MF59 increases the immunogenicity and protective efficacy of subunit influenza vaccine in mice. Vaccine 1997 15 1710-1715. 

Higgins DA, Carlson JR, Van Nest G. MF59 adjuvant enhances the immunogenicity of influenza vaccine in both young and old mice. Vaccine 1996 14 478 484. 

Hagiwara, Y., Komase, K., Chen, Z., Matsuo, K., Suzuki, Y., Aizawa, C., Kurata, T., and Tamura, S. (1999), Mutants of cholera toxin as an effective and safe adjuvant for nasal influenza vaccine, Vaccine, 17, 2918-2926. 

Influenza vaccine viruses are propagated in embryonated chicken eggs. The virus-containing extra-embryonic fluid is harvested, purified, and inactivated with formalin. Inactivated flu vaccine is produced either as whole virus vaccine or ether-disrupted split or subunit preparations. However, many other new or modified influenza vaccines are already available or are expected to appear in the near future, for example vaccines containing new adjuvants, live attenuated vaccines, and vaccines administered by alternative routes. 

Gluck R, Mischler R, Durrer P, Furer E, Lang AB, Herzog C, Cryz SJ Jr. Safety and immunogenicity of intranasally administered inactivated trivalent virosome-formulated influenza vaccine containing Escherichia coli heat-labile toxin as a mucosal adjuvant J Infect Dis 2000 181(3) 1129-32. 

Ruf BR, Colberg K, Frick M, Preusche A (2004) Open, randomized study to compare the immunogenicity and reactogenicity of an influenza split vaccine with an MF59-adjuvanted subunit vaccine and a virosome-based subunit vaccine in elderly. Infection 32 191-198... 

G.A. (1994) Systemic cytokine profiles in BALB/c mice immunized with trivalent influenza vaccine containing MF59 oil emulsion and other advanced adjuvants. J. Immunol. 153, 4029-4039. 

Ghendon, Y., Markushin, S., Krivtsov, G., and Akopova, I. 2008. Chitosan as an adjuvant for parenterally administered inactivated influenza vaccines. Arc/j. Virol. 153 831-837. 

Ghendon, Y, S. Markushin, G. Krivtsov, and 1. Akopova. 2008. Chitosan as an adjuvant forparenterally administered inactivated influenza vaccines. Archives of Virology 153 (5) 831-837. 

HAI ANTIBODY RESPONSE OF YOUNG MONKEYS GIVEN 200 CCA UNITS OF SWINE INFLUENZA VACCINE WITH POLY(ICLC) AS ADJUVANT (N = 4)... 

Davidson LE, Fiorino AM, Snydman DR, Hibberd PL. Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults a randomized double-blind placebo-controlled trial. Eur J Clin Nutr. 2011 65 501-507. 

Three saponin fractions of interest (QH-A, QH-B, QH-C) have been obtained from an aqueous extract of the Quillaja bark by reversed HPLC according to their elution profile. The mixture of these compounds in a ratio 7 0 3 knovvm as ISCO-PREP 7.0.3 has recently been tested as a component of a new ISCOM-adjuvanted human influenza vaccine. ... 

Quil A has been the major saponin mixture used for ISCOM work to date. The major modification to ISCOM technology has been the use of three HPLC-fractions of Quillaja saponaria bark aqueous extract named QH-A, QH-B and QH-C [47]. The ratio 7 0 3 for these fractions known as ISCOPREP 7.0.3. has been recently tested as a component of a new ISCOM-adjuvanted human influenza vaccine. 

Indeed, it is a formulation for a classical, currently marketed influenza vaccine that was first passed to phase I clinical trials [34], whereby PCPP showed an adjuvant effect after a single injection on 3 strains of the virus. Although recommended for phase II trials by the authors, this data does not yet appear to have been published, if they were carried out. 

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