Inactivated influenza H5N1 whole-virus vaccine with aluminum adjuvant induces homologous and heterologous protective immunities against lethal challenge with highly pathogenic H5N1 avian influenza viruses in a mouse model
In response to recent outbreaks of H5N1 highly pathogenic avian influenza virus (HPAIV), the development of an effective H5N1 influenza vaccine is urgently important. We assessed the efficacy of two inactivated H5N1 whole-virus vaccines, rgHK213/03 and rgVNJP1203/04, generated by reverse genetics in a mouse model in the presence or absence of aluminum hydroxide (alum) adjuvant. Mice immunized with rgHK213/03 vaccine produced sufficient levels of serum antibodies that were cross-reactive to recent heterologous HPAIV-H5N1 virus, A/Turkey/12/06. The vaccinated mice also elicited protective immunity against challenge with both homologous and heterologous HPAIV-H5N1 viruses. These immune responses were enhanced by addition of alum adjuvant, resulting in antigen sparing of vaccine. On the other hand, mice immunized with rgVNJP1203/04 vaccine had low levels of serum antibodies and less protective immunity than that elicited with rgHK213/03 vaccine regardless of addition of alum adjuvant. Our study suggests that rgHK213/03 vaccine is still useful as a backup vaccine for recent H5N1 viruses and that if rgVNJP1203/04 vaccine is employed, more vaccine antigen would be necessary to induce sufficient immunity.
"Vaccine virus was propagated in the allantoic cavity of the 10-day-old embryonated chicken's egg. Allantoic fluid was harvested 72 h post infection and was clarified by centrifugation at 8000 rpm for 10 min at 4 8C as described previously (Ninomiya et al., 2007). The virus was harvested and inactivated with formalin and adjuvanted with mineral oil to form a water-in-oil emulsion vaccine. "
"Failure to anticipate the emergence of an epidemic strain with significant antigenic changes compared to the vaccine strain will greatly reduce vaccine-induced protection. Several studies have suggested that proper adjuvant might improve the immunity of influenza vaccine and reduce the dose of vaccine [5-10]. Aluminum hydroxide (alum) is currently the only human vaccine adjuvant approved for use in the United States, and although it is effective at boosting antibody responses, these responses require repeated administration and tend to generate antiparasitic T helper 2 (TH2), rather than antiviral and antibacterial TH1, T cell immunity . "
[Show abstract][Hide abstract] ABSTRACT: Background
Influenza virus has antigen drift and antigen shift effect, vaccination with some influenza vaccine might not induce sufficient immunity for host to the threat of other influenza virus strains. S-OIV H1N1 and H5N1 influenza vaccines in single-dose immunization were evaluated in mice for cross protection to the challenge of A/California/7/2009 H1N1 or NIBRG-14 H5N1 virus.
Both H1N1 and H5N1 induced significant homologous IgG, HAI, and microneutralization antibody responses in the mice, while only vaccines plus adjuvant produced significant heterogeneous IgG and HAI antibody responses. Both alum and MPLA adjuvants significantly reduced the S-OIV H1N1 vaccine dose required to elicit protective HAI antibody titers from 0.05 μg to 0.001 μg. Vaccines alone did not protect mice from challenge with heterogeneous influenza virus, while H5N1 vaccine plus alum and MPLA adjuvants did. Mouse body weight loss was also less significant in the presence of adjuvant than in the vaccine without adjuvant. Furthermore, both H1N1 and H5N1 lung viral titers of immunized mice were significantly reduced post challenge with homologous viruses.
Only in the presence of MPLA adjuvant could the H5N1 vaccine significantly reduce mouse lung viral titers post H1N1 virus challenge, and not vice versa. MPLA adjuvant induced cross protection with a single dose vaccination to the challenge of heterogeneous influenza virus in mice. Lung viral titer seemed to be a better indicator compared to IgG, neutralization antibody, and HAI titer to predict survival of mice infected with influenza virus.
"Although many materials have been reported having adjuvant property, alum (a term for aluminum-based mineral salts) is the first adjuvant approved by the U.S. Food and Drug Administration (FDA) in the influenza vaccines for human use. However, highly heterogeneous, difficult to manufacture in a consistent and reproducible manner, and a boost injection required to generate protection limited alum in influenza vaccine use [9,10]. It is also found that certain antigens do not adsorb well onto alum due to the presence of the same charge on the adjuvant and antigens . "
[Show abstract][Hide abstract] ABSTRACT: Vaccination remains one of the most effective approaches to prevent the spread of infectious diseases. Immune responses to vaccination can be enhanced by inclusion of adjuvant in a vaccine. Paclitaxel extracted from the bark of the Pacific yew tree Taxus brevifola was previously demonstrated to have adjuvant property. Compared to paclitaxel, docetaxel is another member of taxane family, and is more soluble in water and easier to manipulate in medication. To investigate the adjuvant effect of this compound, we measured the immune responses induced by co-administration of a split inactivated influenza H1N1 vaccine antigen with docetaxel.
When co-administered with docetaxel, lower dose antigen (equivalent to 10 ng HA) induced similar levels of IgG and IgG isotypes as well as HI titers to those induced by higher dose antigen (equivalent to 100 ng HA). Docetaxel promoted splenocyte responses to H1N1 antigen, ConA and LPS, mRNA expressions of cytokines (IFN-gamma, IL-12, IL-4 and IL-10) and T-bet/GATA-3 by splenocytes. The enhanced immunity was associated with up-expressed microRNAs (miR-155, miR-150 and miR-146a) in docetaxel-stimulated RAW264.7 cells. Docetaxel promoted similar IgE level to but alum promoted significantly higher IgE level than the control.
Docetaxel has adjuvant effect on the influenza H1N1 vaccine by up-regulation of Th1/Th2 immune responses. Considering its unique vaccine adjuvant property as well as the safe record as an anti-neoplastic agent clinically used in humans during a long period, docetaxel should be further studied for its use in influenza vaccine production.
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