Vaccines used against seasonal influenza are poorly effective against influenza A viruses of novel subtypes that may cause pandemic. Pre-pandemic influenza vaccines are poorly immunogenic against the upcoming pandemic virus that might be overcome by the use of a potent adjuvant. In humans, a limited number of adjuvants has been approved for human use and mostly human influenza vaccines are not adjuvanted.Furthermore, pre-pandemic influenza vaccines are poorly immunogenic to the upcoming pandemic. Thus, there is a need for alternative safe and effective adjuvants that can enhance the immunogenicity of influenza vaccines and that promote the induction of broad-protective T cell responses. Most studies of pandemic outbreaks have been done in humans. Also in animal spp problems exist with influenza virus infections. However, in the animal field the situation is different where one and the same influenza virus strain may circulate in the population finding new accessible victims in new non-exposed individuals.
Influenza virus infections cause severe morbidity and mortality in the human population . For overcoming such problems annual vaccination of high risk groups is recommended. The inactivated trivalent influenza vaccines are used that elicit strain-specific antibodies [2,3]. However, these vaccines fail to afford long lasting protection due to antigenic drift of influenza viruses [4-6] but also human Influenza vaccines are not highly immunogenic requiring regular updating.
Vaccine strains not matching the infecting virus have reduced effectiveness . The emergence of an antigenically distinct influenza virus of a novel subtype triggers a pandemic to which inactivated seasonal influenza vaccines afford little
protection . Thus, it is obvious that influenza virusvaccine should be formulated that not only induce neutralizing
antibodies to seasonal influenza viruses but also induce more broadly protective immune responses over alternative protective antigenic determinants also on alternative proteins and recruiting alternative immune mechanisms.
In a recent study at Carolien E,et al. , Dept of viroscience, Erasmus university MC,) Rotterdam, The Netherlands evaluated a novel nanoparticle, G3, as an adjuvant in a seasonal trivalent inactivated influenza vaccine in a mouse model. The G3 adjuvant was formulated with (G3/DT: DT, for diterpenoid). or without steviol glycoside diterpenoid. The use of both formulations enhanced potently the virus-specific antibody responses to all three vaccine strains. The adjuvants were well tolerated without any signs of discomfort. To assess the protective potential of the vaccine-induced immune responses, an antigenically distinct H1N1 influenza virus strain, A/Puerto Rico/8/34 (A/PR/8/34), was used for challenge infection. This strain was selected because it like the H1N1 virus in the most recent influenza virus outbreak lacked hemagglutination (HI) and virus neutralizing (VN) epitopes on the HA-protein.The vaccine-induced antibodies did not recognize HI or VN antigenic determinants on the challenge virus i.e. it did not cross-react with strain A/PR/8/34 in HI and VN assays. However, mice immunized with the G3/DT-adjuvanted vaccine showed Protective immunity against A/PR/8/34 infection, which correlated with the induction of anamnestic virus-specific CD8+ T cell responses to epiotopes located on the structural nukleo protein (NP) and more remarkable on the non-structural polymerase A (PA), which were not observed with the use of G3 without DT.
G3 and G3/DT enhance the vaccine-induced antibody responses upon vaccination none of the mice displayed any signs of discomfort. Limited weight loss (<2%) was observed during two days post vaccination in some mice randomly distributed
over the experimental groups, including those that received PBS
only All mice that received the trivalent inactivated influenza
vaccine i.e. non-adjuvanted vaccine or vaccine adjuvanted
with G3 alternatively with G3/DT developed HI antibody titres
against the three vaccine strains (A/California/7/2009, A/
Victoria/361/2011 and B/Hubei-Wujiang/158/2009) after the
first vaccination. The geometric mean titers (GMTs) of mice
that received the vaccine with adjuvant G3/DT or G3 were
significantly higher than those of mice that received the nonadjuvanted
vaccine.Four weeks after the second vaccination the
GMTs against the vaccine strains increased in the mice receiving
the non-adjuvanted vaccine. Although the GMTs of groups that
received the G3/DT and the G3 adjuvanted vaccine respectively,
did not increase after the second vaccination, they remained
significantly higher than the GMTs of receiving non-adjuvanted
vaccine adjuvant) (p<0.01).
In none of the mice, vaccine-induced antibodies were
cross-reactive with the influenza virus challenge strain A/
PR/8/34. Virus-specific CD8+ T cells were detected in the G3/
DT adjuvanted vaccine group only. The CD8+ T cells were specific
for the NP366-374 and the PA224-233 epitopes present in the A/
PR/8/34 influenza A vaccine strains and the A/PR/8/34 virus
used for challenge infection. Thus, CD8+ T cells had contributed
to the protection observed in mice that received the G3/DTadjuvanted
vaccine. Weight loss is a disease criterion and all
mice vaccinated or not displayed similar weight loss, starting at
day 2 p.i. until day 4 p.i. From day 5 p.i. onwards mice vaccinated
with the G3/DT-adjuvanted vaccine started to gain weight and
recovery. Furthermore, The G3/DT adjuvanted vaccine restricted
virus replication in the lungs compared to the other two vacc8ine
groups van De Sandt
G3/DT improves the protective efficacy of the split virion
vaccine against an antigenically distinct influenza virus
challenged two weeks after the second vaccination mice with a
lethal dose of influenza A/PR/8/34.
Regardless the influenza virus infects man or animal there
is a need for update of Influenza virus vaccines. Here we give
clear evidence that influenza virus vaccine can be formulated to
inducing broadened immune protection. Most important now
is to define & design efficient adjuvants recruiting new antigen
and antigen determinants and alternative immune mechanisms.
Here, I like to underline an innovative mechanism of the G3/DT
adjuvant that can enhance the immune mechanism harboured in
RNA by promoting expression of the non-structural PA containing
an immune protective epitope. That and other effects named in
this article should stimulate adjuvant development and open
for enhancing protection mechanisms overcoming the evasion
mechanisms of influenza virus as well of other pathogens.