Seasonal Influenza Split Vaccines Confer Partial Cross-Protection against Heterologous Influenza Virus in Ferrets When Combined with the CAF01 Adjuvant

Abstract

Influenza epidemics occur annually, and estimated 5–10% of the adult population and 20–30% of children will become ill from influenza infection. Seasonal vaccines primarily work through the induction of neutralizing antibodies against the principal surface antigen hemagglutinin (HA). This important role of HA-specific antibodies explains why previous pandemics have emerged when new HAs have appeared in circulating human viruses. It has long been recognized that influenza virus-specific CD4(+) T cells are important in protection from infection through direct effector mechanisms or by providing help to B cells and CD8(+) T cells. However, the seasonal influenza vaccine is poor at inducing CD4(+) T-cell responses and needs to be combined with an adjuvant facilitating this response. In this study, we applied the ferret model to investigate the cross-protective efficacy of a heterologous trivalent influenza split-virion (TIV) vaccine adjuvanted with the CAF01 adjuvant, with proven ability to induce CD4(+) T-cell and antibody responses in mice, ferrets, pigs, primates, and humans. Our results indicate that CAF01-adjuvanted vaccine induces HA inhibition (HAI)-independent protection after heterologous challenge, manifested as reduced viral load and fever. On the other hand, we observe increased inflammation in the airways and more neutrophil and mononuclear cell infiltration in these ferrets when compared with optimally protected animals, i.e., ferrets receiving the same vaccine but a homologous challenge. This suggest that HAI-independent immunity induced by TIV + CAF01 can reduce viral shedding and systemic disease symptoms, but does not reduce local inflammation in the nasal cavity.

Influenza NG-34 T cell conserved epitope adjuvanted with CAF01 as a possible influenza vaccine candidate

“…Furthermore, the Addavax + NG-34 group did not boost Th1 and Th2 as demonstrated in other studies [25,26]. In contrast, our results were concordant with results using CAF01 combined with TIV, which conferred protection in an IHAindependent manner [29].…”

A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection

“…Another report indicated that cationic adjuvant formulation (CAF)01-adjuvanted TIV protected not only against homologous but also against heterologous IAV infection despite the absence of neutralization based on HI (34). CAF01 is a newly developed liposomal adjuvant which is based on liposomes formed by N,N′-dimethyl-N,N′-dioctadecylammonium with Fig.…”

“…the synthetic mycobacterial immunomodulator α,α′-trehalose 6,6′-dibehenate inserted into the lipid bilayers. In the study, Christensen et al (34) concluded that CAF01-adjuvanted TIV vaccine can reduce virus shedding and systemic disease symptoms, but does not reduce local inflammation in the nasal cavity. Although the subclass of HA-specific IgGs was not assessed in the study as experiments were primarily conducted in ferrets, we speculated that there were indeed differences in isotype switching for HA-specific IgGs when compared to vaccination with the conventional TIV alone, because CAF01 is known to induce T h 1/T h 17-type T-cell responses.…”

Carbohydrate Immune Adjuvants in Subunit Vaccines

“…CAF01 was also able to stimulate humoral immune responses. Trivalent influenza split-virion (TIV) vaccine was co-administered with CAF01 into ferrets [ 175 ]. The TIV-CAF01-vaccinated ferrets produced significantly higher influenza-specific IgG antibody titers than non-adjuvanted vaccine candidates.…”