The immune correlates of protection for an avian influenza H5N1 vaccine in the ferret model using oil-in-water adjuvants

Abstract

Because of the pathogenicity and low incidence of avian influenza virus infections in humans, the immune correlates of protection for avian influenza vaccines cannot be determined from clinical studies. Here, we used the ferret model to address this for an avian influenza H5N1 vaccine. Using oil-in-water adjuvants, we generated groups of ferrets with undetectable (geometric mean titer [GMT] < 10), low (GMT = 28.3), or high (GMT > 761.1) hemagglutination-inhibition (HAI) titers to the A/Viet Nam/1203/2004 (H5N1) virus. Ferrets were then challenged with the wild-type virus and disease severity and immunologic parameters were studied. The severity of infection and symptom profile were inversely associated with pre-challenge HAI titers in a dose-dependent manner. A vaccinated ferret with no detectable HAI-antibodies but high flu-specific IgG-antibody titers mounted rapid functional antibodies after infection and experienced milder disease compared to other ferrets in the group. Compared to naïve ferrets, all vaccinated ferrets showed improved cellular immunity in the lungs and peripheral blood. High number of IFNγ+ CD8- T cells in the airways was associated with early viral clearance. Thus, while neutralizing antibodies are the best correlate of protection, non-neutralizing antibodies can also be protective. This should be taken into consideration in future avian influenza vaccine trials.

H5N1 influenza vaccine induces a less robust neutralizing antibody response than seasonal trivalent and H7N9 influenza vaccines

“…We have since shown that although neutralizing (HAI and MN) antibodies are the best immune correlate for protection, non-neutralizing antibodies can still reduce disease severity. 46 Hence, despite the possibility of vaccine degradation, this batch of stockpiled vaccine can still afford protection, especially when administered with adjuvants.…”

Immune Imprinting in the Influenza Ferret Model

“…Even with the addition of an adjuvant, the immune response can be weak, especially when compared to the immune response elicited by a live homologous infection [45,46]. The lack of an antibody response is associated with a lack of protection [47]. For instance, naïve ferrets immunized with A(H3N2)/Hong Kong/X31/1968 vaccine were all susceptible to homologous challenge and none produced vaccine-specific serum HAI antibodies [39].…”

“…Due to this issue, pandemic influenza vaccines can be adjuvanted to ensure an efficient immune response [52][53][54][55]. With the inclusion of different adjuvants, different magnitudes of seroconversion and protection can be achieved [47]. Some studies used virus-like particle (VLP) vaccines produced from insect cells using a baculoviral system which results in 100% seroconversion [56,57].…”

Selective induction of antibody effector functional responses using MF59-adjuvanted vaccination

“…Although the development of broadly neutralizing antibody responses against influenza remains a critical goal, emerging evidence suggests that extra-neutralizing antibody functions also play an important role in protection from infection (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Studies with passive transfer of neutralizing monoclonal antibodies in mice have shown that Fcγ receptors are required for protection from lethal infection, via mechanisms that do not block viral entry (18).…”