An Intranasal Virus-Like Particle Vaccine Broadly Protects Mice from Multiple Subtypes of Influenza A Virus

Abstract

Influenza virus infections are a global public health problem, with a significant impact of morbidity and mortality from both annual epidemics and pandemics. The current strategy for preventing annual influenza is to develop a new vaccine each year against specific circulating virus strains. Because these vaccines are unlikely to protect against an antigenically divergent strain or a new pandemic virus with a novel hemagglutinin (HA) subtype, there is a critical need for vaccines that protect against all influenza A viruses, a so-called “universal” vaccine. Here we show that mice were broadly protected against challenge with a wide variety of lethal influenza A virus infections (94% aggregate survival following vaccination) with a virus-like particle (VLP) vaccine cocktail. The vaccine consisted of a mixture of VLPs individually displaying H1, H3, H5, or H7 HAs, and vaccinated mice showed significant protection following challenge with influenza viruses expressing 1918 H1, 1957 H2, and avian H5, H6, H7, H10, and H11 hemagglutinin subtypes. These experiments suggest a promising and practical strategy for developing a broadly protective “universal” influenza vaccine.

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

“…A recent publication by Schwartzman et al suggest that HA group 1/2 transcending immunity can be achieved in mice by intranasal immunization with a mixture of H1, H3, H5, and H7 virus-like particles (VLPs) [45]. In these experiments, mice were protected from lethal challenge with a number of influenza A viruses not contained in the vaccine [45]. These collective data beg the question whether the underlying mechanism, i.e.…”

“…A genetic distance map for H1N1 viruses is shown in Figure 3, and the variants used by [44]. A recent publication by Schwartzman et al suggest that HA group 1/2 transcending immunity can be achieved in mice by intranasal immunization with a mixture of H1, H3, H5, and H7 virus-like particles (VLPs) [45]. In these experiments, mice were protected from lethal challenge with a number of influenza A viruses not contained in the vaccine [45].…”

“…These collective data beg the question whether the underlying mechanism, i.e. EDiP, applies here and whether it may be possible to apply this mechanism to devise a vaccine that provides broad protection against all influenza A viruses [45]. It is not yet clear, however, how many separate components would be required to adequately cover all 16 influenza A HAs.…”

“…When comparing maximal amino acid distances between AMA1 and influenza H1 HA (Figures 2 and 3), it is evident that influenza HA is more variable than AMA1 [41,[43][44][45]. Huber et al have shown that a prime with DNA followed by a live-attenuated virus boost with a mixture of three H3N2 viruses (Hong Kong 1968, Victoria 1975, and Leningrad 1986) covers 20 years of antigenic drift in mice [43].…”

Antigenic variability: Obstacles on the road to vaccines against traditionally difficult targets

“…Thus, vaccination of mice with a mixture of virus-like particles (VLPs) individually displaying 4 different HAs offered significant protection against a variety of influenza A viruses, suggesting a promising strategy for developing a broadly protective or "universal" vaccine. 30 Using a rational design and library screening approach, stable HA stem Ags, bearing smaller versions of full-length HA called "mini-HAs" or HA stem mimics and based on an H1 subtype sequence, were engineered and shown to protect mice in lethal heterologous and hetero-subtypic challenge models and to reduce fever after sub-lethal challenge in cynomolgus monkeys. 31 Application of a lipopeptide-based Toll-like receptor 2 (TLR2) agonist together with an existing seasonal vaccine provided immediate short-term nonspecific antiviral protection and long-term immunity against vaccine-matched as well as unrelated virus strains, probably by simultaneously stimulating and amplifying both the innate and adaptive immune responses.…”