A VLP Vaccine Induces Broad-Spectrum Cross-Protective Antibody Immunity against H5N1 and H1N1 Subtypes of Influenza A Virus

Abstract

The recent threats of influenza epidemics and pandemics have prioritized the development of a universal vaccine that offers protection against a wider variety of influenza infections. Here, we demonstrate a genetically modified virus-like particle (VLP) vaccine, referred to as H5M2eN1-VLP, that increased the antigenic content of NA and induced rapid recall of antibody against HA2 after viral infection. As a result, H5M2eN1-VLP vaccination elicited a broad humoral immune response against multiple viral proteins and caused significant protection against homologous RG-14 (H5N1) and heterologous A/California/07/2009 H1N1 (CA/07) and A/PR/8/34 H1N1 (PR8) viral lethal challenges. Moreover, the N1-VLP (lacking HA) induced production of a strong NA antibody that also conferred significant cross protection against H5N1 and heterologous CA/07 but not PR8, suggesting the protection against N1-serotyped viruses can be extended from avian-origin to CA/07 strain isolated in humans, but not to evolutionally distant strains of human-derived. By comparative vaccine study of an HA-based VLP (H5N1-VLP) and NA-based VLPs, we found that H5N1-VLP vaccination induced specific and strong protective antibodies against the HA1 subunit of H5, thus restricting the breadth of cross-protection. In summary, we present a feasible example of direction of VLP vaccine immunity toward NA and HA2, which resulted in cross protection against both seasonal and pandemic influenza strains, that could form the basis for future design of a better universal vaccine.

Cross-Reactive Neuraminidase-Inhibiting Antibodies Elicited by Immunization with Recombinant Neuraminidase Proteins of H5N1 and Pandemic H1N1 Influenza A Viruses

“…Live attenuated influenza vaccines for seasonal H1N1, H3N2, and pH1N1 strains have been reported as inducing cross-reactive NI antibodies to H5N1 viruses in ferrets (21), and NI antibodies elic-ited by a seasonal trivalent influenza vaccine have been reported as providing cross-protective immunity against lethal H5N1 challenges, also in ferrets (22). Furthermore, NA-based virus-like particles (VLPs) containing NA and matrix proteins M1 and M2 have been shown to elicit more potent NI antibodies and to confer cross-protective immunity against H5N1 and pH1N1 viral challenges in mice (23). NI antibodies have also been detected in humans vaccinated with an H5N1 inactivated vaccine (24), as well as in humans exposed to natural infections (25).…”

Biological and Protective Properties of Immune Sera Directed to the Influenza Virus Neuraminidase

“…The NA antigen has been used for experimental vaccination employing plasmid vectors (32)(33)(34), viral vectored vaccines (35), virus-like particles (36,37), and recombinant subunit vaccines (38,39). In mammalian hosts, these vaccines conferred partial or even complete protection from infection with human or avian influenza viruses (15,19,32,33,(35)(36)(37)(38)(39).…”

“…In mammalian hosts, these vaccines conferred partial or even complete protection from infection with human or avian influenza viruses (15,19,32,33,(35)(36)(37)(38)(39). In contrast, NA vaccines based on recombinant Newcastle disease virus (NDV) or infectious laryngotracheitis virus (ILTV) failed to protect chickens from lethal infection with highly pathogenic avian influenza virus (HPAIV), although the survival times of the animals were prolonged (40)(41)(42).…”

Kinetics, Longevity, and Cross-Reactivity of Antineuraminidase Antibody after Natural Infection with Influenza A Viruses

“…Cross-reactive NI antibodies to H1N1pdm virus have been detected in individuals who were immunized with a live-attenuated seasonal influenza vaccine (24). Cross-reactivity between NI antibodies against H1N1pdm and H5N1 viruses has also been reported (21,(25)(26)(27)(28)(29)(30). NI antibodies to seasonal influenza H1N1 virus provided immunity to mice against H5N1 virus challenge (12).…”