Mini-hemagglutinin vaccination induces cross-reactive antibodies in pre-exposed NHP that protect mice against lethal influenza challenge

Abstract

Seasonal vaccines are currently the most effective countermeasure against influenza. However, seasonal vaccines are only effective against strains closely related to the influenza strains contained in the vaccine. Recently a new hemagglutinin (HA) stem-based antigen, the so-called “mini-HA”, has been shown to induce a cross-protective immune response in influenza-naive mice and non-human primates (NHP). However, prior exposure to influenza can have a profound effect on the immune response to subsequent influenza infection and the protective efficacy of vaccination. Here we show that mini-HA, compared to a trivalent influenza vaccine (TIV), elicits a broadened influenza-specific humoral immune response in NHP previously exposed to influenza. Serum transfer experiments showed that antibodies induced by both mini-HA and seasonal vaccine protected mice against lethal challenge with a H1N1 influenza strain heterologous to the H1 HA included in the TIV. However, antibodies elicited by mini-HA showed an additional benefit of protecting mice against lethal heterosubtypic H5N1 influenza challenge, associated with H5 HA-specific functional antibodies.

Mini-HA Is Superior to Full Length Hemagglutinin Immunization in Inducing Stem-Specific Antibodies and Protection Against Group 1 Influenza Virus Challenges in Mice

“…In particular, even though both antigens contain the stem region of the HA protein, immunization with the H1 FL HA induced significantly less antibodies binding to the stem region. Confirming other studies comparing a HA-stem immunogen to FL HA immunization ( 18 , 19 , 22 , 23 , 26 ), our results show that the mini-HA overcomes these problems caused by the immuno-dominance of the HA head region, and elicits relatively high levels of stem-specific antibodies. We observed a markedly higher ratio between CR9114 competition titers and HA-stem binding antibody titers for mini-HA, relative to H1 FL HA immunization.…”

“…A promising new strategy in the development of broadly protective influenza vaccines is to direct the immune response toward the highly conserved HA stem region. By removing the immunodominant HA head a new so-called “mini-HA” was created and shown to induce cross-reactive and cross-protective antibodies in several animal models ( 22 , 23 , 26 ). However, the fact that a cross-protective immune response can also be observed in mice after multiple immunizations with a seasonal vaccine has raised the question whether in similar conditions, the mini-HA would show superiority over immunization with a H1 FL HA.…”

“…Cross-protection against influenza induced by immunization with the mini-HA or a seasonal vaccine previously has shown to be mediated by the humoral immune response in various studies ( 10 , 23 , 24 , 26 ). This has been confirmed in our experiments by the absence of any detectable HA-specific T-cell responses (data not shown).…”

“…Another strategy directing the immune response to the more conserved HA stem is by removing the immunodominant head region, constructing headless HA stem-based antigens. We recently described a stable trimeric headless group 1 influenza HA, the so-called “mini-HA,” while others pursued a hemagglutinin-stem nanoparticle based approach; both approaches led to formulations that were immunogenic and cross-protective against different phylogenetically distant influenza virus strains in mice, non-human primates (NHP) and ferrets ( 22 – 26 ).…”

Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics

“…universal | stem | influenza | antibody-dependent enhancement (ADE) | vaccine N onneutralizing antibodies may play a role in protection from disease following infection with diverse viruses, including HIV, cytomegalovirus (CMV), and influenza (1)(2)(3), supporting the design of novel influenza vaccines (1,(4)(5)(6). Such antibodies may provide protection in vivo via a plethora of Fc-dependent functions, including antibody-mediated cell cytotoxicity (ADCC) (7), antibody-dependent cell phagocytosis (ADCP), and antibodydependent complement-mediated lysis (ADCL) (6,8). However, nonneutralizing or low-affinity neutralizing antibodies following vaccination or infection have also been correlated with augmenting influenza disease postinfection in animal models and several human observational studies (9)(10)(11)(12)(13)(14)(15).…”