Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Abstract

A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7 -/-mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.Keywords: Antibodies r Immunotherapy r Toll like receptors r Vaccination r Virology IntroductionInfection with influenza virus is a major cause of morbidity as well as mortality throughout the world. Influenza virus is a very dynamic pseudo species and constantly avoids immunity at the population level by accumulating mutations in the hemagglutinin (HA) and neuraminidase molecules in a process called genetic drift. In addition, in a rare process called genetic shift, human influenza viruses may reassort with avian or swine influenza viruses [1]. Since under these circumstances, the virus hits an essentially naive population, the epidemic may become a pandemic with potentially millions of people infected and killed by the virus.Correspondence: Dr. Martin F. Bachmann e-mail: martin.bachmann@me.com Induction of protective immunity against influenza virus, not affected by genetic drift or shift, is therefore a major goal in vaccine development [2,3]. T cells are usually more cross-reactive than antibodies [4][5][6] and additionally recognize more conserved, virus-internal proteins [7,8]. Induction of broadly reactive T cells by vaccination may therefore be a potential avenue to follow [9,10]. This, however, may be a difficult task, since protective T-cell responses are usually short lived in mice [11] and humans [12], and it has not been possible so far to induce long-lived T-cell mediated immunity by vaccination. An alternative approach represents the induction of protective antibody responses directed against conserved viral structures. The extracellular domain of M2 (M2e) is a candidate for such a vaccine. M2e is highly conserved in all influenza A strains and has hardly changed over the last 90 years [13,14]. Although the recently emerged pandemic influ...

Role of human Toll‐like receptors in naturally occurring influenza A infections

“…Nevertheless, recent studies have shown that TLR's role in regulating the adaptive responses can be harnessed to boost immunogenicity of influenza vaccines (e.g., TLR9 or TLR7 ligands as adjuvants). This may be particularly useful in the elderly and the immunologically naïve vaccinees 4, 33, 34, 35, 36, 37, 38, 39, 40. Our data in natural influenza provide additional support to this new vaccination approach.…”

The Magnitude and IgG Subclass of Antibodies Elicited by Targeted DNA Vaccines Are Influenced by Specificity for APC Surface Molecules

“…Recently, broadly neutralizing HA stalk-specific Abs were found to require binding to FcgR for protection against influenza, and protection was restricted to the IgG2a subclass (50,51). In contrast, neutralizing Abs that block the sialic acid-binding receptor of HA can equally well be of the IgG1 subclass (50).…”

Influenza virus A(H1N1)2009 antibody-dependent cellular cytotoxicity in young children prior to the H1N1 pandemic

“…Interestingly, both pre-and postpandemic anti-H1-09 antibodies induced ADCC in response to A(H1N1)2009 HA1, HA or live virus. These ADCC antibodies reconstitute a specific set of antibodies of which the properties are incompletely understood but could provide immune protection: NK cells provide a non-specific first line of immune defence, but NK-mediated ADCC also affects adaptive immunity by enabling or enhancing neutralization and T-cell responses (DiLillo et al, 2014;Schmitz et al, 2012;Tamura et al, 1993).…”

“…Interaction between antibodies on the surface of influenza virus-infected cells and the Fcg-receptor(R) on natural killer (NK) cells results in the killing of those cells, a process called antibodydependent cellular cytotoxicity (ADCC) (reviewed in (Jegaskanda et al, 2014a). It has been suggested that the recruitment of these antibody-mediated Fc-FcgR-expressing effector cells by antibodies is a major in vivo mechanism of antibody-mediated protection from infection (DiLillo et al, 2014;Schmitz et al, 2012). DiLillo et al showed that broadly cross-reactive antibodies (bNAbs) directed against the HA stalk domain were able to induce ADCC, whereas the bNAbs against the head domain were not, showing a poor interaction of the more specific HA-head Ab with the FcgRs.…”