Abstract
ABSTRACTCurrent seasonal influenza virus vaccines target regions of the hemagglutinin (HA) head domain that undergo constant antigenic change, forcing the painstaking annual reformulation of vaccines. The development of broadly protective or universal influenza virus vaccines that induce cross-reactive, protective immune responses could circumvent the need to reformulate current seasonal vaccines. Many of these vaccine candidates target the HA stalk domain, which displays epitopes conserved within and across influenza virus subtypes, including those with pandemic potential. While HA head-mediated antigenic drift is well understood, the potential for antigenic drift in the stalk domain is understudied. Using a panel of HA stalk-specific monoclonal antibodies (MAbs), we applied selection pressure to the stalk domain of A/Netherlands/602/2009 (pdmH1N1) to determine fitness and phenotypes of escape mutant viruses (EMVs). We found that HA stalk MAbs with lower cross-reactivity caused single HA stalk escape mutations, whereas MAbs with broader cross-reactivity forced multiple mutations in the HA. Each escape mutant virus greatly decreased mAb neutralizing activity, but escape mutations did not always ablate MAb binding or Fc-Fc receptor-based effector functions. Escape mutant viruses were not attenuated in vitro but showed attenuation in an in vivo mouse model. Importantly, mice vaccinated with a chimeric HA universal vaccine candidate were protected from lethal challenge with EMVs despite these challenge viruses containing escape mutations in the stalk domain. Our study indicates that while the HA stalk domain can mutate under strong MAb selection pressure, mutant viruses may have attenuated phenotypes and do not evade a polyclonal, stalk-based vaccine-induced response.
Highlights
Current seasonal influenza virus vaccines target regions of the hemagglutinin (HA) head domain that undergo constant antigenic change, forcing the painstaking annual reformulation of vaccines
Generation of HA stalk escape mutant viruses using a panel of cross-reactive stalk-specific monoclonal antibodies (MAbs)
To better understand the effects of escape mutations on the HA stalk domain, we used a panel of stalk-specific MAbs: 6F12 [30], KB2 [32], 045-0513102B06 (2B06) [33], 05-2G02 (2G02) [34], FI6v3 (FI6) [29], and CR9114 [31]
Summary
Current seasonal influenza virus vaccines target regions of the hemagglutinin (HA) head domain that undergo constant antigenic change, forcing the painstaking annual reformulation of vaccines. The development of broadly protective or universal influenza virus vaccines that induce cross-reactive, protective immune responses could circumvent the need to reformulate current seasonal vaccines Many of these vaccine candidates target the HA stalk domain, which displays epitopes conserved within and across influenza virus subtypes, including those with pandemic potential. Mutations acquired in segments that encode the virus’ major glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are drivers of antigenic changes that can lead to escape from preexisting immune responses This process is known as antigenic drift and causes a need for annual reformulation of current seasonal influenza virus vaccines [2, 3]. Several universal influenza virus vaccine candidates that induce long-lasting and broad protection are under development These candidates are designed to redirect the immune response from the head domain toward the stalk domain to induce cross-reactive antibody responses. A prime-boost-boost vaccination strategy with different cHA constructs increased the levels of stalk-reactive antibodies in preclinical ferret models [26] and in a phase 1 clinical trial [27]
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