Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans

Abstract

Humans are repeatedly exposed to variants of influenza virus throughout their lifetime. As a result, preexisting influenza-specific memory B cells can dominate the response after infection or vaccination. Memory B cells recalled by adulthood exposure are largely reactive to conserved viral epitopes present in childhood strains, posing unclear consequences on the ability of B cells to adapt to and neutralize newly emerged strains. We sought to investigate the impact of preexisting immunity on generation of protective antibody responses to conserved viral epitopes upon influenza virus infection and vaccination in humans. We accomplished this by characterizing monoclonal antibodies (mAbs) from plasmablasts, which are predominantly derived from preexisting memory B cells. We found that, whereas some influenza infection–induced mAbs bound conserved and neutralizing epitopes on the hemagglutinin (HA) stalk domain or neuraminidase, most of the mAbs elicited by infection targeted non-neutralizing epitopes on nucleoprotein and other unknown antigens. Furthermore, most infection-induced mAbs had equal or stronger affinity to childhood strains, indicating recall of memory B cells from childhood exposures. Vaccination-induced mAbs were similarly induced from past exposures and exhibited substantial breadth of viral binding, although, in contrast to infection-induced mAbs, they targeted neutralizing HA head epitopes. Last, cocktails of infection-induced mAbs displayed reduced protective ability in mice compared to vaccination-induced mAbs. These findings reveal that both preexisting immunity and exposure type shape protective antibody responses to conserved influenza virus epitopes in humans. Natural infection largely recalls cross-reactive memory B cells against non-neutralizing epitopes, whereas vaccination harnesses preexisting immunity to target protective HA epitopes.

Aging and Options to Halt Declining Immunity to Virus Infections

“…Moreover, these individuals exhibit a reduced accumulation of “ de novo ” mutations in the Ig variable gene affecting the adaptability of their antibody responses to influenza virus ( 337 , 338 ). Therefore, this age group mainly rely on cross-reactive memory B cells generated early in life ( 339 ). Interestingly, a recent study has shown that influenza virus infection predominantly recalls pre-existing memory B cells against non-neutralizing epitopes in contrast to vaccination that mainly targets memory B cells to protective HA epitopes.…”

“…Interestingly, a recent study has shown that influenza virus infection predominantly recalls pre-existing memory B cells against non-neutralizing epitopes in contrast to vaccination that mainly targets memory B cells to protective HA epitopes. One could speculate that boosting pre-existing immunity may play a key role in susceptibility versus protection upon influenza virus infection ( 339 , 340 ). Additional defects influencing the B cell responses to influenza virus infection or vaccination are reviewed elsewhere ( 99 ).…”

Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines

“…A unifying feature of influenza broadly neutralizing/broadly protective antibody responses is their immunological subdominance, a major stumbling block for universal vaccine development. Defined as the tendency of the immune system to respond to complex antigens in a hierarchical manner, the immunodominance patterns enforced following influenza infection and vaccination prioritize the expansion of non-neutralizing antibodies against 'off-target' hypervariable features at the expense of 'on-target' responses engaging functionally conserved epitopes [1,[78][79][80][81][82][83] (Figure 2). Structure-based influenza immunogens applied within transgenic mouse systems bearing user-defined B cell receptor (BCR) repertoires, along with similar approaches using HIV antigens, have enabled experimental manipulation of these parameters [84][85][86][87][88][89][90][91][92].…”

“…HA stalk-focusing vaccine concepts have received much attention due to the relative conservation and presentation of bnAb epitopes that confer broad heterosubtypic neutralization and protection [1,4,31,34,35]. At the level of B cell memory, a major factor shaping the human antibody response to influenza viral antigens is pre-existing immunity, imprinted by prior infection and/or vaccination [82,155,156]. While such memory is skewed for strain-specific reactivity, resulting in potentially confounding antigenic sin effects, studies in animals have demonstrated the capacity to selectively recall broadly protective B cell memory against conserved stalk epitopes by sequential exposure to chimeric strain-variant HA immunogens (cHA) [157][158][159][160] (Figure 4A).…”

“…The memory recall of stalk bnAbs can also occur during natural exposure, as evidenced following infection with the highly divergent 2009 pandemic H1N1 virus [40]. Notably, however, pre-existing immunity is often complex and can vary between individuals [82,155,156]. Thus, ensuring the uniformity of broadly protective memory recall will continue to be an important factor moving forward.…”