Circulating Human Antibody-Secreting Cells during Vaccinations and Respiratory Viral Infections Are Characterized by High Specificity and Lack of Bystander Effect

Abstract

Surges of serum antibodies after immunization and infection are highly specific for the offending antigen, and recent studies demonstrate that vaccines induce transient increases in circulating antibody-secreting cells (ASCs). These ASCs are highly enriched but not universally specific for the immunizing antigen, suggesting that a fraction of these ASCs could arise from polyclonal bystander stimulation of pre-existing memory cells to unrelated antigens. This model is proposed to explain maintenance of long-lived serological memory in the absence of antigen exposure. To test this model, we measure the ability of RSV and influenza virus infection or immunizations to influenza virus, tetanus toxoid, hepatitis B, and human papilloma virus to stimulate bystander memory cells specific for other major environmental antigens that represent a large fraction of the pre-existing memory B compartment. Bystander or non-specific ASC responses to RSV and tetanus could not be detected above the background levels in healthy adults, despite the presence of circulating memory B cells specific for the corresponding antigens. Non-specific ASC responses in the healthy subjects were similar to frequencies in cord blood samples. In contrast, both vaccination and infection induce massive expansion of circulating antigen-specific ASCs without significant increases in the frequencies of ASCs against unrelated antigens. Hence, non-specific stimulation of memory B cells is unlikely to contribute to the mechanisms of long-term serological memory against major human pathogens. Additionally, high specificity of circulating ASC after antigenic challenge highlight the diagnostic value of interrogating ASCs as an ideal one-time-point diagnostic immune surrogate for serology during acute infection.

Plasmablasts Generated during Repeated Dengue Infection Are Virus Glycoprotein–Specific and Bind to Multiple Virus Serotypes

“…The percentages of specific cells are consistent with the PB responses in influenza-immune patients infected with a new serotype of influenza (30). Moreover, Lee et al (38) recently reported that the PB response to respiratory syncytial virus and influenza virus infection measured by ELISPOT was remarkably Ag specific and showed little bystander activation.…”

Characterization of Plasmablasts in the Blood of HIV-Infected Viremic Individuals: Evidence for Nonspecific Immune Activation

“…1B). Taken together, these data show that active HIV replication is associated with and possibly responsible for the presence of ASCs in the blood and that percentages of HIV-specific ASCs are highest in early viremia, although these frequencies are much lower than in other acute viral infections (34)(35)(36)(37).…”

“…However, there are certain similarities between HIV and the other viruses that relate to kinetics of exposure and the Ig isotype of blood PBs. With regard to temporal relationships, the burst of PBs in the blood is surprisingly similar for most non-HIV viruses studied, occurring 6 to 7 days after infection or vaccination (34,35,37,53,54), although the duration that PBs remain present in the blood varies with the persistence of the pathogen (37,46,50). With regard to Ig isotype, PBs that circulate in the blood following parenteral immunizations are mainly IgG (29,32,34) and are likely transiting to and from draining lymph nodes and the spleen (55)(56)(57).…”

“…Under certain circumstances, particularly with transient responses to initial infection, it is also critical to identify individuals during the acute phase of infection. Viral infections in this category include influenza virus, dengue virus, and RSV infections, in which PBs have been shown to undergo a rapid, transient, and mainly pathogen-specific burst in the blood of acutely infected individuals who then resolve their infection with a marked decline in the PBs in question (34)(35)(36)(37). While acutely HIV-infected individuals are difficult to identify, our findings on early infected HIV-viremic individuals indicate that the proportion of PBs in the blood that are HIV specific is much lower than with the three viruses just mentioned.…”

“…Recent studies have shown that IgG becomes the predominant isotype of PBs that circulate transiently in the blood following a secondary response to T-cell-dependent immunogens such as those contained in tetanus and diphtheria vaccines (29), as well as in vaccination or natural infection with influenza virus (32,34). Studies on the burst of PBs seen in peripheral blood that occurs during acute viral infections, including infections with influenza virus, dengue virus, and respiratory syncytial virus (RSV), have shown that a high fraction of these PBs is pathogen specific (34)(35)(36)(37).…”