The role of nasal IgA in children vaccinated with live attenuated influenza vaccine

Ambrose, Christopher S.; Wu, Xiaojie; Jones, Trevor O.; Mallory, Raburn M.

doi:10.1016/j.vaccine.2012.09.018

Cited by 99 publications

(76 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, the activities of monoclonal antibodies can change drastically in polyclonal mixtures (20,21), and vaccine regimens invariably elicit polyclonal responses. In addition, IgA isotype antibodies play an important role in the maintenance of mucosal immunity against respiratory pathogens and may be of particular relevance in terms of protection afforded to individuals immunized with live-attenuated influenza virus vaccines (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

Mullarkey

Duty

et al. 2015

J Virol

View full text Add to dashboard Cite

Current influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and even when perfect matches are achieved, suboptimal vaccine efficacy leaves several high-risk populations vulnerable to infection. However, the recent discovery of broadly neutralizing antibodies that target the hemagglutinin (HA) stalk domain has renewed hope that the development of "universal" influenza virus vaccines may be within reach. Here, we examine the functions of influenza A virus hemagglutinin stalk-binding antibodies in an endogenous setting, i.e., as polyclonal preparations isolated from human sera. Relative to monoclonal antibodies that bind to the HA head domain, the neutralization potency of monoclonal stalk-binding antibodies was vastly inferior in vitro but was enhanced by several orders of magnitude in the polyclonal context. Furthermore, we demonstrated a surprising enhancement in IgA-mediated HA stalk neutralization relative to that achieved by antibodies of IgG isotypes. Mechanistically, this could be explained in two ways. Identical variable regions consistently neutralized virus more potently when in an IgA backbone compared to an IgG backbone. In addition, HA-specific memory B cells isolated from human peripheral blood were more likely to be stalk specific when secreting antibodies of IgA isotypes compared to those secreting IgG. Taken together, our data provide strong evidence that HA stalk-binding antibodies perform optimally when in a polyclonal context and that the targeted elicitation of HA stalk-specific IgA should be an important consideration during "universal" influenza virus vaccine design. IMPORTANCEInfluenza viruses remain one of the most worrisome global public health threats due to their capacity to cause pandemics. While seasonal vaccines fail to protect against the emergence of pandemic strains, a new class of broadly neutralizing antibodies has been recently discovered and may be the key to developing a "universal" influenza virus vaccine. While much has been learned about the biology of these antibodies, most studies have focused only on monoclonal antibodies of IgG subtypes. However, the study of monoclonal antibodies often fails to capture the complexity of antibody functions that occur during natural polyclonal responses. Here, we provide the first detailed analyses of the biological activity of these antibodies in polyclonal contexts, comparing both IgG and IgA isotypes isolated from human donors. The striking differences observed in the functional properties of broadly neutralizing antibodies in polyclonal contexts will be essential for guiding design of "universal" influenza virus vaccines and therapeutics. I nfluenza A viruses (IAVs) remain one of the most pressing global public health concerns due to their widespread distribution, rapid evolution, and potential for reassortment (1). These traits contribute to the abil...

show abstract

Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

Mullarkey

Duty

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…Serum antibody responses, being predominantly of the IgG isotype, are essentially unchanged in VAD mice compared to control mice (4,5). Given that respiratory tract mucosal IgA serves as a correlate of protection against respiratory virus infections and lends to the protection conferred by respiratory virus vaccines (7)(8)(9)(10)(11), the lack of healthy IgA responses may render VAD individuals particularly susceptible to the diseases responsible for one-fifth of all deaths among children under the age of five years (2,12).…”

mentioning

confidence: 99%

Intranasal Administration of Retinyl Palmitate with a Respiratory Virus Vaccine Corrects Impaired Mucosal IgA Response in the Vitamin A-Deficient Host

Surman

Jones

Rudraraju

et al. 2014

Clin Vaccine Immunol

View full text Add to dashboard Cite

“…LAIV induces mucosal IgA antibody responses in children and higher levels of influenza-specific IgA are associated with protection from influenza illness [11,12]. LAIV has also been shown to induce substantial cellular immune responses in young children; higher cellular responses were associated with protection [13].…”

Section: Discussionmentioning

confidence: 99%

An integrated multi-study analysis of serum HAI antibody responses to Ann Arbor strain live attenuated influenza vaccine in children and adults

Coelingh

Wu²,

Mallory³

et al. 2014

Trials in Vaccinology

Self Cite

View full text Add to dashboard Cite

a b s t r a c tSerum hemagglutination-inhibition (HAI) antibodies have been associated with protection from influenza infection. HAI antibody responses to live attenuated influenza vaccines (LAIVs) and their role in protection are not fully elucidated. This study characterizes HAI titers for LAIV. Serum HAI data were pooled from 40 LAIV clinical trials enrolling subjects aged 2-49 years. Using pre-and postvaccination titers, geometric mean fold rises (GMFRs) and seroresponse rates (P4-fold rise) were determined by age and baseline serostatus (seronegative 68, seropositive >8). Responses were generally evaluated after 2 doses for those 2-8 years of age and after 1 dose for those 9-49 years of age. Data were available for 6909 children and 3444 adults. A total of 20 different LAIV formulations were used, representing 6 H1N1 strains, 9 H3N2 strains, 7 B/Yamagata lineage strains and 2 B/Victoria lineage strains. GMFRs were modest overall; GMFRs were higher in children versus adults and higher in baseline seronegatives versus baseline seropositives. This difference was greatest among children, with GMFRs ranging from 2.2 to 5.9 among seronegative and 1.2-1.5 among seropositive children. HAI responses were modest overall, higher in seronegative individuals (10.8-61.6%) relative to seropositive (1.9-17.0%), and higher in children relative to adults. Postvaccination HAI titers were below those associated with protection for inactivated influenza vaccines. The results suggest that LAIV-induced protection is mediated primarily by mucosal antibody and T-cell immunity, although serum HAI has value as strain-specific marker of response to vaccination, particularly among seronegative individuals.

show abstract

The role of nasal IgA in children vaccinated with live attenuated influenza vaccine

Cited by 99 publications

References 46 publications

Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

Intranasal Administration of Retinyl Palmitate with a Respiratory Virus Vaccine Corrects Impaired Mucosal IgA Response in the Vitamin A-Deficient Host

An integrated multi-study analysis of serum HAI antibody responses to Ann Arbor strain live attenuated influenza vaccine in children and adults

Contact Info

Product

Resources

About