Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus.
BACKGROUND
Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection.


OBJECTIVE
To characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development.


METHODS
We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B-cell frequencies and antibody longevity.


RESULTS
Despite moderately high levels of preexisting serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from polymerase chain reaction-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects but correlated with plasmablasts that peaked around Day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, in which virus-specific IgA memory B cells were readily recovered.


CONCLUSIONS
This observed specific defect in IgA memory may partly explain the ability of RSV to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.
1 National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Maximillian S
MS
Habibi
Agnieszka
A
Jozwik
Spyridon
S
Makris
Jake
J
Dunning
Allan
A
Paras
John P
JP
DeVincenzo
Cornelis A M
CA
de Haan
Jens
J
Wrammert
Peter J M
PJ
Openshaw
Christopher
C
Chiu
D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D055815:Young Adult
D000914:Antibodies, Viral; D007070:Immunoglobulin A
antibody-secreting cells; immunologic memory; mucosal immunity; nontherapeutic human experimentation; respiratory syncytial virus vaccines