Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus

Abstract

Rationale: 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.Objectives: 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.Measurements and Main 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.

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…51 Experimental challenges in healthy adults have shown that serum and nasal IgA titers increase after infection but those levels are poorly maintained. 47 Similar results have been reported for neutralizing antibodies levels in a birth cohort followed-up over three hRSV epidemics. 52 These antecedents suggest that acute production of short-life antibody-secreting cells (ACS) is not impaired.…”

“…46 Similar correlation have been obtained for nasal IgA levels in naturally infection and in experimental challenges in healthy adults. 47,48 On the other hand, it has been described in mice that antibodies play a major role during reinfection, even more than in the first infection, giving a principal role to T cells in the clearance of the virus during the first hRSV challenge. 49 Interestingly, prophylactic treatment with Palivizumab reduces severe hRSV-mediated LRTI, 42,50 and consequently diminish hRSV-associated hospitalization of premature infants, children with congenital heart disease (CHD) and children with cystic fibrosis (CF), 50 suggesting that a neutralizing antibody of high affinity and titer is enough to confer a clinical protection against hRSV disease.…”

“…However, a defect occurs in long-lived plasma cells that arise from the ASC population, which normally should migrate to bone marrow and respiratory mucosa. 47 This phenomenon might explain, at least in part, as to why the specific hRSV-IgA generated humoral response is not sufficient to provide protection upon reinfection.…”

“…This notion is supported by the fact that minor symptoms are observed in populations of older children and young adults infected with hRSV, despite of defective responses in IgA B cell memory and in hRSV-specific serum. 47,62 Recently, it has been demonstrated that tissue-resident memory (Trm) T cells are relevant to the capacity of the host to rapidly limiting the spread of pathogens in tissues. 63,64 Thus, hRSV-specific CD4 C and CD8 C Trm T cells could provide immediate immunological protection against hRSV infections.…”

Controlled human infection with RSV: The opportunities of experimental challenge

“…Previous observational studies indicated that local RSV-specific antibodies might be better correlates of protection but suggested that protective antibody levels were not well maintained [40,41]. To address these questions, we used the experimental human infection system to study the relationship between pre-existing local and systemic antibodies with infection [42]. No selection of subjects was made on the basis of pre-existing antibody levels and, among these highly immunologically experienced individuals, approximately 56% become infected following experimental challenge.…”