Since its discovery less than a decade ago, hMPV has been established as a significant respiratory pathogen in adults and children.(23
) Thus, an effective vaccine to prevent infection and serious illness would be highly desirable. Our study is the first report data in humans linking risk of infection with low serum hMPV binding and neutralizing antibody. These results are very similar to the relationship of serum and nasal antibody to risk of infection we previously observed with RSV in the same adult cohort. (19
) Although the absolute differences in mean antibody titers of infected compared to non-infected subjects were quite modest, virus exposure of uninfected controls cannot be guaranteed in studies of natural infection. Therefore, true differences in pre-infection immunity would be more readily identified using experimental challenge studies. Nevertheless, we believe our data provide support for the development of hMPV vaccine candidates that stimulate humoral immunity.
Unlike our previous study of risk factors for severe disease in adults with RSV, we did not find an association of low serum neutralizing antibody levels and risk of hospitalization. (20
) The acute blood samples were drawn significantly later in illness in the hospitalized subjects compared to the outpatients, and this discrepancy could have obscured true baseline levels in the more severely ill group. However, the same issue was noted in our previous study of RSV infected patients in whom a relationship of low antibody status and risk of hospitalization could be demonstrated. It is possible that hMPV re-infection elicits a more brisk amnestic immune response than RSV, although given the close genetic relationship of these viruses this seems unlikely. Alternatively, hMPV related hospitalizations might be driven more by underlying diseases of the host rather than inadequate immunity to the pathogen. Several studies have suggested that illness due to RSV is more severe than hMPV in young children and underlying medical conditions and age appear to be risk factors for severe illness in adults.(24
) Yet, we observed similar rates of underlying cardiopulmonary diseases, diabetes and functional impairment to our previous cohort of patients hospitalized with RSV infection.(21
) Thus, the link between low serum antibody and severe RSV disease and lack of a similar association with hMPV remains unexplained.
Interestingly, we found that older adults exhibited a more robust antibody response as measured by EIA or neutralization assay compared to young adults infected with hMPV illnesses of similar severity. Pre-infection hMPV antibody levels were higher in older subjects, suggesting that aging per se does not result in a defect in humoral immunity. The more exuberant antibody response observed in older adults may be due to immune dysregulation associated with poor viral clearance.(26
) We observed a similar finding in a previous study of young and older adults infected with RSV.(22
) While both viruses are members of the pneumovirus subfamily, these data suggest this observation represents a more general phenomenon associated with aging rather than a viral specific immune response. To fully explore this possibility, the immune responses to other unrelated respiratory viruses such as coronaviruses or adenoviruses should be evaluated.
Our study has several limitations which include the relatively small sample size, especially young adults with symptomatic illness. In addition, hMPV diagnosis was not group A and B specific and EIA and neutralizing assays utilized group A virus. It is possible that different or more dramatic changes might have been detected if group specific antibody levels were evaluated separately in group A and B specific infections. However, we have previously demonstrated nearly identical serologic response by EIA using the either CAN 97-83 (group A) and CAN 98-75 (group B) strains of hMPV as antigen regardless of the infecting viral strain. (8
) In addition, we have recently found that serum neutralizing antibody titers to group A and B viruses are highly correlated (R = 0.87) (27
). Minimal differences in neutralizing activity directed against group A and B viruses is not surprising since the conserved F protein has been found to be highly immunogenic and protective, whereas the antigenically more diverse G protein is not. (28
) Lastly, by using purified whole virus in our EIA, we are not able to detect F or G antibody specific immune responses.
In summary, mean serum antibody levels are significantly lower in adults who subsequently become infected with hMPV compared to those who remain infection free. These data suggest that serum antibody plays a protective role in hMPV infection and support development of an hMPV vaccine.