In this study we have demonstrated that a cohort of older adults has a significant amount of antibody that cross-reacts with the 2009 pandemic H1N1 strain. However, these antibodies are generally non-neutralizing. Vaccination against a related virus, A/New Jersey/1976, enhanced these neutralizing responses. Since neutralizing responses were very low in adults who did not receive the “swine flu” vaccine in 1976 (GMT of 11.3, 95% CI -1.9-24.4, and only 3 of 70 subjects had a titer ≥ 160), it is unlikely that virus neutralization accounts for the low clinical attack rate and relatively low hospitalization rate observed in elderly persons without chronic medical conditions. Indeed, the epidemiology of pandemic H1N1 from many countries where the 1976 “swine flu” vaccine was never used is similar to that in the United States [16
]. However, our data suggest that vaccination against a homologous or even closely related strain is likely to significantly boost neutralizing responses to the pandemic H1N1. The limited data published so far on vaccination with the monovalent H1N1 vaccine show good responses by HI in the elderly [17
], but only limited data on neutralizing responses have been reported [19
Our study differs in several important ways from previously published data on pre-existing immune responses to the 2009 pandemic H1N1 and the effect of 1976 “swine flu” vaccination [8
]. The current study was prospective, and measured antibody responses in persons in 2009, while the only other study which examined responses to the 1976 vaccine utilized stored sera from prior studies in prior years, primarily influenza vaccine studies [8
]. Immunity to the 1976 “swine flu” vaccine was thus assessed immediately after vaccination against the virus, rather than now after more than 30 years have passed. In that study, Hancock et al. found that more than 30% of ser225 a from persons born in the 1940s showed neutralizing responses ≥ 40 to the 2009 pandemic H1N1, and the 1976 “swine flu” vaccine boosted these responses such that more than 60% had an MN titer against the 2009 H1N1 of ≥ 160 [8
]. In our population, only 18.1% of the overall cohort had MN titers of ≥ 40 against pandemic H1N1, and of the sub-group who received the 1976 vaccine, only 17.4% retained MN titers ≥ 160 to the present day. Two other studies which reported neutralization titers to the 2009 pandemic H1N1 showed either no responses (retrospective study of stored sera from April, 2009 from hospital employees and patients) [20
], or responses similar to ours (pre-vaccination titers in a monovalent H1N1 vaccine study) [19
], but neither assessed the impact of the 1976 vaccine.
A major difference from previous studies appears to be that our population was highly vaccinated; 91.4% overall received the seasonal vaccine in 2008-2009, and most of the cohort has had repeated annual immunization because of their status as health-care workers [21
]. Thus, overall HI titers against seasonal H1N1 were very high in comparison to other published data [8
], and cross-reactive responses against the pandemic H1N1 were similar to those against the seasonal H1N1. Hancock et al. showed very low post-vaccination GMTs against the 2009 H1N1 (GMT 10-11 by HI, 95% CI 7- 14) in their cohorts of older adults (> 60y) receiving recent seasonal influenza vaccines, and only saw predicted seroprotective responses (≥ 40) in 12-13% of subjects [8
]. Greenberg et al. saw low pre-vaccination baseline GMTs against the 2009 H1N1 (GMT 15.0 and 13.8 by HI in two vaccine groups, 95% CI 11.4-19.6 and 8.4-14.3, respectively) in their cohort of older adults (50-64y), and only 27.4% and 13.8% in the two groups had predicted seroprotective responses [19
]. Thus, their populations, s, which were selected for inclusion in vaccine trials and had low baseline titers to influenza virus, are likely different from our population who are routinely immunized annually and in whom higher GMTs and more frequent seroprotective responses were identified.
This study has several important limitations that must be considered to best understand the data. First, this was a highly vaccinated population, so probably represents the upper end of the spectrum in terms of antibody responses. This is partly due to the study design which was a convenience sampling of employees and partly due to a likely selection bias in that persons who volunteered were aware that we were studying responses to the 1976 “swine flu” vaccine and nearly 40% of all participants had received the vaccine previously. We did not attempt to assess other groups that might be more representative of the general population as we were focused on the central hypothesis that 1976 vaccine would enhance responses to the current 2009 pandemic strain. Therefore, generalization of these results to other groups should be done cautiously. Finally, the assays in use are subject to some variation between laboratories, although we attempted to minimize the effect of this by utilizing the same methods and definitions as those in the previously reported study [8
In summary, we present the first prospective data analyzing antibody responses to the 2009 pandemic H1N1 influenza virus in relation to the 1976 “swine flu” vaccine. Our findings are notable in that little neutralizing activity is seen in our highly vaccinated cohort of older adults despite high titers of cross-reactive antibody by HI. Prior receipt of the 1976 vaccine, however, enhanced these neutralizing responses. These results suggest that neutralizing immunity against the 2009 pandemic H1N1 strain is unlikely to account for the low morbidity seen in the elderly during the current pandemic, and the results of vaccine trials that report only HI data need to be interpreted cautiously.