Four hundred adults whose age ranged between 56 and 103 years were enrolled in the study. Of these, 2 subjects were not vaccinated, and 29 were excluded from all statistical analyses (see Sect. 2
). Thus, there were 369 subjects in the total vaccinated cohort, of which 260 (70 %) were eligible for inclusion in ATP analyses (Fig. ). More females (68.3 %) than males (31.7 %) were enrolled. The two treatment groups were comparable in terms of demographic characteristics (Table ).
Fig. 1 Subject flow through the study. ATP according to protocol, SAE serious adverse event. *Twenty-nine subjects (randomized and vaccinated) who were enrolled via the mobile unit prior to approval and who did not re-consent after mobile unit approval (more ...)
Summary of demographic characteristics (total vaccinated cohort)
One subject (an 84-year-old subject in the MenPS group) withdrew from the study because of a serious adverse event. This subject suffered a cerebrovascular accident and died 21 days after vaccination. The event was considered unrelated to vaccination by the investigator.
After a single dose of MenACWY-TT, the VR rate in the MenACWY-TT group was 76.6 % for serogroup A, 80.3 % for serogroup C, 77.5 % for serogroup W-135 and 81.9 % for serogroup Y (Table ). VR rates in the MenPS group were 91.7, 84.8, 87.1 and 89.1 %, respectively.
Percentage of subjects with a vaccine response 1 month after vaccination: all subjects and by age strata (ATP cohort for immunogenicity)
One month after vaccination, at least 97.4 % in the MenACWY-TT group and at least 95.5 % in the MenPS group had rSBA titers ≥1:8 (Table ). The percentage with rSBA ≥1:128 was at least 93.2 % in the MenACWY-TT group and at least 93.9 % in the MenPS group. In each group, GMTs increased by at least 13-fold for each serogroup (Table ).
Percentage of subjects with rSBA titers ≥1:8 and ≥1:128 and GMTs (ATP cohort for immunogenicity)
Exploratory analyses did not detect any statistically significant differences between groups in terms of the percentage of subjects who reached the 1:8 and 1:128 thresholds after vaccination. However, these analyses suggested that the magnitude of the response was statistically significantly lower in MenACWY-TT recipients than in MenPS recipients in terms of VR rate for serogroup A and rSBA GMTs for serogroups A and C. VR rates in individuals with pre-existing rSBA titers ≥1:128 tended to be lower for each serogroup in MenACWY-TT recipients (65.7–72.6 %) than in MenPS recipients (75.9–91.3 %), while the majority of initially seronegative subjects in both groups demonstrated VRs to each serogroup after vaccination (for serogroup A, 93.3 % in the MenACWY-TT group and 100 % in the MenPS group; for serogroup C, 96.3 and 90.9 %; for W-135, 88.7 and 86.4 %; and for Y, 100 % in both groups).
Effect of Age and Previous Meningococcal Polysaccharide Vaccination on the Immune Response
VR rates tended to be lower in subjects who were >65 years of age at the time of vaccination, compared to younger (56- to 65-year-old) subjects (Table ). This trend was more pronounced in MenPS recipients for serogroups A, C and Y. Possible differences between groups were not statistically tested as these tests are not powered to do so, because of the low numbers of subjects in each subgroup.
The percentage of subjects with rSBA titers ≥1:128 and the rSBA GMT were within the same range in the 56–65 year and >65 year subgroups, although the small number of subjects in each group means that conclusions cannot be drawn (Supplementary table 1).
Approximately one-quarter of subjects had a history of having received a meningococcal polysaccharide vaccine more than 5 years previously (Table ). Prior to vaccination, the percentage of subjects with rSBA ≥1:128 was between 57.5 and 60.7 % for serogroup A, 43.9 and 45.3 % for serogroup C, 48.4 and 52.1 % for serogroup W-135 and 62.4 and 71.9 % for serogroup Y (Table ). The percentage of subjects with pre-vaccination titers ≥1:128 and rSBA GMTs for serogroups A and C, but not W-135 or Y, tended to be higher in subjects with a history of meningococcal vaccination than in unvaccinated subjects (Supplementary table 2). In the MenACWY-TT group, the post-vaccination rSBA GMTs in subjects who had not received a meningococcal dose previously were in the same range as in subjects who had received a prior meningococcal vaccination, although lower point values for rSBA-W-135 titers were observed in those previously vaccinated: for serogroup A, 1,372.0 [95 % CI 1,088.3; 1,729.6] versus 1,726.4 [1,067.5; 2,792.0]; for serogroup C, 2,584.3 [1,836.2; 3,637.2] versus 2,412.1 [1,504.7; 3,866.7]; for serogroup W-135, 1,791.7 [1,369.7; 2,343.7] versus 756.2 [406.2; 1,407.7]; and for serogroup Y, 2,664.0 [2,107.0; 3,368.3] versus 2,219.6 [1,324.1; 3,720.6]. In the MenPS group, the rSBA GMTs were: for serogroup A, 2,640.3 [1,768.5; 3,941.9] versus 3,968.1 [2,248.5; 7,003.0]; for serogroup C, 5,054.1 [2,661.9; 9,595.9] versus 4,712.0 [1,483.6; 14,965.4]; for serogroup W-135, 2,217.4 [1,363.6; 3,606.0] versus 1,325.9 [334.1; 5,261.7]; and for serogroup Y, 4,370.4 [2,756.7; 6,928.6] versus 3,710.3 [2,042.1; 6,741.0]. Due to the low numbers of subjects in each subgroup, comparisons between groups are not reliable (Supplementary table 2).
Response to Tetanus Toxoid
Few subjects had anti-TT antibodies ≥0.1 IU/ml prior to vaccination (12 subjects, 6.3 % in the MenACWY-TT group and 6 subjects, 9.1 % in the MenPS group). The anti-TT response after MenACWY-TT vaccination was low (Table ).
Percentage of subjects with anti-TT concentrations ≥0.1 and 1 IU/ml and GMCs (ATP cohort or immunogenicity)
A post-hoc analysis assessed rSBA GMTs in subjects according to pre- and post-vaccination anti-TT antibody status in the MenACWY-TT group. In adults with anti-TT antibodies ≥0.1 IU/ml prior to vaccine, post-vaccination rSBA GMTs after MenACWY-TT were as high or higher than those observed in the MenPS group for serogroups C, W-135 and Y, but not for serogroup A (rSBA GMT 2,479.8 [95 % CI 1,211.4; 5,076.2] for serogroup A, 7,492.7 [2,069.9; 27,121.6] for serogroup C, 3,250.5 [521.4; 20,263.8] for serogroup W-135, and 3,992.0 [1,028.7; 15,491.2] for serogroup Y, Supplementary table 3). Furthermore, the post-vaccination rSBA GMTs were between 1.9- and 4-fold higher in subjects who responded to TT: That is, the point values of the rSBA GMT for each serogroup was higher (no statistical test performed because of the low number of subjects) in subjects with post-vaccination anti-TT concentrations ≥1.0 IU/ml (3,581.8 [95 % CI 2,211.4; 5,801.4] for serogroup A, 3,891.4 [1,605.7; 9,430.6] for serogroup C, 3,750.9 [1,985.8; 7,084.8] for serogroup W-135 and 7,600.5 [4,588.7; 12,589.3] for serogroup Y) and was lower in subjects in whom the anti-TT concentration remained <0.1 IU/ml after vaccination (1,147.8 [891.5; 1,477.7] for serogroup A, 2,101.0 [1,510.1; 2,923.0] for serogroup C, 1,045.1 [788.0; 1,385.9] for serogroup W-135 and 1,831.1 [1,441.2; 2,326.6] for serogroup Y) (Supplementary table 3).
Reactogenicity and Safety
Incidences of local and general solicited symptoms were very low in both groups. In the MenACWY-TT group pain was reported by six subjects (2.3 % [95 % CI 0.8; 4.9]) and redness and swelling each by three subjects (1.1 % [0.2; 3.3]). No local symptoms were reported by subjects in the MenPS group. No local symptoms of grade 3 intensity were reported in either group.
Fatigue was reported by five subjects in the MenACWY-TT group (1.9 % [95 % CI 0.6; 4.3]) and no subjects in the MenPS group. Headache was reported by eight subjects (3.0 % [1.3; 5.9]) in the MenACWY-TT group and by two subjects (2.2 % [0.3; 7.9]) in the MenPS group. Fever (defined as axilliary temperature ≥37.5°C) was reported by six subjects (2.3 % [0.8; 4.9]) in the MenACWY-TT group and by one subject (1.1 % [0.0; 6.1]) in the MenPS group. All fever episodes were ≤38.0°C except one, which was >38.0°C and one >38.5°C in the MenACWT-TT group. No subject in either group reported gastrointestinal symptoms during the solicited follow-up period.
No grade 3 local or general symptoms were reported by either group, and no solicited symptom led to a medically-attended visit. On observing the low incidences of adverse reactions after vaccination, the investigator re-questioned the subjects before the database was unblinded and the statistical analysis performed, and additional adverse events were not identified.
One serious adverse event was reported during the study (reported above). No cases of new onset of chronic disease were reported during the 31-day follow-up period.