Major disadvantages of meningococcal polysaccharide vaccines in adults include their short-lived protection and the induction of hyporesponsiveness on repeated exposure. These two factors combined make it difficult to maintain long-term protective antibody titers in adults in highly endemic regions using polysaccharide vaccines. Although the clinical implications of hyporesponsiveness are not well understood, there is a theoretical risk of increased disease susceptibility.15
This may be particularly important in settings where meningococcal epidemics regularly occur—for example, during the Hajj pilgrimage and in countries within the African meningitis belt; and in older age groups when the immune response to vaccination is attenuated. Conjugate vaccines induce boostable responses and do not induce hyporesponsiveness on repeated exposure,15
thereby overcoming the major limitations of polysaccharide vaccines.
This study demonstrated lot-to-lot consistency of the ACWY-TT vaccine and showed that ACWY-TT was non-inferior to commercially available MenPS in terms of VR rates. Statistically significantly higher VR rates and rSBA GMTs were observed in ACWY-TT recipients for 3 out of 4 serogroups (exploratory analysis) suggesting a more robust immune response than that following MenPS.
Prior to vaccination the majority of adults were seropositive for rSBA against all 4 vaccine serogroups, despite only 4 individuals reporting a prior history of meningococcal polysaccharide vaccination (> 5 y previously). High pre-existing rSBA levels ≥ 1:8 have also been reported in other studies in adults conducted in the US (between 30–100% initially seropositive for each serogroup26
) and in India (between 88–92% initially seropositive27
). Circulating meningococcal or cross-reacting strains causing asymptomatic nasopharyngeal carriage and/or cross-reactivity of antibodies with other bacteria may have contributed to the high seropositivity rate observed. The observation that IMD incidence decreases with age7
suggests that the observed rSBA provides protection against meningococcal invasion. Notably, the percentage of subjects in the ACWY-TT group with rSBA titers ≥ 1:128 increased from between 48.8% and 79% for each serogroup pre-vaccination, to between 98.9% and 99.5% post vaccination, suggesting a benefit of vaccination in conferring immunity across all 4 serogroups. The high pre-vaccination seropositivity supports use of defined VRs as a key endpoint of the study, since it measures the percentage of participants that had a response to vaccination, rather than simply seropositivity.
Comparisons between studies that differ in design, population studied and in serological methods should be made cautiously. However, the results of this study showing robust immunogenicity of ACWY-TT in adults are broadly consistent with those of other ACWY-conjugate vaccines in the US and South America and a monovalent MenA-TT vaccine that has been developed for use in the African Meningitis Belt for which immunogenicity in adults was also demonstrated.26-30
The safety profile of ACWY-TT was acceptable, with a low reported incidence of grade 3 symptoms. Increased reactogenicity following vaccination with meningococcal conjugate vaccines conjugated to diphtheria toxoid and diphtheria toxoid variant (CRM197) as compared with a polysaccharide vaccine has been observed in adolescents and children,31,32
and the monovalent MenA-TT conjugate was shown to have higher local reactogenicity than a quadrivalent MenPS vaccine.30
Thus the higher incidence of local symptoms in ACWY-TT recipients as compared with MenPS recipients is not unexpected, and may be due to the TT component, for which local reactogenicity has been well described.33
Potential limitations of the study include the lack of a licensed conjugate ACWY vaccine as a control. This is because at the time of the study, none was licensed in the countries where the study took place. However, a head-to-head study of ACWY-TT and another ACWY-conjugate vaccine showed that the immune responses induced by the two vaccines and their respective safety profiles were comparable.19
Additionally, the current study was conducted as open-blind with respect to receipt of ACWY-TT vs. MenPS control, primarily because the routes of vaccine administration were different (intramuscular route for the ACWY-TT vaccine and subcutaneous route for the MenPS control). However, the risk of bias in the analysis of immunogenicity was reduced since laboratory personnel were blinded as to age and group. Attribution of the relationship of AEs to vaccination could have been influenced by the open design, but reporting bias would more likely be against the investigational product. A final limitation was that numerous statistical comparisons were made without adjustment for multiplicity, increasing the risk that a significant difference may have arisen by chance alone.
ACWY-TT was immunogenic against all four meningococcal serogroups (A, C, W-135 and Y) in healthy adults 18–55 y of age, with VRs that were non-inferior to MenPS, and rSBA GMTs that were significantly higher than MenPS for serogroups A, W-135 and Y (exploratory analysis). These data suggest potential benefits of ACWY-TT conjugate vaccination over MenPS in this age-group, although this would need to be confirmed with antibody persistence studies. ACWY-TT had an acceptable safety profile in healthy adults, and lot-to-lot consistency of 3 ACWY-TT lots was demonstrated. These data suggest that, if licensed, ACWY-TT could provide enhanced protection against IMD in healthy adults.