SBA is the accepted correlate of protection for meningococcal disease. In the MITT analysis of this study, non-inferiority was demonstrated between full and 1/5 and 1/10 fractional doses of TPSV in SBA response against the meningococcal serogroups W135 and Y. Non-inferiority was only shown between the full and 1/5 doses for serogroup A in the pre-vaccination, non-immune population. Non-inferiority was rejected for serogroup C in all analyses. Safety and tolerability data were favourable, as observed with TPSV in other studies 
In analyzing the proportion of responders per serogroup, we observed a decline in response for serogroup A and C from the full versus 1/5 dose, and this decrease was accentuated versus the 1/10 dose. For serogroup A, which is the most important serogroup to protect against in sub-Saharan Africa, the response in the MITT analysis decreased from 86% to 77%. Several elements must be considered in the interpretation of these results. A notable proportion of volunteers (51.4%) had high SBA titers against serogroup A prior to vaccination, presumably resulting from natural immunity. In demonstrating non-inferiority between the full and 1/5 dose groups in the non-immune population, the difference in responses occurred mainly in the naturally immune subgroup. These results suggest that the full dose may elicit higher increase in SBA titers for subjects with pre-vaccination SBA titers ≥128 compared with 1/5 of the dose. However, assuming that a post-vaccination SBA titer ≥128 is a proxy for vaccine efficacy, we believe that 1/5 of the dose induced an acceptable increase of SBA for non-immune populations, although it did not strictly meet the criteria we designed for the total population. When considering the response for children under five, overall fractional doses do not affect the chance of response compared to full dose. For serogroup A, the response could be possibly better in children under five with fractional doses, though the study was not powered to demonstrate this hypothesis.
For all serogroups, the IgG concentrations decreased with fractional doses. However, the SBA titer/IgG ratios showed similar results between arms for all serogroups (data not shown), indicating a higher proportion of bactericidal antibodies in fractional doses. This could be due to differences in antibody avidity, though this hypothesis would require further studies. In an epidemic response setting, the goal of a mass vaccination campaign is short term immunity-basically protection through to the end of the epidemic season. Therefore, longer duration of protection (presumably predicted by higher titers) is a less important issue.
Licensed meningococcal polysaccharide vaccines are known to confer an immunity of short duration (2–3 years) and are therefore not recommended in expanded vaccination programs 
. But this characteristic may not impact the use of fractional dosing in a reactive mass vaccination campaign aimed at preventing further new cases during an ongoing epidemic. Study subjects in this trial were followed up to 2 years, and the duration of protection will be addressed later on.
Several potential limitations of this study must be addressed. Tolerability data were excellent; however, the weekly visits between the vaccination and four weeks later may not have been optimal to capture adverse events often occurring in the first days after vaccination. HIV testing was not systematically performed. Considering the epidemiological indicators of HIV in the adult population aged 15–49 years (HIV prevalence rate 6.7% [5.7–7.6]) 
, and the exclusion criteria of known or suspected cases in our study population, the impact of HIV is unlikely to be noticeable. Injections of fractional doses with “insulin syringes” were considered relatively simple to perform in the field for the 1/5 (0.1 mL) dose, but the 1/10 (0.05 mL) dose was more difficult to inject. Such difficulty may have hampered the delivery of the 1/10 fractional dose. This evaluation was based on the informal evaluation from the study team. Considering the absence of difficulties to inject 1/5 of the dose providing the use of appropriate syringes and training, health workers engaged in an outbreak response during an epidemic should not faced major problems to implement this vaccination. The unexpected high background rate of immunity to serogroup A in the study population has been a constraint to demonstrate the impact of the vaccination for this serogroup. Despite the fact that no large outbreak of meningococcal meningitis due to serogroup A had been declared in southern Uganda in the years prior to the study, it is likely that the strain was circulating in the region, following the outbreaks of serogroup A in neighbouring countries, Burundi and Rwanda in 2002 
Quality control of the SBA titers showed satisfactory results for serogroups A, C, and Y. However, a discrepancy was found for the W135 serogroup. This discrepancy was found to be due to the use of a different strain between the two laboratories. Once repeated with same strain, there was no significant difference between the results of the two laboratories (p
0.31). As the proportion of responders for serogroup W135 was the same in the two laboratories and the source of the discrepancy was identified, we believe that our overall results of serogroup W135 are validated.
Baby rabbit complement was used in the SBA assays in accordance with international standard protocols to evaluate polysaccharide vaccines against meningococcal disease, but SBA with human complement might be more relevant to elucidate the immune response after disease and vaccination. Additional insight would be gained by assaying these sera in a human complement SBA assay, and such analyses are ongoing.
The two prevailing serogroups that cause N. meningitidis
epidemics in the African Meningitis Belt are A and W135, and serogroups C and Y are not presently reported as the causal agent of meningitis epidemics in the region 
. The WHO states that problems regarding the availability and affordability of protective meningococcal vaccines over the coming years need to be addressed urgently 
. A risk-benefit analysis of the use of fractional doses should guide decision-makers. Similar strategies with other vaccines have already proved successful 
. Assuming 90%, short-term protection by the licensed meningococcal polysaccharide vaccines, and a conservative protection of 80% using a reduced 1/5 dose, the same amount of resources invested in vaccine purchase would protect 4.4 times more subjects. Although the cost of immunization is not a primary interest of this strategy in the context of a global shortage, the use of a fractional dose would decrease the cost per person vaccinated by approximately half (data not shown). While the advent of conjugate A vaccine will largely contribute to control serogroup A outbreaks in Africa, the scale-up of its production will not cover the entire “meningitis belt” target population over the next 3 to 5 years (Laforce M., Meningitis Vaccine Project, personal communication January 2008). Considering the current shortage of meningococcal vaccines for Africa and the prevalence of serogroups A and W135, the use of 1/5 fractional doses should be explored as an alternative strategy in mass vaccination campaigns.