Abstract
BackgroundAlthough the 2009 (H1N1) influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation.MethodsWe searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis.ResultsEighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects). After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (> = 70%) in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses < = 6 µg (even with as little as 1.875 µg of hemagglutinin antigen) was not significantly lower than that achieved after higher doses. Finally, the rate of serious vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of 22826 vaccinated subjects). However, mild to moderate adverse reactions were more (and very) frequent for oil-in-water adjuvanted vaccines.ConclusionsSeveral one-dose formulations might be valid for future vaccines, but 2 doses may be needed for children, especially if a low-dose non-adjuvanted vaccine is used. Given that 15 RCTs were sponsored by vaccine manufacturers, future trials sponsored by non-industry agencies and comparing vaccines using different types of adjuvants are needed.
Highlights
According to WHO statistics, from April 2009 to August 2010 more than 214 countries reported laboratory confirmed cases of pandemic influenza 2009 H1N1, with over 18,449 deaths [1]
The pandemic officially ended in August 2010 [5], the virus was detected in 13.4% of the specimens tested in USA during 2010–11 season [6], and WHO recommended that an A/ California/7/2009 (H1N1)-like virus be used for influenza vaccines in the 2010–11 season [7]
There are several outstanding questions: how do the seroconversion rates, at various ages, compare for diverse vaccine formulations? Which is the lowest dose inducing a satisfactory immunogenicity for adjuvanted and non-adjuvanted formulations? Does the second dose relevantly increase the immunogenicity of the various vaccine formulations? Are adjuvanted 2009 H1N1 vaccines more immunogenic than non-adjuvanted vaccines at equal doses of hemagglutinin antigen (HA)? Among the adjuvants, is aluminum more/less immunogenic than other oil-inwater adjuvants (i.e. MF-59, AS03) at equal dosages? To help answer these questions, we performed a meta-analysis of all clinical trials on H1N1 vaccines
Summary
According to WHO statistics, from April 2009 to August 2010 more than 214 countries reported laboratory confirmed cases of pandemic influenza 2009 H1N1, with over 18,449 deaths [1]. The pandemic officially ended in August 2010 [5], the virus was detected in 13.4% of the specimens tested in USA during 2010–11 season [6], and WHO recommended that an A/ California/7/2009 (H1N1)-like virus be used for influenza vaccines in the 2010–11 season [7]. To help answer these questions, we performed a meta-analysis of all clinical trials on H1N1 vaccines We used both traditional meta-analysis and multiple treatment meta-analysis (MTM) [40,41] to combine data across a large number of diverse comparisons of different formulations. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and metaanalysis is needed to identify the best formulation
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