Addressing Unmet Medical Needs Through Tailored Vaccine Design: The Importance of Adjuvant Systems - It is now possible to combine antigens with specific adjuvant systems to create more-effective vacc
Clinical Experience with the H5N1/AS03 Formulation
Several clinical studies support the benefits of AS03 for a pandemic influenza vaccine.
The formulation with AS03 showed significant antigen sparing capabilities compared to the non-adjuvanted vaccine. With the
AS03-adjuvanted formulation, >80% of subjects who received two (3.75 μg) doses of antigen (as a comparison, seasonal vaccine
contains 15 μg of antigen per strain) showed a strong seroprotective immune response, and all the European Committee for Medicinal
Products for Human use (CHMP) and US Food and Drug Administration (FDA) criteria for immunogenicity were met.6 At the highest dose (30 μg) the non-adjuvanted formulation met only two out of three CHMP criteria and none of the FDA criteria
for immunogenicity.
The same study provided convincing evidence that the AS03-adjuvanted pandemic influenza vaccine induces a high level of cross-reactive
immunity to drifted strains of H5N1 in humans.6 These results are in line with cross-protective responses observed in animal models.9 Additional clinical data showed broad cross-clade reactive neutralizing antibody response with AS03, compared with no response
in the non-adjuvanted group.10
Preliminary study results obtained with the AS03-adjuvanted H5N1 vaccine in elderly volunteers and in children have also shown
a satisfactory immune response against the vaccine strain.11–12
A recent study has shown that administration of the second dose of vaccine from 6 up to 12 months after the first dose induced
similar levels of cross-clade immunity, as compared to the standard schedule (two doses, 21 days apart, currently recommended
for adults 18–60 years of age in Europe). These data suggest that the timing of second dose administration of the H5N1/AS03
vaccine can be flexible without reducing the robustness of the immune response achieved.13
The safety of the H5N1/AS03-adjuvanted vaccine has been assessed in several clinical studies. The safety data set includes
more than 10,000 subjects, mainly enrolled in large studies in Europe and Asia, who received injections of the AS03/H5N1 vaccine
formulation.14–15 Across studies, it was observed that the H5N1/AS03-adjuvanted vaccine increased the frequency and intensity of injection
site reactions in comparison with non-adjuvanted vaccines. Solicited general adverse events such as headache, fatigue, and
myalgia were also more frequently observed with the adjuvanted vaccine. However, these solicited adverse events were mild
to moderate in intensity and of short duration. The overall safety profile of the adjuvanted vaccine has been considered clinically
acceptable.
Benefits of the H5N1/AS03 Vaccine
In conclusion, the formulation of the H5N1 pandemic influenza vaccine with AS03 results in an effective vaccine with a favorable
safety profile. A first crucial benefit is antigen-sparing which allows more people to be vaccinated more rapidly. Other key
advantages include high flexibility with regard to second dose vaccine administration and cross-reactive immunity against
drifted strains, which is important because that virus mutation is likely to continue during a pandemic (Box 1). These benefits
may be explained by a tailored and enhanced interaction of the adjuvant–antigen combination with cells of the innate immune
system and consequently a better stimulation of the adaptive immune response compared to the formulation without adjuvant.
Nathalie Garçon, PhD, is the vice president and head of the Global Adjuvant Center for Vaccines at GlaxoSmithKline Biologicals, Wavre, Belgium, +32 (0)1 085 8856, nathalie.garcon@gskbio.com.
Articles by Nathalie Garçon, PhD
Philippe Monteyne, MD, PhD, is the senior vice president of global vaccine development all at GlaxoSmithKline Biologicals
Articles by Philippe Monteyne, MD, PhD,
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