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Split-virus H1N1 vaccine more effective than whole-virus vaccine

An adjuvanted split-virus H1N1 vaccine offered children more immunologic protection than a non-adjuvanted whole-virus vaccine but caused more adverse events, a head-to-head study in England found.

Both vaccines were purchased in bulk by the United Kingdom Department of Health and are currently given to children there. The split-virus version, GlaxoSmithKline’s AS03B (tocopherol-based oil in water emulsion) adjuvanted vaccine, is derived from egg culture and contains 1.875 mcg of hemagglutinin antigen. The whole-virus non-adjuvanted vaccine, from Baxter, is derived from cell culture and contains 7.5 mcg of hemagglutinin.

A total of 943 children aged 6 months to 12 years were randomly assigned to receive either vaccine in two doses 21 days apart. The vaccines were administered across five centers in England during the second pandemic wave, from September to December.

After both doses, the researchers saw higher seroconversion rates for the adjuvanted vaccine in children younger than 3 years (98.2% vs. 80.1%; P<.001) and children older than 3 years (99.1% vs. 95.9%; P=.03). Seroconversion, defined as a fourfold increase to titer of at least 1:40 from before vaccination to three weeks after dose two, was measured with the microneutralization and the hemagglutination inhibition assays.

The researchers observed a significant interaction between immunogenticity and age (P<.001), noting a 3% decrease in titer per year of age for the split-virus vaccine and a 16% increase per year for the whole-virus vaccine.

“The favorable immunogenicity of the adjuvanted split-virion vaccine in the youngest children in our study suggests that novel adjuvants could be used to improve the immunogenicity of seasonal influenza vaccines in this population,” the researchers wrote.

Both vaccines were generally well tolerated, but higher rates of local and systemic reactions were reported for the split-virus vaccine. These included severe local reactions, irritability, decreased feeding and activity, muscle pain and a state of being generally unwell. Younger children who received the split-virus vaccine were more likely to experience fever of at least 100.4·F after the second dose (22.4% vs. 8.9%, P<.001).

“Our observed local and systemic rates of reactogenicity were generally in keeping with data in the summary of product characteristics,” the researchers wrote.

Scientific and regulatory discussion on appropriate pandemic influenza vaccines have been intensified on an EU-wide level from 2003 onwards. Numerous consultations led by the European Medicines Agency (EMA) in London finally resulted in a commonly agreeable concept of so-called pandemic mock-up vaccines aimed at collecting as much as possible of data on the quality, safety and efficacy of pandemic candidate vaccines. Those data, once accepted by regulatory agencies, were considered to be sufficient to be extrapolated to true pandemic vaccines, thus allowing regulators and industry to significantly shorten the time frame normally needed for licensing vaccines, which in the context of a pandemic scenario would offer a unique advantage.

Both vaccines described in the article by Waddington and colleagues evolved from the concept of pandemic mock-up vaccines. That is to say, they were licensed long before the current pandemic was identified. Both mock-up licenses were based on the highly pathogenic avian H5N1 subtype of Influenza A virus and were rapidly adapted to the novel pandemic H1N1 subtype discovered in early April 2009.

However, although following the same licensing strategy, the two products are individual and independent developments from different companies. The concept of unadjuvanted cell culture-derived whole virion vaccine was developed by Baxter Vaccines (Vienna, Austria) while the concept of an AS03 adjuvanted split virion vaccine was developed by GlaxoSmithKline Vaccines (Rixensart, Belgium). Beyond those fundamental differences both concepts address two basic principles of pandemic preparedness:

1. pandemic influenza vaccines should be highly immunogenic in order to achieve adequate priming of the immune system and, finally, to induce protective immunity after only two doses; and
2. the antigen amount needed to meet these goals should be significantly reduced compared to seasonal influenza vaccines in order exploit existing manufacturing capacity best possible ensuring that large parts of a population have access to such vaccines before a first pandemic wave arrives.

Vaccine concepts such as described above evolved from earlier studies demonstrating that unadjuvanted split virion or subunit vaccine antigens are not sufficiently immunogenic in an unprimed population and, consequently, do not meet requirements listed under 1) and 2). Adequate immunological priming of a population exposed to a novel influenza virus can only be achieved by adding a potent adjuvanting system to purified vaccine antigens or by using whole (unsplit) virions where internal viral proteins are believed to act as an intrinsic adjuvanting system.

The two concepts were thoroughly evaluated and found to be sufficiently immunogenic and safe either as a mock-up (H5N1) formulation or as the true pandemic (H1N1v) formulation. However, a head-to-head comparison between individual pandemic influenza vaccines had never been performed in order to identify potentially important differences between them.

The paper describes such a head-to-head comparison and presents differences in immunogenicity and safety profiles. Results confirm two observations made already previously in separated studies performed with these two vaccines:

1. A whole virion based pandemic HN1 influenza vaccine is less immunogenic compared to a split virion-based vaccine formulated with a squalene- based adjuvanting system (AS03); and
2. The AS03 containing vaccine is slightly more reactogenic, specifically in children younger than 5.

These findings are not necessarily surprising. Increasing immunogenicity of vaccine antigens by using potent adjuvanting systems will always be coincident with an increased rate of local and systemic reactions. This is neither a regulatory nor a medical problem as long as the reactogenicity profile remains within an acceptable margin ensuring that the benefit of vaccination by far outweighs the risks of vaccination. Such a risk-benefit analysis primarily depends on the health burden to which a population is exposed to when a novel (pandemic) influenza virus evolves. The higher the health risk, the less potential vaccination risks count. For the present pandemic, the risk-benefit ratio of vaccines containing novel adjuvanting systems has always been favorable, even though the current pandemic is widely considered to be mild.

Moreover, available clinical data indicate that it is just a matter of correctly titrating the optimal amount of antigen against the optimal amount of adjuvant in order to reduce local and systemic reactions to an unavoidable minimum for any age category.

Of note, higher immunogenicity inherent to less purified vaccine preparations is often paralleled by (occasionally unacceptably) high reactogenicity profiles. This is precisely the reason why vaccine development moved towards purified antigen preparations being much less reactogenic, however also less immunogenic. In conclusion, and looking back into history of vaccine development, there are, if any, only few options to enhance immunogenicity specifically of highly purified vaccine antigens. Consequently, novel adjuvanting systems seem to be the only remaining strategy to create superior vaccines. This is probably the most important lesson learned from the recent pandemic.

– Michael Pfleiderer, MD
Head of Viral Vaccines Section, Paul-Ehrlich-Institut, Federal Agency for Vaccines and Biomedicines

Waddington CS. BMJ. 2010;340:c2649.