The new adjuvanted bird flu vaccine

The big pandemic flu vaccine news of the moment has to be The Lancet report that vaccine maker GlaxoSmithKline has been able to get excellent antibody production against H5N1 with a new adjuvanted preparation that contains remarkably little viral antigen. This is important because the currently the only FDA approved pre-pandemic H5N1 vaccine uses more than 20 times as much (90 micrograms versus 3.8 micrograms) in an unadjuvanted preparation with much worse antibody response.

In today's Lancet, Isabel Leroux-Roels and colleagues report safety and immunogenicity data from a phase-1 dose-sparing study of egg-derived inactivated split A/Vietnam/1194/2004, a clade 1 vaccine adjuvanted with a proprietary adjuvant, ASO3, an oil-in-water-based emulsion containing DL-alpha-tocopherol squalene, and non-ionic detergent polysorbate 80. Vaccinees received two doses of vaccine 21 days apart, containing 3·8, 7·5, 15, or 30 micrograms of haemagglutinin (HA) protein with or without adjuvant. In this study, 3·8 micrograms HA combined with the ASO3 adjuvant induced haemagglutination inhibition (HI) antibody titres of 1:40 or higher and four-fold increases in neutralisation titres in 84% and 86% of vaccinees, respectively. Unadjuvanted vaccine at 3·8 micrograms induced HI titres of 1:40 or higher and four-fold increases in neutralisation titres in only 16% and 37% of vaccinees, respectively. Unadjuvanted vaccine even at the highest dose (30 micrograms HA) induced HI titres of 1:40 or higher and four-fold increase in neutralisation titers in only 43% and 65% of the vaccinees, which is consistent with previous reports. These findings are important to anyone involved in pandemic preparedness because the number of prepandemic vaccine doses can be stretched 20 - 25-fold, when compared to the 90 micrograms dose required by the current A/H5N1 vaccine approved by the US Food and Drug Administration. (Lancet [cites omitted; registration required])

This is a remarkable result. 3.8 micrograms is 75% lower than used in currently conventional seasonal flu vaccine. The results are still on the basis of antibody response, not demonstrated protection, but we have no other way to evaluate an H5N1 vaccine at the moment. Moreover, again on the basis of antibody generation, there seems to be neutralizing activity against genetic variants of H5N1 other than the specific antigen in the vaccine preparation. So that's the good news. Is there a downside?

One obvious one is that we know little about the safety profile of this novel antigen. Clearly it has a fairly dramatic immune boosting effect and there is evidence, even in a small sample, of increased side effect (which in this report were not serious). When you start giving it to tens of millions or a hundred million or more people (and that's just in the US) there is potential for many rare but extremely serious reactions. As we saw in 1976 in the Swine Flu program, this can cause a serious loss of public confidence in any vaccination program, or even in vaccination in general. This is a real risk that is difficult to evaluate at this stage, the more so if such an adjuvanted vaccine is used in advance of a pandemic.

The accompanying Commentary by Sambhara and Poland in the Lancet also makes another interesting comment, almost as an after thought:

Additionally, because vaccine may be in limited quantity at the start of a pandemic, a multipronged strategy will be required to minimise the effect of a pandemic. Also, strategies to boost host antiviral defences to overcome antiviral resistance and disease management approaches to modulate excessive inflammatory responses (cytokine storms) with immunomodulatory drugs are needed to mitigate the effect of a pandemic.

The citation for the possible promise of immunomodulatory drugs is one of David Fedson's pleas (Fedson DS. Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin Infect Dis 2006; 43: 199-205) to examine the value of statins for use in cytokine storm (see our previous posts here, here and here).

We still wonder why more hasn't been done to investigate this further. No one at Big Pharma will make money off statins. Maybe that's the answer.