Saturday, August 06, 2005

Flu vaccine vaporware, Acambis-style

It's all over the newswires again: Hope is On the Way. The UK-based biotech vaccine company Acambis is all but promising a one-size-fits-all flu vaccine, one "jab" good for life. Works for all strains of flu. Wow.

This is pretty good news. Especially for Acambis:
Shares in the biotech group were given an injection on Thursday, on the back of a Times report on the jab, which could help eradicate the threat of a pandemic influenza outbreak. At the close of trading on Wednesday night the shares were trading at 230p[ence].

On Thursday they closed at 239p and yesterday they added a further 11p to 250p.The improvement marks something of a revival for the company’s shares, which have sunk from a high of nearly 400p reached in 2003. The shares came under pressure on concerns that once a key contract to supply smallpox vaccines to the US had been fulfilled its prospects were limited. (TimesOnline)
Kind of puts you on your guard. So what's this all about? Here is the idea. If you can find a viral protein that is found on all influenza strains but mutates very little, you can use it to make an all-purpose vaccine that doesn't change from year-to-year. And Acambis claims to have found one:
A major component of the new candidates will be M2e, the extracellular domain of the ion channel protein M2, which is specific to influenza A. Being highly conserved, M2e is intended to elicit protective immune responses against all strains of influenza A. M2e is incorporated in a unique carrier system that forms highly immunogenic virus-like particles.

The initial vaccine candidate against influenza A is currently in pre-clinical development. It is manufactured using recombinant bacterial fermentation technology, which aims to provide time and cost efficiencies compared with traditional egg-based production methods. (via MarketWire [sic])
Sounds good, huh? (If you aren't quite sure what the M2 protein is and what it does, hop on over to the Flu Wiki and read the Influenza Primer II, written by yours truly).

But wait. There's more. Order before midnight tonight and you'll receive . . . nothing for several years and even then, probably more nothing. If you read the press release snippet above you will see that the M2e strategy is in "pre-clinical" development. That means they are still doing tests on animals and in test tubes. And they aren't the only ones. People have been talking about using M2e for years, so the idea isn't even original. And what previous researchers have discovered isn't all that encouraging. Here's a sampling:
Fan J, et al. "Preclinical study of influenza virus A M2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys," Vaccine. 2004 Aug 13;22(23-24):2993-3003

The conjugate vaccines were highly immunogenic in all species tested and were able to confer both protection against lethal challenge of either H1N1 or H3N1 virus in mice and reduce viral shedding in the lower respiratory tracts of mice and ferrets. [snip]. In addition, we showed that M2 antisera were cross reactive with M2 peptides derived from a wide range of human influenza A strains, but they failed to react with M2 peptides of the pathogenic H5N1 virus (A/Hong Kong/97).

Translation: Doesn't work for bird flu in mice or ferrets.


Jegerlehner A, Schmitz N, Storni T, Bachmann MF, "Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity," J Immunol. 2004 May 1;172(9):5598-605

The present study demonstrates that protection is mediated exclusively by Abs, a very important feature of a successful preventive vaccine. However, these Abs neither bind efficiently to the free virus nor neutralize virus infection, but bind to M2 protein expressed on the surface of virus-infected cells. The presence of NK cells is important for protection, whereas complement is not, supposing that protection is mediated via Ab-dependent, cell-mediated cytotoxicity. The absence of neutralizing Abs results in much weaker protection than that achieved by vaccination with UV-inactivated influenza virus. Specifically, whereas neutralizing Abs completely eliminate signs of disease even at high viral challenge doses, M2-specific Abs cannot prevent infection, but merely reduce disease at low challenge doses. M2-specific Abs fail to protect from high challenge doses, as vaccinated mice undergo lethal infection under these conditions. In conclusion, protection mediated by M2-hepatitis B core vaccine would be insufficient during the yearly epidemics, for which full protection is desirable, and overall is clearly inferior to protection achieved by immunization with classical inactivated viral preparations.

Translation: M2 vaccine didn't work by neutralizing the virus but required assistance of T-cells. This means it would be insufficient for routine protection against influenza viruses.


Heinen PP et al. "Vaccination of pigs with a DNA construct expressing an influenza virus M2-nucleoprotein fusion protein exacerbates disease after challenge with influenza A virus," J Gen Virol. 2002 Aug;83(Pt 8):1851-9

In mice, vaccines inducing antibodies to the extracellular domain of the M2 protein (M2e) can confer protection to influenza A virus infection. Unlike the surface glycoproteins, haemagglutinin and neuraminidase, this domain of M2 is highly conserved and is therefore a potential broad-spectrum immunogen. In this study, the protection conferred by vaccines inducing antibodies to M2e was evaluated in a challenge model for swine influenza in pigs. A protein resulting from the fusion between M2e and the hepatitis B virus core protein (M2eHBc), with or without adjuvant, was evaluated. In addition, a DNA construct expressing a fusion protein between M2e and influenza virus nucleoprotein (M2eNP) was evaluated to see if the broad-spectrum protection conferred by antibodies could be further enhanced by T helper cells and cytotoxic T cells. All vaccines induced an antibody response against M2e, and the M2eNP DNA vaccine additionally induced an influenza virus-specific lymphoproliferation response. However, after challenge with a swine influenza virus (H1N1), no protection was observed in the vaccinated groups compared with the non-vaccinated control group. On the contrary, vaccinated pigs showed more severe clinical signs than the control pigs. The M2eNP DNA-vaccinated pigs showed the most severe clinical signs and three out of six pigs died on days 1 and 2 post-challenge. These results indicate that antibodies to M2e, especially in combination with cell-mediated immune responses, exacerbate disease. Thus, clinical signs after infection should be observed closely in further studies using M2e as an immunogen and caution should be exercised in using M2e in humans.

Translation: This one's the kicker. Vaccination against M2e worked in pigs to produce a good antibody response. Unfortunately, it set off a reaction that killed the virus-challenged vaccinated pigs faster than the unvaccinated ones.
So don't go out and sink your fortune in Acambis stock yet. And don't think the biotech cavalry is going to ride to your rescue from bird flu assault anytime soon.

The Acambis announcement used to be called vaporware in the software business. In the medicine business we just call it Snakeoil.