Prof Nikolai Petrovsky, Research Director, Vaxine, Australia

Aug 2010: The recent H1N1 2009 ‘swine flu’ pandemic, whilst modest in its overall clinical impact, has hopefully driven home to regional policy makers the message that the Asian region is extremely vulnerable and ill prepared to deal with a serious influenza pandemic, when this eventuates, as it surely will. History tells us that serious influenza pandemics, due to major shifts in the prevailing viral serotype as a new serotype crosses from birds to humans, occur on average
every 30-40 years. H1N1 2009 should provide no consolation for the fact that the next pandemic is overdue, as it did not represent a completely new serotype, multiple strains of H1N1 circulating in humans since the Spanish flu of 1918. Indeed, it is cross-protection from past H1N1 infections that may explain the extremely benign impact of H1N1 2009 in elderly population, who generally are the group most severely affected by seasonal influenza. This meant it was the more immunologically naive younger adults with chronic medical conditions, pregnant women and young children that bore the brunt of H1N1 2009 mortality and morbidity. Looking at with the benefit of hindsight, the overall global mortality figures of H1N1 2009 confirm it was extremely benign even when compared with a typical seasonal flu strain.

The irony of H1N1 2009 was that its reproductive vigour enabled it to essentially displace all other normally circulating seasonal flu strains, which would normally cause mortality in the elderly. Hence, based on typical seasonal influenza death rates, H1N1 2009 may paradoxically have protected more than it maimed. For example, it is commonly quoted that in a typical season influenza kills up to 3,000 elderly Australians. Put this figure of typical seasonal deaths against the total of less than 200 influenza-related deaths in Australia during the entire 2009 flu season (almost entirely H1N1 2009) and the conclusion is that H1N1 2009 was unlike any other influenza pandemic previously experienced, in being extraordinarily benign given its ability to protect rather than harm the elderly.

Lessons from 2009 H1N1 outbreak

The first danger, therefore, is that the highly atypical H1N1 pandemic will generate complacency amongst, rather than deliver a wake up call to, regional policy makers. Unfortunately, those regional governments that procrastinated in securing initial H1N1 2009 vaccine supplies, and were effectively locked out of the market as large developed countries in Europe and US contracted all foreseeable future supply, now look financially savvy as overly hasty governments in Australia, Europe, and US try to buy their way out of unneeded vaccine contracts and destroy billions of dollars of unused H1N1 vaccine. Before patting themselves on the back for their procrastination, regional health authorities should instead be asking themselves the question ‘but what if H1N1 2009 had been more serious?’ Hindsight is a wonderful thing but if nothing else H1N1 2009 clearly showed us is that regional influenza surveillance systems to monitor and provide the critical early information on the clinical severity of a particular outbreak and thereby inform vaccine purchasing decisions, is inadequate and needs much more government support and funding.

The second lesson from H1N1 2009 is that if the South East Asian region wants secure pandemic vaccine supply, then it needs to invest in local vaccine manufacturing capacity. In particular, the region cannot rely on early supply from large pharma companies based in Europe, the US or Australia who will first supply their own countries and then will sell what is left to the highest bidder. Of course, once the worst of the pandemic is over in the developed countries, these large vaccine companies will then make available excess vaccine stocks to the developing world. At a time when the major demand has dissipated. Hence while large vaccine companies are extremely valuable for regular supply of childhood and other routine vaccines, they are unlikely to be the best partners for developing countries looking for security of future pandemic vaccine supply.

Developing countries would be better served building relationships with and financially supporting smaller, more nimble, regionally-based, vaccine companies, who will respond more quickly to regional needs, and fill any vaccine gap created by global vaccine companies with their focus elsewhere. If a single SE Asian country like Malaysia doesn’t feel that they have sufficient population size to support their own vaccine manufacturing operation, then why don’t they partner with neighbouring countries and build a shared vaccine facility? Such multilateral agreements and resource sharing are common in other, much more sensitive, sectors such as defence, so why not in vaccine manufacturing where regional security is similarly at stake?

Stop imitating big players

If South East Asian countries were to invest in new vaccine manufacturing capacity, the one thing that they should avoid is investing in the obsolete vaccine technology currently used by the major global flu vaccine manufacturers. The big vaccine manufacturers are trapped in using outdated technology by existing massive infrastructure investments. A smart new vaccine entrant would seek to leapfrog over the existing big entrenched players by only using the latest cutting-edge vaccine technologies, ensuring a higher quality, and potentially lower cost, vaccine with attributes that cannot be matched by the existing producers.

The converse of this approach would be to replicate what happened with hepatitis B vaccines where, by copying the existing hepatitis B vaccines as they came off patent, developing world producers could only seek to match the existing 20-year-old product and were therefore forced to compete solely on price with the result that all the new vaccines were pushed down to extremely low prices, thereby depriving the new manufacturers of sufficient margins and profits needed to invest in development of new vaccines.

This is not a sustainable model, as clearly shown by the situation in Japan where only world-leading vaccine manufacturers who introduced new vaccines like the acellular pertussis vaccine 20 years ago, had access to insufficient profit to develop or improve their vaccine due to poor policies. The result is that Japan now has to import new vaccines including pneumococcal and human papilloma virus vaccines and even its H1N1 2009 vaccines last year, from overseas manufacturers. This is a classic example of the damage inflicted when purchasers attempt to drive down vaccine prices to unsustainably low margins that do not allow reinvestment in future
vaccine R&D.

The lesson here should be for vaccine manufacturers in developing country to always aim to introduce an improved vaccine, not just a cheaper copy. This should be the approach to implementing new regional influenza vaccine manufacturing. Any new regional vaccine enterprise should seek to implement new technologies and approaches rather than just copying what is already being done elsewhere.

New approaches

Our company Vaxine Pty Ltd, based in Adelaide Australia, is a leading proponent of this philosophy of focussing on building new and improved vaccines. Faced with the urgent global need for pandemic influenza vaccines, be it against H1N1 2009 or avian H5N1, our investigations rapidly identified the latest recombinant hemagglutinin protein approaches being driven by small biotech companies such as Protein Sciences in US and Medicago in Canada represent revolutionary advances that are almost certain to become successor technologies to current inactivated virus flu vaccines. Indeed, human clinical trials performed by ourselves and others, have confirmed and utility and benefits of the recombinant approach to flu vaccine manufacture.

The only drawback to the recombinant vaccine approach has traditionally been the poor immunogenicity of recombinant proteins. As we have shown, however, this problem is conveniently solved by addition of a compatible adjuvant, namely our Advax polysaccharide adjuvant, which can easily double the seroconversion rates of unadjuvanted vaccine. Other advantages of Advax-adjuvanted flu vaccine as demonstrated in animal models, include significant antigen-sparing thereby reducing cost and increasing supply, and enhanced anti-influenza T-cell immunity thereby broadening protection against other flu strains.

An Advax-adjuvanted recombinant flu vaccine is just one example of novel, cutting-edge vaccines suited for small to large scale manufacture in South East Asia that can be created when the latest vaccine technology is put to use. For example, Vaxine has also built a novel increased-potency, prophylactic, and potentially therapeutic, hepatitis B vaccine using a similar approach.

These are the type of novel vaccines that currently have no global peer that new regional vaccine manufacturing operations should be seeking to produce, thereby providing future regional vaccine growth opportunities. Most importantly, introduction of novel regionally-produced vaccines would allow South East Asia to profitably build its vaccine manufacturing infrastructure, such that come the next pandemic, South East Asia is better placed to supply its own pandemic vaccine needs rather than remain totally dependent on uncertain suppliers external to the region.