The future of vaccine R&D

Published: 11-Apr-2014

Vaccine development has produced some of the greatest human health benefits since the start of medicinal science, but can future developments match those of the past?

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Although two-thirds of vaccine research and development (R&D) globally is carried out by European firms, manufacturers in China, India and Brazil are becoming increasingly muscular and ‘moving from dependency to self-sufficiency’, experts at a two-day conference in Brussels on vaccine research heard in late March. Dr Suresh Jadhav, Executive Director, Serum Institute of India, said there is a declining interest by major international pharma companies in the Expanded Programme on Immunisation (EPI) funded by the World Bank, leaving a gap that developing country manufacturers are striving to fill.

The audience at the conference organised by the European Commission (EC), ‘New Horizons for Vaccine Research and Innovation’ heard that BRICS countries in particular, along with innovative emerging market countries such as South Africa, have pharma players looking to meet this demand from healthcare systems. And indeed, the global vaccine market is no longer an EU, USA, Japan triad. The market size has increased from US$5bn (£3bn) in 2000 to $24bn (£14.5bn) last year, according to the Developing Countries Vaccine Manufacturing Network (DCVMN). In 2012, emerging market manufacturers catered for 50% of procurement by value of UNICEF-purchased vaccines.

‘Emerging markets are in transition,’ Dr Jadhav told delegates. ‘Local industries are becoming stronger because affordable vaccinations hold the key. They are not only assessing local markets but eyeing up global ones as well.’ Their business model, as recommended by the World Health Organisation (WHO), he noted, is for high value at low cost. Some of this manufacturing capacity will be achieved through increased acquisitions and partnerships between local manufacturers.

Looking ahead, he added that vaccine industries in emerging countries could develop an incentive to research vaccines suitable for more ‘neglected diseases’, for which larger companies find it difficult to make a business case.

The last decade has seen great advances in the introduction of new vaccines which are expanding their reach

The need to ensure that resulting pharmaceuticals were affordable where they are needed most was a recurring conference theme. There was agreement among participants that while research costs are soaring, vaccines, accounting for only 3% of the pharmaceutical market, are highly cost-effective. Dr Jadhav added: ‘The last decade has seen great advances in the introduction of new vaccines which are expanding their reach. For example, the number of deaths caused by traditional vaccine preventable diseases (measles, diphtheria, neonatal tetanus, etc.) have fallen from an estimated 900,000 in 2000 to 400,000 in 2014.’

Currently there are 29 infectious diseases that are preventable by vaccination, according to GlaxoSmithKline (GSK), although the big three – tuberculosis (TB), HIV/AIDs and malaria – loomed over many of the conference presentations. These took place just days after the EC awarded German company CureVac €2m ($2.7m) as an ‘inducement prize for pioneering work in vaccine technology’. Its aim is to create a system able to produce within a few weeks (particularly if there is a pandemic) prophylactic vaccines that are effective in high temperatures and freezing temperatures. In other words, the products would not need to be distributed through the traditional cold chain logistics, which hamper their dispersal in the world’s most remote locations, many of which struggle with extreme temperatures.

This invention is based on messenger ribonucleic acid (RNA) molecules that stimulate the immune system and have the ability to protect production against deterioration through high temperatures or accidental freezing. The prize jury highlighted the potential of this new technology for global health benefits. Its members said that, given the technology could be applied to many diseases and a number of vaccines, it might allow formulating a combination of vaccines and also allow the production of many vaccine units in a single factory.

Prize-winning CureVac has shown that one of its vaccines remained viable after being stored at 40°C for six months

Prize-winning CureVac has shown that one of its vaccines remained viable after being stored at 40°C for six months

EU research, innovation and science Commissioner Máire Geoghegan-Quinn said: ‘CureVac’s success opens up the possibility of a real European breakthrough in delivering vaccines where they are needed most.’ She expressed the hope that science was at the start of ‘a second golden age of vaccine discovery’. This, she believes, is the result of new cell culture techniques and major innovations in recombinants in molecular biology.

The Commissioner stressed three points:

  • Vaccine development is vital not just for humans but also for animal health because much of what is learned about vaccine efficacy has been developed and tested in animals. There are many areas where vaccine research should be considered together not separately
  • The best vaccine in the world is worth nothing if it is not used, either because it does not reach the would-be user, because it is too expensive, or because the health system does not reach the most vulnerable populations
  • Lastly, who pays for vaccine innovation? Innovation never happens in isolation, so we all need to think about organisational and financial models and finding the right partners for vaccine research.

Geoghegan-Quinn said that, thanks to EU funding, there are now early stage research and clinical trials on a number of so-called neglected infectious diseases, such as leishmaniasis or schistosomiasis, mostly found in the tropics and attracting very little private sector research. ‘Success could improve close to a billion lives and support economic growth in countries held back by poor health,’ she said. She promised more inducement prizes will be allotted next year under Horizon 2020, the EU’s 2014–2020 research and innovation programme.

New vaccines are not as cheap nor as effective as they used to be

But just as the Commissioner is duty bound to keep the subject of vaccine development politically buoyant, others were more doubtful about an approaching golden age. Mitchell Warren, Executive Director at AIDS Vaccine Advocacy Coalition (AVAC), was one. ‘New vaccines are not as cheap nor as effective as they used to be,’ he told the delegates. ‘Nor are they easy to administer as part of EPI programmes.’

The mantra is: ‘Vaccines are the most effective public health interventions, but will this be true in the future?’ So far there are 29 infectious diseases that are preventable by vaccine.

‘The dream of eradication is at best rocky – for instance, the failures against hookworm, yellow fever and malaria. The struggle against polio has raised new questions of whether abolishing any disease is achievable and whether the cost of the effort is worth it, given all the diseases which need attention.’

Nonetheless, these days, polio remains endemic in only three nations: Afghanistan, Nigeria and Pakistan.

The struggle against polio has raised new questions of whether abolishing any disease is achievable

Gerald Voss, Director of GSK Biologicals, Belgium, queried whether all the easy vaccines have already been made. This is true to some degree, he stated. The development of new ones is lengthy and costly – ‘anything north of 10 years and $1bn,’ he said, warning that licence commitments are also costly and must be included in the final bill.

Rino Rappuoli, Head of Vaccine Research at Novartis Vaccines and Diagnostics, in Siena, Italy, posed the rhetorical question of whether robot production would speed up manufacturing and thereby reduce costs. His answer was an emphatic negative on the grounds that vaccine production should be compared to vineyards: it needs close, personal attention; also everyone says that ‘their’ disease is worse than anyone else’s and therefore is more deserving of resources. But all such debate must be science-driven, he maintained.

‘Will it be possible to have an AIDs-free generation?’ asked Hansi Dean, Director of New Alliances at the International AIDS Vaccine Initiative, USA, indicating that she rather thought it would. But others were a little more doubtful, given the slow-down in recent years of effective vaccine discovery across the board.

Experimental medicine research should look more closely at trial designs and ask whether they can be simplified

With the burden of costs hanging heavily over the proceedings, some of the other 25 featured speakers were keen to suggest ways in which it could be lessened. The favourite was to have smaller clinical trials. Penny Heaton, Director of Vaccine Development at the Bill and Melinda Gates Foundation, was a particularly strong advocate for this.

‘Small clinical trials are going to be crucial in the near future,’ she emphasised, claiming it can cost at least $1m just to hold a Phase I trial. People might be more amenable to smaller scale testing if it was understood to be in the experimental medicine category and not for marketing purposes, she argued.

Heaton said there was an imperative to hold more focused clinical trials much earlier in the exploratory stage: ‘Experimental medicine research should look more closely at trial designs and ask whether they can be simplified. This would help everyone, though we should never, ever lower safety standards.’

She also challenged regulators by asking if they might consider in future vaccines which are partially effective rather than wholly so. ‘I don’t think it should be all or none,’ she said. Because vaccines are becoming more complex all the time, perhaps we should consider as part of the next generation of vaccines whether we could meet needs via vaccines that ‘are reasonably effective though not completely so.’ She added that as part of such a strategy, a much greater focus should be put on the role of small-and-medium-sized enterprises (SMEs).

Given global competition, the EU has to enhance its long-term growth potential by investing in R&D, innovation and infrastructure

This chimed conveniently with the simultaneous approval of the European Investment Bank (EIB) of €5.6bn ($7.7bn) to benefit SMEs across the continent. In announcing this largesse, EIB president Werner Hoyer, said: ‘Given global competition, the EU has to enhance its long-term growth potential by investing in R&D, innovation and infrastructure. Europe must unlock its bottlenecks to sustainable growth.’

Professor Adrian Hill, Director of Oxford University’s Jenner Institute, agreed that small-scale rapid clinical trials were the way forward. Test concepts would get a lot further if they were more widely deployed. He cited that so far there has been only one aerosol immunisation method in a clinical trial. What is lacking is head-to-head comparisons much earlier than licensing and marketing, but this rarely happens, he claimed. Perhaps this might help to identify biomarkers of efficacy. ‘That way we would get a much clearer signal much earlier,’ Hill said.

A broad consensus emerged from the discussions. First, there was agreement on the need for innovation at all levels from discovery to implementation; and second, that partnerships are needed for sustainable future development. In particular, product development arrangements with developing and emerging market countries are not only desirable but essential.

So too are broad alliances for implementation. No delegate seriously disagreed that vaccines are the most efficient weapons to fight serious disease, both for their preventive effects and cost-effectiveness, referring to the eradication of smallpox, while polio and diphtheria have almost disappeared.

However, the potential of vaccines has to be more fully realised while at the same time doctors, scientists, economists and others cannot take vaccine protection for granted; and it should not be forgotten that there are no vaccines at all against HIV/AIDs, malaria, TB (the biggest killer of all time), hepatitis C or Dengue fever.

In the meantime, the EU is funding five research projects that may, or may not, point the way towards a universal flu vaccine that would banish the need for an annual vaccine by taking account of the constant variation in flu strains.

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