Select Committee on Science and Technology Fourth Report

CHAPTER 7: A LONG-TERM STRATEGY

7.1.  Up to this point we have concentrated on the steps that can be taken to prevent a pandemic happening and on the measures that will be required to minimise the disruption that a pandemic would cause. We now turn to longer term planning and research.

Vaccines

MANUFACTURING TECHNOLOGY

7.2.  We have already noted, in our overview of the treatment and prevention of influenza, that it would probably take seven to nine months from the initial outbreak of a pandemic to prepare a vaccine. In other words, by time a vaccine was ready there would be a chance that the pandemic would have passed its peak—as happened in 1957 and 1968. On the other hand, if vaccine production can be accelerated, the time cut from, say, nine to six months, there would be huge benefits not only in the event of an influenza pandemic (in protecting the population from second and subsequent waves), but more generally in improving our ability to respond to new diseases.

7.3.  At present the killed virus from which vaccines are manufactured is incubated in hens' eggs, a technology dating back to the 1950s, which would appear to be particularly vulnerable in the event of a pandemic of avian-derived influenza. New methods of production are long overdue, and their importance was underlined on 1 November by President Bush's announcement of a $2.8 billion programme to promote the development of cell-culture technology, which he argued would "produce enough vaccine for every American within six months of the start of a pandemic".[12] Work on cell-culture of vaccines is also underway in Europe, and Dr Bryett, of Chiron, told us that his company would "be looking to have the product available" in "about a couple of years". (Q 55)

7.4.  However, it is not entirely clear how much difference the introduction of cell-culture would make to the time taken to produce a vaccine. Dr Bryett down-played expectations of a radical improvement, telling us that cell-culture would remove "the delay of getting the hens' eggs into the system" (one egg for each dose of vaccine), but that the actual time taken to cultivate the virus would remain broadly similar. He did not put a figure on the time that would be saved by moving to cell-culture. (Q 56)

INTER-PANDEMIC DEMAND

7.5.  Even when a vaccine is ready, limited manufacturing capacity within the industry means that there will be a significant delay before orders can be fulfilled and the vaccine made generally available. Both Chiron and the UK Vaccine Industry Group (UVIG), which represents all six UK-based vaccine manufacturers, argued, in Chiron's words, that "Current production capacity reflects ongoing inter-pandemic demand, and is far from sufficient to meet a global pandemic requirement … the Government needs to take steps to increase inter-pandemic demand for vaccines, and drive investment in new production facilities". (p 24)

7.6.  In other words, the manufacturers argue that the Government should both increase take-up of the normal annual flu-jab by those at risk, and broaden their definition of "at-risk" groups, so as to build up manufacturing capacity and help manufacturers to increase output in the event of a pandemic.

7.7.  Chiron went on to state that "despite relatively high coverage in the age group 65 years and over, only an estimated 42 percent of at-risk patients in the UK are currently vaccinated". The Minister, on the other hand, defended the Government's record, although she was vague about the exact figures: "We have a very good track record in terms of achieving the targets we have set, which was something like 70 per cent of people over 65, or 60; I cannot remember which." In effect, she blamed other countries: "There are some countries that are not up to the level that we are in terms of seasonal flu vaccination and manufacturing thereof." (p 24, Q 229)

7.8.  We are sceptical about both sides of this argument. On the one hand, increasing the take-up of the annual flu-jab will not in itself be sufficient to raise manufacturing capacity to the point where the companies can respond rapidly to the requirements of a pandemic, in which governments around the world will be urgently seeking to vaccinate their entire populations. On the other hand, we are disturbed by the complacency of the Minister's response, and the implication that other countries are to blame for the shortfall in manufacturing capacity. Increasing the take-up of the annual flu-jab among at-risk groups will bring its own health benefits, and should be a high priority for the Government regardless of the danger of a pandemic. Furthermore, the distribution problems that resulted in the announcement on 22 November that stocks of seasonal influenza vaccine were all but exhausted suggest that the Government need urgently to review guidance for general practitioners as well as the public.[13]

7.9.  There is a related issue to do with advance purchase agreements for any new vaccine. We were told that the Government would, by this means, secure delivery in the event of a pandemic of 120 million doses of vaccine (enough to provide the necessary two doses to each person in the United Kingdom). However, the precise commercial arrangements are as yet unclear, and even Dr Bryett, of Chiron, noted that "so far we do not have any details". (Q 58)

7.10.  While the existence of an advance purchase agreement offers some comfort to the people of the United Kingdom, it also opens up the possibility that those developed countries able to negotiate such agreements will, in the event of a pandemic, take up all the manufacturing capacity, leaving none for developing and other countries. This could potentially have a dramatic effect on international relations.

7.11.  We note the comment of Mr Richard Stubbins of UVIG, that the industry has discussed ways "to distribute vaccines as equitably as possible" between countries, possibly providing vaccines "on a proportional basis, based on a government's purchase of the vaccines in the inter-pandemic period". Though this arrangement would provide an incentive to all governments to increase their take-up of annual influenza vaccine, it is debatable whether it would be any more equitable than a first-come-first-served distribution. It would also mean that the United Kingdom, which normally purchases around 12 million doses of trivalent influenza vaccine,[14] would have access to just 36 million doses of monovalent pandemic vaccine, well short of the 120 million doses required to cover the whole population. (Q 60)

REDUCING THE DOSE

7.12.  Other measures, both to improve the efficacy of vaccines and to speed up the regulatory and bureaucratic processes necessary before a new vaccine can be approved, hold out more promise. On efficacy, various vaccine manufacturers, including Chiron and GlaxoSmithKline, are currently studying the potential for incorporating an "adjuvant" in the influenza vaccine, which will allow the vaccine to be delivered in much lower doses without diminishing its effectiveness. In effect this would mean that any given volume of virus cultivated, whether in eggs or cell-culture, would yield many more doses than at present.

7.13.  Trials by Chiron of an adjuvant known as MF59 have shown that the amount of antigen required to produce an immunological response can be reduced from the normal monovalent dose of 15 micrograms to 7.5 micrograms without loss of efficacy. This would have a significant effect upon the industry's ability to manufacture large quantities of vaccine in a limited time. However, MF59 is a proprietary product, which can only be used by other manufacturers subject to licensing arrangements. Asked whether this could be a barrier to large-scale production, Dr Bryett, Managing Director of Chiron UK, said merely that the company was "reviewing the capacity for the adjuvant very actively." (QQ 48-49)

REGULATION AND "MOCK-UP" DOSSIERS

7.14.  Rapid regulatory clearance for a new vaccine will also be critical. The European Medicines Evaluation Agency (EMEA) has already established a "mock-up dossier" for a pandemic vaccine. This will allow the manufacturers to go through many of the stages of regulatory approval (quality tests, trials and so on) on the basis of one of the strains of the virus already circulating. Once the actual pandemic strain is identified it would then simply replace the mock-up strain without having to go through the whole regulatory process from scratch. As Dr Salisbury said, the objective is that "the various regulatory processes that are necessary in that period of time can be brought together and made to run concurrently rather than sequentially so that the interval between having a pandemic virus and having the seed material for production is brought down to the absolute minimum". (Q 243)

7.15.  However, mock-up dossiers are expensive—of the order of €11-13 million per candidate vaccine—and Dr Bryett noted that "it would be a mock-up file for each vaccine; it is not a question of a single generic mock-up file. Each manufacturer will have a different way of producing the vaccine and probably different testings." Approval in principle by the EMEA is therefore not in itself sufficient to ensure that this investment will be made. The evidence we received from the Minister and her colleagues was somewhat vague, but there does not seem to be any guarantee that the Government will finance mock-up dossiers. (QQ 37, 223-228, 243)

7.16.  In light of the proposed fast-tracking of the regulatory checks on a new vaccine, the manufacturers also expressed concerns over their potential liability should any vaccine have adverse effects. The Minister emphasised that "it goes without saying that we would do everything to make sure that safety was not compromised." Nevertheless, Dr Salisbury conceded that the manufacturers felt "very vulnerable", and that "indemnity will have to be resolved one way or another between the industry and those that are buying vaccines." The same day as we heard this evidence, proposals to indemnify manufacturers were backed by President Bush, who, in announcing his $7.1 billion pandemic influenza programme, called on Congress to "pass liability protection for the makers of life-saving vaccines". (QQ 243-244)

Other treatments

7.17.  Although the focus of our inquiry, as of the Contingency Plan, was on vaccines and antivirals, there remains the possibility of other treatments. For example the Academy of Medical Sciences mentioned the "fractionation" of blood plasma from convalescent patients, which could ultimately produce a "bank of immune immunoglobulin for future prophylaxis". That is to say, the antibodies derived from the plasma could either prevent or attenuate infection in others. Dr Wood, of the NIBSC, believed that the preparation of immune immunoglobulin "would be quicker than making vaccine". However, this approach is precluded by current precautions to prevent the spread of vCJD. Dr Wood suggested that in the event of an emergent pandemic there would have to be "a risk analysis" to identify whether the benefits of fractionation outweighed the risks—though it is doubtful whether such an analysis could be completed in time in such circumstances. However, some preparatory risk analysis could be undertaken using reasonable assumptions for the risk of transmission of vCJD and the benefit or reducing influenza morbidity and mortality. (p 132, QQ 79-80)

Research opportunities

7.18.  While an influenza pandemic would be a destructive and costly event, it would also be a unique opportunity for research. As Professor Menon, of the Intensive Care Society, noted, one of the reasons the world is so poorly prepared for a potential pandemic is that "previous pandemics have not been subjected to the rigorous research that modern research techniques allow". (Q 178)

7.19.  Some of this research—for instance, into the impact of different combinations of antiviral drugs on patient outcomes and into the incidence and type of secondary infections such as pneumonia—would feed directly back into the health service response to the pandemic. In Professor Menon's words, "If we are going to use antivirals, we need to know: does it make a difference … whether the antiviral was given on day one or day four? If, on day four, it was making no difference to the severity of the illness, then that makes a difference to how we treat people at the end of the pandemic."
(Q 178)

7.20.  Other research would have longer term significance. For instance, we have already drawn attention to the high mortality among young adults in 1918-19, and to the theory that they were killed by their own immune response. In the event of a new pandemic it would be possible to show definitively "whether what is killing [patients] is the disease or whether it is the host response." Professor Menon noted that such extreme immune responses may be "genetically-driven … There is a case to be made for trying to understand the genetics underlying how badly people do or how well they do". This would in turn "inform our understanding of a lot of major illnesses both infectious and non-infectious"; undertaking such research would be "not only a duty but also an opportunity". (Q 178)

7.21.  Once a pandemic starts, however, there will be formidable practical, ethical review and regulatory barriers to getting research underway. Professor Troop of the HPA noted that there needed to be "rapid access to research funds", which had proved "very difficult to achieve in SARS" (Q 125). Nor will there be time to go through the normal system of regulatory approval for such research. Professor Menon pointed out some of the potentially time-consuming regulatory requirements:

• Assessments of drug efficacy would probably be construed as clinical trials, falling with the ambit of the Clinical Trials Directive.
• With regard to children or those too sick to give informed consent, such consent would have to sought in accordance with the terms of the Mental Capacity Act 2005.
• The storage of blood and DNA samples would have to be conducted in compliance with the Human Tissue Act 2004. (Q 181)

7.22.  Professor Menon supported the suggestion that in the event of a pandemic normal legal requirements should be suspended in order to facilitate research. Professor Zambon, of the HPA, recommended "planning ahead" in order "to engage the research councils and ensure that there are rapidly responsive mechanisms for funding research proposals and ethics approvals". (Q 125)

7.23.  The Minister refused to be drawn on these points in her oral evidence, repeatedly assuring us that "these are all issues which are being looked at very closely at the moment", but offering no clear guarantees. In a follow-up letter she drew a distinction between "collection and analysis of data for public health and health protection surveillance purposes" and "research projects". The former (which we assume could include collection of data on patient responses to antiviral treatment) would not require "the formal approval of a Research Ethics Committee". However, by implication the latter, which would include many of the projects described by Professor Menon, would require approval. In practice research projects would probably never get off the ground in time. (Q 291, p. 104)

CONCLUSIONS

7.24.  In the event of a pandemic the speed with which a vaccine can be prepared, manufactured and distributed will be crucial. We therefore make the following recommendations:

• The Government should follow the example of the United States in making a major investment in developing new vaccine production techniques. The industry has been too conservative in relying on tried and tested methods; it is time for the Government to show leadership;
• The Government should explore mechanisms to encourage the free exchange of proprietary technology between vaccine manufacturers;
• With a view to promoting public health, the Government should continue to encourage take-up of the annual "flu jab" by at-risk groups. However, we do not believe that the corresponding increase in manufacturing capacity will be sufficient to meet the challenges of a pandemic. The Government should explore other incentives to the industry to develop surge capacity;
• In the event of a global pandemic, inequitable distribution of limited vaccine stocks could have serious implications for international relations. We therefore urge the Government, in conjunction with United Nations agencies, to examine ways to develop vaccine manufacturing capacity globally;
• We welcome the initiative of the European Medicines Evaluation Agency in developing a "mock-up" dossier for a pandemic vaccine. We recommend that the Government invest in one or more "mock-up" dossiers with a view to removing the regulatory barriers to a new vaccine.

7.25.  We recommend that the Government fund further research on alternative treatments for pandemic influenza. This should include a full assessment of the risks and benefits of fractionation. If such risk analysis is left until a pandemic outbreak it will be too late.

7.26.  We agree with Professor Menon that a pandemic would present a unique opportunity for detailed research into the effectiveness of treatments, immune responses, the causes of mortality, and related issues, which could offer enormous long-term health benefits. The Government have a duty to facilitate such research, which will not be possible without advance ethical clearance, rapid access to funding, and the suspension of various legal and regulatory requirements.

7.27.  We therefore recommend that the Government initiate a public dialogue on the regulatory barriers to research in the event of a pandemic. We believe the public would support this research if its benefits were properly explained.

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12   White House press release: http://www.whitehouse.gov/news/releases/2005/11/20051101-1.html.  Back

13   See HL Deb., 22 November 2005, cols. 1534-39. Back

14   Take-up in 2005 was higher, with the result that the Government announced on 22 November that the 14.5 million doses ordered by GPs had been exhausted.  Back