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  • WHO CONSULATION FOR DEVELOPMENT OF A GLOBAL [vaccine] ACTION PLAN

    WHO CONSULATION FOR THE DEVELOPMENT OF A GLOBAL ACTION PLAN TO INCREASE THE SUPPLY OF PANDEMIC INFLUENZA VACCINES

    2-3 May 2006

    The Global Pandemic Vaccine Challenge

    The global pandemic vaccine challenge is to (1) develop the formulation for the most antigen sparing vaccine, (2) produce supplies of this vaccine that are large enough to meet global needs, and (3) rapidly and equitably distribute them to all countries that wish to use them.

    This background document explores five issues related to increasing the supply of pandemic vaccines. Although it is focused on pandemic vaccines, it recognizes that the global capacity to produce seasonal influenza vaccines will be the basis for producing pandemic vaccines. The comments that follow are based on the following principles:

    Efforts to develop pandemic vaccines must reflect the expectation that the next pandemic might be imminent. Thus, pandemic vaccines will have to be produced in existing vaccine production facilities and use currently available technologies and resources. The primary goal for pandemic vaccine development must be to define the most antigen sparing formulation for a vaccine that will be acceptably immunogenic for a population, not optimally immunogenic for an individual. The formulation must be one that can be used by all influenza vaccine companies. It must be one that guarantees that the largest number of doses of an affordable pandemic vaccine can be produced worldwide. Because immunologically na?ve individuals will require two doses, an adjuvanted inactivated vaccine is likely to be required. Clinical development must determine the vaccine formulation that is most antigen sparing and can be produced by all companies. The best way to ensure that this is done is to organize publicly funded, international collaborative trials that are conducted according to a common protocol and that include candidate pre-pandemic vaccines prepared by all vaccine companies.
    Adapted from J Public Health Policy 2005; 26: 4-29.


    I. Support research and development of pandemic vaccines

    Adjuvanted inactivated vaccines. The most important efforts to increase the supply of pandemic vaccines will likely involve an adjuvanted formulation for one or more candidate pre-pandemic vaccines (e.g., H5N1). Adjuvanted vaccines promise to reduce the amount of virus antigen (hemagglutinin, HA) required for each dose; i.e., they will be antigen sparing. Alum is the most practical choice of adjuvant because it is universally available, inexpensive, not covered by patents, widely accepted as safe by regulatory authorities, and has been used by most vaccine companies to produce many other vaccines. If alum is not suitably antigen sparing, other adjuvants (e.g., MF59) might need to be considered, but limits on their global availability and patent rights might present problems.

    The results of clinical trials for several adjuvanted pre-pandemic vaccines have either been published or announced. It seems clear that for some vaccines (H2, H9), a low-dose HA, antigen sparing adjuvanted formulation will be readily achievable. However, adjuvanted formulations for H5N1 and earlier H5N3 vaccines have not been sufficiently antigen sparing. Two recent reports of the results of clinical trials of alum adjuvanted H5N1 vaccines indicate that adequate immunogenicity was achieved only with two 30 mg HA doses. Moreover, several vaccine companies have reported that yields of HA antigen in their production systems have been 30-50% of what they would normally expect. Given poor replication of the reverse genetics-engineered H5N1 virus and the high level (30 mg) of HA antigen required for each dose of adjuvanted vaccine, all of the world?s vaccine companies could today produce (within 6 months) enough doses of H5N1 vaccine to vaccinate no more than 100 million people (300 M doses of seasonal vaccine = 900 M doses of pandemic vaccine @15 mg HA per dose = 450 M doses @ 30 mg HA per dose = 225 M doses @ 2 doses per person = < 100M doses @ 30-50% HA production yields). This is one-third the number currently vaccinated with seasonal influenza vaccines.

    Determining the formulation of an acceptably immunogenic vaccine for a population. One of the most important decisions that will have to be made for pandemic vaccination will be to determine a vaccine formulation for that will provide the greatest amount of protection for a population. The principles that are involved can be illustrated by an example drawn from the only published results of a pre-pandemic H5N1 vaccine (N Engl J Med 2006; 354: 1343-51). The results were obtained in a trial that involved two doses of a non adjuvanted H5N1 vaccine. As can be seen from the results, 54% of study

    mg HAper dose % with neuttiter ? 1:40 Number vaccinated Number protected
    90 54 100 54
    45 43 200 86
    15 22 600 132
    7.5 9 1200 108


    subjects who received the highest vaccine dose (90 mg HA) had neutralizing antibody titers ? 1:40 after two doses. (For seasonal influenza vaccines, an antibody titer ? 1:40 is generally accepted as protective.) The proportions with protective antibody levels were lower with lower strength vaccines. However, if it is assumed that by lowering the amount of HA antigen in each vaccine dose the total number of doses that can be produced is correspondingly increased, it becomes evident that the largest number of people that can be protected in a population can be achieved by choosing a vaccine formulation that contains only 15 mg HA per dose. Moreover, at the lowest dose level (7.5 mg HA), greater protection could be achieved at a population level than by choosing either of the two highest dose levels.

    The example above is greatly simplified and does not consider an alternative strategy of administering only one priming dose of vaccine to each individual. (Prior to the emergence of a new pandemic virus itself, it would be very difficult to determine what dose of HA antigen would constitute an effective priming dose.) Nonetheless, a decision on how to formulate a pandemic vaccine that will be adequately immunogenic for a population rather than optimally immunogenic for an individual must consider the principles illustrated in the table.

    Intradermal vaccination. An alternative approach to antigen sparing pandemic vaccination would be to administer a low dose inactivated vaccine intradermally (ID). However, this approach might be difficult to implement because (1) there is very little information on the immunogenicity of ID influenza vaccination in immunologically na?ve individuals, (2) successful ID vaccination of large populations might require specially trained vaccination personnel, (3) supplying vaccines for ID administration in multi-dose vials may be difficult, and (4) special ID syringes might be required that might not be widely available or affordable. By comparison, if an antigen sparing adjuvanted vaccine could be produced in sufficient amounts for easier IM administration, it would allow health officials to achieve the same goal of vaccinating large populations.

    Live-attenuated vaccines. Another alternative to an inactivated adjuvanted IM vaccine is a live attenuated influenza vaccine (LAIV). A seasonal LAIV was recently introduced into the US market, and LAIVs have been used for many years in the former Soviet Union and Russia. The ease of preparing vaccine virus seed strains by reverse genetics and of administering the vaccine intra-nasally make it an attractive alternative for quickly vaccinating large populations in the setting of a pandemic. However, several obstacles would need to be overcome, including (1) limited LAIV production capacity, (2) uncertain regulatory approval in many countries, and (3) unresolved IP issues for LAIV technologies that could increase vaccine costs and limit LAIV use.

    Cross-protective (universal) vaccines. There is growing interest in the discovery and development of broadly cross-protective (universal) influenza vaccines, and several potential antigens have been identified (e.g., the ectodomain of the M2 protein, the NS antigen). Proof-of principle for several of these antigens has been obtained in animal models of infection, and Phase I and Phase II human trials will soon begin. Issues of long-term safety will inevitably be raised and be difficult to sort out. Equally important will be deciding whether these antigens will be used to supplement existing seasonal inactivated vaccines or as replacements for current vaccines. The regulatory and commercial implications of the choice between these two alternatives are very different and could be difficult to resolve. Nonetheless, incorporating one or more cross protective antigens in seasonal vaccines could provide a measure of protection against a newly emergent pandemic virus.

    Cell culture-produced vaccines. New cell culture systems for producing vaccine virus are being developed privately by several vaccine companies and will eventually find their place in the seasonal influenza vaccine market. In Western Europe, these developments are being funded by companies themselves and not by governments. In the US, government funds have been provided for accelerating cell culture vaccine production. The situation in Canada is uncertain because details of the recent agreement between GSK/ID Biomedical and the Canadian government are not publicly available. Important as these developments will be in the longer term, it is unlikely that cell culture vaccine virus production will play a substantial role in the global production of seasonal and pandemic vaccines within the next few years.

    Other vaccines and vaccine production technologies. A large number of research projects have been undertaken by academic and government scientists and by vaccine companies to develop new types of influenza vaccines (new adjuvants, recombinant HA antigens, mucosally administered vaccines, DNA vaccines) and new vaccine production systems (insect cell culture). While several of these technologies are promising, they are unlikely to contribute meaningfully to global vaccination for an imminent pandemic.

    WHO?s role in pandemic vaccine development. WHO has convened several meetings to discuss the development of pandemic vaccines. Although the meetings have been useful as forums for sharing information, they have not provided effective guidance for developing a universal pandemic vaccine formulation that is (1) adequately immunogenic for populations, (2) guarantees that the maximal number of doses can be produced, and (3) can be adopted by all vaccine companies. In the absence of WHO guidance, each vaccine company is developing its own formulation for its own pandemic vaccine. One result of this approach has been that companies have been conservative in choosing the vaccine formulations they will test. For example, they have used split virus rather than whole virus preparations and have chosen not to test very low dose HA adjuvanted vaccine formulations in their small-scale clinical trials. As one vaccine company executive said, ?We don?t want our vaccine to fail.?

    These developments indicate that companies are approaching pandemic vaccine development as a ?vaccine? problem. With few exceptions, public health officials in vaccine producing countries have been passively complicit with the companies? approach and have allowed them to set the development agenda. If instead, health officials were to approach pandemic vaccine development as a ?public health? problem, they would direct companies to prepare different formulations for their pre-pandemic vaccines and require different designs for their trials.

    Several attempts have been made to persuade the staff of WHO?s Global Influenza Programme and its Collaborating Centers to take firm control of the global pandemic vaccine development agenda by publishing guidelines for publicly funded, international collaborative clinical trials of pandemic vaccines. WHO has thus far chosen not to take on this leadership responsibility and has relied instead on advocacy. The November 2005 statement on the current status of vaccine research and development says, ?WHO has encouraged companies to test vaccine formulations that include an adjuvant.? WHO needs to do much more.

    What WHO should do

    1. WHO must take firm control of the international agenda for pandemic vaccine development. WHO?s activities must be guided by the principles set forth at the beginning of this background paper. WHO must insist on the absolute need for public funding, international collaboration and a common clinical trial protocol that specifies the dose levels (mg HA) to be studied in trials of antigen sparing vaccines. It must make it clear to everyone that pandemic vaccine development is first and foremost a public health problem, not a vaccine problem.

    2. WHO must ensure that the problems of poor replication and poor immunogenicity of the H5N1 vaccine virus are definitively resolved. For an imminent pandemic, this is a matter of utmost urgency.

    3. WHO must explore ways in which the development of live attenuated pre-pandemic vaccines can be accelerated, determine whether these vaccines could be produced by all vaccine companies, and identify obstacles that would need to be overcome to obtain their registration.

    3. For the time being, WHO should remain ?agnostic? on the issue of whether cell culture or egg-based influenza vaccine production should be favoured. Choices between the two are already being made by vaccine companies. The decisions are based on business considerations and are best left to the companies themselves. With an effective antigen sparing vaccine formulation, cell based production of pandemic vaccines will not be essential.

    4. WHO should recognize that the market for seasonal influenza vaccines in developed and rapidly developing countries has become increasingly attractive to vaccine companies. Thus, additional incentives and financial support for R&D for newer vaccines should not be necessary; companies themselves and national research agencies (e.g., NIH) should be able to provide the support needed. Moreover, for pandemic vaccination, support for R&D on newer vaccines (newer adjuvants, recombinant DNA, cross-protective) or vaccination technologies (ID vaccination) must be guided by sound practical public health considerations regarding the feasibility of global vaccine production, affordability and ease of administration.


    II. Support regulatory oversight and manufacture of influenza vaccines

    Regulatory convergence. Accelerated procedures to generate and provide reference strains and reagents for pandemic vaccine development are already in place in the US, the UK and elsewhere, so additional external assistance is probably not needed. Regulatory convergence for registering pandemic vaccines has already occurred in Europe, following publication of the EMEA (now MHRA) ?Notes for Guidance? on pandemic vaccine development and market authorization. Recent announcements by the FDA indicate improved regulatory relationships with Canada and Europe. There is an international awareness of the importance of common technical and scientific issues related to vaccine registration and batch release (as well as reagents, etc.). Continued WHO guidance will be necessary, but regulatory problems are not among the most urgent and should not require additional interventions by WHO or other international agencies or institutions.

    Intellectual property. WHO is fully aware of the essential need for reverse genetics (RG) in preparing virus reference strains that can be used for producing pre-pandemic vaccines based on highly pathogenic avian influenza viruses. WHO has done a commendable job in providing guidance on risk assessment and risk management for this technology, but it has not become involved in resolving issues related to RG intellectual property (IP) rights.

    Until recently, ownership of the RG-IP for influenza viruses was split between two institutions. This led to uncertainty over RG-IP issues and delayed the development of pre-pandemic H5N1 vaccines by several Western European vaccine companies. Ownership of RG-IP has recently been consolidated in the hands of MedImmune. MedImmune has informed WHO and all companies that RG-engineered viruses can be used for pandemic vaccine R&D without paying royalties. Moreover, for pandemic vaccination itself, royalty payments will not be required for vaccines used in public programs.

    Pandemic vaccine production. Assuming that an international consensus can be reached on how to formulate an antigen sparing pandemic vaccine and that regulatory and RG-IP issues can be resolved, a detailed understanding of how each vaccine company will produce its pandemic vaccine will still be essential. The information needed for each company includes (but is not limited to) the following:

    1. Knowing the safety and security of the sources of embryonated eggs and how quickly supplies can be obtained,

    2. The number of weeks that will be required from the time a reverse genetics-engineered vaccine seed strain is received until the first doses of pandemic vaccine can be produced,

    3. The yield per egg of reverse genetics-engineered pandemic vaccine virus,

    4. The company?s capacity to inactivate and purify vaccine virus and the comparative yields of whole virus and split virus preparations,

    5. Access to supplies of alum and/or proprietary adjuvants, including their timeliness and costs,

    6. Processes for formulating adjuvanted vaccines,

    7. Capacity to fill 10-dose vials,

    8. Capacity to operate vaccine production facilities on a 24/7 basis,

    9. Cost of producing a single dose,

    10. Number of doses of pandemic vaccine that can be produced each week,

    11. Company requirements for rapidly registering their pandemic vaccines in all countries,

    12. Company requirements for national governments to assume responsibility for liability for vaccine-associated adverse events,

    13. Company requirements for purchase guarantees for the supplies of pandemic vaccine it will produce, and

    14. Company requirements regarding the logistics of national and international distribution of the vaccine it produces.

    The information must be obtained from all companies that intend to produce pandemic vaccines, and any problems that are identified must be dealt with during the pre-pandemic period. The information must be aggregated internationally in order to give health officials in national governments and international institutions a precise idea of the number of doses of pandemic vaccines that can be produced globally each week.

    It should not be forgotten that supplies of pandemic vaccines must be matched by supplies of syringes.

    What WHO should do

    1. Regulatory convergence for licensing pandemic vaccines is taking place, although there is common recognition by WHO and regulatory authorities that remaining problems need to be resolved. Their successful resolution will have a positive impact on the international market for seasonal influenza vaccines; indeed, the growing attractiveness of this market is probably an important driving force behind the convergence process. More flexible international markets for influenza vaccines made possible by regulatory convergence will help companies and nations manage sudden shortfalls in seasonal vaccine supply, as experienced by the US in 2004. It is unlikely that regulatory issues will be serious obstacles to registering pandemic vaccines. As long as companies have consistently shown they can produce seasonal vaccines and have demonstrated competence in producing adjuvanted pre-pandemic vaccines, the immediate public health need for true pandemic vaccines will take precedence over any regulatory concerns.

    2. WHO must not neglect intellectual property rights issues for any of the technologies essential for producing and distributing pandemic vaccines. If WHO cannot become directly involved in resolving outstanding IP issues, it must ensure that some other process or institution is empowered to do so.

    3. WHO or another international institution must establish a process for obtaining detailed information on how each vaccine company will produce its pandemic vaccine and use this aggregated information as the basis for planning the global financing, distribution and administration of pandemic vaccines.


    III. Increase and diversify vaccine production capacity to
    expand access to pandemic (and seasonal) vaccines

    The macroepidemiology of seasonal influenza vaccination. The international production and distribution of inter-pandemic influenza vaccines through year 2003 has been documented by the Influenza Vaccine Supply International Task Force (IFPMA) (Wkly Epidemiol Rec 2004; 79: 366-7) and the Macroepidemiology of Influenza Vaccination Study Group. Approximately 95% of the almost 300 million doses produced in 2003 were produced by vaccine companies located in nine developed countries (Australia, Canada, France, Germany, Japan, Italy, the Netherlands, the UK and the US). Vaccines for domestic consumption were also produced in China, Hungary, Russia and Romania. Virtually all of the vaccines sent to non vaccine-producing countries were produced in five Western European countries. In 2003, these ?have not? countries used 38% of the global vaccine supply, and this proportion is likely to increase substantially in the years ahead.

    What increasing the demand for seasonal vaccine means for pandemic vaccination. All but one of the vaccine companies in nine major developed countries, as well as companies in China, Hungary and Russia, are already engaged in developing pre-pandemic H5N1 vaccines. Yet the companies are concerned that they will not be able to meet the global demand for pandemic vaccines. Together with health officials they hope that increasing the demand for seasonal influenza vaccines will help promote the scaling up of global vaccine production capacity before the pandemic virus emerges. While this is a reasonable assumption, it is worth noting that it took 10 years for the global demand for influenza vaccine to double (112% increase from 1994 to 2003). Another decade will probably be needed to double seasonal demand once again. When the next pandemic virus emerges, the demand for a vaccine will be immediate; it is reasonable to assume that it might exceed the demand for seasonal vaccines by 10-fold or more. Companies will need to produce a very large number of doses in a very short period of time. The principle advantage of increasing seasonal vaccine demand and production capacity will be to provide companies with increased leverage to produce a larger number of doses of an antigen sparing vaccine more quickly.

    Producing seasonal and pandemic vaccines in developing countries. The Developing Countries Vaccine Manufacturers? Network is fully aware of pandemic vaccine issues. One company (Butantan in Brazil) will soon begin seasonal vaccine production and others are in negotiations for technology transfer from vaccine companies in developed countries. Indigenous vaccine production will probably begin in Taiwan within 2-3 years, and South Korea may follow soon thereafter. In China, several companies already produce influenza vaccines, and Sinovac has taken a leading role in developing an alum adjuvanted H5N1 vaccine.

    Given international regulatory convergence and continued open markets, it could be argued that the global industrial capacity for producing seasonal vaccines is well matched by international demand, and that special efforts to increase vaccine manufacturing capacity in developing countries are not really needed. This argument, however, ignores the immediate need for pandemic vaccines that will be experienced equally by ?have? (vaccine-producing) and ?have not? countries. When the next pandemic virus emerges, vaccine-producing countries will likely withhold their vaccines from the international market until their domestic needs have been met. Advance purchase agreements that have been negotiated between ?have not? countries and individual vaccine companies probably will not be honoured. Consequently, supplies of pandemic vaccines will be delayed in reaching the ?have not ? countries, and decisions as to which of these countries will receive them are likely to be made on the basis of political considerations instead of immediate public health needs. Largely for this reason, there is widespread interest in developing new influenza vaccine production capacity, especially in developing countries.

    Financing increased use of seasonal and pandemic vaccines in developing countries. One of the important findings of the Macroepidemiology of Influenza Vaccination Study Group survey was that in 2003, several countries with Gross National Incomes (GNIs) per capita of < $10,000 had vaccine distribution rates that were greater than rates in countries with much higher GNIs per capita. Almost all of these countries had some form of public reimbursement for influenza vaccination of recommended target groups. These findings indicate that with enlightened public health leadership and the support of public financing, most middle income developing countries (at least those with GNIs per capita > $5000) should be able to manage the costs of increasing demand for seasonal influenza vaccine on their own. This is not to say that they will be equally capable of self-financing a sudden and much greater increase in demand for a pandemic vaccine. The key to understanding whether these countries will need external financial assistance will be a precise understanding of what their demands for pandemic vaccines will be.

    Using other facilities to produce pandemic vaccines. There is little reason to think that in order to create an international capacity to produce the number of doses of pandemic vaccine that will meet world demand it will be necessary to use other facilities to produce pandemic vaccines. GMP and other regulatory concerns alone would make it extremely difficult to use manufacturing facilities for other (cell culture) human vaccines or animal vaccines to produce vaccines for human use. What will be required for the timely production and equitable international distribution of adequate supplies of pandemic vaccines will be (1) understanding how to formulate the most antigen sparing vaccine possible, (2) detailed knowledge of the weekly production capacities of every influenza vaccine production facility in the world, (3) detailed demand forecasts of the amounts of pandemic vaccine each country will want to use, and (4) detailed understanding of how that vaccine will be paid for and distributed. If all of these requirements are met, it should not be necessary to use other facilities to produce pandemic vaccines.

    What WHO should do

    1. WHO, other international institutions, national development assistance agencies and vaccine companies should actively support the efforts of developing countries to establish new influenza vaccine production facilities.

    2. Responsibility for monitoring the annual production of seasonal influenza vaccines and the annual distribution of vaccines to individual countries must be assumed by WHO or another institution. These data will provide the essential quantitative basis for planning global programs for pandemic vaccination.

    3. There is no urgent need for WHO to establish an international financing mechanism to support increases in seasonal vaccine demand in countries with GNIs per capita >$5000. Aggregating demand for seasonal vaccine from several countries in a given region through mechanisms such as PAHO?s revolving fund could be useful in simplifying vaccine ordering and financing. Consideration could be given to assist individual countries with lower GNIs per capita in financing purchases of seasonal vaccine on a case-by-case basis.

    4. WHO or another institution must prepare a detailed global forecast of future demand for pandemic vaccines. It should obtain accurate information on existing and future advance purchase agreements between individual countries and individual vaccine companies and determine the political likelihood that these agreements will be honoured once a new pandemic virus emerges. Data on the overall demand for pandemic vaccines by individual countries must be aggregated and the findings communicated to all vaccine companies that will produce them.

    5. WHO must establish an international process or institution to manage the financing of pandemic vaccine purchases by all countries (especially middle income and developing countries) that do not have vaccine companies. Advance purchase agreements between these individual ?have not? countries and individual vaccine companies will be at risk of not being honoured because the national governments of vaccine-producing countries are likely to exercise political control over the distribution of vaccine produced in their countries. An international process for financing vaccine purchases might give ?have not? countries the necessary political leverage to obtain timely and adequate supplies of pandemic vaccines.


    IV. Support the development of strategies for rapid and effective deployment of pandemic vaccines

    Pre-pandemic vaccination. Some have proposed that using a pre-pandemic H5N1 vaccine to vaccinate persons at occupational or other risk of avian influenza virus infections might prevent the emergence of a new human strain of H5N1 pandemic virus. There is little reason to expect this strategy would be effective. Untold millions of people are at risk of exposure to the waste of poultry flocks in countries where avian H5N1 infections are occurring. The H5N1 virus has already demonstrated a capacity for viral mutation within its avian hosts, and vaccinating human bystanders should not be expected to have any effect on this evolutionary process.

    A stronger case can be made for using seasonal vaccine to vaccinate people in close contact with H5N1 infected birds or human cases of H5N1 infection in order to prevent co-infection with, say, H3N2 and H5N1 viruses. Such co-infection could lead to the emergence of a new reassortant virus that has the receptor binding and transmissibility characteristics of the H3N2 virus and the virulence of the H5N1 virus. Vaccinating healthcare workers caring for H5N1 patients in hospitals can be easily implemented and has probably already been done in many settings. Vaccinating cullers has also been done in some settings, but is much more difficult to implement. Vaccinating other people who are simply at increased risk of coming into contact with H5N1-contaminated material is impractical and unlikely to succeed.

    Supplies of bulk antigen for pre-pandemic H5N1 vaccine are currently being produced in several countries. Whether these vaccines will be used to prime healthcare workers and other risk groups at high risk of exposure to a future pandemic virus has yet to be decided. Some of the newer strains of H5N1 virus isolated in Indonesia have been reported to represent a different clade, and antibodies to the H5N1 viruses found in Vietnam do not appear to be cross-reactive against the Indonesian viruses. An alternative (and probably more practical) strategy for future (if ever) use of this pre-pandemic H5N1 vaccine would be to use it only after a new pandemic virus has emerged and antibodies to the H5N1 vaccine virus have been shown to be cross-reactive against the new pandemic virus.

    Mathematical modeling and establishing priorities for pre-pandemic vaccination. Many influenza scientists and health officials are interested in modelling the impact of different vaccination (and antiviral) strategies to determine which ones might improve pandemic control. While these studies are generally not costly and should be encouraged, it is uncertain whether their findings could be applied to the real challenges of pandemic control. Regardless of what the models might indicate, political factors will likely motivate government officials in vaccine-producing countries to vaccinate their entire populations. In ?have not? countries, health officials will have no alternative but to develop priority strategies for using limited and often late arriving supplies of pandemic vaccines. The process for developing criteria for defining specific target groups should be open to widespread public discussion in all countries, recognizing that implementation of any priority vaccination strategy in a real pandemic will be heavily influenced by social and political pressures as well as epidemiological factors.

    International distribution of pandemic vaccines. Developing strategies for the rapid deployment of pandemic vaccines once they become available involves two distinct processes. The first is the actual distribution of vaccines from individual vaccine companies to the countries in which they will be used. Determining which countries will get vaccines first (after the needs of the vaccine-producing countries have been met) will be very difficult. No process currently exists for coordinating pandemic vaccine distribution to ?have not? countries on the basis of need alone. Vaccine company executives do not want to be the ones to decide which countries will and will not receive pandemic vaccines; i.e., decide who will live and who will die. Public health officials should not expect company executives to make these decisions.

    There is an urgent need to develop a process for managing the international ?political logistics? of pandemic vaccine distribution. Among all of the challenges that face global pandemic vaccination, this is the most important and the problems it presents will probably be the most difficult to solve, especially if supplies of pandemic vaccines are limited.

    The second aspect of rapid deployment involves the activities of health officials within individual countries. It must be assumed that each country will have a national pandemic influenza preparedness plan, and that its plan will describe how it will ensure that the vaccine supplies it receives are rapidly deployed to vaccination centers and administered according to pre-existing criteria that define priority groups. Most health officials will be able to call upon their experience with other vaccination programs to guide them in how to do this. However, they will have greater incentive to clarify plans for this second phase of vaccine deployment if they have confidence that the first phase ? the international distribution of vaccine supplies to individual countries ? has been worked out in advance.

    What WHO should do

    1. WHO and the international community must recognise that the most important problem they will face for pandemic vaccination will be the timely and equitable distribution of supplies of pandemic vaccines to individual countries. Currently, there is no process to ensure that this will be done, and no existing international institution has stepped forward to accept this challenge. This problem can no longer be ignored; WHO and the international community must see that it is solved.

    2. WHO must insist that once a country begins to receive its supply of pandemic vaccine, the vaccine should be administered according to a set of predefined criteria that designate priority groups. Previous experience with other vaccination programs will guide the organization of each national vaccination program. To the greatest extent possible, the program should be guided by epidemiological principles rather than social or political factors.

    3. WHO should ensure that all healthcare workers caring for H5N1-infected patients (and wherever possible poultry cullers) are vaccinated with seasonal influenza vaccines to limit opportunities for the emergence of human/avian reassortant viruses.

    4. Vaccinating health care workers and others at risk with a pre-pandemic H5N1 vaccine stands little chance of preventing the emergence of a new strain of pandemic virus. Once an acceptable antigen sparing formulation has been defined, supplies of H5N1 vaccines should be stockpiled until the next pandemic virus emerges. When this happens, serologic studies should be able to quickly determine whether antibodies to the pre-pandemic H5N1 vaccine will be protective against the new pandemic virus. If they are, the stockpiled H5N1 vaccine can be rapidly administered to prime (with one dose) or fully vaccinate (with two doses) healthcare workers and other pre-defined target groups.

    5. Modelling the impact of different vaccination strategies for pandemic control might be useful, but when the real pandemic arrives, implementing strategies that appear promising in the models will be difficult for logistical, social and political reasons.


    V. Strengthening surveillance, diagnostic capacity and pathophysiological understanding of influenza

    Virological and non virological surveillance and diagnosis. There is a general consensus that enhanced surveillance of both avian and human influenza viruses would increase the likelihood of detecting new influenza viruses that are likely to cause seasonal epidemics, viruses that have pandemic potential and a new pandemic virus itself. However, improvements in laboratory capabilities alone will not suffice; in addition there must be willingness by all countries to obtain and share such information internationally. Enhanced virological surveillance will improve the ability of the WHO Collaborating Centers to prepare specific reagents needed to characterize and select strains for seasonal and pandemic vaccines. It will also validate the findings of epidemiological studies of influenza-related diseases, especially in middle income and developing countries.

    Periodic reports by WHO on its global influenza surveillance are generally limited to virological investigations. However, influenza surveillance and diagnosis should not be limited to virological measures. Epidemiological information can also indicate the onset of seasonal influenza epidemics or a pandemic. Monitoring the Internet can provide important signals of local outbreaks. Increased worker absence, school closures, physician visits and hospital admissions often provide epidemiological information that strongly suggests influenza outbreaks. Rapid detection of these events can prompt focused virological investigation. Efforts to improve international coordination of influenza surveillance and diagnosis should include these non virological elements of disease surveillance.

    The molecular pathophysiology of seasonal and H5N1 influenza. One area of influenza research that has been neglected is the clinical investigation of individual patients with influenza. Unlike many other diseases, very little is known about the molecular pathophysiology of influenza and its complications. A small number of clinical studies suggest that cytokine dysregulation plays an important role in cases of severe or fatal influenza, and might be an especially important factor underlying the very high case fatality rate seen in human H5N1 infections. Better understanding of the molecular pathophysiologiy of severe and fatal influenza might suggest other approaches to treatment and prevention using agents that are widely available as generic medications (e.g., statins). Although enhanced clinical research might not be directly related to influenza vaccination, it might provide the basis for other approaches to influenza control.

    Given the limited availability of antiviral agents and the unavoidable delays that will affect pandemic vaccine supply, knowing that existing medications could be for used treatment and prevention at the onset of a pandemic before supplies of vaccines become available could be crucially important for the pandemic control.

    What WHO should do

    1. Enhanced virological surveillance and diagnostic capacity will improve the ability of influenza virologists and epidemiologists to detect more rapidly new strains of avian and human influenza viruses with epidemic and pandemic potential. However, WHO must ensure that enhanced surveillance also includes non virological parameters and that these parameters are included in an improved global information system for epidemic and pandemic surveillance.

    2. WHO must give much greater attention to clinical investigation into the molecular pathophysiology of seasonal and H5N1 influenza virus infections in order to better understand (1) how to successfully manage individual cases and (2) discover new approaches to treatment and prevention.


    Summary of the underlying principles for increasing
    the supply of pandemic vaccines

    In considering what WHO should do to enhance global efforts to increase the supply of pandemic vaccines, especially if the pandemic is imminent, it is essential to keep in mind the following:

    1. The scientific basis for formulating an antigen sparing inactivated pandemic vaccine is mostly known. A reverse genetics-engineered reassortant virus that incorporates genes for the surface antigens of the pandemic virus and the internal genes of another influenza virus that can replicate in embryonated eggs can be prepared in approximately two weeks and given to all vaccine companies that will produce pandemic vaccines. However, preparing reverse genetics- engineered H5N1 vaccine viruses that replicate well in vaccine company production facilities and are immunogenic remains a serious problem that requires an urgent solution.

    2. Two doses of an antigen sparing pandemic vaccine formulated to contain a low dose of hemagglutinin (HA) and an appropriate adjuvant will almost certainly generate an adequate immune response for a population and will allow the maximum number of doses to be produced worldwide.

    3. The search for newer influenza vaccines (both seasonal and pandemic) is one that has already attracted a great deal of scientific interest and research investment because these vaccines could become important products in developed countries. Similarly, cell culture influenza vaccine production has attracted increasing investment by vaccine companies. However, despite the mid- and long- term promise of several of these new technologies and no matter what the source of the investment in their development, it is unlikely that any of them will make a substantial contribution to pandemic vaccination within the next five years.

    Summary of what WHO should do

    WHO must recognize that the steps necessary for successful formulation of an antigen sparing pandemic vaccine are straightforward, but until now there has been no international focus of responsibility (including WHO) for guiding companies and health officials in this direction. WHO must ensure that this happens.

    WHO must recognize that producing the maximum number of doses of pandemic vaccine will be more difficult than developing the vaccine formulation. Detailed logistical planning will be required if it is to succeed.

    WHO must recognize that the timely and equitable distribution of pandemic vaccines will be far more difficult than their production. This will require an international process that organizes national demand forecasts, the financing of vaccine purchases and the politics and logistics of vaccine distribution to individual countries.

    The most important challenges for global preparedness for pandemic vaccination, especially vaccination for an imminent pandemic, are organizational, logistical and political. WHO must take the lead in creating a process that can organize and manage the development, production and distribution of pandemic vaccines. The process must have international political legitimacy, managerial authority and financial accountability if it is to succeed.





    Suggested readings

    1. Hennessy AV, Davenport FM. Relative merits of aqueous and adjuvant influenza vaccines when used in a two-dose schedule. Public Health Rep 1961; 76: 411-9.
    2. Fedson DS. Preparing for pandemic vaccination: an international policy agenda for vaccine development. J Public Health Policy 2005; 26: 4-29.
    3. Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepidemiology of influenza vaccination in 56 countries, 1997-2003. Vaccine 2005; 23: 5133-43
    4. Fedson DS. Vaccine development for an imminent pandemic: why we should worry, what we must do. Human Vaccines 2006; 2: 38-42.
    5. Treanor JJ, Campbell JD, Zangwill KM, Rowe T, Wolff M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006; 354: 1343-51.
    6. Germann TC, Kadau K, Longini IM Jr, Macken CA. Mitigation strategies for pandemic influenza in the United States. Proc Natl Acad Sci USA 2006; 103: 5935-40.
    7. Fidler DP. Germs, governance, and global public heath in the wake of SARS. J Clin Invest 2004; 113: 799-804.




    Prepared by:

    David S. Fedson, MD


    17 April 2006
    Last edited by sharon sanders; July 5, 2006, 08:36 PM. Reason: delete personal info
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