Vaccine 24 (2006) 6367–6370
A global pandemic inﬂuenza vaccine action plan
Abstract In case of an influenza pandemic, the world will be in a situation where potential vaccine supply will fall short by several billion doses from global needs. The World Health Organization (WHO) convened in Geneva on May 2–3, 2006 a consultation of all stakeholders in influenza vaccines and immunization to identify practical solutions to fill this gap. The consultation resulted in a global action plan outlining promising specific strategies to increase influenza vaccine production and surge-capacity before and during an influenza pandemic. Although the timing and severity of the next influenza pandemic cannot be predicted, vaccines are considered the one of the most important medical interventions for reducing morbidity and mortality if and when such an event occurs. Despite this acknowledged role, current limitations on influenza vaccine manufacturing capacity mean that, should a pandemic virus emerge in the near future, vaccine supplies would fall short of the anticipated global demand by several billion doses. Concern about this situation was formally acknowledged in May 2005, when the World Health Assembly approved a resolution  on strengthening pandemic influenza preparedness and response. That resolution called on the World Health Organization (WHO) to seek solutions with international and national partners, including the private sector, to reduce the present global shortage of influenza vaccines. More specifically, the resolution asked WHO to look at strategies for economizing on the use of antigen and transferring production technologies from industrialized to developing countries. In response to this request, WHO convened a consultation from 2–3 May 2006 attended by representatives of the major stakeholders in the area of influenza vaccines and immunization. The consultation had two main objectives: (1) To prepare a global action plan with specific short-, medium-, and long-term activities designed to increase influenza vaccine production and surge-capacity, to identify key obstacles and driving forces, and to estimate funding needs. (2) To strengthen the engagement and collaboration of key partners and stakeholders.
Keywords: Pandemic influenza; Vaccine; Production capacity; Immunization
Production of a vaccine that matches the strain causing human-to-human transmission cannot begin until after the pandemic virus has emerged. All populations in all countries are expected to be susceptible to infection with a pandemic virus, and hence the task of vaccinating a global population of more than 6 billion people will place enormous operational and logistic demands on countries. Current global influenza vaccine production capacity, which is concentrated primarily in nine industrialized countries, is estimated at 350 million doses per year of trivalent (15 ug per haemagglutinin antigen) vaccine, conferring protection against two influenza A strains and one influenza B strain. Table 1 presents an estimate of the current production of seasonal influenza vaccines and of veterinary vaccines for use against avian influenza in birds. If all existing capacity was converted to
0264-410X/$ – see front matter doi:10.1016/j.vaccine.2006.07.021
production of a monovalent pandemic influenza vaccine, the current theoretical maximum production capacity for a pandemic vaccine (at current antigen content levels) would be about 1 billion doses per year. Actual yields could, however, be considerably lower. For example, current production yields of influenza A (H5N1) viruses have been significantly inferior to those obtained using present seasonal human influenza strains. Moreover, while most adults and many children require only one dose of seasonal influenza vaccine, two doses of a pandemic vaccine may be needed to induce protective immunity, reducing by half the number of people who could be protected. On the other hand, efforts by existing manufacturers are already under way to expand production capacity. On present trends, annual global manufacturing capacity could more than double by 2009,
Meeting report / Vaccine 24 (2006) 6367–6370
Table 1 Human influenza and avian influenza vaccine production (2006 estimate) Region
Influenza human vaccine production in million dosesa
Avian influenza vaccine production in million dosesb
Latin America North America Europe Asia Africa
19 73 223 32 0
6000c 1000 3000 40000 0
a b c
HA content 15 g/strain/dose. HA content in veterinary vaccines is between 0.1 and 1 g/dose. Including production in Mexico.
to approximately 780 million doses of seasonal influenza vaccine per year. Three main approaches were identified to increase capacity for production of pandemic influenza vaccines (Table 2).
way. Steps for implementing this strategy include reviewing the use of influenza vaccination in countries already using influenza vaccines (or planning to do so) to raise current levels of vaccine coverage and promoting seasonal influenza immunization. A second activity is to carry out national or regional studies of the influenza-related disease burden and of influenza vaccine cost-effectiveness, in order to provide additional evidence for the introduction of seasonal influenza immunization. It will be important to mobilize resources to assist already resource-constrained countries to purchase seasonal influenza vaccines. This could be achieved through group purchases that allow reductions in vaccine prices, because of economies of scale. This model is already used successfully for vaccine procurement in the region of the Americas. Even so, current seasonal influenza vaccines will not be affordable for the poorest countries, given other competing health priorities. It is estimated that implementation of these steps could result in at least a doubling of the current demand for seasonal influenza vaccines.
1. Increase seasonal vaccine demand to stimulate market forces and augment supply Seasonal epidemics of influenza cause an estimated 500,000 deaths worldwide each year, with most deaths occurring in well-defined risk groups. Countries where influenza vaccination is already recommended for these high-risk groups should be encouraged to increase coverage to reach the targets set by WHO and agreed on in 2003 . Despite these targets, population coverage of high-risk groups in most countries having an influenza immunization policy remains low. A more concerted effort to reach the targets would increase the demand for influenza vaccines, thus stimulating industry to expand its production capacity in a sustainable
2. Increase production capacity for pandemic vaccines The second approach is to increase current production capacity for pandemic vaccines without consideration of utilization of seasonal vaccines. The most direct mechanism would be to improve the production yield and immunogenicity of H5N1-based vaccines to levels similar to those regularly obtained for seasonal human influenza virus vaccines. If gains in these areas can be accomplished relatively inexpensively and in the short-term, they will effectively double or triple the current capacity to produce an H5N1 vaccine, if such a
Table 2 Approaches and strategies to increase capacity for pandemic influenza vaccines in the next 5 years Priority approaches and strategies
Potential impact on vaccine supplya
Increase use of seasonal influenza vaccine National Immunization Programs (NIP) to review the coverage of seasonal influenza immunization programs Estimate disease burden and cost-effectiveness of seasonal influenza immunization Mobilize resources for seasonal vaccination programs in resource-constrained countries Assess the potential of pooled purchases to decrease cost of seasonal influenza vaccines
Increase production capacity for pandemic vaccines Improve production yield and immunogenicity of vaccine prototype H5N1 Build new capacity in developing/industrialized countries Develop adjuvanted vaccines Produce more LAIV Move to vaccines based on whole virus Deliver vaccine by intradermal route using needle-free delivery devices, e.g. jet injector. Research and develop new technologies Enhance protective efficacy and immunogenicity of vaccines (novel adjuvants, mucosal route, enhance vaccine strain selection) Explore new concepts (recombinant sub-unit, viral vectored, DNA vaccines, . . .) Improve evaluation of vaccine performance (standardization, animal models, correlates of protection)
3× Proportional to investment 2–5× Billion doses possible 1.5× >2× No impact expected in the 5 year time-frame
a Potential impact in the 5 year time-frame (increase of number of doses of pandemic vaccine available in 1 year). Figures provided are indicative and need to be refined and confirmed.
Meeting report / Vaccine 24 (2006) 6367–6370
vaccine would be needed and produced instead of seasonal influenza vaccine. Establishment of new production capacity in developing and industrialized countries will require a financial investment that is proportional to the desired increase in vaccine supply. There is evidence that the production yields for live attenuated influenza vaccines (LAIV) are significantly higher than those obtained for inactivated vaccines, but, currently, LAIV production is restricted to a few million doses per year. The most cost-effective investment may therefore come from focusing on increasing the capacity to produce live attenuated influenza vaccine (estimated US$ 0.1 per dose compared to 1 US$ per dose investment  for producing inactivated vaccine). Another mechanism for enhancing capacity would be to convert veterinary vaccine production facilities, which produce influenza vaccines for poultry, to produce human influenza pandemic vaccines. LAIV might be more suitable for this adaptation, since the technologies for human and poultry inactivated influenza vaccines are markedly different. Additional activities will be needed to assure egg supplies or to transfer cell-culture technology, especially to manufacturers located in developing countries. Potent adjuvants might enhance immune responses to influenza vaccines, allowing lower antigen content, thereby “stretching” the number of vaccine doses available. Thus, it is a matter of urgency to develop adjuvanted inactivated vaccines using adjuvants with a proven record of safety in humans. Whole virus preparations may be more immunogenic than sub-unit vaccines and clinical trials are in progress. Switching to this process would pose a number of challenges, including demonstration of equivalent safety, but in a pandemic, it could conceivably increase vaccine supplies by 50% or more. Lastly, dose-sparing could be achieved using an intradermal rather than intramuscular route of administration for inactivated pandemic influenza vaccine. However, it also was recognized that administration of such a technique is difficult, requiring specialized training; other delivery devices, such as jet injectors, might be preferable. Investment is needed for further development and licensing of such a combination of vaccine and delivery device.
on novel concepts (recombinant sub-unit, viral vectored, DNA vaccines, and protein vaccines, among others). The above research strategies were assessed as most promising for the longer term, even if unlikely to have an impact on vaccine supply in the short-term. There is also a need to improve ways to evaluate vaccine performance, through standardization of existing immune assays, validation of animal models and definition of correlates of protection. Additional topics discussed included stockpiling of materials such as non-formulated H5N1 antigen, adjuvants, syringes and needles. There was also much discussion on the management and coordination of a global action plan and on roles and responsibilities for the various stakeholders and for WHO. In conclusion, a number of strategies have been identified to bridge the anticipated gap between vaccine demand and supply in the event of a pandemic. Importantly, none of the possible approaches will bridge this gap in the short-term, but should begin to bear fruit in a 3–5 years timeframe. Implementation of the global pandemic action plan will require substantial funding from the international community (preliminary estimates indicate from US$ 3 to 10 billion US$). All stakeholders have important but different and complementary roles to play. Countries that decide that increased coverage with seasonal influenza vaccines suits national health priorities will contribute to a sustained augmentation of influenza vaccines manufacturing capacity. The international community will need to shoulder some of the financial burden for improving seasonal influenza vaccine coverage in resourceconstrained countries and establishing vaccine production capacity, including through technology transfer, in developing or middle-income countries. The private sector needs to invest more in expanding its manufacturing capacity and developing new production technologies. International organizations, including WHO, need to take a leading role in coordinating and streamlining a number of activities. A collaborative approach is indispensable as is a commitment to sustain the effort over 3–10 years. References
3. Develop new technologies The third approach builds on research and development of novel types of vaccines along with improvements in influenza vaccine evaluation. For example, an influenza vaccine that can induce a broad heterotypic immunity with long lasting cross-protective antibodies is of obvious benefit for both seasonal and pandemic influenza when it could be used pre-pandemic. Two important areas of research are the enhancement of immunogenicity of potential pandemic vaccines using novel adjuvants, as well as exploration of mucosal routes of delivery. Modelling to predict future viral evolution and enhanced vaccine strain selection is considered important, as is development of vaccines based
 Prevention and control of influenza pandemics and annual epidemics. World Health Assembly resolution WHA56.19. Geneva: World Health Organization; 2003.  Strengthening pandemic-influenza preparedness and response. World Health Assembly resolution WHA58.5. Geneva: World Health Organization; 2005.  Cost estimate for the USA and Europe for bulk manufacturing of attenuated or inactivated pandemic influenza vaccine containing 15 g HA.
Marie Paule Kieny ∗ Alejandro Costa Joachim Hombach Peter Carrasco Yuri Pervikov World Health Organization, Geneva, Switzerland
Meeting report / Vaccine 24 (2006) 6367–6370
David Salisbury Department of Health, London, United Kingdom
Guus Rimmelzwaan Erasmus Medical Center, Rotterdam, The Netherlands
Michel Greco 41 quai Fulchiron, Lyon, France
Ruth Karron John Hopkins Bloomberg School of Public Health, Baltimore, USA
Ian Gust Department of Microbiology and Immunology, Melbourne, Australia Marc LaForce PATH, Ferney, France Carlos Franco-Paredes Jos´e Ignacio Santos Hospital Infantil, Mexico, Mexico Eric D’Hondt Rupelmondestraat 166, Bazel, Belgium
Keiji Fukuda World Health Organization, Geneva, Switzerland ∗ Corresponding
author. Tel.: +41227913591. E-mail address: [email protected]
(M.P. Kieny) 12 July 2006 Available online 28 July 2006