This paper summarises the available evidence required for informing research and investment priority setting on cross-protective emerging influenza vaccines. While the experts expressed very high level of optimism for deliverability, impact on equity, and acceptability to health workers and end users, they expressed concerns over answerability, low development cost, low product cost, low implementation cost, affordability and, to a lesser extent sustainability. In addition they felt that the vaccine would have higher efficacy and impact on disease burden reduction on overall influenza-associated disease rather than specifically influenza-associated pneumonia. In some cases low scores on some criteria partly reflect lack of evidence. It is anticipated that in November 2012, based on the current evidence, the same panel of experts would score some of these criteria (especially the low scoring ones like answerability) quite differently.
This is the first time such an exercise has been attempted to make a structured assessment of emerging vaccines. The scores express the collective opinion of a panel of 20 experts. While there is always an element of uncertainty when predicting impact of interventions which do not exist, we feel that the results would be reproducible with another panel in a different setting. There might be some biases in the literature search as only we searched for studies published in English language. Inclusion of experts from five pharmaceutical companies manufacturing influenza vaccines and investing in research and development of emerging influenza vaccines may have also contributed to some bias. However, this is unlikely to have altered the final scores significantly.
Current research and developments are moving away from the egg-based technology and into cell cultured vaccines, which would effectively overcome the limitations of egg-based productions. Cell-culture production capacity can be scaled up quickly when needed and the product is free from animal contaminants. However, the cost of developing cell-cultured influenza vaccines is more expensive compared to egg-based production for quantities less than 25 million doses per year. The technology is also relatively new with new regulatory paths and therefore needs to be further refined in order to achieve the same level of success as EBIV.
The developmental success and limitations of LAIV are largely dependent on that of egg-based technology. Although still in clinical trial phases, cell-derived LAIV have shown promising results and may be able to replace the conventional egg-based LAIV in the near future. LAIV are administered intranasally and provides an exciting platform for the development of newer ‘friendly use’ vaccine delivery methods.
Currently, the development of recombinant vaccines using VLPs is one of the main focuses of the influenza vaccine industry. The very fact that numerous drug companies are currently researching this technology shows that there is great confidence in the efficacy and deliverability of these vaccines. VLP-produced vaccines are quicker to manufacture and potentially cheaper than currently available influenza vaccines, making these the forerunner in the race to develop a new vaccine platform to overcome the threat of a pandemic outbreak. However, questions remain as to whether the technology will be suitable for large scale production to overcome the production constraint of current vaccine technologies.
The development of a universal influenza vaccine has long been the ultimate goal of the industry. However, the feasibility of developing such a vaccine remains unclear as participating drug companies remain stagnant in their clinical trials. If successfully produced, the vaccine will have the potential to offer recipients long term and cross-protective immunisation against different virus strains. However, the scientific challenges notwithstanding, there are major economic and political impediments to the development of cross-protective influenza vaccine. A truly cross-protective vaccine that confers long-term protection (several years or more) would completely change the entire influenza vaccine market. The present market reflects many billions of dollars of investment and is highly profitable. Even today, additional egg-based vaccine capacity is being added by major manufacturers. A cross-protective influenza vaccine that confers long-term protection would represent a direct and major threat to the established business model. Such a novel vaccine would need to carry a very high price tag to compensate for the massive losses in income from the present annual vaccination model and the cost of developing entirely new production facilities (or retrofitting existing systems when feasible). Therefore, there is actually very little motivation for industry-sponsored research targeted at developing a universal vaccine. If such a vaccine is eventually developed, it will likely be the result of government and/or academic research.
Early studies of vector based vaccines have shown to increase the immunogenicity of traditional TIV and may be used in combination with current vaccines to provide a level of cross protection that is not characteristic of conventional influenza vaccines. Similarly, DNA vaccines are still in very premature stages of development and therefore it is difficult to predict its potential outcome. Although still in early stages, these vaccines show a great amount of potential in clinical trials in terms of their immunogenicity and production capacities.
Production and uptake of seasonal influenza vaccines is an integral part of pandemic influenza preparedness planning. In order to meet the demands for a surge in vaccine production during pandemics, technology transfer and establishment of regional centres for vaccine manufacture in resource poor settings have already been incorporated as part of the Global Action Plan (GAP) for influenza vaccines. However, integration of seasonal influenza vaccine into the EPI schedule (along with the vaccines against bacterial pneumonia) remains the key to decreasing childhood pneumonia morbidity and mortality.