The vaccine market has evolved rapidly in the past decade. Marcel Thalen, of SynCo Bio Partners, looks at the changes from a manufacturer's perspective
From the very start of mass vaccination in the 1950s, the vaccine market has been dominated by pediatric vaccines, with the primary aim of protecting against infant mortality. This arm of biotechnology was characterised by low growth and low profit margins, but since the late 1980s the situation has changed.
The main drivers for change were the development of acellular pertussis vaccines and conjugate vaccines, which can be seen as new, improved vaccines to fight the same diseases. The added value, especially for conjugate vaccines, was that these offered much longer protection than polysaccharide vaccines, or fewer side-effects, as in the case of the acellular pertussis vaccines.
Over the past two decades a significant number of these vaccines have been registered and many are included in National Vaccination Programs (NVP) in an increasing number of countries. Some examples of vaccines recently included in NVPs are conjugate vaccines against N. meningitis group C, combination vaccines against N. meningitis group A, C,W and Y, H. influenzae, multivalent S.pneumoniae vaccines, as well as a number of acellular vaccines against whooping cough.
A second important driver behind the increased market value of the vaccine industry, in terms of the number of doses per year, is that the aim of vaccination has broadened. While vaccines traditionally protected almost exclusively against infant mortality, nowadays vaccines are intended to protect against disease morbidity, not just in infants, but also in adolescents and the elderly. Additionally, the economic impact of a disease has also become an important factor in the decision-making process of whether or not to include a vaccine in an NVP.
With the exception of the vaccine against the Human Papilloma virus, most of the registered vaccines are products that have been around for two to three decades; it is mainly the combinations that are new. The conjugate vaccines and acellular pertussis vaccines are made by a relatively small number of large pharmaceutical companies. Typically, the investment required to enter the vaccine market can be afforded only by large biotech companies, which inherently reduces loss of market share to follow on biologics.
rare pathogens
The third driver for the change in the vaccine market can be considered to be a joint consequence of the bio-defence initiative in the US and globalisation in general, which has led to the development of a number of vaccines against fairly rare diseases. The bio-defence initiative, for example, has sparked the development of vaccines against pathogens that could be used in biological warfare, such as smallpox, anthrax, Ebola and Marburg viruses.
Smallpox was effectively eradicated decades ago, while the other, rarer diseases do not occur often enough in normal circumstances to warrant the development of a vaccine. In the bio-defence scenario, typically a stockpile is created, after which relatively small amounts of these products need to be made on a yearly basis to maintain it.
On the other hand, globalisation has made flying to exotic destinations, for business or pleasure, increasingly common for a large part of the population. Contracting equally exotic diseases due to poor preparation or precautions is not uncommon. Good preparation prior to travelling now includes vaccination, typically against pathogens that are not endemic in the country of departure. As a consequence, the market for travellers" vaccines has increased tremendously over the past few decades.
In terms of number of doses, fairly small volumes are required, compared with typical pediatric or flu vaccines. Some examples of travellers" vaccines include oral typhoid vaccine, hepatitis A and B vaccines, as well as yellow fever vaccine. There are also a number of other vaccines in clinical trials, such as vaccines against food poisoning.
In recent years, the term "vaccine" has acquired a different meaning. While it was traditionally used for biologicals aimed at fighting external pathogens, the term is increasingly now also used for products that tackle "internal" diseases, i.e. cancer, auto-immune diseases, or diabetes type II. As a result, the term "vaccine" is applied to both therapeutic and prophylactic biologicals, which target either external or internal threats. These vaccines use the immune system selectively to attack cancers or a sub-population of disease cells, as opposed to the use of radiation or chemicals with limited specificity and many undesirable side-effects.
In terms of number of doses required, these "vaccines" will also be produced only in fairly small volumes, but since their value is high, the development of these types of biologicals is economically attractive for a number of reasons. For a start, the clinical trials associated with this type of product are less complicated and therefore less costly than those for a multivalent pediatric vaccine. The Phase I study is often conducted directly on people who have the targeted disease, rather than on healthy volunteers. The numbers required for Phase II and III trials are generally smaller, which enables a shorter total development time than the 10 to 15 years typically required for a traditional vaccine.
For the reasons mentioned above, the overall number of "vaccines" in development has risen exponentially. Most of these are not developed by large biotechnology companies but by small, highly specialised, start-up biotech companies or university spin-outs.
As witnessed by recent acquisitions, successful companies are often bought by "big pharma" as a means to increase the number of products in their development pipeline. All "big pharma" have their own pilot plants to generate material for Phase I/II trials. However, these facilities nowadays are generally fully occupied, and are not equipped to deal with the number of Investigational New Drugs (IND) requiring process development and clinical production.
Facing the capacity limitations of the internal organisation, all major vaccine producers have used or are using contract manufacturing organisations (CMOs) to undertake process development and produce GMP material for use in clinical trials. As a consequence, the number of CMOs around the world has also grown exponentially, passing the 100-mark several years ago.
More than 90% of all CMOs cater only for process development and GMP production for Phase I/II studies, since this is the area of greatest demand. Unfortunately, in many cases during Phase I/II studies the interest of the client and the experience of the chosen CMO are not geared towards yield, scalability or cost of goods of the process that is developed. Once Phase II studies are completed successfully, these aspects can jeopardise the economical viability of the product.
As one of the few CMOs that routinely produces registered products and clinical material for Phase III studies, SynCo Bio Partners is regularly asked for help by clients that have completed their Phase II clinical trials successfully with a process that is either not scaleable or has a very low yield. Usually a significant portion of the process needs to be re-developed, costing precious time and money, sometimes even requiring clinical bridging studies.
attractive alternative
While CMOs were, and are, mostly used for process development and the generation of GMP material for clinical studies, the changes in the vaccine industry have also made CMOs an attractive alternative for in-house commercial production. As described above, the fairly low number of doses required for many new vaccines does not warrant the investment in a dedicated production facility since its utilisation would be too low. Also, the decision to build can be taken only after successful completion of Phase III studies, which means that by the time the product is registered, the new facility will not be ready.
Therefore, the first commercial material will need to be manufactured by the CMO that produced the material for the Phase III trials anyway. Also, if the IND required fairly rare operational expertise, such as the production and lyophilisation of live biologicals, in many cases it will save time and effort if these activities are outsourced to a CMO that has the relevant expertise. Since a CMO's existence depends on its ability efficiently to schedule production runs of many different products, manufacturing at a CMO is often at least as cost effective as in-house production.
The changes in the vaccine industry will probably not increase the number of large companies producing vaccines, since most successful products will be brought out by major players in the market. However, the total number of parties involved in the development and manufacture of new vaccines will increase largely outside of the premises of the large vaccine producers. Next to CMOs, CROs and external testing laboratories will also be involved, as the vaccine field requires more diverse, specialised knowledge than large manufacturers have available in house.
As a result, the interdependence in the industry will increase, leading to new challenges such as how to deal with confidentiality, intellectual property rights of processes developed, or even competition within the CMO between products of the same client.
All in all, the vaccine field is, and will remain, an interesting and changing field to work in.