Immunization is rightly regarded as one of the great medical successes of the past two hundred years, particularly in the 20th century. In developing countries, decades of immunization programmes have led to the elimination of smallpox and polio, and the control and near elimination of once-common and often debilitating, even life-threatening, diseases such as measles, mumps, rubella, diptheria and tetanus. Despite being viewed as the poor relative of traditional drug development, the vaccine market was estimated at more than US $6 billion in 2002 (Fig. 1), with a projected annual growth rate of 10–15%. The recent media attention surrounding new emerging infections, such as West Nile virus, severe acute respiratory syndrome (SARS) and monkeypox, have all increased interest in developing new vaccines against these potentially lethal pathogens. The added fear that known (and unknown) pathogens could be used as bioweapons has renewed researchers' interest in diseases such as smallpox, anthrax and the plague.

Figure 1
figure 1

Global vaccine market share by company.

Bioterrorism spurs vaccine research

Although not a new concept, the use of bacteria and viruses as bioweapons has become a greater topic of conversation following the anthrax attacks in the United States in 2001. Since then, many governments have accelerated efforts to develop, produce and stockpile drugs and vaccines against a number of pathogens potentially used in bioweapons, including Bacillus anthracis (anthrax), Clostridium botulinum (botulism), Yersinia pestis (plague), Francisella tularensis (tularemia), variola (smallpox) and hantavirus (hantavirus pulmonary syndrome). As part of this effort, President Bush's 'Project BioShield' bill will invest up to US $5.6 billion during the next decade into researching new preventative treatments. This includes private and public efforts, both in the United States and through collaborations with other research bodies around the world.

For infectious agents such as smallpox, effective vaccines already exist, which have helped to eradicate the disease globally (the last known case of smallpox was reported in 1977). Despite this, smallpox still poses a significant threat as a bioweapon because it is highly contagious and in most countries immunization programmes have ceased, resulting in a large pool of unprotected people. Serious side effects with the existing smallpox vaccine (DryVax; Wyeth), and the threat of new virulent forms of smallpox, mean that there is still a need for new, safer versions of the vaccine. New strategies include the use of a live attenuated vaccinia virus (modified vaccinia Ankara), such as MVA-BN (Bavarian) and TBC-MVA (Therion), both of which are in Phase I trials; the alternatively manufactured vaccinia vaccines ACAM2000 (Acambis) and CCSV (DynPort) are in Phase II and I trials, respectively.

SARS — a new challenge

The recent outbreak of SARS reminded us that new virulent viruses can suddenly emerge at anytime, and spread rapidly around the globe. The World Health Organization estimated that more than 8,400 people were infected with SARS in 30 countries, which killed an estimated 830 people. Although not nearly on the same scale as the influenza pandemics of 1918/19 and 1968, SARS remains a menace to global public health, especially if it turns out to be a seasonal disease.

Following the first reported cases of SARS in late February 2003, health agencies quickly realized that they were not dealing with one of the 'typical' respiratory viruses that cause diseases such as pneumonia and the flu (for example, respiratory syncytial virus and influenza virus), but instead a new, virulent strain of a coronavirus1,2,3, which are not often associated with such severe pathology. Fortunately, the SARS epidemic was short lived, but it still placed a considerable strain on the health systems of many of the affected countries. The threat remains and as such there is still a great need for a SARS vaccine to prevent further loss of life on a potentially larger scale. To this end, a large number of public and private initiatives are underway to develop a SARS vaccine (for example, the National Institutes of Health, Merck, GenVec and Avant Immunotherapeutics are active in this area), although even the most optimistic estimates are that such a vaccine is still at least five years away.

A high hurdle set for HIV vaccines

The hunt for an HIV vaccine is arguably one of the most urgent tasks of our time. Millions of dollars have been spent on trying to understand every aspect of the virus and its role in pathogenesis. Many of the 19 antiretrovirals available to treat HIV have side effects and associated resistance issues. None of them offer a cure; instead, they prolong the time until the onset of AIDS. In addition, these drugs exert a heavy financial toll, which developing countries are often unable to bear. So, the hope is that the development of an effective HIV vaccine could help to ease this economic burden.

Unfortunately, HIV, like malaria and tuberculosis, is turning out to be very tricky to develop effective vaccines against, because of the high degree of antigenic variability that exists among HIV strains. An example of this is the recent failure of the gp120 subunit vaccine AIDSVAX B/B (VaxGen), the most advanced HIV vaccine in development4. However, the results have not dampened researchers' efforts in the field, which on the contrary has seen an explosion of activity during the past few years. At present there are more than 15 Phase I, II or III trials ongoing involving a variety of different strategies, including the use of more complex subunit vaccines (for example, oligomeric proteins), recombinant viral vectors (including, attenuated adenovirus 5, canarypox, modified vaccinia Ankara, BCG and Semliki forest virus), prime–boost strategies and DNA vaccines. Some are designed to protect patients, whereas others attempt to strengthen the immune response, prolonging the progression to AIDS.

Market indicators

'Teak-root chair', courtesy of Java Nola,

Traditional vaccines will continue to generate the majority of the US $6 billion in vaccine sales each year (Fig. 2), although we believe future growth will be driven by new vaccines, including those with improved delivery mechanisms (for example, MedImmune's intranasal FluMist), as well as vaccines for emerging diseases and to pathogens that pose a threat as possible bioweapons (Tables 1 and 2). Infectious agents such as HIV, which presently affects an estimated 42 million people around the globe, highlight the great need for future vaccines, whereas the virus has also shown us that significant difficulties (for example, antigenic variation) must be overcome before truly global vaccines can be developed.

Figure 2
figure 2

Number of US vaccines approved by indication.

Table 1 Vaccine candidates under investigation for smallpox, HIV and SARS
Table 2 Vaccine candidates under investigation for biodefence purposes